Terence Ketter

All Publications

• Expert consensus recommendations on the use of randomized clinical trials for drug approval in psychiatry- comparing trial designs. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology Similon, M. v., Paasche, C., Krol, F., Lerer, B., Goodwin, G. M., Berk, M., Meyer-Lindenberg, A., Ketter, T. A., Yatham, L. N., Goldberg, J. F., Malhi, G. S., El-Mallakh, R., Licht, R. W., Young, A. H., Kapczinski, F., Swartz, M., Hagin, M., Torrent, C., Serretti, A., Yildiz, A., Martinez-Aran, A., Strejilevich, S., Rybakowski, J., Sani, G., Grunze, H., Vazquez, G., Pinto, A. G., Azorin, J. M., Nolen, W., Sentissi, O., Lopez-Jaramillo, C., Frey, B. N., Nierenberg, A., Parker, G., Bond, D. J., Cohen, A., Tortorella, A., Perugi, G., Vieta, E., Popovic, D. 2022; 60: 91-99

  Abstract

  The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular.

  View details for DOI 10.1016/j.euroneuro.2022.05.002

  View details for PubMedID 35665655

• Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder. Acta psychiatrica Scandinavica Wrobel, A. L., Kohler-Forsberg, O., Sylvia, L. G., Russell, S. E., Dean, O. M., Cotton, S. M., Thase, M., Calabrese, J. R., Deckersbach, T., Tohen, M., Bowden, C. L., McInnis, M., Kocsis, J. H., Friedman, E. S., Ketter, T. A., Shelton, R. C., Ostacher, M. J., Iosifescu, D. V., Berk, M., Turner, A., Nierenberg, A. A. 2022

  Abstract

  BACKGROUND: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied.METHODS: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool).RESULTS: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment.CONCLUSION: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

  View details for DOI 10.1111/acps.13420

  View details for PubMedID 35243620

• Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes. The Australian and New Zealand journal of psychiatry Kohler-Forsberg, O., Sylvia, L. G., Thase, M., Calabrese, J. R., Tohen, M., Bowden, C. L., McInnis, M., Iosifescu, D. V., Kocsis, J. H., Friedman, E. S., Ketter, T. A., McElroy, S. L., Shelton, R. C., Fung, V., Ostacher, M. J., Nierenberg, A. A. 2022: 48674221077619

  Abstract

  OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied.METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24weeks of treatment.RESULTS: Among 379 outpatients (57% female, mean age 38years, mean Clinical Global Impression 4.4), users of Li+AP (N=50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement=1.6, standard deviation=1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N=149, mean Clinical Global Impression improvement=1.7, standard deviation=1.4) (p=0.59). Users of Li+AC (N=107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement=1.2, standard deviation=1.3) and users of Li+AP+AC (N=73, mean Clinical Global Impression improvement=1.1, standard deviation=1.3) showed worse response compared to lithium-only users (all p<0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p=0.05) and manic symptoms (p=0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome.CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

  View details for DOI 10.1177/00048674221077619

  View details for PubMedID 35164524

• Cardiometabolic risk markers during mood-stabilizing treatment: Correlation with drug-specific effects, depressive symptoms and treatment response. Journal of affective disorders Kuperberg, M., Kohler-Forsberg, O., Shannon, A. P., George, N., Greenebaum, S., Bowden, C. L., Calabrese, J. R., Thase, M., Shelton, R. C., McInnis, M., Deckersbach, T., Tohen, M., Kocsis, J. H., Ketter, T. A., Friedman, E. S., Iosifescu, D. V., Ostacher, M. J., Sylvia, L. G., McElroy, S. L., Nierenberg, A. A. 1800

  Abstract

  BACKGROUND: Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response.METHODS: We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models.RESULTS: Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response.LIMITATIONS: Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors.CONCLUSIONS: Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression.

  View details for DOI 10.1016/j.jad.2021.12.047

  View details for PubMedID 34952123

• Response and remission rates during 24 weeks of mood-stabilizing treatment for bipolar depression depending on early non-response. Psychiatry research Kohler-Forsberg, O., Sloth, K. H., Sylvia, L. G., Thase, M., Calabrese, J. R., Tohen, M., Bowden, C. L., McInnis, M., Kocsis, J. H., Friedman, E. S., Ketter, T. A., McElroy, S. L., Shelton, R. C., Iosifescu, D. V., Ostacher, M. J., Nierenberg, A. A. 2021; 305: 114194

  Abstract

  BACKGROUND: We aimed to study the probability of bipolar depression response at 24 weeks given initial non-response.METHODS: We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS<10).RESULTS: We included 592 participants with bipolar depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks.CONCLUSIONS: Among patients with bipolar depression and non-response after 6 weeks treatment, representing an adequate bipolar depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for bipolar depression.

  View details for DOI 10.1016/j.psychres.2021.114194

  View details for PubMedID 34500184

• Expanding bipolar outreach during college. Journal of affective disorders Singh, M. K., Miller, S., Hooshmand, F., Wang, P. W., Chang, L., Ketter, T. A. 2021; 295: 28-32

  Abstract

  OBJECTIVES: To assess feasibility and clinical significance of tracking mania and depression in community college students before and after early identification and intervention.METHODS: From Affective Illness to Recovery: STudent Access to Rapid Treatment (FAIRSTART) is an early intervention program to provide diagnostic therapeutic consultation, short-term care, and community ongoing care referral for 18-28 year-old outpatient community college students (mean age 22.9±4.0 years) experiencing manic symptoms. Over three years, 54 FAIRSTART participants (70% with DSM-IV bipolar I/II/not otherwise specified disorder, BDI/II/NOS) were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation (ADE) and followed (range: one-time consult to 4.3±3.6 visits over 3-6 month follow-up) with the STEP-BD Clinical Monitoring Form.RESULTS: 38/54 patients (70%) had BDI/II/NOS, 11 unipolar depression (20%), 1 psychosis spectrum disorder (2%), 2 dysthymia/persistent depressive disorder (4%), and 2 incomplete intake with mood disorder diagnosis undetermined (4%). Average illness duration was 9.1±5.3 years. Among the 38 BD I/II/NOS patients, depression (SUM-D, t(30)=6.5; p<0.001) and mania (SUM-M, t(30)=4.7; p<0.001) scores improved significantly from baseline to last visit, with 17 (44.7%) reporting recovery by time transitioned from FAIRSTART to community care (after 4.3±3.6 visits).CONCLUSIONS: Short-term, early intervention in community college students with mood symptoms appeared feasible and yielded significant improvements in depression and mania scores. However, additional studies, with longer-term follow-ups, larger sample sizes, and comparison to current care standards, are needed to determine this early intervention program's impact on trajectory of mania symptoms in transitional age young adult populations.

  View details for DOI 10.1016/j.jad.2021.08.001

  View details for PubMedID 34391959

• Antidepressants in bipolar disorder: Analysis of correlates overall, and in BD-I and BD-II subsamples. Journal of affective disorders Dell'Osso, B., Arici, C., Cafaro, R., Vismara, M., Cremaschi, L., Benatti, B., Macellaro, M., Vigano, C., Ketter, T. A. 2021; 292: 352-358

  Abstract

  BACKGROUND: Clinical therapeutic approaches to Bipolar Disorders (BDs) include diverse pharmacotherapies, targeting different symptomatic BD presentations. To date, guidelines about pharmacological treatment of BDs have focused on short-term treatment of mood episodes, at the expense of longer-term treatment, especially for (the most common) predominantly depressive polarity patients.METHODS: A database of BD-I and BD-II patients was collected between 2013 and 2019 at the University Psychiatric Clinic of Ospedale Policlinico and Ospedale Luigi Sacco of Milan. Only patients in euthymic phases (no current mood episode) were included in the study. We then analyzed socio-demographic and clinical characteristic overall and in the subgroup BD-I and BD-II, comparing patients taking vs. not taking ADs.RESULTS: Our results showed that approximately 1/3 of BD patients between acute episodes took ADs, also among patients from the subgroup with BD-I, especially those first presenting with a depressive episodes, and those with a most recent depressive (as opposed to elevated, irritable, or mixed) polarity episode.LIMITATIONS: Although patients included in our study were primarily in follow up for Bipolar Disorder, use of ADs could be explained by other comorbidities, such as Anxiety or Eating Disorders.CONCLUSIONS: These data shed light on how managing depressive symptoms is a very important aspect of treating BDs, highlighting the need for wider and more specific studies on the use of ADs in BDs.

  View details for DOI 10.1016/j.jad.2021.05.043

  View details for PubMedID 34139408

• Has Bipolar Disorder become a predominantly female gender related condition? Analysis of recently published large sample studies. International journal of bipolar disorders Dell'Osso, B. n., Cafaro, R. n., Ketter, T. A. 2021; 9 (1): 3

  Abstract

  Bipolar Disorders (BD) are disabling and severe psychiatric disorders, commonly perceived as equally affecting both men and women. The prevalence of BD in the general population has been growing over the last decade, however, few epidemiological studies are available regarding BD gender distribution, leaving unanswered the question whether the often reported increment of BD diagnosis could be gender specific. In fact, BD in female patients can often be misdiagnosed as MDD, leaving such women non correctly treated for longer times than their male counterparts. From this perspective, we searched literature for large sample (> 1000 subjects) studies published in the last decade (2010 onward) on BD patients. We included ten large sample studies that reported the gender distribution of their samples, and we therefore analysed them. Our results show a higher preponderance of female patients in every sample and sub-sample of BDI and BDII, supporting our hypothesis of an increase in BD diagnosis in females. BD in women presents with higher rates of rapid cycling, depressive polarity and suicide attempts, characteristics of non inferior severity compared to males; prompt recognition and adequate treatment of BD is therefore crucial to reduce risks and improve quality of life of affected women. In this regard, our results could lead the way for national or international epidemiological studies with the aim of more accurately assessing gender-specific prevalence of BD.

  View details for DOI 10.1186/s40345-020-00207-z

  View details for PubMedID 33392912

• Illness stage and predominant polarity in bipolar disorder: Correlation with burden of illness and moderation of treatment outcome. Journal of psychiatric research Kamali, M., Pegg, S., Janos, J. A., Bobo, W. V., Brody, B., Gao, K., Ketter, T. A., McElroy, S. L., McInnis, M. G., Rabideau, D. J., Reilly-Harrington, N. A., Shelton, R. C., Sylvia, L. G., Tohen, M., Nierenberg, A. 2021; 140: 205-213

  Abstract

  Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

  View details for DOI 10.1016/j.jpsychires.2021.05.082

  View details for PubMedID 34118638

• Adjunctive antidepressant treatment among 763 outpatients with bipolar disorder: Findings from the Bipolar CHOICE and LiTMUS trials. Depression and anxiety Kohler-Forsberg, O., Sylvia, L. G., Fung, V., Overhage, L., Thase, M., Calabrese, J. R., Deckersbach, T., Tohen, M., Bowden, C. L., McInnis, M., Kocsis, J. H., Friedman, E. S., Ketter, T. A., McElroy, S. L., Shelton, R. C., Ostacher, M. J., Iosifescu, D. V., Nierenberg, A. A. 2020

  Abstract

  BACKGROUND: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response.METHODS: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N=482) and Lithium Treatment Moderate-Dose Use Study (N=281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts.RESULTS: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales.CONCLUSIONS: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants.

  View details for DOI 10.1002/da.23069

  View details for PubMedID 32598093

• Familial severe psychiatric history in bipolar disorder and correlation with disease severity and treatment response. Journal of affective disorders Kohler-Forsberg, O., Sylvia, L. G., Ruberto, V. L., Kuperberg, M., Shannon, A. P., Fung, V., Overhage, L., Calabrese, J. R., Thase, M., Bowden, C. L., Shelton, R. C., McInnis, M., Deckersbach, T., Tohen, M., Kocsis, J. H., Ketter, T. A., Friedman, E. S., Iosifescu, D. V., McElroy, S., Ostacher, M. J., Nierenberg, A. A. 2020; 273: 131–37

  Abstract

  BACKGROUND: Bipolar disorder is a heritable disorder, and we aimed to assess the impact of family history of mental disorders in first-degree relatives on the severity and course of bipolar disorder.METHODS: The Bipolar CHOICE (lithium versus quetiapine) and LiTMUS (optimized treatment with versus without lithium) comparative effectiveness studies were similar trials among bipolar disorder outpatients studying four different randomized treatment arms for 24 weeks. Patients self-reported on six severe mental disorders among first-degree relatives. We performed ANOVA and linear regression regarding disease severity measures, sociodemographic and cardiometabolic markers and mixed effects linear regression to evaluate treatment response.RESULTS: Among 757 patients, 644 (85.1%) reported at least one first-degree relative with a severe mental disorder (mean=2.8; standard deviation=2.2; range=0-13). Depression (67.1%), alcohol abuse (51.0%) and bipolar disorder (47.0%) were the most frequently reported disorders. Familial psychiatric history correlated with several disease severity measures (hospitalizations, suicide attempts, and earlier onset) and sociodemographic markers (lower education and household income) but not with cardiometabolic markers (e.g. cholesterol or waist circumference) or cardiovascular risk scores, e.g. the Framingham risk score. Patients with familial psychiatric history tended to require more psychopharmacological treatment (p=0.054) but responded similarly (all p>0.1) to all four treatment arms.CONCLUSIONS: Our findings indicate that familial psychiatric history is common among outpatients with bipolar disorder and correlates with disease severity and sociodemographic measures. Patients with a greater familial psychiatric load required more intense treatment but achieved similar treatment responses compared to patients without familial psychiatric history.

  View details for DOI 10.1016/j.jad.2020.03.157

  View details for PubMedID 32421593

• The impact of binge eating behavior on lithium- and quetiapine-associated changes in body weight, body mass index, and waist circumference during 6 months of treatment: Findings from the bipolar CHOICE study JOURNAL OF AFFECTIVE DISORDERS Yaramala, S. R., McElroy, S. L., Geske, J., Winham, S., Gao, K., Reilly-Harrington, N. A., Ketter, T. A., Deckersbach, T., Kinrys, G., Kamali, M., Sylvia, L. G., McInnis, M. G., Friedman, E. S., Thase, M. E., Kocsis, J. H., Tohen, M., Calabrese, J. R., Bowden, C. L., Shelton, R. C., Nierenberg, A. A., Bobo, W. 2020; 266: 772–81

  View details for DOI 10.1016/j.jad.2018.09.025

  View details for Web of Science ID 000520892700099

• A Modified Delphi Consensus Study of the Screening, Diagnosis, and Treatment of Tardive Dyskinesia. The Journal of clinical psychiatry Caroff, S. N., Citrome, L., Meyer, J., Sajatovic, M., Goldberg, J. F., Jain, R., Lundt, L., Lindenmayer, J., McEvoy, J. P., McIntyre, R. S., Tohen, M., Ketter, T. A. 2020; 81 (2)

  Abstract

  OBJECTIVE: A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence.PARTICIPANTS: A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate.EVIDENCE: A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included.CONSENSUS PROCESS: Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation).CONCLUSIONS: Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.

  View details for DOI 10.4088/JCP.19cs12983

  View details for PubMedID 31995677

• Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode. International clinical psychopharmacology Dell'Osso, B., Cremaschi, L., Arici, C., Altamura, A. C., Hooshmand, F., Do, D., Shah, S., Gershon, A., Holsinger, A., Yeon Park, D., Miller, S., Wang, P. W., Ketter, T. A. 2019

  Abstract

  Assess bipolar disorder subtype and treatment location effects on bipolar disorder core pharmacotherapy. Outpatients not in a syndromal episode referred to the University of Milan and Stanford University Bipolar Disorder Clinics were assessed with SCID for the fourth Edition of the Diagnostic and Statistical Manual of Mood Disorders, and the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation, respectively. Prevalence and clinical correlates of antidepressant, antipsychotic, and mood stabilizer use, in aggregate and individually, were compared in bipolar I (BDI) versus II (BDII) patients in Milan/Stanford and in Milan versus Stanford patients, stratified by subtype. Milan/Stanford pooled BDI versus BDII patients significantly more often took antipsychotic (69.8 versus 44.8%), mood stabilizers (68.6 versus 57.7%), and valproate (40.1 versus 17.5%), and less often took antidepressants (23.1 versus 55.6%) and lamotrigine (9.9 versus 25.2%). Milan versus Stanford patients (stratified by bipolar disorder subtype) significantly more often took antipsychotic (BDI and BDII), antidepressants (BDII), and valproate (BDII), and less often took lamotrigine (BDI). Research regarding bipolar disorder core pharmacotherapy relationships with bipolar subtype and treatment location is warranted to enhance clinical management.

  View details for DOI 10.1097/YIC.0000000000000282

  View details for PubMedID 31609786

• Antipsychotic use in Northern Italian inter-episode bipolar disorder patients: considering both second- and first-generation agents. International clinical psychopharmacology Cremaschi, L., Arthur Ketter, T., Arici, C., Miller, S., Hooshmand, F., Dell'Osso, B. 2019

  Abstract

  Evidence supports increasing antipsychotic use in bipolar disorder, especially second-generation antipsychotics. However, data regarding first-generation antipsychotic contemporary use are limited. We studied 380 Northern Italian bipolar disorder inter-episode patients, grouped according to current antipsychotic use, stratified by bipolar subtype (BDI vs. BDII). Furthermore, we compared first-generation antipsychotic users vs. non-users. In our sample (n = 357), 81.8% were taking antipsychotics (74% second-generation antipsychotics, 24.1% first-generation antipsychotics), with antipsychotic use in BDI significantly more prevalent than in BDII (85.2% vs. 72.0%). Overall, antipsychotic users vs. non-users had higher rates of hypo/manic last episode, lifetime psychiatric hospitalization, psychosis, and current psychotropic use, but lower rates of anxiety disorder main comorbidity and current antidepressant use. First-generation antipsychotic use rates (30.3% in BDI vs. 6.5% in BDII) were associated with more frequently being unpartnered, having elevated first/last episodes, higher lifetime hospitalization, involuntary commitment, psychosis, and psychosocial rehabilitation rates, and more current psychotropic use, but lower Global Assessment Functioning scores and less current antidepressant use. Bipolar disorder patients had robust antipsychotic (second-generation antipsychotic > first-generation antipsychotic) use, consistently with previous reports. FGAs were still prescribed for a substantial group of patients, likely suffering from severe bipolar disorder. Prescriptions need to be monitored to assess their appropriateness and adherence to evidence-based recommendations.

  View details for DOI 10.1097/YIC.0000000000000283

  View details for PubMedID 31453901

• Anxiety disorders anticipate the diagnosis of bipolar disorder in comorbid patients: Findings from an Italian tertiary clinic. Journal of affective disorders Caricasole, V., Di Bernardo, I., Varinelli, A., Galimberti, C., Zanello, R., Bosi, M., Ketter, T. A., Vigano, C. A., Dell'Osso, B. 2019; 257: 376–81

  Abstract

  BACKGROUND: Studies indicate bipolar disorder (BD) syndromal symptoms are commonly preceded by sub-syndromal BD symptoms, dysregulated sleep, irritability, and anxiety. We aimed to evaluate prevalence and clinical correlates of anxiety disorders (ADs) at BD onset in outpatients with versus without at least one AD at BD onset.METHODS: 246 bipolar spectrum outpatients, according to the text revision of the fourth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM- IV-TR), attending Sacco University Hospital in Milan, were recruited and their onset and clinical features assessed retrospectively. Patients were stratified into those with versus without an AD at BD onset (w/A and wo/A), according to a semi-structured clinical interview to provide diagnoses according to (DSM- IV-TR).RESULTS: 29% of patients reported being w/A, among whom Panic Disorder (PD, in 55.6%) was the most frequent AD, and first AD occurred approximately 4 years before BD diagnosis. Patients w/A versus wo/A had higher (p < 0.05) rates of BDII and first mood episode being depression versus elevation (mania/hypomania), and lifetime rates of separation anxiety disorder, substance poly-abuse and benzodiazepine abuse. In contrast, patients wo/A had higher lifetime rates of alcohol and illicit drug use.CONCLUSION: In this naturalistic sample, ADs, in particular PD, preceded BD in almost 1/3 of BD outpatients, and had distinctive clinical correlates. Further investigation into relationships between BD and AD at onset may enhance early BD diagnosis and treatment.

  View details for DOI 10.1016/j.jad.2019.07.033

  View details for PubMedID 31302527

• Patterns of changes in bipolar depressive symptoms revealed by trajectory analysis among 482 patients with bipolar disorder BIPOLAR DISORDERS Behrendt-Moller, I., Madsen, T., Sorensen, H., Sylvia, L., Friedman, E. S., Shelton, R. C., Bowden, C. L., Calabrese, J. R., McElroy, S. L., Ketter, T. A., Reilly-Harrington, N. A., Gao, K., Thase, M., V Bobo, W., Tohen, M., McInnis, M., Kamali, M., Kocsis, J. H., Deckersbach, T., Kohler-Forsberg, O., Nierenberg, A. A. 2019; 21 (4): 350–60

  View details for DOI 10.1111/bdi.12715

  View details for Web of Science ID 000473072200007

• Antidepressants have complex associations with longitudinal depressive burden in bipolar disorder. Journal of affective disorders Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D. Y., Yuen, L. D., Dell'Osso, B., Wang, P. W., Miller, S., Ketter, T. A. 2019; 246: 836-842

  Abstract

  Antidepressants are common in bipolar disorder (BD), but controversial due to questionable efficacy/tolerability. We assessed baseline antidepressant use/depression associations in BD.Stanford BD Clinic outpatients, enrolled during 2000-2011, assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, were monitored up to two years with the STEP-BD Clinical Monitoring Form while receiving naturalistic expert treatment. Prevalence/correlates of baseline antidepressant use in recovered (euthymic ≥8 weeks)/depressed patients were assessed. Kaplan-Meier survival analyses assessed times to depressive recurrence/recovery in patients with/without baseline antidepressant use, and Cox Proportional Hazard regression analyses assessed covariate effects.Baseline antidepressant use was significantly (albeit without Bonferroni multiple comparison correction) less among 105 recovered (31.4%) versus 153 depressed (44.4%) patients, and among recovered patients (again without Bonferroni correction), associated with Caucasian race, earlier onset, worse Clinical Global Impression scores, and hastened depressive recurrence (only if mood elevation episodes were not censored), driven by lifetime anxiety disorder, and more (even with Bonferroni correction) bipolar II disorder, lifetime anxiety and eating disorders, and core psychotropics. Baseline antidepressant use among depressed patients was associated with significantly (again without Bonferroni correction) older age, female gender, and more (even with Bonferroni correction) anxiolytics/hypnotics, complex pharmacotherapy, and core psychotropics, but no other unfavorable illness characteristic/current mood symptom, and not time to depressive recovery.Tertiary BD clinic referral sample receiving open naturalistic expert treatment. Analyses without/with Bonferroni correction.Additional research is required to assess the complex associations between baseline antidepressant use and longitudinal depressive burden in BD.

  View details for DOI 10.1016/j.jad.2018.12.074

  View details for PubMedID 30795488

• Comorbid anxiety in bipolar CHOICE: Insights from the bipolar inventory of symptoms scale JOURNAL OF AFFECTIVE DISORDERS Kinrys, G., Bowden, C. L., Nierenberg, A. A., Hearing, C. M., Gold, A. K., Rabideau, D. J., Sylvia, L. G., Gao, K., Kamali, M., Bobo, W. V., Tohen, M., Deckersbach, T., McElroy, S. L., Ketter, T. A., Shelton, R. C., Friedman, E. S., Calabrese, J. R., McInnis, M. G., Kocsis, J., Thase, M. E., Singh, V., Reilly-Harrington, N. A. 2019; 246: 126–31

  View details for DOI 10.1016/j.jad.2018.12.039

  View details for Web of Science ID 000457276200016

• Antidepressants have complex associations with longitudinal depressive burden in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D., Yuen, L. D., Dell'Osso, B., Wang, P. W., Miller, S., Ketter, T. A. 2019; 246: 836–42

  View details for DOI 10.1016/j.jad.2018.12.074

  View details for Web of Science ID 000457276200102

• 41 A Modified Delphi Consensus Approach to Clinical Guidelines for Tardive Dyskinesia. CNS spectrums Caroff, S. N., Citrome, L., Meyer, J., Riggs, K., Sajatovic, M., Lundt, L., Ketter, T. A. 2019; 24 (1): 197–98

  Abstract

  OBJECTIVE: Vesicular monoamine transporter 2 (VMAT2) inhibitors are the first class of drugs approved to treat tardive dyskinesia (TD). With the recent approval of these medications, a modified Delphi process was implemented to address the need for updated clinical guidelines for TD screening, diagnosis, and treatment.METHODS: A Steering Committee of 11 TD experts met in a Nominal Group meeting format to discuss/prioritize questions to be addressed about TD and identify individuals to be invited to serve as Delphi survey panelists. Two survey rounds were conducted anonymously; responses were collected, collated, and analyzed. Respondent agreement was defined a priori by the Steering Committee as unanimous (100%), consensus (75-99%), or majority (50-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with 75% agreement).RESULTS: Online surveys were sent to 60 individuals; 29 agreed to participate as panelists (23 psychiatrists; 6 neurologists). Respondents unanimously agreed (100%) that all patients currently taking dopamine receptor blocking agents (DRBAs) should be screened for TD, and that the Abnormal Involuntary Movement Scale (AIMS) is the standard structured assessment for monitoring severity of TD. There was consensus (76%) that a semi-structured assessment could be used for more frequent routine TD screening. Respondents unanimously agreed that treatment with first generation antipsychotics, older age, and longer cumulative exposure to antipsychotics were risk factors for TD. For TD diagnosis, consensus (89%) was reached that a patient with an AIMS score >2 (mild) affecting 1 body area should be considered as having possible TD; consensus (93%) was also reached that TD was most often evident in orofacial musculature, although other body areas may be affected and should not be neglected. Consensus was not reached on minimum cumulative duration of DRBA exposure for TD diagnosis, but a majority (70%) agreed that minimum cumulative exposure of 1month may be sufficient. For TD treatment, unanimity or consensus was reached on 4 strategies to consider: discussion of treatment options with patients/caregivers (100%), modification of antipsychotic regimen (100%), treatment with VMAT2 inhibitor (100%), and modification of anticholinergic regimen (86%).CONCLUSIONS: Using a Nominal Group and modified Delphi process, consensus was reached within 1-2 rounds on several key aspects of TD screening, diagnosis, and treatment. This process may offer an expedient method to identify gaps in agreement and facilitate updated management guidelines.Funding Acknowledgements: Sponsored by Neurocrine Biosciences,Inc.

  View details for PubMedID 30859969

• New Mechanisms, New Opportunities: Integrating Novel Antidepressants in the Treatment of Major Depressive Disorder. The Journal of clinical psychiatry Citrome, L. n., Gaynes, B. N., Goldberg, J. F., Ketter, T. n., Murrough, J. W. 2019; 80 (5)

  Abstract

  Listen to experts and view their slides from a panel session at the American Society of Clinical Psychopharmacology (ASCP) meeting, held on May 29, 2019, in Scottsdale, Arizona. Dr Murrough described the current understanding of depression etiology and new insights into antidepressant development. Dr Goldberg shared his expertise about whether antidepressant drugs with novel mechanisms of action can improve outcomes in patients with major depressive disorder. Dr Gaynes reviewed the link between major depressive disorder and elevated mortality risk and whether recovery from depression can reverse patients' mortality risk. Dr Citrome discussed current best practices and new medications for the treatment of depression. Finally, Dr Ketter provided his thoughts on his colleagues' presentations.

  View details for DOI 10.4088/JCP.TK18061AS2C

  View details for PubMedID 31365193

• Neural responses to monetary incentives in bipolar disorder. NeuroImage. Clinical Johnson, S. L., Mehta, H. n., Ketter, T. A., Gotlib, I. H., Knutson, B. n. 2019; 24: 102018

  Abstract

  Although behavioral sensitivity to reward predicts the onset and course of mania in bipolar disorder, the evidence for neural abnormalities in reward processing in bipolar disorder is mixed. To probe neural responsiveness to anticipated and received rewards in the context of bipolar disorder, we scanned individuals with remitted bipolar I disorder (n = 24) and well-matched controls (n = 24; matched for age and gender) using Functional Magnetic Resonance Imaging (FMRI) during a Monetary Incentive Delay (MID) task. Relative to controls, the bipolar group showed reduced NAcc activity during anticipation of gains. Across groups, this blunting correlated with individual differences in impulsive responses to positive emotions (Positive Urgency), which statistically accounted for the association of blunted NAcc activity with bipolar diagnosis. These results suggest that blunted NAcc responses during gain anticipation in the context of bipolar disorder may reflect individual differences in Positive Urgency. These findings may help resolve discrepancies in the literature on neural responses to reward in bipolar disorder, and clarify the relationship between brain activity and the propensity to experience manic episodes.

  View details for DOI 10.1016/j.nicl.2019.102018

  View details for PubMedID 31670069

• Bipolar depression and suicidal ideation: Moderators and mediators of a complex relationship. Journal of affective disorders Kamali, M. n., Reilly-Harrington, N. A., Chang, W. C., McInnis, M. n., McElroy, S. L., Ketter, T. A., Shelton, R. C., Deckersbach, T. n., Tohen, M. n., Kocsis, J. H., Calabrese, J. R., Gao, K. n., Thase, M. E., Bowden, C. L., Kinrys, G. n., Bobo, W. V., Brody, B. D., Sylvia, L. G., Rabideau, D. J., Nierenberg, A. A. 2019; 259: 164–72

  Abstract

  Not all patients with bipolar depression have suicidal ideation (SI). This study examines some factors that link bipolar depression to SI.482 individuals with bipolar I or II were randomized to either lithium or quetiapine plus adjunctive personalized therapy in a 24 week comparative effectiveness trial. Severity of depression and SI were assessed with the Bipolar Inventory of Symptoms Scale (BISS). We examined potential moderators (age, gender, age of illness onset, bipolar type, comorbid anxiety, substance use, past suicide attempts, childhood abuse and treatment arm) and mediators (severity of anxiety, mania, irritability, impairment in functioning (LIFE-RIFT) and satisfaction and enjoyment of life (Q-LES-Q)) of the effect of depression on SI. Statistical analyses were conducted using generalized estimating equations with repeated measures.Bipolar type and past suicide attempts moderated the effect of depression on SI. Life satisfaction mediated the effect of depression and SI. The relationship between anxiety, depression and SI was complex due to the high level of correlation. Treatment with lithium or quetiapine did not moderate the effect of depression on SI.Suicide assessment was only done using an item on BISS. Patient population was not specifically chosen for high suicide risk.Individuals with Bipolar II experienced more SI with lower levels of depression severity. A history of suicide predisposed patients to higher levels of SI given the same severity of depression. Reduced life satisfaction mediates the effect of depression on SI and may be a target for therapeutic interventions.

  View details for DOI 10.1016/j.jad.2019.08.032

  View details for PubMedID 31445343

• Clinical features and patterns of psychopharmacological prescription in bipolar patients with vs without anxiety disorders at onset. Early intervention in psychiatry Galimberti, C. n., Caricasole, V. n., Bosi, M. F., Viganò, C. A., Ketter, T. A., Dell'Osso, B. n. 2019

  Abstract

  Up to just over half of bipolar disorder (BD) patients report at least one-lifetime anxiety disorder (AD). In some, anxiety represents the earliest psychiatric manifestation, prior to any mood episode. We sought to investigate prevalence of AD subtypes as first psychiatric manifestations and AD's relations with duration of untreated illness (DUI) and treatment among BD outpatients.We recruited patients referred to the Centre for the Treatment of Depressive Disorders in Milan, diagnosed with BD-I, BD-II, BD not otherwise specified (BD-NOS) and cyclothymia according to Diagnostic and Statistical Manual fourth edition-text revision criteria. Several clinical characteristics were assessed through retrospective chart review and/or direct patient interviews. Based on presence/absence of an AD at psychiatric onset, eligible subjects were stratified into two groups (A+ and A-) and clinical features were compared between these groups and between BD subtypes.We analysed 260 BD patients (77 BD-I, 122 BD-II, 45 BD-NOS and 16 cyclothymia). An AD was the first psychiatric manifestation in 69 patients (26.5%). BD-II and BD-NOS more frequently had an AD at psychiatric onset, with panic disorder being the most common AD. Among A+ vs A-, age at BD onset was younger, duration of untreated BD illness (DUI) was longer, and a mood stabilizer/antipsychotic was less often prescribed at psychiatric onset.Considering BD in its longitudinal course, over one in four BD patients presenting with an AD at psychiatric onset belatedly access adequate treatment, with subsequent prolonged DUI and prospective worse outcome compared to patients with a mood episode at psychiatric onset.

  View details for DOI 10.1111/eip.12900

  View details for PubMedID 31733039

• Correlation between white blood cell count and mood-stabilising treatment response in two bipolar disorder trials. Acta neuropsychiatrica Köhler-Forsberg, O. n., Sylvia, L. G., Bowden, C. L., Calabrese, J. R., Thase, M. E., Shelton, R. C., McInnis, M. n., Tohen, M. n., Kocsis, J. H., Ketter, T. A., Friedman, E. S., Deckersbach, T. n., Ostacher, M. J., Iosifescu, D. V., McElroy, S. n., Nierenberg, A. A. 2019: 1–5

  Abstract

  Immune system markers may predict affective disorder treatment response, but whether an overall immune system marker predicts bipolar disorder treatment effect is unclear.Bipolar CHOICE (N = 482) and LiTMUS (N = 283) were similar comparative effectiveness trials treating patients with bipolar disorder for 24 weeks with four different treatment arms (standard-dose lithium, quetiapine, moderate-dose lithium plus optimised personalised treatment (OPT) and OPT without lithium). We performed secondary mixed effects linear regression analyses adjusted for age, gender, smoking and body mass index to investigate relationships between pre-treatment white blood cell (WBC) levels and clinical global impression scale (CGI) response.Compared to participants with WBC counts of 4.5-10 × 109/l, participants with WBC < 4.5 or WBC ≥ 10 showed similar improvement within each specific treatment arm and in gender-stratified analyses.An overall immune system marker did not predict differential treatment response to four different treatment approaches for bipolar disorder all lasting 24 weeks.

  View details for DOI 10.1017/neu.2019.19

  View details for PubMedID 31169098

• Electronic Ecological Momentary Assessment (EMA) in youth with bipolar disorder: Demographic and clinical predictors of electronic EMA adherence. Journal of psychiatric research Gershon, A. n., Kaufmann, C. N., Torous, J. n., Depp, C. n., Ketter, T. A. 2019; 116: 14–18

  Abstract

  Ecological momentary assessment (EMA) is increasingly used to characterize patients' daily lives, monitor mood, and test efficacy of treatment interventions. However, few studies have examined patient characteristics impacting adherence with EMA protocols, and to our knowledge, no such study has been conducted in youth with bipolar disorder (BD).As part of a larger observational study, 14- to 21-year-olds diagnosed with BD, and who were between episodes of illness (n = 39, 19.0 ± 2.05 Mean ± Standard Deviation years old, 74.4% female) and psychiatrically healthy controls (n = 47, 18.3 ± 2.40 years old, 66.0% female) completed baseline diagnostic and symptom severity interviews, and were instructed to complete diary assessments of mood, sleep, and behavior electronically three times per day for 21 consecutive days (i.e., in total 5418 (or 63 per person) diary entries). Multiple regression was used to examine effects of BD participants' demographic and clinical characteristics on diary completion rates.53.8 ± 9.3 diary entries per person were actually completed. Adherence rates were high (87.5% of healthy controls and 80.4% of adolescents with BD), but were still significantly poorer in youth with BD. Adequate adherence (≥80%) rates were also significantly poorer in youth with BD relative to healthy controls (56.4% versus 83.0%). Among youth with BD, more lifetime suicide attempts and higher current mood elevation symptom severity predicted significantly poorer adherence.Limited sample size/generalizability.Findings highlight the importance of considering the impact of patient characteristics on adherence with EMA protocols among youth with severe mental illness.

  View details for DOI 10.1016/j.jpsychires.2019.05.026

  View details for PubMedID 31176107

• Complex polypharmacy in bipolar disorder: Side effect burden, adherence, and response predictors. Journal of affective disorders Fung, V. C., Overhage, L. N., Sylvia, L. G., Reilly-Harrington, N. A., Kamali, M. n., Gao, K. n., Shelton, R. C., Ketter, T. A., Bobo, W. V., Thase, M. E., Calabrese, J. R., Tohen, M. n., Deckersbach, T. n., Nierenberg, A. A. 2019; 257: 17–22

  Abstract

  Complex polypharmacy (CP) is common in bipolar disorder (BD). We assessed the associations between CP, adherence, and side effect burden, and patient traits associated with clinical improvement in relationship to CP.We conducted a secondary analysis of 482 adult BD participants in the Bipolar CHOICE trial. We examined the associations between CP (use of ≥3 BD medications) and non-adherence (missing >30% of BD medication doses in the last 30 days) and side effect burden (Frequency, Intensity and Burden of Side Effects Rating scale) using multivariate models with patient random effects. We used logistic regression to assess the patient traits associated with remission among those with majority CP use (Clinical Global Impression-Severity for BD score ≤2 for 8+ weeks).43% of patients had any CP and 25% had CP for the majority of the study. CP was associated with non-adherence (OR = 2.51, 95% CI [1.81, 3.50]), but not worse side effect burden. Among those with CP, 16% achieved remission; those with non-adherence, comorbid social or generalized anxiety disorder, or BD I vs. II were less likely to achieve remission among those with CP.There could be unmeasured confounding between use of CP and side effect burden or adherence. Adherence was measured by self-report, which could be subject to reporting error.BD patients with CP were less likely to adhere to therapy, and those with worse adherence to CP were less likely to clinically respond. Clinicians should assess medication adherence prior to adding another agent to medication regimens.

  View details for DOI 10.1016/j.jad.2019.06.050

  View details for PubMedID 31299400

• Comorbid anxiety in bipolar CHOICE: Insights from the bipolar inventory of symptoms scale. Journal of affective disorders Kinrys, G., Bowden, C. L., Nierenberg, A. A., Hearing, C. M., Gold, A. K., Rabideau, D. J., Sylvia, L. G., Gao, K., Kamali, M., Bobo, W. V., Tohen, M., Deckersbach, T., McElroy, S. L., Ketter, T. A., Shelton, R. C., Friedman, E. S., Calabrese, J. R., McInnis, M. G., Kocsis, J., Thase, M. E., Singh, V., Reilly-Harrington, N. A. 2018; 246: 126–31

  Abstract

  BACKGROUND: Approximately 86-89% of patients with BD have a comorbid anxiety disorder associated with poor quality of life and reduced likelihood of recovery from an acute mood episode. The purpose of this study is to assess the prevalence and impact of comorbid anxiety using the Bipolar Inventory of Symptoms Scale (BISS) in patients with BD who participated in a 6-month pragmatic trial.METHODS: Participants (N = 482) in the Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE) study were adults with BD I or II. Anxiety diagnoses were assessed with the MINI. Global illness severity was assessed using the Clinical Global Impression-Bipolar Version. Mood symptoms and anxiety severity were assessed using the BISS.RESULTS: 61% of the study sample met criteria for a current anxiety disorder. Patients with a higher BISS anxiety score at baseline had a higher overall BD illness severity, depressive severity, and manic episode severity (p < 0.001). A single cutoff value of BISS anxiety had great sensitivity, yet poor specificity for determining a comorbid anxiety diagnosis. There were no significant differences in outcomes for individuals treated for anxiety disorders with anxiolytics compared with those who were not treated with anxiolytics.LIMITATIONS: Sample size limitations prevented an analysis of whether the BISS cutoff score of 10 performed differently across varied anxiety disorders.CONCLUSIONS: Given its ability to identify patients with co-occurring anxiety, the BISS anxiety subscale shows clinical utility as a screening measure though its application as a clinical assessment measure may not be advisable.

  View details for PubMedID 30580198

• Daytime midpoint as a digital biomarker for chronotype in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Kaufmann, C. N., Gershon, A., Depp, C. A., Miller, S., Zeitzer, J. M., Ketter, T. A. 2018; 241: 586–91

  Abstract

  Bipolar disorder (BD) is associated with later sleep and daily activity (evening rather than morning chronotype). Objective chronotype identification (e.g., based on actigraphs/smartphones) has potential utility, but to date, chronotype has mostly been assessed by questionnaires. Given the ubiquity of accelerometer-based devices (e.g. actigraphs/smartphones) worn/used during daytime and tendency to recharge rather than wear at night, we assessed chronotype using daytime (rather than sleep) interval midpoints.Sixty-one participants with BD type I (BD-I) or II (BD-II) and 61 healthy controls completed 25-50 days of continuous actigraphy. The Composite Scale of Morningness (CSM) was completed by a subset of this group. Daytime activity midpoint was calculated for each daytime interval, excluding naps. Evening chronotype was defined as having a daytime interval midpoint at or after 16:15:00 (4:15:00 PM).BD versus controls had delayed daytime midpoint (mean ± standard deviation) (16:49:07 ± 01:26:19 versus 16:12:51 ± 01:02:14, p < 0.01), and greater midpoint variability (73.3 ± 33.9 min versus 58.1 ± 18.3 min, p < 0.01). Stratifying by gender and age, females and adolescents with BD had delayed and more variable daytime midpoints versus controls. Adults with BD had greater midpoint variability than controls. Within-person mean and standard deviations of daytime midpoints were highly correlated with sleep midpoints (r = 0.99, p < 0.01 and r = 0.86, p < 0.01, respectively). Daytime midpoint mean was also significantly correlated with the CSM (r = -0.56, p < 0.01).Small sample size; analyses not fully accounting for daytime napping.Wrist actigraphy for determination of daytime midpoints is a potential tool to identify objective chronotype. Exploration of the use of consumer devices (wearables/smartphones) is needed.

  View details for PubMedID 30172210

• Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Parker, G., Tavella, G., Macqueen, G., Berk, M., Grunze, H., Deckersbach, T., Dunner, D. L., Sajatovic, M., Amsterdam, J. D., Ketter, T. A., Yatham, L. N., Kessing, L., Bassett, D., Zimmerman, M., Fountoulakis, K. N., Duffy, A., Alda, M., Calkin, C., Sharma, V., Anand, A., Singh, M. K., Hajek, T., Boyce, P., Frey, B. N., Castle, D. J., Young, A. H., Vieta, E., Rybakowski, J. K., Swartz, H. A., Schaffer, A., Murray, G., Bayes, A., Lam, R. W., Bora, E., Post, R. M., Ostacher, M. J., Lafer, B., Cleare, A. J., Burdick, K. E., O'Donovan, C., Ortiz, A., Henry, C., Kanba, S., Rosenblat, J. D., Parikh, S. V., Bond, D. J., Grunebaum, M. F., Frangou, S., Goldberg, J. F., Orum, M., Osser, D. N., Frye, M. A., McIntyre, R. S., Fagiolini, A., Manicavasagar, V., Carlson, G. A., Malhi, G. S. 2018; 52 (12): 1173–82

  View details for DOI 10.1177/0004867418808382

  View details for Web of Science ID 000453215000004

• Patterns of changes in bipolar depressive symptoms revealed by trajectory analysis among 482 patients with bipolar disorder. Bipolar disorders Behrendt-Moller, I., Madsen, T., Sorensen, H. J., Sylvia, L., Friedman, E. S., Shelton, R. C., Bowden, C. L., Calabrese, J. R., McElroy, S. L., Ketter, T. A., Reilly Harrington, N. A., Gao, K., Thase, M., Bobo, W. V., Tohen, M., McInnis, M., Kamali, M., Kocsis, J. H., Deckersbach, T., Kohler-Forsberg, O., Nierenberg, A. A. 2018

  Abstract

  INTRODUCTION: Depressive episodes are often prevalent among patients with bipolar disorder, but little is known regarding the differential patterns of development over time. We aimed to determine and characterize trajectories of depressive symptoms among adults with bipolar disorder during 6 months of systematic treatment.METHOD: The pragmatic clinical trial, Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE) randomized 482 outpatients with bipolar disorder to lithium or quetiapine. Depressive symptoms were rated at up to 9 visits using the Montgomery-Asberg Depression Rating Scale (MADRS). Growth Mixture Modelling was utilized to identify trajectories and multinomial regression analysis estimated associations with potential predictors.RESULTS: Four distinct trajectories of depressive symptoms were identified. The Responding class (60.3%) with a rapid reduction and subsequent low level; the Partial-responding class (18.4%) with an initial reduction followed by an increase during the remaining weeks; the Fluctuating class (11.6%) with a fluctuation in depressive symptoms; the Non-responding class (9.7%) with sustained moderate-severe depressive symptoms. Bipolar type I predicted membership of the Non-responding class and randomization to quetiapine predicted membership of either the Responding or the Non-responding class.CONCLUSION: Approximately 30% experienced a partial or fluctuating course and almost 10% had a chronic course with moderate-severe depression during 6 months. Patients diagnosed with bipolar type 1 had higher risk of being categorized into a class with a worse outcome. While no differences in average overall outcomes occurred between the lithium and quetiapine groups, trajectory analysis revealed that the lithium group had more variable courses. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30383333

• Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project. The Australian and New Zealand journal of psychiatry Parker, G., Tavella, G., Macqueen, G., Berk, M., Grunze, H., Deckersbach, T., Dunner, D. L., Sajatovic, M., Amsterdam, J. D., Ketter, T. A., Yatham, L. N., Kessing, L. V., Bassett, D., Zimmerman, M., Fountoulakis, K. N., Duffy, A., Alda, M., Calkin, C., Sharma, V., Anand, A., Singh, M. K., Hajek, T., Boyce, P., Frey, B. N., Castle, D. J., Young, A. H., Vieta, E., Rybakowski, J. K., Swartz, H. A., Schaffer, A., Murray, G., Bayes, A., Lam, R. W., Bora, E., Post, R. M., Ostacher, M. J., Lafer, B., Cleare, A. J., Burdick, K. E., O'Donovan, C., Ortiz, A., Henry, C., Kanba, S., Rosenblat, J. D., Parikh, S. V., Bond, D. J., Grunebaum, M. F., Frangou, S., Goldberg, J. F., Orum, M., Osser, D. N., Frye, M. A., McIntyre, R. S., Fagiolini, A., Manicavasagar, V., Carlson, G. A., Malhi, G. S. 2018: 4867418808382

  Abstract

  OBJECTIVE:: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations.METHOD:: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified.RESULTS:: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders.CONCLUSION:: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

  View details for PubMedID 30378461

• Clinically relevant and simple immune system measure is related to symptom burden in bipolar disorder ACTA NEUROPSYCHIATRICA Kohler-Forsberg, O., Sylvia, L., Deckersbach, T., Ostacher, M., McInnis, M., Iosifescu, D., Bowden, C., McElroy, S., Calabrese, J., Thase, M., Shelton, R., Tohen, M., Kocsis, J., Friedman, E., Ketter, T., Nierenberg, A. 2018; 30 (5): 297–305

  Abstract

  Immunological theories, particularly the sickness syndrome theory, may explain psychopathology in mood disorders. However, no clinical trials have investigated the association between overall immune system markers with a wide range of specific symptoms including potential gender differences.We included two similar clinical trials, the lithium treatment moderate-dose use study and clinical and health outcomes initiatives in comparative effectiveness for bipolar disorder study, enrolling 765 participants with bipolar disorder. At study entry, white blood cell (WBC) count was measured and psychopathology assessed with the Montgomery and Aasberg depression rating scale (MADRS). We performed analysis of variance and linear regression analyses to investigate the relationship between the deviation from the median WBC, and multinomial regression analysis between different WBC levels. All analyses were performed gender-specific and adjusted for age, body mass index, smoking, race, and somatic diseases.The overall MADRS score increased significantly for each 1.0×109/l deviation from the median WBC among 322 men (coefficient=1.10; 95% CI=0.32-1.89; p=0.006), but not among 443 women (coefficient=0.56; 95% CI=-0.19-1.31; p=0.14). Among men, WBC deviations were associated with increased severity of sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, inability to feel, and suicidal thoughts. Among women, WBC deviations were associated with increased severity of reduced appetite, concentration difficulties, lassitude, inability to feel, and pessimistic thoughts. Both higher and lower WBC levels were associated with increased severity of several specific symptoms.Immune system alterations were associated with increased severity of specific mood symptoms, particularly among men. Our results support the sickness syndrome theory, but furthermore emphasise the relevance to study immune suppression in bipolar disorder. Due to the explorative nature and cross-sectional design, future studies need to confirm these findings.

  View details for PubMedID 29212563

• Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Caldieraro, M., Walsh, S., Deckersbach, T., Bobo, W. V., Gao, K., Ketter, T. A., Shelton, R. C., Reilly-Harrington, N. A., Tohen, M., Calabrese, J. R., Thase, M. E., Kocsis, J. H., Sylvia, L. G., Nierenberg, A. A. 2018; 52 (10): 994–1002

  Abstract

  Activation encompasses energy and activity and is a central feature of bipolar disorder. However, the impact of activation on treatment response of bipolar depression requires further exploration. The aims of this study were to assess the association of decreased activation and sustained remission in bipolar depression and test for factors that could affect this association.We assessed participants with Diagnostic and Statistical Manual of Mental Disorders (4th ed) bipolar depression ( n = 303) included in a comparative effectiveness study of lithium- and quetiapine-based treatments (the Bipolar CHOICE study). Activation was evaluated using items from the Bipolar Inventory of Symptoms Scale. The selection of these items was based on a dimension of energy and interest symptoms associated with poorer treatment response in major depression.Decreased activation was associated with lower remission rates in the raw analyses and in a logistic regression model adjusted for baseline severity and subsyndromal manic symptoms (odds ratio = 0.899; p = 0.015). The manic features also predicted lower remission (odds ratio = 0.934; p < 0.001). Remission rates were similar in the two treatment groups.Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. Patients with these features may require specific treatment approaches, but new studies are necessary to identify treatments that could improve outcomes in this population.

  View details for PubMedID 29143534

• Suicide attempts and clinical correlates in patients with bipolar I vs II disorder EUROPEAN PSYCHIATRY Vismara, M., Grancini, B., Cremaschi, L., Oldani, L., Arici, C., de Carlo, V., Miller, S., Ketter, T. A., Altamura, A., Dell'Osso, B. 2018; 52: 113–15

  View details for PubMedID 29778833

• Clinical characterization of Italian suicide attempters with bipolar disorder CNS SPECTRUMS Dell'Osso, B., Vismara, M., Dobrea, C., Cremaschi, L., Grancini, B., Arici, C., Benatti, B., Buoli, M., Ketter, T. A., Altamura, A. 2018; 23 (4): 271–77

  Abstract

  IntroductionBipolar disorder (BD) is a chronic, highly disabling condition associated with psychiatric/medical comorbidity and substantive morbidity, mortality, and suicide risks. In prior reports, varying parameters have been associated with suicide risk.To evaluate sociodemographic and clinical variables characterizing Italian individuals with BD with versus without prior suicide attempt (PSA).A sample of 362 Italian patients categorized as BD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR) was assessed and divided in 2 subgroups: with and without PSA. Sociodemographic and clinical variables were compared between prior attempters and non-attempters using corrected multivariate analysis of variance (MANOVA).More than one-fourth of BD patients (26.2%) had a PSA, with approximately one-third (31%) of these having>1 PSA. Depressive polarity at onset, higher number of psychiatric hospitalizations, comorbid alcohol abuse, comorbid eating disorders, and psychiatric poly-comorbidity were significantly more frequent (p<.05) in patients with versus without PSA. Additionally, treatment with lithium, polypharmacotherapy (≥4 current drugs) and previous psychosocial rehabilitation were significantly more often present in patients with versus without PSA.We found several clinical variables associated with PSA in BD patients. Even though these retrospective findings did not address causality, they could be clinically relevant to better understanding suicidal behavior in BD and adopting proper strategies to prevent suicide in higher risk patients.

  View details for PubMedID 28631584

• Differential prevalence and demographic and clinical correlates of antidepressant use in American bipolar I versus bipolar II disorder patients. Journal of affective disorders Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D. Y., Kim, H., Yuen, L. D., Dell'Osso, B., Wang, P. W., Ketter, T. A., Miller, S. 2018; 234: 74–79

  Abstract

  AIMS: Antidepressant use is controversial in bipolar disorder (BD) due to questionable efficacy/psychiatric tolerability. We assessed demographic/clinical characteristics of baseline antidepressant use in BD patients.METHODS: Prevalence and correlates of baseline antidepressant use in 503 BD I and BD II outpatients referred to the Stanford Bipolar Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation.RESULTS: Antidepressant use was 39.0%, overall, and was higher in BD II versus BD I (46.9% versus 30.5%, p = 0.0002). Both BD I and BD II antidepressant compared to non-antidepressant users had higher rates of complex pharmacotherapy (≥ 4 mood stabilizers, antipsychotics, and/or antidepressants) and use of other psychotropics. Antidepressant use in BD II versus BD I was higher during euthymia (44.0% vs. 28.0%) and subsyndromal symptoms (56.1% vs. 28.6%), but not depression or mood elevation.LIMITATIONS: American tertiary BD clinic referral sample receiving open naturalistic treatment.CONCLUSIONS: In our sample, antidepressant use was higher in BD II versus BD I patients, and was associated with markers of heightened illness severity in both BD I and BD II patients. Additional research is warranted to investigate these complex relationships.

  View details for PubMedID 29524749

• Differential prevalence and demographic and clinical correlates of antidepressant use in American bipolar I versus bipolar II disorder patients JOURNAL OF AFFECTIVE DISORDERS Hooshmand, F., Do, D., Shah, S., Gershon, A., Park, D., Kim, H., Yuen, L. D., Dell'Osso, B., Wang, P. W., Ketter, T. A., Miller, S. 2018; 234: 74–79

  View details for DOI 10.1016/j.jad.2018.02.091

  View details for Web of Science ID 000429308000012

• Longer-Term Effectiveness and Tolerability of Adjunctive Open Lurasidone in Patients With Bipolar Disorder. Journal of clinical psychopharmacology Miller, S., Do, D., Gershon, A., Wang, P. W., Hooshmand, F., Chang, L. S., Ketter, T. A. 2018; 38 (3): 207–11

  Abstract

  PURPOSE: To retrospectively assess lurasidone effectiveness/efficacy/tolerability in bipolar disorder (BD) patients.METHODS: Outpatients assessed with Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation received naturalistically administered (primarily adjunctive) open lurasidone while monitored at visits with the Systematic Treatment Enhancement Program for BD Clinical Monitoring Form.RESULTS: Sixty-one patients (32 type I, 26 type II, 3 type not otherwise specified; mean ± SD age, 45.1 ± 14.0 years; 63.9% were female) received lurasidone with 3.1 ± 1.4 (≥2 in 88.5%, monotherapy in only 3.3%) other nonanxiolytic/hypnotic prescription psychotropics, started during syndromal depression in 57.4%, subsyndromal depression in 23.0%, and euthymia in 19.7%. Lurasidone was taken for median 126 days, with final dose 55.6 ± 30.8 mg/d. By final visit taking lurasidone, syndromal depression rate decreased by nearly one-half to 31.1%, and euthymia rate more than doubled to 42.6%, whereas subsyndromal depression rate was unchanged at 23.0%. Clinical Global Impressions-BD-Overall Severity improved significantly only in patients with baseline syndromal depression. Seventy-seven percent of patients discontinued lurasidone after median 103 days, because of adverse events in 54.1% (most often akathisia, sedation/somnolence, nausea, and weight gain), inefficacy in 16.4%, and other reasons in 6.6%; 12.1% had equal to or greater than 7% weight gain, and 3.3% developed hypomania. Limitations to this study were the open design and demographically homogeneous (relatively affluent, predominantly white female) small sample taking complex pharmacotherapy.CONCLUSIONS: In American specialty clinic BD outpatients, adjunctive longer-term lurasidone commonly relieved syndromal depression and maintained euthymia, suggesting possible effectiveness/efficacy. However, lurasidone was discontinued in 54.1% because of adverse events, suggesting tolerability limitations in these challenging patients, nearly 90% of whom were already taking at least 2 other nonanxiolytic/hypnotic prescription psychotropics.

  View details for PubMedID 29620693

• Longer-Term Effectiveness and Tolerability of Adjunctive Open Lurasidone in Patients With Bipolar Disorder JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Miller, S., Do, D., Gershon, A., Wang, P. W., Hooshmand, F., Chang, L. S., Ketter, T. A. 2018; 38 (3): 207–11

  View details for DOI 10.1097/JCP.0000000000000867

  View details for Web of Science ID 000431001500008

• Does Binge Eating at Baseline Influence Lithium- and Quetiapine-Associated Changes in Anthropometric Measures Over 6 Months of Treatment? Findings From Bipolar Choice Bobo, W., Yaramala, S., Geske, J. R., Winham, S., Kamali, M., Deckersbach, T., McElroy, S., Tohen, M., Sylvia, L., Shelton, R., Gao, K., Nierenberg, A., Ketter, T., Thase, M. ELSEVIER SCIENCE INC. 2018: S390–S391

  View details for Web of Science ID 000433001900398

• Treatment outcomes of acute bipolar depressive episode with psychosis DEPRESSION AND ANXIETY Caldieraro, M., Dufour, S., Sylvia, L. G., Gao, K., Ketter, T. A., Bobo, W. V., Walsh, S., Janos, J., Tohen, M., Reilly-Harrington, N. A., McElroy, S. L., Shelton, R. C., Bowden, C. L., Deckersbach, T., Nierenberg, A. A. 2018; 35 (5): 402–10

  Abstract

  The impact of psychosis on the treatment of bipolar depression is remarkably understudied. The primary aim of this study was to compare treatment outcomes of bipolar depressed individuals with and without psychosis. The secondary aim was to compare the effect of lithium and quetiapine, each with adjunctive personalized treatments (APTs), in the psychotic subgroup.We assessed participants with DSM-IV bipolar depression included in a comparative effectiveness study of lithium and quetiapine with APTs (the Bipolar CHOICE study). Severity was assessed by the Bipolar Inventory of Symptoms Scale (BISS) and by the Clinical Global Impression Scale-Severity-Bipolar Version (CGI-S-BP). Mixed models were used to assess the course of symptom change, and Cox regression survival analysis was used to assess the time to remission.Psychotic features were present in 10.6% (n = 32) of the depressed participants (n = 303). Those with psychotic features had higher scores on the BISS before (75.2 ± 17.6 vs. 54.9 ± 16.3; P < .001) and after (37.2 ± 19.7 vs. 26.3 ± 18.0; P = .003) 6-month treatment. The CGI-S-BP yielded similar results. Participants with and without psychosis had similar course of symptom improvement and similar time to remission. There was no significant difference in the treatment outcomes of lithium (n = 11) and quetiapine (n = 21) among the psychotic subgroup.Bipolar depressive episodes with psychotic features are more severe, and compared to nonpsychotic depressions, present a similar course of improvement. Given the small number of participants presenting psychosis, the lack of statistically significant difference between lithium- and quetiapine-based treatment of psychotic bipolar depressive episodes needs replication in a larger sample.

  View details for PubMedID 29329498

• Episode accumulation associated with hastened recurrence and delayed recovery in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Park, D., Do, D., Chang, L., Shah, S., Yuen, L. D., Hooshmand, F., Wang, P. W., Miller, S., Ketter, T. A. 2018; 227: 657–64

  Abstract

  Assess episode accumulation (≥ 10 prior mood episodes) associations with demographic/baseline clinical characteristics and mood episode recurrence/recovery in bipolar disorder (BD).Stanford BD Clinic outpatients enrolled during 2000-2011 were assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Among recovered and syndromal mood episode patients, we assessed episode accumulation associations with demographic/baseline clinical characteristics and with recurrence/recovery (by Kaplan-Meier survival analyses, with mediators assessed with Cox Proportional Hazard Ratio (HR) analyses).Among all 450 BD outpatients, almost twice as many had versus lacked episode accumulation (65.8% versus 34.2%), which was less common among 92 recovered versus 193 syndromal mood episode patients (51.1% versus 69.9%). Among recovered patients, episode accumulation was associated with 14/18 (77.7%) demographic/other baseline clinical characteristics, and hastened mood episode recurrence. Among syndromal mood episode patients, episode accumulation was associated with 13/18 (72.2%) demographic/other baseline clinical characteristics, and delayed mood episode recovery.American tertiary BD clinic referral sample.Studies are needed to confirm episode accumulation is associated with hastened mood episode recurrence and delayed mood episode recovery in BD, and to further explore its' associations with hastened mood elevation recurrence and delayed recovery from depressive and mood elevation episodes, considered separately.

  View details for PubMedID 29174739

• Definition of the term "mood stabilizer" BIPOLAR DISORDERS Ketter, T. A. 2018; 20 (1): 74–75

  View details for PubMedID 29214704

• The impact of binge eating behavior on lithium- and quetiapine-associated changes in body weight, body mass index, and waist circumference during 6 months of treatment: Findings from the bipolar CHOICE study. Journal of affective disorders Yaramala, S. R., McElroy, S. L., Geske, J. n., Winham, S. n., Gao, K. n., Reilly-Harrington, N. A., Ketter, T. A., Deckersbach, T. n., Kinrys, G. n., Kamali, M. n., Sylvia, L. G., McInnis, M. G., Friedman, E. S., Thase, M. E., Kocsis, J. H., Tohen, M. n., Calabrese, J. R., Bowden, C. L., Shelton, R. C., Nierenberg, A. A., Bobo, W. V. 2018

  Abstract

  Lithium and quetiapine can cause weight gain, but their comparative longer term anthropometric effects are unknown, as are the potential moderating effects of baseline binge-eating (BE) behavior.We assessed 6 month changes in body weight, body mass index (BMI) and waist circumference in 482 adults with DSM-IV bipolar disorders who participated in a comparative effectiveness study of lithium and quetiapine with evidence-based adjunctive treatment (Bipolar CHOICE). Anthropometric measurements were obtained at baseline, and at 2, 4, 6, 8, 12, 16, 20, and 24 weeks. BE behavior was defined as affirmative responses to MINI items M1 and M3 at baseline. Data were analyzed using a mixed model repeated measures approach, adjusted for baseline values of dependent measures.On average, body weight and BMI increased over 6 months with lithium and quetiapine. However, those treated with quetiapine experienced greater increases from baseline in body weight (peak change, + 3.6 lbs. vs. + 1.4 lbs.) and BMI (peak change, + 0.6 kg/m2 vs. + 0.3 kg/m2), starting at 2 weeks (group x time, F8,3052 = 2.9, p = 0.003 for body weight, F8,3052 = 3.0, p = 0.002 for BMI). Significant increases in waist circumference were observed only with quetiapine. The relationship between drug treatment and changes in body weight (group x time x binge eating status, F1,2770 = 2.0, p = 0.002), BMI (F1,2767 = 2.0, p = 0.002), and waist circumference (women only, F25,1621 = 2.9, p < 0.0001) were moderated by BE behavior. The largest increases over 24 weeks in body weight and BMI, and waist circumference in women, occurred for quetiapine-treated patients with baseline binge-eating, relative to quetiapine-treated patients without binge eating and lithium-treated patients with or without baseline binge-eating.Bipolar CHOICE was not designed to study anthropometric outcomes.Greater changes in body weight, BMI, and waist circumference occurred with quetiapine- versus lithium-based treatment over 6 months of treatment. The effects of study drugs on these anthropometric measures were moderated by BE behavior at baseline.

  View details for PubMedID 30241956

• Subjective versus objective evening chronotypes in bipolar disorder. Journal of affective disorders Gershon, A., Kaufmann, C. N., Depp, C. A., Miller, S., Do, D., Zeitzer, J. M., Ketter, T. A. 2018; 225: 342-349

  Abstract

  Disturbed sleep timing is common in bipolar disorder (BD). However, most research is based upon self-reports. We examined relationships between subjective versus objective assessments of sleep timing in BD patients versus controls.We studied 61 individuals with bipolar I or II disorder and 61 healthy controls. Structured clinical interviews assessed psychiatric diagnoses, and clinician-administered scales assessed current mood symptom severity. For subjective chronotype, we used the Composite Scale of Morningness (CSM) questionnaire, using original and modified (1, ¾, ⅔, and ½ SD below mean CSM score) thresholds to define evening chronotype. Objective chronotype was calculated as the percentage of nights (50%, 66.7%, 75%, or 90% of all nights) with sleep interval midpoints at or before (non-evening chronotype) vs. after (evening chronotype) 04:15:00 (4:15:00a.m.), based on 25-50 days of continuous actigraph data.BD participants and controls differed significantly with respect to CSM mean scores and CSM evening chronotypes using modified, but not original, thresholds. Groups also differed significantly with respect to chronotype based on sleep interval midpoint means, and based on the threshold of 75% of sleep intervals with midpoints after 04:15:00. Subjective and objective chronotypes correlated significantly with one another. Twenty-one consecutive intervals were needed to yield an evening chronotype classification match of ≥ 95% with that made using the 75% of sleep intervals threshold.Limited sample size/generalizability.Subjective and objective chronotype measurements were correlated with one another in participants with BD. Using population-specific thresholds, participants with BD had a later chronotype than controls.

  View details for DOI 10.1016/j.jad.2017.08.055

  View details for PubMedID 28843917

  View details for PubMedCentralID PMC5626649

• Differentiating multiple vs single lifetime suicide attempters with bipolar disorders: A retrospective study. Comprehensive psychiatry Arici, C., Cremaschi, L., Dobrea, C., Vismara, M., Grancini, B., Benatti, B., Buoli, M., Miller, S., Ketter, T. A., Altamura, A. C., Dell'Osso, B. 2018; 80: 214-222

  Abstract

  The risk of suicide in Bipolar Disorder (BD) has been estimated up to 20-30 times higher compared with the general population. Previous suicide attempts (SAs) represent a well-established risk factor for further attempts and for death by suicide in patients with psychiatric disorders. However, little is known about the socio-demographic and clinical profile of BD patients with a history of multiple SAs (MSAs). The present study sought to characterize BD patients with MSAs versus single suicide attempt (SSA) within a large Italian sample.An original sample of 354 bipolar patients, recruited at the University Clinic and related community services at the Department of Psychiatry, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan (Italy), was screened for the presence of previous SAs (n=95). Socio-demographic and clinical variables were then compared between patients with multiple vs single lifetime suicide attempts.Bipolar patients with MSAs versus SSA had longer bipolar illness duration (26.9±12.6 vs 21.2±12.8years; p=0.05), and more frequently lived alone (38.5% vs 17.2%; p<0.05), had more than one psychiatric comorbidity (39.3% vs 17.5%; p=0.04), and utilized substance ingestion (e.g., overdose) (78.6% vs 47.2%, p=0.009), although the latter was the most common suicide attempt method in both groups.Present findings suggest different socio-demographic and clinical characteristics in bipolar patients with MSAs versus SSA. Further investigation is needed to confirm reported data.

  View details for DOI 10.1016/j.comppsych.2017.10.006

  View details for PubMedID 29145062

• bipolar mixed features - Results from the comparative effectiveness for bipolar disorder (Bipolar CHOICE) study (vol 217, pg 183, 2017) JOURNAL OF AFFECTIVE DISORDERS Tohen, M., Gold, A. K., Sylvia, L. G., Montana, R. E., McElroy, S. L., Thase, M. E., Rabideau, D. J., Nierenberg, A. A., Reilly-Harrington, N. A., Friedman, E. S., Shelton, R. C., Bowden, C. L., Singh, V., Deckersbach, T., Ketter, T. A., Calabrese, J. R., Bobo, W. V., McInnis, M. G. 2018; 225: 775–77

  View details for PubMedID 28826887

• The safety and tolerability of cariprazine in patients with manic or mixed episodes associated with bipolar I disorder: A 16-week open-label study JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A., Sachs, G. S., Durgam, S., Lu, K., Starace, A., Laszlovszky, I., Nemeth, G. 2018; 225: 350–56

  Abstract

  We evaluated the safety/tolerability of longer-term open-label treatment with cariprazine in patients who had responded to cariprazine for acute bipolar mania.In this multinational, multicenter study, open-label, flexible-dose, cariprazine 3-12mg/d was administered for up to 16 weeks to patients (18-65 years) with bipolar mania. Safety evaluations included adverse events (AEs), laboratory values, vital signs, and extrapyramidal symptom (EPS) scales. Symptom change was evaluated by Young Mania Rating Scale (YMRS) total score change from baseline using the last observation carried forward approach.Of the 402 patients taking cariprazine, 33% completed the trial; the most frequent reasons for discontinuation were withdrawal of consent (20%), AEs (16%), and protocol violation (14%). Most common AEs leading to discontinuation were akathisia (4.7%) and depression (1.5%). Mean treatment duration was 57.7 days; mean cariprazine dose was 6.2mg/d. The incidence of serious AEs was 7.5% (most common: mania [2.2%], depression [1.2%]); 83.3% had treatment-emergent AEs, including akathisia (32.6%), headache (16.7%), constipation (10.7%), and nausea (10.4%). Mean body weight increased <1kg; 9.3% had ≥7% weight gain; 5.7% had sedation; 3% had somnolence. Mean changes in laboratory values, vital signs, ECGs, and ophthalmology parameters were not clinically significant. Mean YMRS total score decreased by -15.2 at week 16.Uncontrolled, open-label design.Open-label cariprazine 3-12 (mean 6.2) mg/d for up to 16 weeks was generally well tolerated, with low (<10%) rates of sedation and ≥7% weight gain. Although akathisia occurred in 33%, it yielded discontinuation in <5%.

  View details for PubMedID 28843918

• Sleep disturbance may impact treatment outcome in bipolar disorder: A preliminary investigation in the context of a large comparative effectiveness trial JOURNAL OF AFFECTIVE DISORDERS Sylvia, L. G., Chang, W. C., Kamali, M., Tohen, M., Kinrys, G., Deckersbach, T., Calabrese, J. R., Thase, M. E., Reilly-Harrington, N., Bobo, W. V., Kocsis, J. H., McInnis, M. G., Bowden, C. L., Ketter, T. A., Friedman, E. S., Shelton, R. C., McElroy, S. L., Gao, K., Rabideau, D. J., Nierenberg, A. A. 2018; 225: 563–68

  Abstract

  Bipolar patients experience sleep disturbances during and between mood episodes. Yet the impact of sleep on treatment with different medications has not been fully explored. The purpose of this paper is to explore the potential impact of poor sleep at baseline on outcomes in a randomized effectiveness trial of quetiapine and lithium.The Bipolar CHOICE study was a 6-month, parallel group, multisite randomized controlled trial. Participants with bipolar disorder (N = 482; 59% female and age 18-70 years) received quetiapine or lithium. Patients were allowed to also receive adjunctive personalized treatments, which were guideline-informed, empirically-based medications added to treatment as needed. Medication changes were recorded as necessary clinical adjustments (NCA). Fisher's exact tests, mixed-regression models, and Mann-Whitney U tests were used to assess demographic and clinical characteristics as well as whether sleep disturbance would predict outcomes.63% of patients had baseline sleep disturbance. Individuals with sleep disturbance had worse bipolar illness severity, greater severity of depression, mania, anxiety, irritability, and psychosis, were less likely to have sustained response (17% vs. 29%; adjusted RR: 0.55, 95% CI: 0.38-0.78, p = 0.0006) and had more NCAs (median 0.71 vs. 0.59, p = 0.03).Our findings were limited by how we defined sleep disturbance, and by how severity of sleep disturbance was assessed with one item with a non-sleep specific measure.Baseline sleep disturbance was associated with more severe bipolar symptoms and worse 6-month outcomes. Further research is warranted on improving sleep in bipolar disorder, especially the role of psychosocial interventions.

  View details for PubMedID 28881294

• Differentiating multiple vs single lifetime suicide attempters with bipolar disorders: A retrospective study COMPREHENSIVE PSYCHIATRY Arici, C., Cremaschi, L., Dobrea, C., Vismara, M., Grancini, B., Benatti, B., Buoli, M., Miller, S., Ketter, T. A., Altamura, A., Dell'Osso, B. 2018; 80: 214–22

  View details for DOI 10.1016/j.comppsych.2017.10.006

  View details for Web of Science ID 000417673000027

• Subjective versus objective evening chronotypes in bipolar disorder Journal of Affective Disorders Gershon, A., Kaufmann, C. N., Depp, C. A., Miller, S., Do, D., Zeitzer, J. M., Ketter, T. A. 2018; 225: 342–349

  Abstract

  Disturbed sleep timing is common in bipolar disorder (BD). However, most research is based upon self-reports. We examined relationships between subjective versus objective assessments of sleep timing in BD patients versus controls.We studied 61 individuals with bipolar I or II disorder and 61 healthy controls. Structured clinical interviews assessed psychiatric diagnoses, and clinician-administered scales assessed current mood symptom severity. For subjective chronotype, we used the Composite Scale of Morningness (CSM) questionnaire, using original and modified (1, ¾, ⅔, and ½ SD below mean CSM score) thresholds to define evening chronotype. Objective chronotype was calculated as the percentage of nights (50%, 66.7%, 75%, or 90% of all nights) with sleep interval midpoints at or before (non-evening chronotype) vs. after (evening chronotype) 04:15:00 (4:15:00a.m.), based on 25-50 days of continuous actigraph data.BD participants and controls differed significantly with respect to CSM mean scores and CSM evening chronotypes using modified, but not original, thresholds. Groups also differed significantly with respect to chronotype based on sleep interval midpoint means, and based on the threshold of 75% of sleep intervals with midpoints after 04:15:00. Subjective and objective chronotypes correlated significantly with one another. Twenty-one consecutive intervals were needed to yield an evening chronotype classification match of ≥ 95% with that made using the 75% of sleep intervals threshold.Limited sample size/generalizability.Subjective and objective chronotype measurements were correlated with one another in participants with BD. Using population-specific thresholds, participants with BD had a later chronotype than controls.

  View details for DOI 10.1016/j.jad.2017.08.055

  View details for PubMedCentralID PMC5626649

• Lifetime eating disorder comorbidity associated with delayed depressive recovery in bipolar disorder. International journal of bipolar disorders Balzafiore, D. R., Rasgon, N. L., Yuen, L. D., Shah, S., Kim, H., Goffin, K. C., Miller, S., Wang, P. W., Ketter, T. A. 2017; 5 (1): 25-?

  Abstract

  Although eating disorders (EDs) are common in bipolar disorder (BD), little is known regarding their longitudinal consequences. We assessed prevalence, clinical correlates, and longitudinal depressive severity in BD patients with vs. without EDs.Outpatients referred to Stanford University BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) affective disorders evaluation, and while receiving naturalistic treatment for up to 2 years, were monitored with the STEP-BD clinical monitoring form. Patients with vs. without lifetime EDs were compared with respect to prevalence, demographic and unfavorable illness characteristics/current mood symptoms and psychotropic use, and longitudinal depressive severity.Among 503 BD outpatients, 76 (15.1%) had lifetime EDs, which were associated with female gender, and higher rates of lifetime comorbid anxiety, alcohol/substance use, and personality disorders, childhood BD onset, episode accumulation (≥10 prior mood episodes), prior suicide attempt, current syndromal/subsyndromal depression, sadness, anxiety, and antidepressant use, and earlier BD onset age, and greater current overall BD severity. Among currently depressed patients, 29 with compared to 124 without lifetime EDs had significantly delayed depressive recovery. In contrast, among currently recovered (euthymic ≥8 weeks) patients, 10 with compared to 95 without lifetime EDs had only non-significantly hastened depressive recurrence.Primarily Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability. Small number of recovered patients with EDs limited statistical power to detect relationships between EDs and depressive recurrence.Further studies are warranted to explore the degree to which EDs impact longitudinal depressive illness burden in BD.

  View details for DOI 10.1186/s40345-017-0094-4

  View details for PubMedID 28480483

• Trajectories of suicidal ideation over 6 months among 482 outpatients with bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Kohler-Forsberg, O., Madsen, T., Behrendt-Moller, I., Sylvia, L., Bowden, C. L., Gao, K., Bobo, W. V., Trivedi, M. H., Calabrese, J. R., Thase, M., Shelton, R. C., McInnis, M., Tohen, M., Ketter, T. A., Friedman, E. S., Deckersbach, T., McElroy, S. L., Reilly-Harrington, N. A., Nierenberg, A. A. 2017; 223: 146–52

  Abstract

  Suicidal ideation occurs frequently among individuals with bipolar disorder; however, its course and persistence over time remains unclear. We aimed to investigate 6-months trajectories of suicidal ideation among adults with bipolar disorder.The Bipolar CHOICE study randomized 482 outpatients with bipolar disorder to 6 months of lithium- or quetiapine-based treatment including other psychotropic medications as clinically indicated. Participants were asked at 9 visits about suicidal ideation using the Concise Health Risk Tracking scale. We performed latent Growth Mixture Modelling analysis to empirically identify trajectories of suicidal ideation. Multinomial logistic regression analyses were applied to estimate associations between trajectories and potential predictors.We identified four distinct trajectories. The Moderate-Stable group represented 11.1% and was characterized by constant suicidal ideation. The Moderate-Unstable group included 2.9% with persistent thoughts about suicide with a more fluctuating course. The third (Persistent-low, 20.8%) and fourth group (Persistent-very-low, 65.1%) were characterized by low levels of suicidal ideation. Higher depression scores and previous suicide attempts (non-significant trend) predicted membership of the Moderate-Stable group, whereas randomized treatment did not.No specific treatments against suicidal ideation were included and suicidal thoughts may persist for several years.More than one in ten adult outpatients with bipolar disorder had moderately increased suicidal ideation throughout 6 months of pharmacotherapy. The identified predictors may help clinicians to identify those with additional need for treatment against suicidal thoughts and future studies need to investigate whether targeted treatment (pharmacological and non-pharmacological) may improve the course of persistent suicidal ideation.

  View details for PubMedID 28755622

• Poor quality of life and functioning in bipolar disorder. International journal of bipolar disorders Sylvia, L. G., Montana, R. E., Deckersbach, T., Thase, M. E., Tohen, M., Reilly-Harrington, N., McInnis, M. G., Kocsis, J. H., Bowden, C., Calabrese, J., Gao, K., Ketter, T., Shelton, R. C., McElroy, S. L., Friedman, E. S., Rabideau, D. J., Nierenberg, A. A. 2017; 5 (1): 10-?

  Abstract

  This study explores the association of demographic and clinical features with quality of life and functioning in individuals with bipolar disorder.Adult participants (N = 482) with bipolar I or II disorder were enrolled in a comparative effectiveness study across eleven study sites and completed baseline measures of medical and psychiatric history, current mood, quality of life, and functioning. Participants with at least mildly depressive or manic/hypomanic symptomatic severity were randomized to receive lithium or quetiapine in addition to adjunctive personalized treatment for 6 months.Participants with more severe depressive and irritability symptoms had lower quality of life and higher functional impairment. All psychiatric comorbid conditions except substance use disorder were associated with worse quality of life. On average, females had lower quality of life than males. Patients who were married, living as married, divorced, or separated had worse functional impairment compared with patients who were single or never married. A composite score of social disadvantage was associated with worse functioning and marginally associated with worse quality of life. Symptom severity did not moderate the effect of social disadvantage on quality of life or functioning.Our findings highlight that depression, irritability, and psychiatric comorbid conditions negatively impact quality of life and functioning in bipolar disorder. The study suggests that individuals with social disadvantage are at risk for functional impairment. Trial Registration This study is registered with ClinicalTrials.gov. Identification number: NCT01331304.

  View details for DOI 10.1186/s40345-017-0078-4

  View details for PubMedID 28188565

  View details for PubMedCentralID PMC5366290

• American tertiary clinic-referred bipolar II disorder versus bipolar I disorder associated with hastened depressive recurrence. International journal of bipolar disorders Dell'Osso, B., Shah, S., Do, D., Yuen, L. D., Hooshmand, F., Wang, P. W., Miller, S., Ketter, T. A. 2017; 5 (1): 2-?

  Abstract

  Bipolar disorder (BD) is a chronic, frequently comorbid condition characterized by high rates of mood episode recurrence and suicidality. Little is known about prospective longitudinal characterization of BD type II (BD II) versus type I (BD I) in relation to time to depressive recurrence and recovery from major depressive episode. We therefore assessed times to depressive recurrence/recovery in tertiary clinic-referred BD II versus I patients.Outpatients referred to Stanford BD Clinic during 2000-2011 were assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and with Clinical Monitoring Form during up to 2 years of naturalistic treatment. Prevalence and clinical correlates of bipolar subtype in recovered (euthymic ≥8 weeks) and depressed patients were assessed. Kaplan-Meier analyses assessed the relationships between bipolar subtype and longitudinal depressive severity, and Cox proportional hazard analyses assessed the potential mediators.BD II versus BD I was less common among 105 recovered (39.0 vs. 61.0%, p = 0.03) and more common among 153 depressed (61.4 vs. 38.6%, p = 0.006) patients. Among recovered patients, BD II was associated with 6/25 (24.0%) baseline unfavorable illness characteristics/mood symptoms/psychotropics and hastened depressive recurrence (p = 0.015). Among depressed patients, BD II was associated with 8/25 (33.0%) baseline unfavorable illness characteristics/mood symptoms/psychotropics, but only non-significantly associated with delayed depressive recovery.BD II versus BD I was significantly associated with current depression and hastened depressive recurrence, but only non-significantly associated with delayed depressive recovery. Research on bipolar subtype relationships with depressive recurrence/recovery is warranted to enhance clinical management of BD patients.

  View details for DOI 10.1186/s40345-017-0072-x

  View details for PubMedID 28124233

  View details for PubMedCentralID PMC5267582

• Bipolar mixed features - Results from the comparative effectiveness for bipolar disorder (Bipolar CHOICE) study. Journal of affective disorders Tohen, M., Gold, A. K., Sylvia, L. G., Montana, R. E., McElroy, S. L., Thase, M. E., Rabideau, D. J., Nierenberg, A. A., Reilly-Harrington, N. A., Friedman, E. S., Shelton, R. C., Bowden, C. L., Singh, V., Deckersbach, T., Ketter, T. A., Calabrese, J. R., Bobo, W. V., McInnis, M. G. 2017; 217: 183-189

  Abstract

  DSM-5 changed the criteria from DSM-IV for mixed features in mood disorder episodes to include non-overlapping symptoms of depression and hypomania/mania. It is unknown if, by changing these criteria, the same group would qualify for mixed features. We assessed how those meeting DSM-5 criteria for mixed features compare to those meeting DSM-IV criteria.We analyzed data from 482 adult bipolar patients in Bipolar CHOICE, a randomized comparative effectiveness trial. Bipolar diagnoses were confirmed through the MINI International Neuropsychiatric Interview (MINI). Presence and severity of mood symptoms were collected with the Bipolar Inventory of Symptoms Scale (BISS) and linked to DSM-5 and DSM-IV mixed features criteria. Baseline demographics and clinical variables were compared between mood episode groups using ANOVA for continuous variables and chi-square tests for categorical variables.At baseline, the frequency of DSM-IV mixed episodes diagnoses obtained with the MINI was 17% and with the BISS was 20%. Using DSM-5 criteria, 9% of participants met criteria for hypomania/mania with mixed features and 12% met criteria for a depressive episode with mixed features. Symptom severity was also associated with increased mixed features with a high rate of mixed features in patients with mania/hypomania (63.8%) relative to those with depression (8.0%).Data on mixed features were collected at baseline only and thus do not reflect potential patterns in mixed features within this sample across the study duration.The DSM-5 narrower, non-overlapping definition of mixed episodes resulted in fewer patients who met mixed criteria compared to DSM-IV.

  View details for DOI 10.1016/j.jad.2017.03.070

  View details for PubMedID 28411507

• Commentary on the Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder AMERICAN JOURNAL OF PSYCHIATRY Ketter, T. A., Dell'Osso, B. 2017; 174 (8): 803–4

  View details for PubMedID 28760025

• Clinical correlates of acute bipolar depressive episode with psychosis. Journal of affective disorders Caldieraro, M. A., Sylvia, L. G., Dufour, S., Walsh, S., Janos, J., Rabideau, D. J., Kamali, M., McInnis, M. G., Bobo, W. V., Friedman, E. S., Gao, K., Tohen, M., Reilly-Harrington, N. A., Ketter, T. A., Calabrese, J. R., McElroy, S. L., Thase, M. E., Shelton, R. C., Bowden, C. L., Kocsis, J. H., Deckersbach, T., Nierenberg, A. A. 2017; 217: 29-33

  Abstract

  Psychotic bipolar depressive episodes remain remarkably understudied despite being common and having a significant impact on bipolar disorder. The aim of this study is to identify the characteristics of depressed bipolar patients with current psychosis compared to those without psychosis.We used baseline data of a comparative effectiveness study of lithium and quetiapine for bipolar disorder (the Bipolar CHOICE study) to compare demographic, clinical, and functioning variables between those with and without psychotic symptoms. Of the 482 participants, 303 (62.9%) were eligible for the present study by meeting DSM-IV criteria for an acute bipolar depressive episode. Univariate analyses were conducted first, and then included in a model controlling for symptom severity.The sample was composed mostly of women (60.7%) and the mean age was 39.5±12.1 years. Psychosis was present in 10.6% (n=32) of the depressed patients. Psychotic patients had less education, lower income, and were more frequently single and unemployed. Psychosis was also associated with a more severe depressive episode, higher suicidality, more comorbid conditions and worse functioning. Most group differences disappeared when controlling for depression severity.Only outpatients were included and the presence of psychosis in previous episodes was not assessed.Psychosis during bipolar depressive episodes is present even in an outpatient sample. Psychotic, depressed patients have worse illness outcomes, but future research is necessary to confirm if these outcomes are only associated with the severity of the disorder or if some of them are independent of it.

  View details for DOI 10.1016/j.jad.2017.03.059

  View details for PubMedID 28365478

• Lifetime presence of psychotic symptoms in bipolar disorder is associated with less favorable socio-demographic and certain clinical features. Comprehensive psychiatry Dell'Osso, B., Camuri, G., Cremaschi, L., Dobrea, C., Buoli, M., Ketter, T. A., Altamura, A. C. 2017; 76: 169-176

  Abstract

  The presence of psychotic symptoms in bipolar disorder (BD) is considered a feature of higher severity of illness and, in particular, of manic episodes in bipolar I disorder (BD I). However, the possibility to apply the "with psychotic features" specifier to major depressive episodes in either bipolar II disorder (BD II) or BD I highlights the need for additional research in this area.The present study assessed the lifetime presence of psychotic symptoms and related socio-demographic and clinical features in a large sample of BD patients (N=360), with (BDPs, N=207) and without a lifetime history of psychosis (BDNPs, N=153).An overall less favorable socio-demographic profile was observed in BDPs vs BDNPs. In terms of clinical variables, BDPs vs BDNPs had: earlier age at onset (27.7±10.5 vs 30.1±12.3years; p=0.02), higher rates of BD I diagnosis (95.7% vs 45.8%; p<0.001), more elevated (manic/hypomanic/mixed) polarity of first (55.2% vs 24.4%; p<0.001) and most recent episode (69.8% vs 35.6%; p<0.001), more comorbid alcohol/substance use disorder (38.1% vs 21.9%; p=0.002), more lifetime hospitalizations (3.8±6.1 vs 2±3; p=0.002) and involuntary commitments (1±1.9 vs 0.1±0.4; p<0.001), more history of psychosocial rehabilitation (17.9% vs 5.7%; p=0.001), more current antipsychotic use (90.1% vs 70.9%; p<0.001), and lower GAF (62.3±14.2 vs 69.3±12.5; p<0.001), but shorter duration of most recent episode (34.1±45.4 vs 50.3±65.7days; p=0.04), lower rates of comorbid anxiety disorders (23.9% vs 38.2%; p=0.005), and antidepressant use (19.4% vs 56.6%; p<0.001).The present findings indicate an overall worse profile of socio-demographic and certain clinical characteristics associated with the lifetime presence of psychotic symptoms in bipolar patients.

  View details for DOI 10.1016/j.comppsych.2017.04.005

  View details for PubMedID 28531646

• Abnormal Sleep Duration Associated with Hastened Depressive Recurrence in Bipolar Disorder Gershon, A., Do, D., Satyanarayana, S., Shah, S., Yuen, L., Hooshmand, F., Miller, S., Wang, P., Ketter, T. ELSEVIER SCIENCE INC. 2017: S364

  View details for DOI 10.1016/j.biopsych.2017.02.626

  View details for Web of Science ID 000400348700898

• Lifetime anxiety disorder and current anxiety symptoms associated with hastened depressive recurrence in bipolar disorder. Journal of affective disorders Shah, S., Kim, J. P., Park, D. Y., Kim, H., Yuen, L. D., Do, D., Dell'Osso, B., Hooshmand, F., Miller, S., Wang, P. W., Ketter, T. A. 2017; 219: 165-171

  Abstract

  To assess differential relationships between lifetime anxiety disorder/current anxiety symptoms and longitudinal depressive severity in bipolar disorder (BD).Stanford BD Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form while receiving naturalistic treatment for up to two years. Baseline unfavorable illness characteristics/current mood symptoms and times to depressive recurrence/recovery were compared in patients with versus without lifetime anxiety disorder/current anxiety symptoms.Among 105 currently recovered patients, lifetime anxiety disorder was significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics, hastened depressive recurrence (driven by earlier onset age), and a significantly (> two-fold) higher Kaplan-Meier estimated depressive recurrence rate, whereas current anxiety symptoms were significantly associated with 10/27 (37.0%) demographic/other unfavorable illness characteristics/current mood symptoms/current psychotropics and hastened depressive recurrence (driven by lifetime anxiety disorder), but only a numerically higher Kaplan-Meier estimated depressive recurrence rate. In contrast, among 153 currently depressed patients, lifetime anxiety disorder/current anxiety symptoms were not significantly associated with time to depressive recovery or depressive recovery rate.American tertiary BD clinic referral sample, open naturalistic treatment.Research is needed regarding differential relationships between lifetime anxiety disorder and current anxiety symptoms and hastened/delayed depressive recurrence/recovery - specifically whether lifetime anxiety disorder versus current anxiety symptoms has marginally more robust association with hastened depressive recurrence, and whether both have marginally more robust associations with hastened depressive recurrence versus delayed depressive recovery, and related clinical implications.

  View details for DOI 10.1016/j.jad.2017.05.007

  View details for PubMedID 28558363

• Abnormal sleep duration associated with hastened depressive recurrence in bipolar disorder. Journal of affective disorders Gershon, A., Do, D., Satyanarayana, S., Shah, S., Yuen, L. D., Hooshmand, F., Miller, S., Wang, P. W., Ketter, T. A. 2017; 218: 374-379

  Abstract

  Abnormal sleep duration (ASD, <6 or ≥9h) is common in bipolar disorder (BD), and often persists beyond acute mood episodes. Few longitudinal studies have examined the ASD's impact upon BD illness course. The current study examined the longitudinal impact of ASD upon bipolar depressive recurrence/recovery.Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form at monthly follow-ups for up to two years of naturalistic treatment. Prevalence and clinical correlates of ASD in 93 recovered (euthymic ≥8 weeks) and 153 depressed BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between baseline ASD and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators.ASD was only half as common among recovered versus depressed BD outpatients, but was significantly associated with hastened depressive recurrence (Log-Rank p=0.007), mediated by lifetime anxiety disorder and attenuated by lifetime history of psychosis, and had only a non-significant tendency towards association with delayed depressive recovery (Log-Rank p=0.07). In both recovered and depressed BD outpatients, baseline ASD did not have significant association with any baseline BD illness characteristic.Self-reported sleep duration. Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.Baseline ASD among recovered BD patients may be a risk marker for hastened depressive recurrence, suggesting it could be an important therapeutic target between mood episodes.

  View details for DOI 10.1016/j.jad.2017.05.015

  View details for PubMedID 28500982

• Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: A meta-analysis JOURNAL OF PSYCHIATRIC RESEARCH Bartoli, F., Dell'Osso, B., Crocamo, C., Fiorillo, A., Ketter, T. A., Suppes, T., Clerici, M., Carra, G. 2017; 88: 38-46

  Abstract

  The aim of this systematic review and meta-analysis was testing whether low versus high doses of second-generation antipsychotics (SGAs) are associated with different clinical benefits and harms for the acute treatment of bipolar depression. We included clinical trials comparing different doses of the same SGA monotherapy for bipolar depression. SGAs defined daily doses were used to define high and low doses. Clinical benefit outcomes included improvement, response and remission rates on Montgomery-Asberg Depression Rating Scale. Clinical harm outcomes included all-cause and adverse effect-related discontinuation rates. Data from seven clinical trials testing high and low doses of quetiapine (4 trials), cariprazine, lurasidone, and ziprasidone (1 trial each), showed no differences between lower and higher doses of selected SGAs on improvement, response and remission rates, without significant heterogeneity across studies (I(2) = 0%). Subgroup analyses based on single SGAs confirmed the clinical benefit comparability between low and high doses. However, clinical harm favorable differences for low doses on all-cause (p = 0.01) and adverse effects-related discontinuation (p = 0.001) were found. In sum, this meta-analysis showed that, although no benefits were found in terms of symptoms improvement, response and remission rates, there were clear disadvantages in prescribing higher rather than lower doses of selected SGAs. The uniform methodological strength of studies increases confidence in our findings. These data need to be integrated with individual patient characteristics (e.g., clinical urgency and adverse effect sensitivity) to optimize management of acute bipolar depression.

  View details for DOI 10.1016/j.jpsychires.2016.12.021

  View details for PubMedID 28086127

• Sensitive and Personalized Determinations of Likelihood of Being Helped or Harmed JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Citrome, L. 2017; 78 (5): E554

  View details for PubMedID 28570802

• White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder. Australian and New Zealand journal of psychiatry Köhler, O., Sylvia, L. G., Bowden, C. L., Calabrese, J. R., Thase, M., Shelton, R. C., McInnis, M., Tohen, M., Kocsis, J. H., Ketter, T. A., Friedman, E. S., Deckersbach, T., Ostacher, M. J., Iosifescu, D. V., McElroy, S., Nierenberg, A. A. 2017; 51 (4): 355-365

  Abstract

  Immune alterations may play a role in bipolar disorder etiology; however, the relationship between overall immune system functioning and mood symptom severity is unknown.The two comparative effectiveness trials, the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study (Bipolar CHOICE) and the Lithium Treatment Moderate-Dose Use Study (LiTMUS), were similar trials among patients with bipolar disorder. At study entry, white blood cell count and bipolar mood symptom severity (via Montgomery-Aasberg Depression Rating Scale and Bipolar Inventory of Symptoms Scale) were assessed. We performed analysis of variance and linear regression analyses to investigate relationships between deviations from median white blood cell and multinomial regression analysis between higher and lower white blood cell levels. All analyses were adjusted for age, gender, body mass index, smoking, diabetes, hypertension and hyperlipidemia.Among 482 Bipolar CHOICE participants, for each 1.0 × 10(9)/L white blood cell deviation, the overall Bipolar Inventory of Symptoms Scale severity increased significantly among men (coefficient = 2.13; 95% confidence interval = [0.46, -3.79]; p = 0.013), but not among women (coefficient = 0.87; 95% confidence interval = [-0.87, -2.61]; p = 0.33). Interaction analyses showed a trend toward greater Bipolar Inventory of Symptoms Scale symptom severity among men (coefficient = 1.51; 95% confidence interval = [-0.81, -3.82]; p = 0.2). Among 283 LiTMUS participants, higher deviation from the median white blood cell showed a trend toward higher Montgomery-Aasberg Depression Rating Scale scores among men (coefficient = 1.33; 95% confidence interval = [-0.22, -2.89]; p = 0.09), but not among women (coefficient = 0.34; 95% confidence interval = [-0.64, -1.32]; p = 0.50). When combining LiTMUS and Bipolar CHOICE, Montgomery-Aasberg Depression Rating Scale scores increased significantly among men (coefficient = 1.09; 95% confidence interval = [0.31, -1.87]; p = 0.006) for each 1.0 × 10(9)/L white blood cell deviation, whereas we found a weak association among women (coefficient = 0.55; 95% confidence interval = [-0.20, -1.29]; p = 0.14). Lower and higher white blood cell levels correlated with greater symptom severity and specific symptoms, varying according to gender.Deviations in an overall immune system marker, even within the normal white blood cell range, correlated with mood symptom severity in bipolar disorder, mostly among males. Studies are warranted investigating whether white blood cell count may predict response to mood-stabilizing treatment.

  View details for DOI 10.1177/0004867416644508

  View details for PubMedID 27126391

• White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Kohler, O., Sylvia, L. G., Bowden, C. L., Calabrese, J. R., Thase, M., Shelton, R. C., McInnis, M., Tohen, M., Kocsis, J. H., Ketter, T. A., Friedman, E. S., Deckersbach, T., Ostacher, M. J., Losifescu, D. V., McElroy, S., Nierenberg, A. A. 2017; 51 (4): 355-365

  Abstract

  Immune alterations may play a role in bipolar disorder etiology; however, the relationship between overall immune system functioning and mood symptom severity is unknown.The two comparative effectiveness trials, the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study (Bipolar CHOICE) and the Lithium Treatment Moderate-Dose Use Study (LiTMUS), were similar trials among patients with bipolar disorder. At study entry, white blood cell count and bipolar mood symptom severity (via Montgomery-Aasberg Depression Rating Scale and Bipolar Inventory of Symptoms Scale) were assessed. We performed analysis of variance and linear regression analyses to investigate relationships between deviations from median white blood cell and multinomial regression analysis between higher and lower white blood cell levels. All analyses were adjusted for age, gender, body mass index, smoking, diabetes, hypertension and hyperlipidemia.Among 482 Bipolar CHOICE participants, for each 1.0 × 10(9)/L white blood cell deviation, the overall Bipolar Inventory of Symptoms Scale severity increased significantly among men (coefficient = 2.13; 95% confidence interval = [0.46, -3.79]; p = 0.013), but not among women (coefficient = 0.87; 95% confidence interval = [-0.87, -2.61]; p = 0.33). Interaction analyses showed a trend toward greater Bipolar Inventory of Symptoms Scale symptom severity among men (coefficient = 1.51; 95% confidence interval = [-0.81, -3.82]; p = 0.2). Among 283 LiTMUS participants, higher deviation from the median white blood cell showed a trend toward higher Montgomery-Aasberg Depression Rating Scale scores among men (coefficient = 1.33; 95% confidence interval = [-0.22, -2.89]; p = 0.09), but not among women (coefficient = 0.34; 95% confidence interval = [-0.64, -1.32]; p = 0.50). When combining LiTMUS and Bipolar CHOICE, Montgomery-Aasberg Depression Rating Scale scores increased significantly among men (coefficient = 1.09; 95% confidence interval = [0.31, -1.87]; p = 0.006) for each 1.0 × 10(9)/L white blood cell deviation, whereas we found a weak association among women (coefficient = 0.55; 95% confidence interval = [-0.20, -1.29]; p = 0.14). Lower and higher white blood cell levels correlated with greater symptom severity and specific symptoms, varying according to gender.Deviations in an overall immune system marker, even within the normal white blood cell range, correlated with mood symptom severity in bipolar disorder, mostly among males. Studies are warranted investigating whether white blood cell count may predict response to mood-stabilizing treatment.

  View details for DOI 10.1177/0004867416644508

  View details for Web of Science ID 000399064200007

• Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol do not affect 6-month mood-stabilizing treatment outcome among 482 patients with bipolar disorder. Depression and anxiety Köhler-Forsberg, O., Sylvia, L., Thase, M., Calabrese, J. R., Deckersbach, T., Tohen, M., Bowden, C. L., McInnis, M., Kocsis, J. H., Friedman, E. S., Ketter, T. A., McElroy, S., Shelton, R. C., Nierenberg, A. A. 2017; 34 (3): 281-290

  Abstract

  Many mood disorder patients need analgesics due to increased pain sensitivity. Recent studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit antidepressant treatment, which requires replication before clinical recommendations.The Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study randomized participants to 6 months lithium or quetiapine treatment. Use of NSAIDs and paracetamol was assessed throughout the study period and psychopathology measured with the Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) and Bipolar Inventory of Symptoms Scale (BISS). The effects of NSAIDs and paracetamol on treatment outcome were examined using mixed effects linear regression adjusted for age, gender, body mass index, smoking status, exercise, and somatic diseases.Among 482 participants, 177 (36.7%) used NSAIDs and/or paracetamol during the study. NSAID and paracetamol users did not differ from nonusers with respect to treatment outcome with lithium or quetiapine at any time point during 6 months treatment on the overall CGI-BP (β = 0.001 (95% CI = -0.01 to -0.01), P = .87), the BISS (β = 0.01 (95% CI = -0.17 to 0.15), P = .91), nor the CGI-BP subscales for depression or mania. Users of NSAIDs only (n = 76), paracetamol only (n = 62), and users of both NSAIDs and paracetamol (n = 39) showed no statistical difference compared to nonusers (all P > .3).This is the first trial to show that use of NSAIDs and paracetamol, alone or in combination, does not affect lithium- or quetiapine-based bipolar disorder mood-stabilizing treatment outcomes. Prior studies have suggested that NSAIDs may inhibit antidepressant treatment, whereas our results support findings indicating no detrimental effects of NSAIDs or paracetamol on affective disorder treatment.

  View details for DOI 10.1002/da.22601

  View details for PubMedID 28135023

• Onset polarity in bipolar disorder: A strong association between first depressive episode and suicide attempts JOURNAL OF AFFECTIVE DISORDERS Cremaschi, L., Dell'Osso, B., Vismara, M., Dobrea, C., Buoli, M., Ketter, T. A., Altamura, A. C. 2017; 209: 182-187

  Abstract

  The role of onset polarity (OP) in patients with bipolar disorder (BD) has been increasingly investigated over the last few years, for its clinical, prognostic, and therapeutic implications. The present study sought to assess whether OP was associated with specific correlates, in particular with a differential suicidal risk in BD patients.A sample of 362 recovered BD patients was dichotomized by OP: depressed (DO) or elevated onset (EO: hypomanic/manic/mixed). Socio-demographic and clinical variables were compared between the subgroups. Additionally, binary logistic regression was performed to assess features associated with OP.DO compared with EO patients had older current age and were more often female, but less often single and unemployed. Clinically, DO versus EO had a more than doubled rate of suicide attempts, as well as significantly higher rates of BD II diagnosis, lifetime stressful events, current psychotropics and antidepressants use, longer duration of the most recent episode (more often depressive), but lower rates of psychosis and involuntary commitments.Retrospective design limiting the accurate assessment of total number of prior episodes of each polarity.Our results support the influence of OP on BD course and outcome. Moreover, in light of the relationship between DO and a higher rate of suicide attempts, further investigation may help clinicians in identifying patients at higher risk of suicide attempts.

  View details for DOI 10.1016/j.jad.2016.11.043

  View details for Web of Science ID 000393241400028

  View details for PubMedID 27936451

• Obesity and obstetric complications are associated with rapid-cycling in Italian patients with bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Buoli, M., Dell'Osso, B., Caldiroli, A., Carnevali, G. S., Serati, M., Suppes, T., Ketter, T. A., Altamura, A. C. 2017; 208: 278-283

  Abstract

  Rapid cycling (RC) worsens the course of bipolar disorder (BD) being associated with poor response to pharmacotherapy. Previous studies identified clinical variables potentially associated with RCBD: however, in many cases, results were discordant or unreplicated. The present study was aimed to compare clinical variables between RC and non RC bipolar patients and to identify related risk factors.A sample of 238 bipolar patients was enrolled from 3 different community mental health centers. Descriptive analyses were performed on total sample, and patients were compared in terms of socio-demographic and clinical variables according to the presence of RC by multivariate analyses of variance (MANOVAs, continuous variables) or χ2 tests (qualitative variables). Binary logistic regression was performed to calculate odds ratios.Twenty-eight patients (11.8%) had RC. The two groups were not different in terms of age, age at onset, gender distribution, type of family history, type of substance use disorder, history of antidepressant therapy, main antidepressant, psychotic symptoms, comorbid anxiety disorders, suicide attempts, thyroid diseases, diabetes, type of BD, duration of untreated illness, illness duration, duration of antidepressant treatment and GAF scores. In contrast, RC patients had more often a history of obstetric complications (p<0.05), obesity (p<0.05) and a trend to hypercholesterolemia (p=0.08). In addition, RC bipolar patients presented more frequently lifetime MDMA misuse (p<0.05) than patients without RC.Findings from the present study seem to indicate that obesity and obstetric complications are risk factors for the development of RC in BD. In addition, lifetime MDMA misuse may be more frequent in RC bipolar patients.

  View details for DOI 10.1016/j.jad.2016.10.010

  View details for Web of Science ID 000390732600041

• Abnormal sleep duration associated with hastened depressive recurrence in bipolar disorder Journal of Affective Disorders Gershon, A., Do, D., Satyanarayana, S., Shah, S., Yuen, L., Hooshmand, F., Miller, S., Wang, P., Ketter, T. 2017; 218: 374–79

  Abstract

  Abnormal sleep duration (ASD, <6 or ≥9h) is common in bipolar disorder (BD), and often persists beyond acute mood episodes. Few longitudinal studies have examined the ASD's impact upon BD illness course. The current study examined the longitudinal impact of ASD upon bipolar depressive recurrence/recovery.Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form at monthly follow-ups for up to two years of naturalistic treatment. Prevalence and clinical correlates of ASD in 93 recovered (euthymic ≥8 weeks) and 153 depressed BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between baseline ASD and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators.ASD was only half as common among recovered versus depressed BD outpatients, but was significantly associated with hastened depressive recurrence (Log-Rank p=0.007), mediated by lifetime anxiety disorder and attenuated by lifetime history of psychosis, and had only a non-significant tendency towards association with delayed depressive recovery (Log-Rank p=0.07). In both recovered and depressed BD outpatients, baseline ASD did not have significant association with any baseline BD illness characteristic.Self-reported sleep duration. Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.Baseline ASD among recovered BD patients may be a risk marker for hastened depressive recurrence, suggesting it could be an important therapeutic target between mood episodes.

  View details for DOI 10.1016/j.jad.2017.05.015

• Long-term safety and tolerability of asenapine: A double-blind, uncontrolled, long-term extension trial in adults with an acute manic or mixed episode associated with bipolar I disorder JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A., Durgam, S., Landbloom, R., Mackle, M., Wu, X., Mathews, M. 2017; 207: 384-392

  Abstract

  Asenapine (ASN) is approved in the United States as monotherapy and adjunctive therapy (to lithium or valproate) in adults with bipolar mania, and as monotherapy in pediatric patients with bipolar mania. This is the first long-term study evaluating safety and tolerability of ASN fixed doses in this population.After completing a 3-week, randomized, placebo (PBO)-controlled acute trial, patients could enroll in this 26-week, fixed-dose (5 or 10mg twice daily), double-blind extension study. Select predefined treatment-emergent adverse events (TEAEs) and metabolic parameters were reported.Overall, 164 patients were treated; 88 completed the study. The incidence of ≥1 TEAE was greater for PBO/ASN 5mg (68.3%) versus ASN 5mg/ASN 5mg (54.7%) and ASN 10mg/ASN 10mg (51.0%) with sedation, headache, somnolence, akathisia, and dizziness occurring as the most prevalent TEAEs. Predefined TEAEs were more common for PBO/ASN 5mg (33.3%) versus ASN 5mg/ASN 5mg (15.1%) and ASN 10mg/ASN 10mg (15.7%). Weight gain (≥7% increase from baseline to endpoint) was more frequent for ASN 10mg/ASN 10mg (16.3%) versus ASN 5mg/ASN 5mg (13.7%) and PBO/ASN 5mg (8.9%). No clinically significant metabolic changes were observed. The incidence of serious AEs was low and primarily related to underlying bipolar I disorder.This study lacked a comparator group and was not powered for direct comparisons of ASN regimens. Results may not be applicable to the general bipolar population.ASN was generally safe and well tolerated in adults with an acute manic or mixed episode associated with bipolar I disorder.

  View details for DOI 10.1016/j.jad.2016.09.037

  View details for Web of Science ID 000389088600054

• Carbamazepine, Oxcarbazepine, and Licarbazepine AMERICAN PSYCHIATRIC ASSOCIATION PUBLISHING TEXTBOOK OF PSYCHOPHARMACOLOGY, 5TH EDITION Wang, P. W., Ketter, T. A., Post, R. M., Schatzberg, A. F., Nemeroff, C. B. 2017: 941–82

  View details for Web of Science ID 000550981300055

• Current irritability associated with hastened depressive recurrence and delayed depressive recovery in bipolar disorder. International journal of bipolar disorders Yuen, L. D., Shah, S., Do, D., Miller, S., Wang, P. W., Hooshmand, F., Ketter, T. A. 2016; 4 (1): 15-?

  Abstract

  Current irritability is associated with greater retrospective and current bipolar disorder (BD) illness severity; less is known about prospective longitudinal implications of current irritability. We examined relationships between current irritability and depressive recurrence and recovery in BD.Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation at baseline, and with the Clinical Monitoring Form during follow-up during up to 2 years of naturalistic treatment. Prevalence and clinical correlates of any current irritability in depressed and recovered (euthymic ≥8 weeks) BD patients were assessed. Kaplan-Meier analyses (Log-Rank tests) assessed relationships between current irritability and longitudinal depressive severity, with Cox Proportional Hazard analyses assessing potential mediators.Recovered BD outpatients with vs. without current irritability had significantly higher rates of 13/19 (68.4 %) other baseline unfavorable illness characteristics/current mood symptoms and hastened depressive recurrence (Log-Rank p = 0.020), driven by lifetime history of anxiety disorder and prior year rapid cycling, and attenuated by history of psychosis. Depressed BD outpatients with vs. without current irritability had significantly higher rates of 7/19 (36.8 %) other unfavorable illness characteristics/current mood symptoms and delayed depressive recovery (Log-Rank p = 0.034), NOT mediated by any assessed parameter.Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.Current irritability was associated with hastened depressive recurrence and delayed depressive recovery in BD. Treatment studies targeting irritability may yield strategies to mitigate increased longitudinal depressive burden.

  View details for DOI 10.1186/s40345-016-0056-2

  View details for PubMedID 27473754

  View details for PubMedCentralID PMC4967068

• Longer-Term Lurasidone Efficacy and Tolerability in an American Bipolar Disorder Specialty Clinic Ketter, T., Do, D., Gershon, A., Holsinger, A., Hooshmand, F., Wang, P., Miller, S. NATURE PUBLISHING GROUP. 2016: S493

  View details for Web of Science ID 000440366400059

• Tracking medication changes to assess outcomes in comparative effectiveness research: A bipolar CHOICE study JOURNAL OF AFFECTIVE DISORDERS Reilly-Harrington, N. A., Sylvia, L. G., Rabideau, D. J., Gold, A. K., Deckersbach, T., Bowden, C. L., Bobo, W. V., Singh, V., Calabrese, J. R., Shelton, R. C., Friedman, E. S., Thase, M. E., Kamali, M., Tohen, M., McInnis, M. G., McElroy, S. L., Ketter, T. A., Kocsis, J. H., Kinrys, G., Nierenberg, A. A. 2016; 205: 159-164

  Abstract

  Comparative effectiveness research uses multiple tools, but lacks outcome measures to assess large electronic medical records and claims data. Aggregate changes in medications in response to clinical need may serve as a surrogate outcome measure. We developed the Medication Recommendation Tracking Form (MRTF) to record the frequency, types, and reasons for medication adjustments in order to calculate Necessary Clinical Adjustments (NCAs), medication adjustments to reduce symptoms, maximize treatment response, or address problematic side effects.The MRTF was completed at every visit for 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial.Responders had significantly fewer NCAs compared to non-responders. NCAs predicted subsequent response status such that every additional NCA during the previous visit decreased a patient's odds of response by approximately 30%. Patients with more severe symptoms had a greater number of NCAs at the subsequent visit. Patients with a comorbid anxiety disorder demonstrated a significantly higher rate of NCAs per month than those without a comorbid anxiety disorder. Patients with greater frequency, intensity, and interference of side effects had higher rates of NCAs. Participants with fewer NCAs reported a higher quality of life and decreased functional impairment.The MRTF has not been examined in community clinic settings and did not predict response more efficiently than the Clinical Global Impression-Bipolar Version (CGI-BP).The MRTF is a feasible proxy of clinical outcome, with implications for clinical training and decision-making. Analyses of big data could use changes in medications as a surrogate outcome measure.

  View details for DOI 10.1016/j.jad.2016.07.007

  View details for Web of Science ID 000385440900021

  View details for PubMedID 27449548

• Obesity and obstetric complications are associated with rapid-cycling in Italian patients with bipolar disorder. Journal of affective disorders Buoli, M., Dell'Osso, B., Caldiroli, A., Carnevali, G. S., Serati, M., Suppes, T., Ketter, T. A., Altamura, A. C. 2016; 208: 278-283

  Abstract

  Rapid cycling (RC) worsens the course of bipolar disorder (BD) being associated with poor response to pharmacotherapy. Previous studies identified clinical variables potentially associated with RCBD: however, in many cases, results were discordant or unreplicated. The present study was aimed to compare clinical variables between RC and non RC bipolar patients and to identify related risk factors.A sample of 238 bipolar patients was enrolled from 3 different community mental health centers. Descriptive analyses were performed on total sample, and patients were compared in terms of socio-demographic and clinical variables according to the presence of RC by multivariate analyses of variance (MANOVAs, continuous variables) or χ2 tests (qualitative variables). Binary logistic regression was performed to calculate odds ratios.Twenty-eight patients (11.8%) had RC. The two groups were not different in terms of age, age at onset, gender distribution, type of family history, type of substance use disorder, history of antidepressant therapy, main antidepressant, psychotic symptoms, comorbid anxiety disorders, suicide attempts, thyroid diseases, diabetes, type of BD, duration of untreated illness, illness duration, duration of antidepressant treatment and GAF scores. In contrast, RC patients had more often a history of obstetric complications (p<0.05), obesity (p<0.05) and a trend to hypercholesterolemia (p=0.08). In addition, RC bipolar patients presented more frequently lifetime MDMA misuse (p<0.05) than patients without RC.Findings from the present study seem to indicate that obesity and obstetric complications are risk factors for the development of RC in BD. In addition, lifetime MDMA misuse may be more frequent in RC bipolar patients.

  View details for DOI 10.1016/j.jad.2016.10.010

  View details for PubMedID 27794251

• Long-term safety and tolerability of asenapine: A double-blind, uncontrolled, long-term extension trial in adults with an acute manic or mixed episode associated with bipolar I disorder. Journal of affective disorders Ketter, T. A., Durgam, S., Landbloom, R., Mackle, M., Wu, X., Mathews, M. 2016; 207: 384-392

  Abstract

  Asenapine (ASN) is approved in the United States as monotherapy and adjunctive therapy (to lithium or valproate) in adults with bipolar mania, and as monotherapy in pediatric patients with bipolar mania. This is the first long-term study evaluating safety and tolerability of ASN fixed doses in this population.After completing a 3-week, randomized, placebo (PBO)-controlled acute trial, patients could enroll in this 26-week, fixed-dose (5 or 10mg twice daily), double-blind extension study. Select predefined treatment-emergent adverse events (TEAEs) and metabolic parameters were reported.Overall, 164 patients were treated; 88 completed the study. The incidence of ≥1 TEAE was greater for PBO/ASN 5mg (68.3%) versus ASN 5mg/ASN 5mg (54.7%) and ASN 10mg/ASN 10mg (51.0%) with sedation, headache, somnolence, akathisia, and dizziness occurring as the most prevalent TEAEs. Predefined TEAEs were more common for PBO/ASN 5mg (33.3%) versus ASN 5mg/ASN 5mg (15.1%) and ASN 10mg/ASN 10mg (15.7%). Weight gain (≥7% increase from baseline to endpoint) was more frequent for ASN 10mg/ASN 10mg (16.3%) versus ASN 5mg/ASN 5mg (13.7%) and PBO/ASN 5mg (8.9%). No clinically significant metabolic changes were observed. The incidence of serious AEs was low and primarily related to underlying bipolar I disorder.This study lacked a comparator group and was not powered for direct comparisons of ASN regimens. Results may not be applicable to the general bipolar population.ASN was generally safe and well tolerated in adults with an acute manic or mixed episode associated with bipolar I disorder.

  View details for DOI 10.1016/j.jad.2016.09.037

  View details for PubMedID 27755982

• More inclusive bipolar mixed depression definition by permitting overlapping and non-overlapping mood elevation symptoms. Acta psychiatrica Scandinavica Kim, H., Kim, W., Citrome, L., Akiskal, H. S., Goffin, K. C., Miller, S., HOLTZMAN, J. N., Hooshmand, F., Wang, P. W., Hill, S. J., Ketter, T. A. 2016; 134 (3): 199-206

  Abstract

  The objective of this study was to assess the strengths and limitations of a mixed bipolar depression definition made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by counting not only 'non-overlapping' mood elevation symptoms (NOMES) as in DSM-5, but also 'overlapping' mood elevation symptoms (OMES, psychomotor agitation, distractibility, and irritability).Among bipolar disorder (BD) out-patients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using more inclusive (≥3 NOMES/OMES) and less inclusive DSM-5 (≥3 NOMES) definitions.Among 153 depressed BD, counting not only NOMES but also OMES yielded a three-fold higher mixed depression rate (22.9% vs. 7.2%) and important statistically significant clinical correlates for mixed compared to pure depression (more lifetime anxiety disorder comorbidity, more current irritability, and less current antidepressant use), which were not significant using the DSM-5 threshold.To conclude, further studies with larger numbers of patients with DSM-5 bipolar mixed depression assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including efforts to ascertain whether or not OMES should count toward mixed depression.

  View details for DOI 10.1111/acps.12580

  View details for PubMedID 27137894

• Age at onset in patients with bipolar I and II disorder: a comparison of large sample studies JOURNAL OF AFFECTIVE DISORDERS Dell'Osso, B., Grancini, B., Vismara, M., DeCagna, F., Maggi, M., Molle, M., Cremaschi, L., Miller, S., Ketter, T. A., Altamura, A. C. 2016; 201: 57-63

  Abstract

  Bipolar Disorder (BD) is a leading cause of disability worldwide and factors contributing to its burden include chronic relapsing course, comorbidity, suicide risk, and early age at onset (AAO). In particular, recent investigation has shown that BD onset may occur earlier than previously believed, even though whether BDI and II are different in such regard is still debated. Reduced samples may, moreover, limit the confidence in the published studies, with geographic issues, in turn, representing potentially conditioning factors. The present review was aimed to select and analyze large sample studies comparing AAO in BDI vs II patients.A PubMed literature search was performed, considering English-written articles published up to December 2015, comparing AAO in BDI vs II patients with sample size≥100 subjects per group.Seventeen studies were considered suitable for revision, with 8 studies reporting statistically significant differences and 9 not. Among studies reporting statistically significant differences, mostly conducted in Europe, 6 showed an earlier AAO in BDI, while 2 in BDII subjects.Only studies with large samples included, considering AAO as a continuous variable, and providing a comparison between the bipolar subtypes.Our findings suggest that AAO per se does not seem to reliably differentiate BDI from BDII patients and that such variable should likely be investigated in the context of other clinical characteristics, in order to assess its overall influence over BD course. Geographic factors may, in turn, play a potential role with future investigation warranted to further explore this specific issue.

  View details for DOI 10.1016/j.jad.2016.04.009

  View details for Web of Science ID 000377392900009

  View details for PubMedID 27177297

• More inclusive bipolar mixed depression definitions by requiring fewer non-overlapping mood elevation symptoms. Acta psychiatrica Scandinavica Kim, W., Kim, H., Citrome, L., Akiskal, H. S., Goffin, K. C., Miller, S., HOLTZMAN, J. N., Hooshmand, F., Wang, P. W., Hill, S. J., Ketter, T. A. 2016; 134 (3): 189-198

  Abstract

  Assess strengths and limitations of mixed bipolar depression definitions made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by requiring fewer than three 'non-overlapping' mood elevation symptoms (NOMES).Among bipolar disorder (BD) out-patients assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using less inclusive (≥3 NOMES, DSM-5), more inclusive (≥2 NOMES), and most inclusive (≥1 NOMES) definitions.Among 153 depressed BD, compared to less inclusive DSM-5 threshold, our more and most inclusive thresholds, yielded approximately two- and five-fold higher mixed depression rates (7.2%, 15.0%, and 34.6% respectively), and important statistically significant clinical correlates for mixed compared to pure depression (e.g. more lifetime anxiety disorder comorbidity, more current irritability), which were not significant using the DSM-5 threshold.Further studies assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including assessing the extent to which enhanced statistical power vs. other factors contributes to more vs. less inclusive mixed bipolar depression thresholds having more statistically significant clinical correlates, and whether 'overlapping' mood elevation symptoms should be counted.

  View details for DOI 10.1111/acps.12563

  View details for PubMedID 26989836

• Current irritability robustly related to current and prior anxiety in bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Yuen, L. D., Miller, S., Wang, P. W., Hooshmand, F., Holtzman, J. N., Goffin, K. C., Shah, S., Ketter, T. A. 2016; 79: 101-107

  Abstract

  Although current irritability and current/prior anxiety have been associated in unipolar depression, these relationships are less well understood in bipolar disorder (BD). We investigated relationships between current irritability and current/prior anxiety as well as other current emotions and BD illness characteristics.Outpatients referred to the Stanford Bipolar Disorders Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prevalence and clinical correlates of current irritability and current/prior anxiety and other illness characteristics were examined.Among 497 BD outpatients (239 Type I, 258 Type II; 58.1% female; mean ± SD age 35.6 ± 13.1 years), 301 (60.6%) had baseline current irritability. Patients with versus without current irritability had significantly higher rates of current anxiety (77.1% versus 42.9%, p < 0.0001) and history of anxiety disorder (73.1% versus 52.6%, p < 0.0001). Current irritability was more robustly related to current anxiety than to current anhedonia, sadness, or euphoria (all p < 0.001), and current irritability-current anxiety associations persisted across current predominant mood states. Current irritability was more robustly related to past anxiety than to all other assessed illness characteristics, including 1° family history of mood disorder, history of alcohol/substance use disorder, bipolar subtype, and current syndromal/subsyndromal depression (all p < 0.05).Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.In BD, current irritability was robustly related to current/prior anxiety. Further studies are warranted to assess longitudinal clinical implications of relationships between irritability and anxiety in BD.

  View details for DOI 10.1016/j.jpsychires.2016.05.006

  View details for Web of Science ID 000378179000015

  View details for PubMedID 27218815

• Long-term safety and efficacy of armodafinil in bipolar depression: A 6-month open-label extension study JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A., Amchin, J., Frye, M. A., Gross, N. 2016; 197: 51-57

  Abstract

  Safe/well-tolerated treatments for bipolar I depression remain limited. We assessed safety/tolerability of adjunctive open-label armodafinil, a wakefulness-promoting agent evaluated in 3 acute, controlled efficacy studies with variable efficacy results.Completers of three 8-week, double-blind, placebo-controlled adjunctive armodafinil studies (150-200 mg/day added to ongoing stable maintenance doses of 1 or 2 protocol-defined mood stabilizers) in bipolar I depression could enter this 6-month, open-label extension study. Objectives included evaluation of safety/tolerability (primary) and efficacy (secondary).867 patients enrolled; 863 received ≥1 dose of armodafinil and 506 (58%) completed the 6-month study. Headache, insomnia, and anxiety were the most common adverse events (AEs) reported, whereas akathisia, nausea, sedation/somnolence, and weight increase were uncommon. Mean measures assessing emergence of mania, anxiety, insomnia, or suicidality showed no worsening. Discontinuations due to AEs occurred in 57 (7%) patients. Serious AEs occurred in 27 (3%) patients and were considered treatment-related in 8 (1%) patients. Depressive symptoms improved over the 6 months, as did patient functioning.Lack of placebo control.Adjunctive armodafinil was generally safe and well tolerated over 6 months of open-label treatment at 150-200 mg/day when taken with protocol-defined mood stabilizers for bipolar I depression. This 6-month open-label study suggested that armodafinil augmentation of bipolar maintenance therapies may have a favorable risk profile and may improve depressive symptoms in some patients with bipolar I depression.

  View details for DOI 10.1016/j.jad.2016.02.050

  View details for Web of Science ID 000374374800008

  View details for PubMedID 26970266

• Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients JOURNAL OF PSYCHIATRIC RESEARCH Holtzman, J. N., Miller, S., Hooshmand, F., Wang, P. W., Chang, K. D., Goffin, K. C., Hill, S. J., Ketter, T. A., Rasgon, N. L. 2016; 76: 128-135

  Abstract

  Although bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender.Demographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13-16, and >17 years, respectively) onset-age subgroups.Among 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre-pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients.Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall.We describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes.

  View details for DOI 10.1016/j.jpsychires.2016.02.009

  View details for PubMedID 26926801

• Ketamine: stimulating antidepressant treatment? BJPSYCH OPEN Malhi, G. S., Byrow, Y., Cassidy, F., Cipriani, A., Demyttenaere, K., Frye, M. A., Gitlin, M., Kennedy, S. H., Ketter, T. A., Lam, R. W., McShane, R., Mitchell, A. J., Ostacher, M. J., Rizvi, S. J., Thase, M. E., Tohen, M. 2016; 2 (3): E5–E9

  Abstract

  The appeal of ketamine - in promptly ameliorating depressive symptoms even in those with non-response - has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives - derived from evidence and clinical experience - and to consider strategies for future investigations.G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker's Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; 'paid-for' ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse's employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998-2013.© The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

  View details for PubMedID 27703782

• LURASIDONE IN THE LONG-TERM TREATMENT OF PATIENTS WITH BIPOLAR DISORDER: A 24-WEEK OPEN-LABEL EXTENSION STUDY DEPRESSION AND ANXIETY Ketter, T. A., Sarma, K., Silva, R., Kroger, H., Cucchiaro, J., Loebel, A. 2016; 33 (5): 424-434

  Abstract

  The aim of this study was to evaluate the safety and tolerability of 6 months of open-label, uncontrolled extension treatment with lurasidone in patients with a diagnosis of bipolar depression who completed 6 weeks of acute treatment.Patients completing 6 weeks of double-blind placebo-controlled treatment with either lurasidone monotherapy (one study) or adjunctive therapy with lithium or valproate (two studies), were treated for 6 months with flexible doses of lurasidone, 20-120 mg/day, in an open-label, uncontrolled extension study (N = 813; monotherapy, 38.9%; adjunctive therapy, 61.1%). Changes in safety parameters were calculated from double-blind, acute-phase baseline to month 6 of the extension phase, using a last observation carried forward (LOCF endpoint) analysis.Five hundred fifty-nine of 817 (68.4%) patients completed the extension study. In the monotherapy and adjunctive therapy groups, 6.9 and 9.0%, respectively, discontinued due to an adverse event. For the monotherapy and adjunctive therapy groups, respectively, changes from double-blind baseline to month 6 were +0.8 and +0.9 kg for weight (mean), 0.0 and +2.0 mg/dL for total cholesterol (median), +5.0 and +5.0 mg/dL for triglycerides (median), -1.0 and 0.0 mg/dL for glucose (median); -22.6 and -21.7 for Montgomery-Asberg Depression Rating Scale (MADRS; mean); whereas change from open-label baseline to month 6 were +0.85 and +0.88 kg for weight (mean), and -6.9 and -6.5 for MADRS (mean).Six months of treatment with open-label lurasidone was safe and well tolerated with minimal effect on weight and metabolic parameters; continued improvement in depressive symptoms was observed.

  View details for DOI 10.1002/da.22479

  View details for Web of Science ID 000375154800009

  View details for PubMedID 26918425

• Different characteristics associated with suicide attempts among bipolar I versus bipolar II disorder patients JOURNAL OF PSYCHIATRIC RESEARCH Goffin, K. C., Dell'Osso, B., Miller, S., Wang, P. W., Holtzman, J. N., Hooshmand, F., Ketter, T. A. 2016; 76: 94-100

  Abstract

  Suicide attempts are common in patients with bipolar disorder (BD), and consistently associated with female gender and certain unfavorable BD illness characteristics. Findings vary, however, regarding effects of BD illness subtype and yet other illness characteristics upon prior suicide attempt rates. We explored the effects of demographics and BD illness characteristics upon prior suicide attempt rates in patients stratified by BD illness subtype (i.e., with bipolar I disorder (BDI) versus bipolar II disorder (BDII)).Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Rates of prior suicide attempt were compared in patients with and without diverse demographic and BD illness characteristics stratified by BD subtype.Among 494 BD outpatients (mean ± SD age 35.6 ± 13.1 years; 58.3% female; 48.6% BDI, 51.4% BDII), overall prior suicide attempt rates in were similar in BDI versus BDII patients, but approximately twice as high in BDI (but not BDII) patients with compared to without lifetime eating disorder, and in BDII (but not BDI) patients with compared to without childhood BD onset. In contrast, current threshold-level suicidal ideation and lifetime alcohol use disorder robustly but less asymmetrically increased prior suicide attempt risk across BD subtypes.American tertiary bipolar disorder clinic referral sample, cross-sectional design.Further studies are needed to assess the extent to which varying clinical characteristics of samples of patients with BDI and BDII could yield varying prior suicide attempt rates in patients with BDI versus BDII.

  View details for DOI 10.1016/j.jpsychires.2016.02.006

  View details for Web of Science ID 000373412400012

  View details for PubMedID 26921874

• Differential prevalence and demographic and clinical correlates of second-generation antipsychotic use in bipolar I versus bipolar II disorder JOURNAL OF PSYCHIATRIC RESEARCH Park, D. Y., Goffin, K. C., Shah, S., Yuen, L. D., Holtzman, J. N., Hooshmand, F., Miller, S., Wang, P. W., Ketter, T. A. 2016; 76: 52-58

  Abstract

  To assess second-generation antipsychotic (SGA) use, demographics, and clinical correlates in patients with bipolar I disorder (BDI) versus bipolar II disorder (BDII).Stanford Bipolar Disorder (BD) Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Current SGA use, demographics, and clinical correlates were assessed for BDI versus BDII.Among 503 BD outpatients, in BDI versus BDII, SGA use was more than twice as common (44.0% versus 21.2%), and doses were approximately twice as high. BDI patients taking (N = 107) versus not taking (N = 136) SGAs less often had current full time employment and college degree; and more often had lifetime psychiatric hospitalization, current depression, and current complex pharmacotherapy, and had a higher mean current Clinical Global Impression for Bipolar Version Overall Severity score, and these persisted significantly after covarying for employment and education. Prior psychiatric hospitalization was the most robust correlate of SGA use in BDI patients. In contrast, these demographic and clinical correlates of SGA use were not statistically significant among patients with BDII, although BDII (but not BDI) patients taking (N = 55) versus not taking (N = 205) SGAs were more likely to have current mood stabilizer use (67.3% versus 51.7%).American tertiary bipolar disorder clinic referral sample, cross-sectional design.Current SGA use was robustly associated with prior psychiatric hospitalization in BDI and to a more limited extent with current mood stabilizer use in BDII. SGA use associations with other unfavorable illness characteristics in BDI were less robust.

  View details for DOI 10.1016/j.jpsychires.2016.01.016

  View details for Web of Science ID 000373412400007

  View details for PubMedID 26874463

• A tool to predict suicidal ideation and behavior in bipolar disorder: The Concise Health Risk Tracking Self-Report. Journal of affective disorders Reilly-Harrington, N. A., Shelton, R. C., Kamali, M., Rabideau, D. J., Shesler, L. W., Trivedi, M. H., McElroy, S. L., Sylvia, L. G., Bowden, C. L., Ketter, T. A., Calabrese, J. R., Thase, M. E., Bobo, W. V., Deckersbach, T., Tohen, M., McInnis, M. G., Kocsis, J. H., Gold, A. K., Singh, V., Finkelstein, D. M., Kinrys, G., Nierenberg, A. A. 2016; 192: 212-218

  Abstract

  Few brief, self-report measures exist that can reliably predict adverse suicidality outcomes in patients with BD. This study utilized the Concise Health Risk Tracking Self-Report (CHRT) to assess suicidality in patients with BD and examined its psychometric performance, clinical correlates, and prospective value in predicting adverse events related to suicidality.The CHRT was administered at baseline and follow-up to 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. The Columbia Suicide Severity Rating Scale (CSSRS) was used at baseline to assess lifetime history of suicide attempts and related behaviors. Clinician-rated measures of mood (Bipolar Inventory of Symptoms Scale) and bipolar symptoms (Clinical Global Impressions-Bipolar Version) were conducted at baseline and follow-up.The CHRT showed excellent internal consistency and construct validity and was highly correlated with clinician ratings of depression, anxiety, and overall functioning at baseline and throughout the study. Baseline CHRT scores significantly predicted risk of subsequent suicidality-related Serious Adverse Events (sSAEs), after controlling for mood and comorbidity. Specifically, the hazard of a sSAE increased by 76% for every 10-point increase in baseline CHRT score. Past history of suicide attempts and related behaviors, as assessed by the CSSRS, did not predict subsequent sSAEs.The CSSRS was used to assess static risk factors in terms of past suicidal behaviors and may have been a more powerful predictor over longer-term follow-up.The CHRT offers a quick and robust self-report tool for assessing suicidal risk and has important implications for future research and clinical practice.

  View details for DOI 10.1016/j.jad.2015.12.036

  View details for PubMedID 26748736

• Italian Bipolar II vs I patients have better individual functioning, in spite of overall similar illness severity. CNS spectrums Dell'Osso, B., Dobrea, C., Cremaschi, L., Buoli, M., Miller, S., Ketter, T. A., Altamura, A. C. 2016: 1-8

  Abstract

  Introduction Bipolar disorders (BDs) comprise different variants of chronic, comorbid, and disabling conditions, with relevant suicide and suicide attempt rates. The hypothesis that BD types I (BDI) and II (BDII) represent more and less severe forms of illness, respectively, has been increasingly questioned over recent years, justifying additional investigation to better characterize related sociodemographic and clinical profiles.A sample of 217 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)-described BD (141 BDI, 76 BDII), without a current syndromal mood episode, was recruited, and sociodemographic and clinical characteristics of BDI and II patients were compared.BDII patients had significantly more favorable sociodemographics, in relation to occupational stability, cohabitation, and marital status. However, BDII compared with BDI patients had significantly longer duration of untreated illness, more frequent lifetime anxiety disorders comorbidity, longer most recent episode duration, higher rate of depressive first/most recent episode, and more current antidepressant use. In contrast, BDI compared with BDII patients had significantly more severe illness in terms of earlier age at onset; higher rate of elevated first/most recent episode, lifetime hospitalizations, and involuntary commitments; lower Global Assessment of Functioning score; and more current antipsychotic use. BDI and II patients had similar duration of illness, psychiatric family history, lifetime number of suicide attempts, current subthreshold symptoms, history of stressful life events, and overall psychiatric/medical comorbidity.BDII compared with BDI patients had more favorable sociodemographic features, but a mixture of specific unfavorable illness characteristics, confirming that BDII is not just a milder form of BD and requires further investigation in the field.

  View details for PubMedID 26905615

• Treatment of bipolar disorder: Review of evidence regarding quetiapine and lithium JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A., Miller, S., Dell'Osso, B., Wang, P. W. 2016; 191: 256-273

  Abstract

  Lithium, the prototypical mood stabilizer, and quetiapine, a second-generation antipsychotic, are widely used acute and maintenance pharmacotherapies for bipolar disorder. The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study was the first comparative effectiveness assessment of lithium versus quetiapine (in combination with adjunctive personalized treatment), and found no overall significant differences in efficacy and safety/tolerability outcomes between lithium and quetiapine. Completion of Bipolar CHOICE offers a timely opportunity to review the evidence regarding lithium and quetiapine for bipolar disorder.Controlled clinical trials and real-world observational studies that included quetiapine and lithium as monotherapy or as combination therapy were identified by literature search. Selected studies were reviewed in detail.Review of the available trials suggested comparable efficacy of quetiapine and lithium in acute mania, and possibly greater efficacy for quetiapine compared with lithium in acute bipolar depression and in prevention of recurrent (particularly depressive) episodes. Combination therapy including quetiapine and lithium was generally more effective than either agent alone in acute mania and bipolar maintenance, although adding lithium to quetiapine did not increase efficacy in acute bipolar depression. Safety data for quetiapine and lithium were consistent with the established profiles of the two treatments.Limitations include those of the available efficacy and effectiveness trial data.Quetiapine and lithium have overlapping but distinctive roles in different phases of bipolar disorder, and further studies of these agents (particularly in combination with one another) are warranted.

  View details for DOI 10.1016/j.jad.2015.11.002

  View details for Web of Science ID 000368253400033

• Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder ACTA PSYCHIATRICA SCANDINAVICA McElroy, S. L., Kemp, D. E., Friedman, E. S., Reilly-Harrington, N. A., Sylvia, L. G., Calabrese, J. R., Rabideau, D. J., Ketter, T. A., Thase, M. E., Singh, V., Tohen, M., Bowden, C. L., BERNSTEIN, E. E., Brody, B. D., Deckersbach, T., Kocsis, J. H., Kinrys, G., Bobo, W. V., Kamali, M., McInnis, M. G., Leon, A. C., Faraone, S., Nierenberg, A. A., Shelton, R. C. 2016; 133 (2): 144-153

  View details for DOI 10.1111/acps.12460

  View details for Web of Science ID 000368003600006

• Treatment of bipolar disorder: Review of evidence regarding quetiapine and lithium. Journal of affective disorders Ketter, T. A., Miller, S., Dell'Osso, B., Wang, P. W. 2016; 191: 256-73

  Abstract

  Lithium, the prototypical mood stabilizer, and quetiapine, a second-generation antipsychotic, are widely used acute and maintenance pharmacotherapies for bipolar disorder. The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study was the first comparative effectiveness assessment of lithium versus quetiapine (in combination with adjunctive personalized treatment), and found no overall significant differences in efficacy and safety/tolerability outcomes between lithium and quetiapine. Completion of Bipolar CHOICE offers a timely opportunity to review the evidence regarding lithium and quetiapine for bipolar disorder.Controlled clinical trials and real-world observational studies that included quetiapine and lithium as monotherapy or as combination therapy were identified by literature search. Selected studies were reviewed in detail.Review of the available trials suggested comparable efficacy of quetiapine and lithium in acute mania, and possibly greater efficacy for quetiapine compared with lithium in acute bipolar depression and in prevention of recurrent (particularly depressive) episodes. Combination therapy including quetiapine and lithium was generally more effective than either agent alone in acute mania and bipolar maintenance, although adding lithium to quetiapine did not increase efficacy in acute bipolar depression. Safety data for quetiapine and lithium were consistent with the established profiles of the two treatments.Limitations include those of the available efficacy and effectiveness trial data.Quetiapine and lithium have overlapping but distinctive roles in different phases of bipolar disorder, and further studies of these agents (particularly in combination with one another) are warranted.

  View details for DOI 10.1016/j.jad.2015.11.002

  View details for PubMedID 26688495

• Sleep, residual mood symptoms, and time to relapse in recovered patients with bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Cretu, J. B., Culver, J. L., Goffin, K. C., Shah, S., Ketter, T. A. 2016; 190: 162-166

  Abstract

  Sleep disturbance in bipolar disorder (BD) is common during and between mood episodes. In recovered (euthymic at least two months) BD patients, we assessed sleep compared to controls and its relationships with residual mood symptoms and mood episode recurrence.Recovered Stanford University BD Clinic patients diagnosed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and monitored with the STEP-BD Clinical Monitoring Form (CMF) for >1 year and healthy controls completed the Pittsburgh Sleep Quality Index (PSQI). PSQI parameters were compared in BD patients versus controls, and the most robustly differentiating PSQI parameter was assessed in relationship to residual mood symptoms, and time to mood episode recurrence in BD patients.Eighty nine recovered BD patients compared to 56 healthy controls had significantly worse PSQI global score, more sleep medication use, longer sleep latency, and worse daytime dysfunction. PSQI global score had the greatest BD patient versus control effect size, and among BD patients, correlated significantly with residual mood symptoms and predicted earlier mood episode recurrence, even after covarying for residual mood symptoms.Use of subjective (PSQI) rather objective (polysomnography) sleep metric. Statistical power limited by small sample size. Potential psychotropic medication confound. Northern California tertiary BD clinic referral sample.Further research is needed to confirm that in recovered BD patients, poor sleep quality correlates with residual mood symptoms, and independently predicts mood episode recurrence. If confirmed, these observations suggest potential mood benefit for focusing on sleep quality in interventions for recovered BD patients.

  View details for DOI 10.1016/j.jad.2015.09.076

  View details for Web of Science ID 000366463000026

• Sleep, residual mood symptoms, and time to relapse in recovered patients with bipolar disorder. Journal of affective disorders Cretu, J. B., Culver, J. L., Goffin, K. C., Shah, S., Ketter, T. A. 2016; 190: 162-166

  Abstract

  Sleep disturbance in bipolar disorder (BD) is common during and between mood episodes. In recovered (euthymic at least two months) BD patients, we assessed sleep compared to controls and its relationships with residual mood symptoms and mood episode recurrence.Recovered Stanford University BD Clinic patients diagnosed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and monitored with the STEP-BD Clinical Monitoring Form (CMF) for >1 year and healthy controls completed the Pittsburgh Sleep Quality Index (PSQI). PSQI parameters were compared in BD patients versus controls, and the most robustly differentiating PSQI parameter was assessed in relationship to residual mood symptoms, and time to mood episode recurrence in BD patients.Eighty nine recovered BD patients compared to 56 healthy controls had significantly worse PSQI global score, more sleep medication use, longer sleep latency, and worse daytime dysfunction. PSQI global score had the greatest BD patient versus control effect size, and among BD patients, correlated significantly with residual mood symptoms and predicted earlier mood episode recurrence, even after covarying for residual mood symptoms.Use of subjective (PSQI) rather objective (polysomnography) sleep metric. Statistical power limited by small sample size. Potential psychotropic medication confound. Northern California tertiary BD clinic referral sample.Further research is needed to confirm that in recovered BD patients, poor sleep quality correlates with residual mood symptoms, and independently predicts mood episode recurrence. If confirmed, these observations suggest potential mood benefit for focusing on sleep quality in interventions for recovered BD patients.

  View details for DOI 10.1016/j.jad.2015.09.076

  View details for PubMedID 26519636

• Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder. journal of clinical psychiatry Nierenberg, A. A., McElroy, S. L., Friedman, E. S., Ketter, T. A., Shelton, R. C., Deckersbach, T., McInnis, M. G., Bowden, C. L., Tohen, M., Kocsis, J. H., Calabrese, J. R., Kinrys, G., Bobo, W. V., Singh, V., Kamali, M., Kemp, D., Brody, B., Reilly-Harrington, N. A., Sylvia, L. G., Shesler, L. W., Bernstein, E. E., Schoenfeld, D., Rabideau, D. J., Leon, A. C., Faraone, S., Thase, M. E. 2016; 77 (1): 90-99

  Abstract

  Bipolar disorder is among the 10 most disabling medical conditions worldwide. While lithium has been used extensively for bipolar disorder since the 1970s, second-generation antipsychotics (SGAs) have supplanted lithium since 1998. To date, no randomized comparative-effectiveness study has compared lithium and any SGA.Within the duration of the study (September 2010-September 2013), participants with bipolar I or II disorder (DSM-IV-TR) were randomized for 6 months to receive lithium (n = 240) or quetiapine (n = 242). Lithium and quetiapine were combined with other medications for bipolar disorder consistent with typical clinical practice (adjunctive personalized treatment [APT], excluding any SGA for the lithium + APT group and excluding lithium or any other SGA for the quetiapine + APT group). Coprimary outcome measures included Clinical Global Impressions-Efficacy Index (CGI-EI) and necessary clinical adjustments, which measured number of changes in adjunctive personalized treatment. Secondary measures included a full range of symptoms, cardiovascular risk, functioning, quality of life, suicidal ideation and behavior, and adverse events.Participants improved across all measures, and over 20% had a sustained response. Primary (CGI-EI, P = .59; necessary clinical adjustments, P = .15) and secondary outcome changes were not statistically significantly different between the 2 groups. For participants with greater manic/hypomanic symptoms, CGI-EI changes were significantly more favorable with quetiapine + APT (P = .02). Among those with anxiety, the lithium + APT group had fewer necessary clinical adjustments per month (P = .02). Lithium was better tolerated than quetiapine in terms of the burden of side effects frequency (P = .05), intensity (P = .01), and impairment (P = .01).Despite adequate power to detect clinically meaningful differences, we found outcomes with lithium + APT and quetiapine + APT were not significantly different across 6 months of treatment for bipolar disorder.ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

  View details for DOI 10.4088/JCP.14m09349

  View details for PubMedID 26845264

• Baseline disability and poor functioning in bipolar disorder predict worse outcomes: results from the Bipolar CHOICE study. journal of clinical psychiatry Deckersbach, T., Nierenberg, A. A., McInnis, M. G., Salcedo, S., Bernstein, E. E., Kemp, D. E., Shelton, R. C., McElroy, S. L., Sylvia, L. G., Kocsis, J. H., Bobo, W. V., Friedman, E. S., Singh, V., Tohen, M., Bowden, C. L., Ketter, T. A., Calabrese, J. R., Thase, M. E., Reilly-Harrington, N. A., Rabideau, D. J., Kinrys, G., Kamali, M. 2016; 77 (1): 100-108

  Abstract

  To examine the effects of treatment on functioning impairments and quality of life and assess baseline functioning and employment status as predictors of treatment response in symptomatic individuals from the Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (Bipolar CHOICE) study.Bipolar CHOICE was an 11-site, 6-month randomized effectiveness study comparing lithium to quetiapine, each with adjunctive personalized treatments (APTs). We examined post hoc (1) the effects of treatment on functioning, (2) how changes in functioning differed between treatment responders and nonresponders, and (3) whether functioning and employment status mediated treatment response in 482 participants with DSM-IV-TR bipolar I or II disorder from September 2010 to September 2013.Treatment was associated with significant improvements in functioning and quality of life, regardless of treatment group (P values < .0001). Responders showed greater improvements in quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire P values < .05) and functioning (Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool P values < .05) than nonresponders. Unemployed or disabled participants at baseline had significantly greater illness severity at baseline than employed participants (P values < .05). Over the study duration, employed participants reported greater improvements in physical health and quality of life in leisure activities than both unemployed and disabled participants (P values < .05). Individuals who saw greater improvement in functioning and quality of life tended to show greater improvements in depressive and anxiety symptoms (P values ≤ .0001), as well as overall illness severity (P values < .001). Early (8 weeks) and very early (4 weeks) clinical changes in mood symptoms predicted changes in functioning and quality of life at 6 months (P values < .001).Prior disability status was associated with a worse treatment response and prospective illness course. Results implicate functioning and employment status as important markers of illness severity and likelihood of recovery in bipolar disorder, suggesting that interventions that target functional impairment may improve outcomes.ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

  View details for DOI 10.4088/JCP.14m09210

  View details for PubMedID 26845265

• American tertiary clinic-referred bipolar II disorder compared to bipolar I disorder: More severe in multiple ways, but less severe in a few other ways JOURNAL OF AFFECTIVE DISORDERS Dell'Osso, B., Holtzman, J. N., Goffin, K. C., Portillo, N., Hooshmand, F., Miller, S., Dore, J., Wang, P. W., Hill, S. J., Ketter, T. A. 2015; 188: 257-262

  Abstract

  Prevalence and relative severity of bipolar II disorder (BDII) vs. bipolar I disorder (BDI) are controversial.Prevalence, demographics, and illness characteristics were compared among 260 BDII and 243 BDI outpatients referred to the Stanford University BD Clinic and assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation.BDII vs. BDI outpatients had statistically similar prevalence (51.7% vs. 48.3%), and in multiple ways had more severe illness, having significantly more often: lifetime comorbid anxiety (70.8% vs. 58.4%) and personality (15.4% vs. 7.4%) disorders, first-degree relative with mood disorder (62.3% vs. 52.3%), at least 10 prior mood episodes (80.0% vs. 50.9%), current syndromal/subsyndromal depression (52.3% vs. 38.4%), current antidepressant use (47.3% vs. 31.3%), prior year rapid cycling (33.6% vs. 13.4%), childhood onset (26.2% vs. 16.0%), as well as earlier onset age (17.0±8.6 vs. 18.9±8.1 years), longer illness duration (19.0±13.0 vs. 16.1±13.0), and higher current Clinical Global Impression for Bipolar Disorder-Overall Severity (4.1±1.4 vs. 3.7±1.5). However, BDII vs. BDI patients significantly less often had prior psychosis (14.2% vs. 64.2%), psychiatric hospitalization (10.0% vs. 67.9%), and current prescription psychotropic use, (81.5% vs. 93.0%), and had a statistically similar rate of prior suicide attempt (29.5% vs. 32.1%).American tertiary bipolar disorder clinic referral sample, cross-sectional design.Further studies are warranted to determine the extent to which BDII, compared to BDI, can be more severe in multiple ways but less severe in a few other ways, and contributors to occurrence of more severe forms of BDII.

  View details for DOI 10.1016/j.jad.2015.09.001

  View details for Web of Science ID 000364168100036

  View details for PubMedID 26378735

• Randomized, placebo-controlled, adjunctive study of armodafinil for bipolar I depression: implications of novel drug design and heterogeneity of concurrent bipolar maintenance treatments. International journal of bipolar disorders Frye, M. A., Amchin, J., Bauer, M., Adler, C., Yang, R., Ketter, T. A. 2015; 3 (1): 34-?

  Abstract

  Some, but not all, prior investigations suggest armodafinil may have utility as an adjunctive treatment in bipolar I depression.Multicenter, randomized, double-blind study in patients aged 18 to 65 years experiencing a depressive episode despite maintenance therapy for bipolar I disorder. Patients were randomized to receive adjunctive armodafinil 150 mg/day or adjunctive placebo for 8 weeks. Primary efficacy outcome was change from baseline in 30-Item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) total score at week 8. Safety and tolerability were monitored.Of 656 patients screened, 399 were randomized, of whom 308 (77 %) were taking a protocol-allowed mood stabilizer as monotherapy. The primary efficacy outcome did not reach statistical significance; however, several secondary efficacy outcomes demonstrated statistically significant advantages for adjunctive armodafinil (n = 197) over adjunctive placebo (n = 196), including Clinical Global Impression of Severity of Illness for depression (weeks 6, 8, and endpoint; all P < 0.05), Global Assessment of Functioning (weeks 4, 8, and endpoint; all P < 0.02), IDS-C30 remitter rates (week 8 and endpoint; both P < 0.02), and mean change from baseline in IDS-C30 total score at week 7 (P < 0.05). Adjunctive armodafinil and adjunctive placebo were generally well tolerated. Although adjunctive armodafinil compared with adjunctive placebo yielded a higher headache rate (15 vs 8 %), it yielded similar (generally favorably low) rates of all-cause discontinuation (16 vs 16 %), adverse event discontinuation (4 vs 5 %), nausea (6 vs 4 %), ≥7 % weight gain (2 vs 5 %), anxiety (4 vs 3 %), insomnia (3 vs 2 %), sedation/somnolence (1 vs 1 %), and hypomania (0 vs <1 %).In this study, adjunctive armodafinil compared with adjunctive placebo in bipolar I depression did not separate in the primary efficacy outcome but demonstrated advantages for several secondary efficacy outcomes and was generally well tolerated. Additional research is warranted and necessary to better identify clinical predictors (e.g., atypical depressive symptoms, specific anti-manic/mood-stabilizing agents used) that would provide optimized, individualized therapeutics for bipolar depression.ClinicalTrials.gov: NCT01305408.

  View details for DOI 10.1186/s40345-015-0034-0

  View details for PubMedID 26330288

  View details for PubMedCentralID PMC4556715

• A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR) JOURNAL OF PSYCHIATRIC RESEARCH Ostacher, M. J., Nierenberg, A. A., Rabideau, D., Reilly-Harrington, N. A., Sylvia, L. G., Gold, A. K., Shesler, L. W., Ketter, T. A., Bowden, C. L., Calabrese, J. R., Friedman, E. S., Iosifescu, D. V., Thase, M. E., Leon, A. C., Trivedi, M. H. 2015; 71: 126-133

  Abstract

  People with bipolar disorder are at high risk of suicide, but no clinically useful scale has been validated in this population. The aim of this study was to evaluate the psychometric properties in bipolar disorder of the 7- and 12-item versions of the Concise Health Risk Tracking Self-Report (CHRT-SR), a scale measuring suicidal ideation, suicidal behavior, and associated symptoms.The CHRT was administered to 283 symptomatic outpatients with bipolar I or II disorder who were randomized to receive lithium plus optimized personalized treatment (OPT), or OPT without lithium in a six month longitudinal comparative effectiveness trial. Participants were assessed using structured diagnostic interviews, clinician-rated assessments, and self-report questionnaires.The internal consistency (Cronbach α) was 0.80 for the 7-item CHRT-SR and 0.90 for the 12-item CHRT-SR with a consistent factor structure, and three independent factors (current suicidal thoughts and plans, hopelessness, and perceived lack of social support) for the 7-item version. CHRT-SR scores are correlated with measures of depression, functioning, and quality of life, but not with mania scores.The 7- and 12-item CHRT-SR both had excellent psychometric properties in a sample of symptomatic subjects with bipolar disorder. The scale is highly correlated with depression, functioning, and quality of life, but not with mania. Future research is needed to determine whether the CHRT-SR will be able to predict suicide attempts in clinical practice.

  View details for DOI 10.1016/j.jpsychires.2015.10.004

  View details for Web of Science ID 000365053900016

  View details for PubMedID 26476489

• Recovery in bipolar depression: Post-hoc analysis of a placebo-controlled lurasidone trial followed by a long-term continuation study. Journal of affective disorders Loebel, A., Siu, C., Rajagopalan, K., Pikalov, A., Cucchiaro, J., Ketter, T. A. 2015; 186: 376-382

  Abstract

  In this post-hoc analysis, rates of remission and recovery were evaluated in patients with bipolar depression treated with lurasidone.Outpatients meeting DSM-IV-TR criteria for bipolar I depression, were randomized to 6 weeks of once-daily, double-blind treatment with lurasidone 20-60mg, lurasidone 80-120mg or placebo, followed by a 6-month, open-label, flexible-dose, lurasidone continuation study. Recovery was defined as meeting criteria for combined symptomatic remission (Montgomery-Asberg Depression Rating Scale total score ≤12) and functional remission (all Sheehan Disability Scale domain scores ≤3) sustained for at least 3 months in the 6-month continuation study.A significantly higher proportion of lurasidone-treated patients met criteria for combined symptomatic remission and functional remission (33.3%, 91/273) compared to the placebo group (21.0%, 30/143, p<0.05, NNT=9) at the 6-week study endpoint. In the 6-month continuation study, the proportion of lurasidone-treated patients achieving sustained recovery was 60.7% (85/140) and 44.9% (31/69), for patients who continued lurasidone treatment and who switched from placebo to lurasidone, respectively.The definition of recovery used has not been previously validated and the analysis was post hoc. Lack of a control group in the continuation study limits data interpretation.Recovery in patients with bipolar depression was assessed based on rates of combined symptomatic and functional remission sustained over time. A majority of patients initially treated with lurasidone in the acute phase achieved recovery status in the continuation study. Treatment with lurasidone (vs. placebo) earlier in the course of the bipolar depressive episode increased the likelihood of subsequent recovery.

  View details for DOI 10.1016/j.jad.2015.07.033

  View details for PubMedID 26363720

• Clinical Observations About The Strange Case of Dr. Jekyll and Mr. Hyde in Relation to Bipolar Disorder. Academic psychiatry Dell'Osso, B., Ketter, T. A. 2015; 39 (5): 607-608

  View details for DOI 10.1007/s40596-015-0394-x

  View details for PubMedID 26223315

• Recognizing the Extent of Overlap Between Bipolar Disorder and Anxiety Disorders EBIOMEDICINE Ketter, T. A. 2015; 2 (10): 1284–85

  View details for PubMedID 26629510

• Recurrence rates in bipolar disorder: Systematic comparison of long-term prospective, naturalistic studies versus randomized controlled trials EUROPEAN NEUROPSYCHOPHARMACOLOGY Vazquez, G. H., Holtzman, J. N., Lolich, M., Ketter, T. A., Baldessarini, R. J. 2015; 25 (10): 1501-1512

  Abstract

  Bipolar disorder (BD) is a recurrent, lifelong illness with high risks of disability and excess mortality. Despite many treatment options with demonstrated short-term efficacy, evidence concerning long-term treatment effectiveness in BD remains limited and the relative value of naturalistic studies versus randomized, controlled trials (RCTs) in its assessment, uncertain. Systematic computer-searching yielded 10 naturalistic studies and 15 RCTs suitable for analysis of recurrence rates and their association with treatments and selected clinical factors. In naturalistic studies (3904 BD subjects, 53.3% women, 85.8% BD-I, mean onset age 29.1, followed up to 2.1 years), the pooled recurrence rate was 55.2% (26.3%/year). In RCTs (4828 subjects, 50.9% women, 96.0% BD-I, mean onset age 23.1, followed up to 1.9 years), the pooled recurrence rate was 39.3% (21.9%/year) with mood-stabilizing drug-treatment versus 60.6% (31.3%/year) with placebo; drug-versus-placebo outcomes favored antipsychotics over lithium, and disfavor an approved anticonvulsant. Depressive episode-polarity increased from 27.7% at intake to 52.0% at first-recurrence (p<0.0001). Recurrence rate (%/year) did not differ by study-type, was greater with younger onset and rapid-cycling, and paradoxically declined with longer observation. In short, recurrences of major affective episodes up to two years during putative mood-stabilizing treatment of BD patients in prospective, naturalistic studies and RCTs were substantial and similar (26.3 vs. 21.9%/year). Episode-polarity shifted strongly toward depressive first-recurrences. These findings support the value of naturalistic studies to complement long-term RCTs, and add to indications that control of depression in BD remains particularly unsatisfactory.

  View details for DOI 10.1016/j.euroneuro.2015.07.013

  View details for Web of Science ID 000364031800001

  View details for PubMedID 26238969

• Number Needed to Treat Can Be Helpful: A Response to Andrade JOURNAL OF CLINICAL PSYCHIATRY Citrome, L., Ketter, T. A. 2015; 76 (9): E1136

  View details for Web of Science ID 000365412500009

  View details for PubMedID 26455680

• Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder JOURNAL OF AFFECTIVE DISORDERS Ketter, T., Yang, R., Frye, M. A. 2015; 181: 87-91

  Abstract

  In a previous study, adjunctive armodafinil 150 mg/day significantly improved depressive symptoms associated with bipolar I disorder.Multicenter, double-blind study of patients with a major depressive episode despite bipolar I disorder maintenance therapy randomized to adjunctive placebo or adjunctive armodafinil 150 or 200mg/day for 8 weeks; for logistical reasons, assignment to armodafinil 200mg/day was discontinued early. Primary efficacy was measured by change from baseline to week 8 in 30-Item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) total score.Patients were randomized to adjunctive placebo (n=230), adjunctive armodafinil 150 mg/day (n=232), or adjunctive armodafinil 200mg/day (n=30; analyzed for safety only). Least-square mean change in IDS-C30 total score was numerically superior for adjunctive armodafinil 150 mg/day vs adjunctive placebo, but was not statistically significant (p=0.13). Armodafinil was well-tolerated. Adverse events (AEs) observed in >5% with adjunctive armodafinil 150 mg/day and more frequently than with adjunctive placebo were headache (16% [38/231] vs 13% [30/229]) and nausea (7% [17/231] vs 2% [5/229]). The most common AEs with adjunctive armodafinil 200mg/day were diarrhea and dry mouth (17% [5/30] each vs 6% [13/229] and 1% [3/229], respectively, with adjunctive placebo).Early study discontinuation for logistical reasons by the sponsor limited adjunctive armodafinil 200-mg/day assessment.FDA-approved bipolar I depression treatments are limited. Adjunctive armodafinil 150 mg/day reduced depressive symptoms associated with bipolar I disorder to a greater extent than adjunctive placebo, although the difference failed to reach statistical significance. Safety data indicate treatment with adjunctive armodafinil was well-tolerated.

  View details for DOI 10.1016/j.jad.2015.04.012

  View details for Web of Science ID 000354777100011

  View details for PubMedID 25933099

• Pharmacotherapy for bipolar depression: comparative efficacy and acceptability is in the eye of the beholder. Evidence-based mental health Citrome, L., Ketter, T. A. 2015; 18 (3): 88-?

  View details for DOI 10.1136/eb-2015-102062

  View details for PubMedID 25989992

• Childhood-compared to adolescent-onset bipolar disorder has more statistically significant clinical correlates JOURNAL OF AFFECTIVE DISORDERS Holtzman, J. N., Miller, S., Hooshmand, F., Wang, P. W., Chang, K. D., Hill, S. J., Rasgon, N. L., Ketter, T. A. 2015; 179: 114-120

  Abstract

  The strengths and limitations of considering childhood-and adolescent-onset bipolar disorder (BD) separately versus together remain to be established. We assessed this issue.BD patients referred to the Stanford Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Patients with childhood- and adolescent-onset were compared to those with adult-onset for 7 unfavorable bipolar illness characteristics with replicated associations with early-onset patients.Among 502 BD outpatients, those with childhood- (<13 years, N=110) and adolescent- (13-18 years, N=218) onset had significantly higher rates for 4/7 unfavorable illness characteristics, including lifetime comorbid anxiety disorder, at least ten lifetime mood episodes, lifetime alcohol use disorder, and prior suicide attempt, than those with adult-onset (>18 years, N=174). Childhood- but not adolescent-onset BD patients also had significantly higher rates of first-degree relative with mood disorder, lifetime substance use disorder, and rapid cycling in the prior year. Patients with pooled childhood/adolescent - compared to adult-onset had significantly higher rates for 5/7 of these unfavorable illness characteristics, while patients with childhood- compared to adolescent-onset had significantly higher rates for 4/7 of these unfavorable illness characteristics.Caucasian, insured, suburban, low substance abuse, American specialty clinic-referred sample limits generalizability. Onset age is based on retrospective recall.Childhood- compared to adolescent-onset BD was more robustly related to unfavorable bipolar illness characteristics, so pooling these groups attenuated such relationships. Further study is warranted to determine the extent to which adolescent-onset BD represents an intermediate phenotype between childhood- and adult-onset BD.

  View details for DOI 10.1016/j.jad.2015.03.019

  View details for PubMedID 25863906

• Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder. Acta psychiatrica Scandinavica McElroy, S. L., Kemp, D. E., Friedman, E. S., Reilly-Harrington, N. A., Sylvia, L. G., Calabrese, J. R., Rabideau, D. J., Ketter, T. A., Thase, M. E., Singh, V., Tohen, M., Bowden, C. L., BERNSTEIN, E. E., Brody, B. D., Deckersbach, T., Kocsis, J. H., Kinrys, G., Bobo, W. V., Kamali, M., McInnis, M. G., Leon, A. C., Faraone, S., Nierenberg, A. A., Shelton, R. C. 2015

  Abstract

  Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder.The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models.At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome.Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

  View details for DOI 10.1111/acps.12460

  View details for PubMedID 26114830

• An exploratory study of responses to low-dose lithium in African Americans and Hispanics JOURNAL OF AFFECTIVE DISORDERS Arnold, J. G., Salcedo, S., Ketter, T. A., Calabrese, J. R., Rabideau, D. J., Nierenberg, A. A., Bazan, M., Leon, A. C., Friedman, E. S., Iosifescu, D., Sylvia, L. G., Ostacher, M., Thase, M., Reilly-Harrington, N. A., Bowden, C. L. 2015; 178: 224-228

  Abstract

  Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS).LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) vs. OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes.African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups.African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group.

  View details for DOI 10.1016/j.jad.2015.02.035

  View details for Web of Science ID 000352716600030

  View details for PubMedID 25827507

  View details for PubMedCentralID PMC4397978

• Treating Insomnia Improves Mood State, Sleep, and Functioning in Bipolar Disorder: A Pilot Randomized Controlled Trial JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY Harvey, A. G., Soehner, A. M., Kaplan, K. A., Hein, K., Lee, J., Kanady, J., Li, D., Rabe-Hesketh, S., Ketter, T. A., Neylan, T. C., Buysse, D. J. 2015; 83 (3): 564-577

  Abstract

  To determine if a treatment for interepisode bipolar disorder I patients with insomnia improves mood state, sleep, and functioning.Alongside psychiatric care, interepisode bipolar disorder I participants with insomnia were randomly allocated to a bipolar disorder-specific modification of cognitive behavior therapy for insomnia (CBTI-BP; n = 30) or psychoeducation (PE; n = 28) as a comparison condition. Outcomes were assessed at baseline, the end of 8 sessions of treatment, and 6 months later. This pilot was conducted to determine initial feasibility and generate effect size estimates.During the 6-month follow-up, the CBTI-BP group had fewer days in a bipolar episode relative to the PE group (3.3 days vs. 25.5 days). The CBTI-BP group also experienced a significantly lower hypomania/mania relapse rate (4.6% vs. 31.6%) and a marginally lower overall mood episode relapse rate (13.6% vs. 42.1%) compared with the PE group. Relative to PE, CBTI-BP reduced insomnia severity and led to higher rates of insomnia remission at posttreatment and marginally higher rates at 6 months. Both CBTI-BP and PE showed statistically significant improvement on selected sleep and functional impairment measures. The effects of treatment were well sustained through follow-up for most outcomes, although some decline on secondary sleep benefits was observed.CBTI-BP was associated with reduced risk of mood episode relapse and improved sleep and functioning on certain outcomes in bipolar disorder. Hence, sleep disturbance appears to be an important pathway contributing to bipolar disorder. The need to develop bipolar disorder-specific sleep diary scoring standards is highlighted.

  View details for DOI 10.1037/a0038655

  View details for PubMedID 25622197

• Psychotherapy use in bipolar disorder: Association with functioning and illness severity AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Sylvia, L. G., Thase, M. E., Reilly-Harrington, N. A., Salcedo, S., Brody, B., Kinrys, G., Kemp, D., Shelton, R. C., McElroy, S. L., Kocsis, J. H., Bobo, W. V., Kamali, M., McInnis, M., Friedman, E., Tohen, M., Bowden, C. L., Ketter, T. A., Singh, V., Calabrese, J., Nierenberg, A. A., Rabideau, D. J., Elson, C. M., Deckersbach, T. 2015; 49 (5): 453-461

  Abstract

  This study examines characteristics of individuals with bipolar disorder who sought psychotherapy versus those who did not.Bipolar CHOICE was an 11-site comparative effectiveness study of lithium versus quetiapine in symptomatic outpatients (N = 482) with bipolar disorder. At baseline, participants' psychotherapy use within the past 3 months, mood, functioning, and overall health were assessed. Logistic regressions were used to test whether psychotherapy users and non-users differed on various demographic and clinical variables at baseline. Mixed-effects regression was used to determine whether psychotherapy groups differed on response to treatment over the 6-month study. Kaplan-Meier plots and log-rank tests were employed to test whether there were any differences in time to recovery (CGI-BP ≤ 2 for at least 8 weeks) between the groups.Thirty one percent of participants reported using psychotherapy services. Psychotherapy users reported greater medication side effect burden than non-users and were more likely to have moderate to high suicide risk and at least one anxiety disorder. Participants not utilizing medications or psychotherapy had greater mania symptom severity, were younger, and less educated than medication only users. Medication only users were more likely to be married than the other participants.These data suggest that a minority of individuals with bipolar disorder attend psychotherapy services, and those that do have greater illness burden.

  View details for DOI 10.1177/0004867415569803

  View details for Web of Science ID 000353214700008

  View details for PubMedID 25680360

• Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) BIPOLAR DISORDERS Sylvia, L. G., Shelton, R. C., Kemp, D. E., Bernstein, E. E., Friedman, E. S., Brody, B. D., McElroy, S. L., Singh, V., Tohen, M., Bowden, C. L., Ketter, T. A., Deckersbach, T., Thase, M. E., Reilly-Harrington, N. A., Nierenberg, A. A., Rabideau, D. J., Kinrys, G., Kocsis, J. H., Bobo, W. V., Kamali, M., McInnis, M. G., Calabrese, J. R. 2015; 17 (2): 212-223

  Abstract

  Individuals with bipolar disorder have high rates of other medical comorbidity, which is associated with higher mortality rates and worse course of illness. The present study examined common predictors of medical comorbidity.The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) enrolled 482 participants with bipolar I or bipolar II disorder in a six-month, randomized comparative effectiveness trial. Baseline assessments included current and lifetime DSM-IV-TR diagnoses, demographic information, psychiatric and medical history, severity of psychiatric symptoms, level of functioning, and a fasting blood draw. Medical comorbidities were categorized into two groups: cardiometabolic (e.g., diabetes, hyperlipidemia, and metabolic syndrome) and non-cardiovascular (e.g., seizures, asthma, and cancer). Additionally, we looked at comorbid substance use (e.g., smoking and drug dependence).We found that 96.3% of participants had at least one other medical comorbidity. Older age predicted a greater likelihood of having a cardiometabolic condition. Early age of onset of bipolar symptoms was associated with a lower chance of having a cardiometabolic condition, but a greater chance of having other types of medical comorbidity. Additional predictors of other medical comorbidities in bipolar disorder included more time spent depressed, less time spent manic/hypomanic, and longer duration of illness. Medications associated with weight gain were associated with low high-density lipoprotein and abnormal triglycerides.There appears to be a substantial medical burden associated with bipolar disorder, highlighting the need for collaborative care among psychiatric and general medical providers to address both psychiatric and other medical needs concomitantly in this group of patients.

  View details for DOI 10.1111/bdi.12243

  View details for Web of Science ID 000350906500010

  View details for PubMedID 25130321

• Assessing Cognitive Function in Bipolar Disorder: Challenges and Recommendations for Clinical Trial Design JOURNAL OF CLINICAL PSYCHIATRY Burdick, K. E., Ketter, T. A., Goldberg, J. F., Calabrese, J. R. 2015; 76 (3): E342-E350

  Abstract

  Neurocognitive impairment in schizophrenia has been recognized for more than a century. In contrast, only recently have significant neurocognitive deficits been recognized in bipolar disorder. Converging data suggest the importance of cognitive problems in relation to quality of life in bipolar disorder, highlighting the need for treatment and prevention efforts targeting cognition in bipolar patients. Future treatment trials targeting cognitive deficits will be met with methodological challenges due to the inherent complexity and heterogeneity of the disorder, including significant diagnostic comorbidities, the episodic nature of the illness, frequent use of polypharmacy, cognitive heterogeneity, and a lack of consensus regarding measurement of cognition and outcome in bipolar patients. Guidelines for use in designing future trials are needed.The members of the consensus panel (each of the bylined authors) were selected based upon their expertise in bipolar disorder. Dr Burdick is a neuropsychologist who has studied cognition in this illness for 15 years; Drs Ketter, Calabrese, and Goldberg each bring considerable expertise in the treatment of bipolar disorder, both within and outside of controlled clinical trials. This consensus statement was derived from work together at scientific meetings (eg, symposium presentation at the 2014 Annual Meeting of the American Society of Clinical Psychopharmacology, among others) and ongoing discussions by conference call. With the exception of the public presentations on this topic, these meetings were closed to outside participants.A literature review was undertaken by the authors to identify illness-specific challenges relevant to the design and conduct of treatment trials targeting neurocognition in bipolar disorder. Expert opinion from each of the authors guided the consensus recommendations.Consensus recommendations, reached by unanimous opinion of the authors, are provided here as a preliminary guide for future trial design. Recommendations comprise exclusion of certain syndromal-level comorbid diagnoses and current affective instability, restrictions on numbers and types of medications, and use of prescreening assessment to ensure enrollment of subjects with adequate objective evidence of baseline cognitive impairment.Clinical trials to address cognitive deficits in bipolar disorder face distinctive design challenges. As such trials move from proof-of-concept to confirmation of clinical efficacy, it will be important to incorporate distinctive design modifications to adequately address these challenges and increase the likelihood of demonstrating cognitive remediation effects. The field is now primed to address these challenges, and a comprehensive effort to formalize best practice guidelines will be a critically important next step.

  View details for DOI 10.4088/JCP.14cs09399

  View details for Web of Science ID 000354955400003

  View details for PubMedID 25830456

  View details for PubMedCentralID PMC4472380

• Assessing cognitive function in bipolar disorder: challenges and recommendations for clinical trial design. journal of clinical psychiatry Burdick, K. E., Ketter, T. A., Goldberg, J. F., Calabrese, J. R. 2015; 76 (3): e342-50

  Abstract

  Neurocognitive impairment in schizophrenia has been recognized for more than a century. In contrast, only recently have significant neurocognitive deficits been recognized in bipolar disorder. Converging data suggest the importance of cognitive problems in relation to quality of life in bipolar disorder, highlighting the need for treatment and prevention efforts targeting cognition in bipolar patients. Future treatment trials targeting cognitive deficits will be met with methodological challenges due to the inherent complexity and heterogeneity of the disorder, including significant diagnostic comorbidities, the episodic nature of the illness, frequent use of polypharmacy, cognitive heterogeneity, and a lack of consensus regarding measurement of cognition and outcome in bipolar patients. Guidelines for use in designing future trials are needed.The members of the consensus panel (each of the bylined authors) were selected based upon their expertise in bipolar disorder. Dr Burdick is a neuropsychologist who has studied cognition in this illness for 15 years; Drs Ketter, Calabrese, and Goldberg each bring considerable expertise in the treatment of bipolar disorder, both within and outside of controlled clinical trials. This consensus statement was derived from work together at scientific meetings (eg, symposium presentation at the 2014 Annual Meeting of the American Society of Clinical Psychopharmacology, among others) and ongoing discussions by conference call. With the exception of the public presentations on this topic, these meetings were closed to outside participants.A literature review was undertaken by the authors to identify illness-specific challenges relevant to the design and conduct of treatment trials targeting neurocognition in bipolar disorder. Expert opinion from each of the authors guided the consensus recommendations.Consensus recommendations, reached by unanimous opinion of the authors, are provided here as a preliminary guide for future trial design. Recommendations comprise exclusion of certain syndromal-level comorbid diagnoses and current affective instability, restrictions on numbers and types of medications, and use of prescreening assessment to ensure enrollment of subjects with adequate objective evidence of baseline cognitive impairment.Clinical trials to address cognitive deficits in bipolar disorder face distinctive design challenges. As such trials move from proof-of-concept to confirmation of clinical efficacy, it will be important to incorporate distinctive design modifications to adequately address these challenges and increase the likelihood of demonstrating cognitive remediation effects. The field is now primed to address these challenges, and a comprehensive effort to formalize best practice guidelines will be a critically important next step.

  View details for DOI 10.4088/JCP.14cs09399

  View details for PubMedID 25830456

• Complexity of Illness and Adjunctive Benzodiazepine Use in Outpatients With Bipolar I or II Disorder: Results From the Bipolar CHOICE Study. Journal of clinical psychopharmacology Bobo, W. V., Reilly-Harrington, N. A., Ketter, T. A., Brody, B. D., Kinrys, G., Kemp, D. E., Shelton, R. C., McElroy, S. L., Sylvia, L. G., Kocsis, J. H., McInnis, M. G., Friedman, E. S., Singh, V., Tohen, M., Bowden, C. L., Deckersbach, T., Calabrese, J. R., Thase, M. E., Nierenberg, A. A., Rabideau, D. J., Schoenfeld, D. A., Faraone, S. V., Kamali, M. 2015; 35 (1): 68-74

  Abstract

  Benzodiazepines are widely prescribed for patients with bipolar disorders in clinical practice, but very little is known about the subtypes of patients with bipolar disorder or aspects of bipolar illness that contribute most to benzodiazepine use. We examined the prevalence of and factors associated with benzodiazepine use among 482 patients with bipolar I or II disorder enrolled in the Bipolar CHOICE study. Eighty-one subjects were prescribed benzodiazepines at study entry and were considered benzodiazepine users. Stepwise logistic regression was used to model baseline benzodiazepine use versus nonuse, using entry and exit criteria of P < 0.1. In bivariate analyses, benzodiazepine users were prescribed a significantly higher number of other psychotropic medications and were more likely to be prescribed lamotrigine or antidepressants as compared with benzodiazepine nonusers. Benzodiazepine users were more likely to have a diagnosis of bipolar I disorder and comorbid anxiety disorder, but not comorbid alcohol or substance use disorders. Benzodiazepine users also had experienced more anxiety and depressive symptoms and suicidality, but not irritability or manic symptoms, than did benzodiazepine nonusers. In the multivariate model, anxiety symptom level (regardless of diagnosis), lamotrigine use, number of concomitant psychotropic medications, college education, and high household income predicted benzodiazepine use. Benzodiazepine use in patients with bipolar disorders is associated with greater illness complexity as indicated by a higher number of concomitant psychotropic medications and higher anxiety symptom burden, regardless of a comorbid anxiety disorder diagnosis. Demographic factors were also important determinants of benzodiazepine use, which may be related to access to care and insurance coverage for benzodiazepines.

  View details for DOI 10.1097/JCP.0000000000000257

  View details for PubMedID 25514063

• Bipolar therapeutics update 2014: A tale of 3 treatments. journal of clinical psychiatry Ketter, T. A., Wang, P. W., Miller, S. 2015; 76 (1): 69-70

  Abstract

  In the 2010s, advances in the treatment of bipolar disorder slowed, with only 1 agent approved by the US Food and Drug Administration (FDA) for acute bipolar I depression (in 2013), compared to the robust progress in the 2000s, during which 7 agents were approved for acute mania, 2 for acute bipolar depression, and 6 for bipolar disorder preventive treatment. This slowing of progress may have been in part due to decreased pharmaceutical company enthusiasm for developing compounds for psychiatric indications, as well as the tendency for periods of consolidation (development of derivative and better-tolerated treatments) to follow periods of rapid advances (development of efficacious novel treatments) in pharmacotherapy advancement.

  View details for DOI 10.4088/JCP.14ac09649

  View details for PubMedID 25650673

• Advances in Treatment of Bipolar Disorders Preface ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Ketter, T. A. 2015: IX-X

  View details for Web of Science ID 000364631900001

• Treatment of Acute Manic and Mixed Episodes ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Miller, S., Ketter, T. A. 2015: 65–111

  View details for Web of Science ID 000364631900004

• Diagnosis and Treatment of Bipolar Disorder ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Miller, S., Wang, P. W., Ketter, T. A. 2015: 1–16

  View details for Web of Science ID 000364631900002

• Mood Stabilizers and Second-Generation Antipsychotics Pharmacology, Drug Interactions, Adverse Effects, and Dosing ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Ketter, T. A. 2015: 249–310

  View details for Web of Science ID 000364631900009

• Treatment of Women With Bipolar Disorder ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Rasgon, N. L., Vemuri, M., Ketter, T. A. 2015: 199–216

  View details for Web of Science ID 000364631900007

• Bipolar Disorder Preventive Treatment ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Miller, S., Culver, J., Ketter, T. A. 2015: 113–70

  View details for Web of Science ID 000364631900005

• Treatment of Pediatric Bipolar Disorder ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Chang, K. D., Singh, M. K., Ketter, T. A. 2015: 171–98

  View details for Web of Science ID 000364631900006

• Treatment of Older Adults With Bipolar Disorder ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Brooks, J. O., Ketter, T. A. 2015: 217–47

  View details for Web of Science ID 000364631900008

• Treatment of Acute Bipolar Depression ADVANCES IN TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Miller, S., Wang, P. W., Culver, J., Ketter, T. A. 2015: 17–63

  View details for Web of Science ID 000364631900003

• Clinical characteristics of bipolar disorder: a comparative study between Argentina and the United States. International journal of bipolar disorders Holtzman, J. N., Lolich, M., Ketter, T. A., Vázquez, G. H. 2015; 3: 8-?

  Abstract

  Bipolar disorder presents with diverse clinical manifestations. Numerous investigators have sought to identify variables that may predict a more severe illness course.With the objective of studying the clinical characteristics of bipolar patients between South and North America, a comparison was performed between a sample from Argentina (n = 449) and a sample from the United States (n = 503) with respect to demographics and clinical characteristics, including presence of comorbidities.The Argentinian sample had more unfavorable demographics and higher rates of prior psychiatric hospitalization and prior suicide attempt but a better social outcome. However, the sample from the United States had a higher rate of prior year rapid cycling, as well as younger bipolar disorder onset age (mean ± SD, 17.9 ± 8.4 vs. 27.1 ± 11.4 years) and more severe clinical morbidity, though there was no significant difference in terms of the total duration of the illness. Argentinian compared to American patients were taking more mood stabilizers and benzodiazepines/hypnotics, but fewer antipsychotics and other psychotropic medications, when considering patients in aggregate as well as when stratifying by illness subtype (bipolar I versus bipolar II) and by illness onset age (≤21 vs. >21 years). However, there was no significant difference in rate of antidepressant prescription between the two samples considered in aggregate.Although possessing similar illness durations, these samples presented significant clinical differences and distinctive prescription patterns. Thus, though the Argentinian compared to North American patients had more unfavorable demographics, they presented a better social outcome and, in several substantive ways, more favorable illness characteristics. In both samples, early onset (age ≤ 21 years) was a marker for poor prognosis throughout the illness course, although this phenomenon appeared more robust in North America.

  View details for DOI 10.1186/s40345-015-0027-z

  View details for PubMedID 25909050

  View details for PubMedCentralID PMC4406987

• Distinguishing Bipolar Disorder From Other Psychiatric Disorders in Children CURRENT PSYCHIATRY REPORTS Singh, M. K., Ketter, T., Chang, K. D. 2014; 16 (12)

  Abstract

  Pediatric onset bipolar disorder (BD) is a challenging diagnosis with potentially debilitating outcomes. This review aims to critically evaluate recently published literature relevant to the diagnosis of BD in youth, emphasizing interesting and important new findings characterizing pediatric BD and reporting updates in the diagnostic and statistical manual relevant to this disorder in youth. Challenges regarding the diagnosis of BD will be discussed, in addition to important distinctions with other childhood disorders, including other bipolar spectrum disorders; major depressive disorder; dysthymia; disruptive mood dysregulation disorder (DMDD); attention-deficit/hyperactivity disorder (ADHD) and other disruptive behavioral disorders; anxiety disorders, including post-traumatic stress disorder (PTSD); psychotic disorders; autism spectrum disorders; substance use disorders; and borderline personality disorder. The review concludes with a comment on past research limitations and future directions in the field.

  View details for DOI 10.1007/s11920-014-0516-2

  View details for Web of Science ID 000343893600004

• The effect of personalized guideline-concordant treatment on quality of life and functional impairment in bipolar disorder. Journal of affective disorders Sylvia, L. G., Rabideau, D. J., Nierenberg, A. A., Bowden, C. L., Friedman, E. S., Iosifescu, D. V., Thase, M. E., Ketter, T., Greiter, E. A., Calabrese, J. R., Leon, A. C., Ostacher, M. J., Reilly-Harrington, N. 2014; 169: 144-148

  Abstract

  The aims of this study were to evaluate correlates and predictors of life functioning and quality of life in bipolar disorder during a comparative effectiveness trial of moderate doses of lithium.In the Lithium treatment moderate-dose use study (LiTMUS), 283 symptomatic outpatients with bipolar disorder type I or II were randomized to receive lithium plus "optimal personalized treatment (OPT)", or OPT alone. Participants were assessed using structured diagnostic interviews, clinician-rated blinded assessments, and questionnaires. We employ linear mixed effects models to test the effect of treatment overall and adjunct lithium specifically on quality of life or functioning. Similar models are used to examine the association of baseline demographics and clinical features with quality of life and life functioning.Quality of life and impaired functioning at baseline were associated with lower income, higher depressive severity, and more psychiatric comorbid conditions. Over 6 months, patients in both treatment groups improved in quality of life and life functioning (p-Values<0.0001); without a statistically significant difference between the two treatment groups (p-Values>0.05). Within the lithium group, improvement in quality of life and functioning was not associated with concurrent lithium levels at week 12 or week 24 (p-Values>0.05). Lower baseline depressive severity and younger age of onset predicted less improvement in functioning over 6 months.Optimized care for bipolar disorder improves overall quality of life and life functioning, with no additional benefit from adjunct moderate doses of lithium. Illness burden and psychosocial stressors were associated with worse quality of life and lower functioning in individuals with bipolar disorder.

  View details for DOI 10.1016/j.jad.2014.08.019

  View details for PubMedID 25194782

  View details for PubMedCentralID PMC4172551

• Advances in the diagnosis and treatment of bipolar depression Preface JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A. 2014; 169: S1–S2

  View details for PubMedID 25533908

• Adjunctive Armodafinil 150 mg/d in Combination with Lamotrigine, Olanzapine, or Quetiapine Maintenance Therapy for Bipolar I Depression: A Pooled Sub-group Analysis of Efficacy from Phase 3 Studies Ketter, T., Amchin, J., Yang, R., Frye, M. A. NATURE PUBLISHING GROUP. 2014: S383–S384

  View details for Web of Science ID 000345905001134

• The prevalence and burden of bipolar depression. Journal of affective disorders Miller, S., Dell'Osso, B., Ketter, T. A. 2014; 169: S3-11

  Abstract

  Bipolar disorder is characterized by debilitating episodes of depression and mood elevation (mania or hypomania). For most patients, depressive symptoms are more pervasive than mood elevation or mixed symptoms, and thus have been reported in individual studies to impose a greater burden on affected individuals, caregivers, and society. This article reviews and compiles the literature on the prevalence and burden of syndromal as well as subsyndromal presentations of depression in bipolar disorder patients.The PubMed database was searched for English-language articles using the search terms "bipolar disorder," "bipolar depression," "burden," "caregiver burden," "cost," "costs," "economic," "epidemiology," "prevalence," "quality of life," and "suicide." Search results were manually reviewed, and relevant studies were selected for inclusion as appropriate. Additional references were obtained manually from reviewing the reference lists of selected articles found by computerized search.In aggregate, the findings support the predominance of depressive symptoms compared with mood elevation/mixed symptoms in the course of bipolar illness, and thus an overall greater burden in terms of economic costs, functioning, caregiver burden, and suicide.This review, although comprehensive, provides a study-wise aggregate (rather than a patient-wise meta-analytic) summary of the relevant literature on this topic.In light of its pervasiveness and prevalence, more effective and aggressive treatments for bipolar depression are warranted to mitigate its profound impact upon individuals and society. Such studies could benefit by including metrics not only for mood outcomes, but also for illness burden.

  View details for DOI 10.1016/S0165-0327(14)70003-5

  View details for PubMedID 25533912

• Balancing benefits and harms of treatments for acute bipolar depression. Journal of affective disorders Ketter, T. A., Miller, S., Dell'Osso, B., Calabrese, J. R., Frye, M. A., Citrome, L. 2014; 169: S24-33

  View details for DOI 10.1016/S0165-0327(14)70006-0

  View details for PubMedID 25533911

• The prevalence and burden of bipolar depression. Journal of affective disorders Miller, S., Dell'Osso, B., Ketter, T. A. 2014; 169: S3-11

  View details for DOI 10.1016/S0165-0327(14)70003-5

  View details for PubMedID 25533912

• Balancing benefits and harms of treatments for acute bipolar depression. Journal of affective disorders Ketter, T. A., Miller, S., Dell'Osso, B., Calabrese, J. R., Frye, M. A., Citrome, L. 2014; 169: S24-33

  Abstract

  Bipolar depression is more pervasive than mania, but has fewer evidence-based treatments.Using data from multicenter, randomized, double-blind, placebo-controlled trials and meta-analyses, we assessed the number needed to treat (NNT) for response and the number needed to harm (NNH) for selected side effects for older and newer acute bipolar depression treatments.The 2 older FDA-approved treatments for bipolar depression, olanzapine-fluoxetine combination (OFC) and quetiapine (QTP) monotherapy, were efficacious (response NNT=4 for OFC, NNT=6 for QTP), but similarly likely to yield harms (OFC weight gain NNH=6; QTP sedation/somnolence NNH=5). Commonly used unapproved agents (lamotrigine monotherapy and adjunctive antidepressants) tended to be well-tolerated (with double-digit NNHs), although this advantage was at the cost of inadequate efficacy (response NNT=12 for lamotrigine, NNT=29 for antidepressants). In contrast, the newly approved agent lurasidone was not only efficacious (response NNT=5 for monotherapy, NNT=7 as adjunctive therapy), but also had enhanced tolerability (NNH=15 for akathisia [monotherapy], NNH=16 for nausea [adjunctive]). Although adjunctive armodafinil appeared well tolerated, its efficacy in bipolar depression has not been consistently demonstrated in randomized controlled trials.NNT and NNH are categorical metrics; only selected NNHs were assessed; limited generalizability of efficacy (versus effectiveness) studies.For acute bipolar depression, older approved treatments may have utility in high-urgency situations, whereas lamotrigine and antidepressants may have utility in low-urgency situations. Newly approved lurasidone may ultimately prove useful in diverse situations. New drug development needs to focus on not only efficacy but also on tolerability.

  View details for DOI 10.1016/S0165-0327(14)70006-0

  View details for PubMedID 25533911

• The effect of personalized guideline-concordant treatment on quality of life and functional impairment in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Sylvia, L. G., Rabideau, D. J., Nierenberg, A. A., Bowden, C. L., Friedman, E. S., Iosifescu, D. V., Thase, M. E., Ketter, T., Greiter, E. A., Calabrese, J. R., Leon, A. C., Ostacher, M. J., Reilly-Harrington, N. 2014; 169: 144-148

  Abstract

  The aims of this study were to evaluate correlates and predictors of life functioning and quality of life in bipolar disorder during a comparative effectiveness trial of moderate doses of lithium.In the Lithium treatment moderate-dose use study (LiTMUS), 283 symptomatic outpatients with bipolar disorder type I or II were randomized to receive lithium plus "optimal personalized treatment (OPT)", or OPT alone. Participants were assessed using structured diagnostic interviews, clinician-rated blinded assessments, and questionnaires. We employ linear mixed effects models to test the effect of treatment overall and adjunct lithium specifically on quality of life or functioning. Similar models are used to examine the association of baseline demographics and clinical features with quality of life and life functioning.Quality of life and impaired functioning at baseline were associated with lower income, higher depressive severity, and more psychiatric comorbid conditions. Over 6 months, patients in both treatment groups improved in quality of life and life functioning (p-Values<0.0001); without a statistically significant difference between the two treatment groups (p-Values>0.05). Within the lithium group, improvement in quality of life and functioning was not associated with concurrent lithium levels at week 12 or week 24 (p-Values>0.05). Lower baseline depressive severity and younger age of onset predicted less improvement in functioning over 6 months.Optimized care for bipolar disorder improves overall quality of life and life functioning, with no additional benefit from adjunct moderate doses of lithium. Illness burden and psychosocial stressors were associated with worse quality of life and lower functioning in individuals with bipolar disorder.

  View details for DOI 10.1016/j.jad.2014.08.019

  View details for Web of Science ID 000342616400021

  View details for PubMedCentralID PMC4172551

• Distinguishing bipolar disorder from other psychiatric disorders in children. Current psychiatry reports Singh, M. K., Ketter, T., Chang, K. D. 2014; 16 (12): 516-?

  Abstract

  Pediatric onset bipolar disorder (BD) is a challenging diagnosis with potentially debilitating outcomes. This review aims to critically evaluate recently published literature relevant to the diagnosis of BD in youth, emphasizing interesting and important new findings characterizing pediatric BD and reporting updates in the diagnostic and statistical manual relevant to this disorder in youth. Challenges regarding the diagnosis of BD will be discussed, in addition to important distinctions with other childhood disorders, including other bipolar spectrum disorders; major depressive disorder; dysthymia; disruptive mood dysregulation disorder (DMDD); attention-deficit/hyperactivity disorder (ADHD) and other disruptive behavioral disorders; anxiety disorders, including post-traumatic stress disorder (PTSD); psychotic disorders; autism spectrum disorders; substance use disorders; and borderline personality disorder. The review concludes with a comment on past research limitations and future directions in the field.

  View details for DOI 10.1007/s11920-014-0516-2

  View details for PubMedID 25315116

• Differential abnormalities of functional connectivity of the amygdala and hippocampus in unipolar and bipolar affective disorders. Journal of affective disorders Benson, B. E., Willis, M. W., Ketter, T. A., Speer, A., Kimbrell, T. A., Herscovitch, P., George, M. S., Post, R. M. 2014; 168: 243-253

  Abstract

  The amygdala and hippocampus - two structures intimately associated with mood and cognition - have been reported to exhibit altered neural activity or volume in affective disorders. We hypothesized the amygdala and hippocampus would show altered and differential patterns of connectivity in patients with bipolar (BPs) and unipolar (UPs) disorder compared to healthy volunteers.Thirty BPs, 34 UPs, and 66 healthy volunteers were imaged using F-18-fluorodeoxyglucose and positron emission tomography while performing an auditory continuous performance task (CPT). Normalized mean activity of the amygdala and hippocampus was correlated with the rest of the brain.In BPs, the amygdalae displayed exaggerated positive metabolic correlations with prefrontal and ventral striatal areas, while the hippocampus showed a paucity of normal inter-relations compared to controls. In contrast, in UPs the amygdala was significantly negatively correlated with prefrontal and anterior cingulate cortex, while the hippocampus was significantly more positively correlated to these same prefrontal areas.During a simple cognitive task, the functional connectivity of the amygdala and hippocampus, regions usually associated with emotion and memory regulation, was substantially different in affective illness compared to healthy controls whether or not there were baseline abnormalities in these areas. These striking differences in functional connectivity of amygdala and hippocampus should be further explored in ill and well states and using more specific emotion and cognitive evocative tasks.

  View details for DOI 10.1016/j.jad.2014.05.045

  View details for PubMedID 25069080

• Effect of adjunctive benzodiazepines on clinical outcomes in lithium- or quetiapine-treated outpatients with bipolar I or II disorder: Results from the bipolar CHOICE trial (vol 161, pg 30, 2014) JOURNAL OF AFFECTIVE DISORDERS Bobo, W. V., Reilly-Harrington, N. A., Ketter, T. A., Brody, B. D., Kinrys, G., Kemp, D. E., Shelton, R. C., McElroy, S. L., Sylvia, L. G., Kocsis, J. H., McInnis, M. G., Friedman, E. S., Singh, V., Tohen, M., Bowden, C. L., Deckersbach, T., Calabrese, J. R., Thase, M. E., Nierenberg, A. A., Rabideau, D. J., Schoenfeld, D. A., Faraone, S. V., Kamali, M. 2014; 167: 259–60

  View details for DOI 10.1016/j.jad.2014.06.025

  View details for Web of Science ID 000341335700040

• Efficacy and Safety of Adjunctive Armodafinil in Adults With Major Depressive Episodes Associated With Bipolar I Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial JOURNAL OF CLINICAL PSYCHIATRY Calabrese, J. R., Frye, M. A., Yang, R., Ketter, T. A. 2014; 75 (10): 1054-?

  Abstract

  To examine the efficacy and safety of adjunctive armodafinil for major depressive episodes associated with bipolar I disorder.Adults meeting DSM-IV-TR criteria for bipolar I disorder and currently experiencing a major depressive episode while taking at least 4 weeks of conventional maintenance medication were enrolled in a placebo-controlled evaluation of adjunctive armodafinil 150 or 200 mg (conducted January 2010-March 2012). The primary efficacy measure was change from baseline to week 8 on the 30-item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) total score in the 150-mg armodafinil group versus placebo.Of 786 patients screened, 433 were randomized (placebo, n = 199; armodafinil 150 mg, n = 201; armodafinil 200 mg, n = 33). The 200-mg armodafinil group was discontinued by protocol amendment due to lower than expected patient enrollment. For the 150-mg armodafinil group versus placebo, there was a significantly greater decrease in least squares mean (standard error of mean [SEM]) IDS-C30 total score at week 8 (-21.7 [1.1] vs -17.9 [1.1]; P = .0097; Cohen d therapeutic effect size = 0.28). The proportion of IDS-C30 responders (≥ 50% decrease from baseline) was significantly higher for the 150-mg armodafinil group versus placebo at final visit (46% [91/197] vs 34% [67/196]; P = .0147). The proportion of IDS-C30 remitters (total score ≤ 11) was 21% (42/197) for armodafinil 150 mg versus 17% (34/196) for placebo (P = .3343) at final visit. Adverse events (AEs) observed in > 5% of either the armodafinil 150 mg or placebo groups and more frequently with 150 mg armodafinil were diarrhea (9% [17/198] vs 7% [13/199]), and nausea (6% [11/198] vs 5% [9/199]), respectively. In the 200-mg armodafinil group, there were 2 serious AEs (n = 1, hepatic failure leading to death; n = 1, acute hepatitis). The death was not considered related to study treatment.Adjunctive armodafinil 150 mg significantly improved symptoms of major depressive episodes associated with bipolar I disorder versus placebo and was generally well tolerated.ClinicalTrials.gov identifier: NCT01072929.

  View details for DOI 10.4088/JCP.13m08951

  View details for Web of Science ID 000345557300019

  View details for PubMedID 25099397

• A novel application of the Intent to Attend assessment to reduce bias due to missing data in a randomized controlled clinical trial University-of-Pennsylvania 6th Annual Conference on Statistical Issues in Clinical Trials - Dynamic Treatment Regimes Rabideau, D. J., Nierenberg, A. A., Sylvia, L. G., Friedman, E. S., Bowden, C. L., Thase, M. E., Ketter, T. A., Ostacher, M. J., Reilly-Harrington, N., Iosifescu, D. V., Calabrese, J. R., Leon, A. C., Schoenfeld, D. A. SAGE PUBLICATIONS LTD. 2014: 494–502

  Abstract

  Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient's intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment - Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis.The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data.We fit marginal models to assess whether a patient's self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods.Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time.LiTMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well specified.In LiTMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial.

  View details for DOI 10.1177/1740774514531096

  View details for Web of Science ID 000340305800014

  View details for PubMedCentralID PMC4247354

• A novel application of the Intent to Attend assessment to reduce bias due to missing data in a randomized controlled clinical trial. Clinical trials (London, England) Rabideau, D. J., Nierenberg, A. A., Sylvia, L. G., Friedman, E. S., Bowden, C. L., Thase, M. E., Ketter, T. A., Ostacher, M. J., Reilly-Harrington, N., Iosifescu, D. V., Calabrese, J. R., Leon, A. C., Schoenfeld, D. A. 2014; 11 (4): 494-502

  Abstract

  Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient's intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment - Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis.The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data.We fit marginal models to assess whether a patient's self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods.Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time.LiTMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well specified.In LiTMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial.

  View details for DOI 10.1177/1740774514531096

  View details for PubMedID 24872362

  View details for PubMedCentralID PMC4247354

• Effect of adjunctive benzodiazepines on clinical outcomes in lithium- or quetiapine-treated outpatients with bipolar I or II disorder: Results from the Bipolar CHOICE trial JOURNAL OF AFFECTIVE DISORDERS Bobo, W. V., Reilly-Harrington, N. A., Ketter, T. A., Brody, B. D., Kinrys, G., Kemp, D. E., Shelton, R. C., McElroy, S. L., Sylvia, L. G., Kocsis, J. H., McInnis, M. G., Friedman, E. S., Singh, V., Tohen, M., Bowden, C. L., Deckersbach, T., Calabrese, J. R., Thase, M. E., Nierenberg, A. A., Rabideau, D. J., Schoenfeld, D. A., Faraone, S. V., Kamali, M. 2014; 161: 30-35

  Abstract

  Little is known about the longer-term effects of adjunctive benzodiazepines on symptom response during treatment in patients with bipolar disorders.The study sample consisted of 482 patients with bipolar I or II disorder enrolled in a 6-month, randomized, multi-site comparison of lithium- and quetiapine-based treatment. Changes in clinical measures (BISS total and subscales, CGI-BP, and CGI-Efficacy Index) were compared between participants who did and did not receive benzodiazepine treatment at baseline or during follow-up. Selected outcomes were also compared between patients who did and did not initiate benzodiazepines during follow-up using stabilized inverse probability weighted analyses.Significant improvement in all outcome measures occurred within each benzodiazepine exposure group. Benzodiazepine users (at baseline or during follow-up) experienced significantly less improvement in BISS total, BISS irritability, and CGI-BP scores than did benzodiazepine non-users. There were no significant differences in these measures between patients who did and did not initiate benzodiazepines during follow-up in the weighted analyses. There was no significant effect of benzodiazepine use on any outcome measure in patients with comorbid anxiety or substance use disorders.This is a secondary analysis of data from a randomized effectiveness trial that was not designed to address differential treatment response according to benzodiazepine use.Adjunctive benzodiazepines may not significantly affect clinical outcome in lithium- or quetiapine-treated patients with bipolar I or II disorder over 6 months, after controlling for potential confounding factors.

  View details for DOI 10.1016/j.jad.2014.02.046

  View details for Web of Science ID 000334741200006

  View details for PubMedID 24751304

• Medication adherence in a comparative effectiveness trial for bipolar disorder. Acta psychiatrica Scandinavica Sylvia, L. G., Reilly-Harrington, N. A., Leon, A. C., Kansky, C. I., Calabrese, J. R., Bowden, C. L., Ketter, T. A., Friedman, E. S., Iosifescu, D. V., Thase, M. E., Ostacher, M. J., Keyes, M., RABIDEAU, D., Nierenberg, A. A. 2014; 129 (5): 359-365

  Abstract

  Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium.The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N = 283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire.We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms.Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

  View details for DOI 10.1111/acps.12202

  View details for PubMedID 24117232

  View details for PubMedCentralID PMC3975824

• Update on best practices for managing bipolar depression. journal of clinical psychiatry Sachs, G. S., Ketter, T. A. 2014; 75 (5): e413-6

  View details for DOI 10.4088/JCP.12065co3c

  View details for PubMedID 24922493

• Acute and maintenance treatments for bipolar depression. The Journal of clinical psychiatry Ketter, T. A. 2014; 75 (4): e10

  Abstract

  Patients with bipolar disorder are symptomatic about half of the time, experiencing depression more often than mania/hypomania. Because patients usually seek treatment during a depressive episode (rather than a manic episode), bipolar depression is commonly misdiagnosed as unipolar depression. Providing an accurate and timely bipolar depression diagnosis is critical for the proper treatment of the patient. Some FDA-approved treatments are helpful during acute and maintenance phases of therapy, but there is a significant unmet need for effective bipolar depression treatments with favorable side-effect profiles. Newer agents offer the promise of improvements in tolerability, but additional research is needed to actualize this promise into better treatments for patients struggling with bipolar depression.

  View details for DOI 10.4088/JCP.13010tx2c

  View details for PubMedID 24813411

• Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS). pharmacogenomics journal Beech, R. D., Leffert, J. J., Lin, A., Sylvia, L. G., Umlauf, S., Mane, S., Zhao, H., Bowden, C., Calabrese, J. R., Friedman, E. S., Ketter, T. A., Iosifescu, D. V., Reilly-Harrington, N. A., Ostacher, M., Thase, M. E., Nierenberg, A. 2014; 14 (2): 182-191

  Abstract

  This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n=28) or without (n=32) Li. Peripheral blood gene-expression was measured before and 1 month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n=9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li.

  View details for DOI 10.1038/tpj.2013.16

  View details for PubMedID 23670706

• Blood levels of brain derived neurotrophic factor in women with bipolar disorder and healthy control women. Journal of affective disorders Kenna, H. A., Reynolds-May, M., Stepanenko, A., Ketter, T. A., Hallmayer, J., Rasgon, N. L. 2014; 156: 214-218

  Abstract

  Brain-derived neurotrophic factor (BDNF) protein has been implicated in the pathophysiology of mood disorders, with early data suggesting that blood levels may vary by severity of mood symptoms. BDNF polymorphism, val66met, has also been implicated in mood disorders.Euthymic women with bipolar disorder (BD) (n=47) and healthy control women (n=26), ages 18-45, were clinically rated using the Montgomery-Asberg Depression Rating Scale (MADRS) and sampled for plasma BDNF concentration, with a subset undergoing genetic analysis for the val66met.BD and control groups did not differ on any demographic variables, nor in plasma BDNF levels or val66met polymorphism. Plasma BDNF concentration did not differ by val66met or BD subtype, nor was it correlated with age or illness duration. Within women with BD, lower plasma BDNF concentrations were significantly associated with higher MADRS scores, even after controlling for psychotropic medication use and illness duration.The sample was relatively small and exclusive to women, with further research needed to investigate the links between BDNF markers and mood symptom severity in both men and women.The study provides a gender-specific investigation of plasma BDNF levels and mood, and the results add further evidence of a significant interplay between BDNF markers and psychiatric symptomatology. Further, this association did not appear to be confounded by use of psychotropic medication. Studies with larger samples of both genders are needed to further delineate this relationship.

  View details for DOI 10.1016/j.jad.2013.01.054

  View details for PubMedID 24398043

• Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls. Bipolar disorders Reynolds-May, M. F., Kenna, H. A., Marsh, W., Stemmle, P. G., Wang, P., Ketter, T. A., Rasgon, N. L. 2014; 16 (1): 37-47

  Abstract

  The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

  View details for DOI 10.1111/bdi.12149

  View details for PubMedID 24262071

• A profile approach to impulsivity in bipolar disorder: the key role of strong emotions. Acta psychiatrica Scandinavica Muhtadie, L., Johnson, S. L., Carver, C. S., Gotlib, I. H., Ketter, T. A. 2014; 129 (2): 100-108

  Abstract

  Bipolar disorder has been associated with elevated impulsivity - a complex construct subsuming multiple facets. We aimed to compare specific facets of impulsivity in bipolar disorder, including those related to key psychological correlates of the illness: reward sensitivity and strong emotion.Ninety-one individuals diagnosed with bipolar I disorder (inter-episode period) and 80 controls completed several well-validated impulsivity measures, including those relevant to reward (Fun-seeking subscale of the Behavioral Activation System scale) and emotion (Positive Urgency and Negative Urgency scales).Bipolar participants reported higher impulsivity scores than did controls on all of the impulsivity measures, except the Fun-seeking subscale of the Behavioral Activation System scale. Positive Urgency - a measure assessing the tendency to act impulsively when experiencing strong positive emotion - yielded the largest group differences: F(1,170) = 78.69, P < 0.001, partial η(2)  = 0.316. Positive Urgency was also associated with poorer psychosocial functioning in the bipolar group: ΔR(2)  = 0.24, b = -0.45, P < 0.001.Individuals with bipolar I disorder appear to be at particular risk of behaving impulsively when experiencing strong positive emotions. Findings provide an important first step toward developing a more refined understanding of impulsivity in bipolar disorder with the potential to inform targeted interventions.

  View details for DOI 10.1111/acps.12136

  View details for PubMedID 23600731

• Clinical assessment of lurasidone benefit and risk in the treatment of bipolar I depression using number needed to treat, number needed to harm, and likelihood to be helped or harmed JOURNAL OF AFFECTIVE DISORDERS Citrome, L., Ketter, T. A., Cucchiaro, J., Loebel, A. 2014; 155: 20-27

  Abstract

  Prior to recent FDA approval of lurasidone for treatment of bipolar depression there were only two approved treatments for this condition (quetiapine and olanzapine-fluoxetine combination), and these were as likely to provide therapeutic benefit as adverse effects. We assessed the efficacy, safety, and tolerability of lurasidone for major depressive episodes associated with bipolar I disorder, using number needed to treat (NNT, for benefits), number needed to harm (NNH, for harms), and likelihood of being helped or harmed (LHH, ratio of NNH to NNT, for trade-offs between benefits vs. harms).Data was collected from two 6-week multicenter, randomized, double-blind, placebo-controlled, flexibly-dosed acute bipolar I depression studies, one using lurasidone monotherapy at 20-60mg/d or 80-120mg/d, and the other using lurasidone 20-120mg/d adjunctive to lithium or valproate. The NNT or NNH was calculated for lurasidone vs. placebo for the following dichotomous outcomes: response (≥50% reduction from baseline on Montgomery Asberg Depression Rating Scale (MADRS) total score); remission (final MADRS total score ≤12); discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; and incidence of total cholesterol ≥240mg/dl, low-density lipoprotein cholesterol ≥160mg/dl, fasting triglycerides ≥200mg/dl and glucose ≥126mg/dl post-baseline.NNT vs. placebo for response was 5 for lurasidone monotherapy (both dose ranges) and 7 for adjunctive therapy. NNT vs. placebo for remission for lurasidone monotherapy was 6 for 20-60mg/d and 7 for 80-120mg/d and 7 for adjunctive lurasidone. NNH vs. placebo for discontinuation due to an AE for lurasidone monotherapy was 642 for 20-60mg/d and -181 for 80-120mg/d, and for adjunctive lurasidone was -54 (negative NNH denotes an advantage for lurasidone). Lurasidone was not associated with any clinically meaningful mean weight or metabolic changes compared to placebo; NNH vs. placebo for weight gain ≥7% was 29 for 20-60mg/d and 5550 for 80-120mg/d and 42 for adjunctive lurasidone. The three most frequently occurring AEs with the largest difference in incidence for lurasidone vs. placebo were nausea, akathisia, and somnolence, with NNH values for lurasidone vs. placebo ranging from 11 (nausea with lurasidone monotherapy 80-120mg/d) to 130 (somnolence with lurasidone monotherapy 20-60mg/d). LHH was substantially and consistently >1 (indicating benefit being more likely than harm) when contrasting response or remission vs. AEs or weight gain.Additional studies, including longer-term and open-label, "real world" data is needed to confirm the results reported here.NNT, NNH, and LHH help quantify relative benefits (efficacy) and harms (side effects), thus placing lurasidone findings in research studies into clinical perspective. Lurasidone, compared to other treatments approved for bipolar depression, yielded comparable benefits (all had single-digit NNT vs. placebo for response or remission), and less risk of harm (double-digit or greater NNHs with lurasidone compared to single-digit NNHs for sedation with quetiapine and for ≥7% weight gain with olanzapine-fluoxetine combination), and thus a substantially more favorable LHH (> or >1) with lurasidone monotherapy and adjunctive therapy, compared to quetiapine and olanzapine-fluoxetine combination (LHH

  View details for DOI 10.1016/j.jad.2013.10.040

  View details for Web of Science ID 000329574500003

  View details for PubMedID 24246116

• Trends in pharmacotherapy in patients referred to a bipolar specialty clinic, 2000-2011 JOURNAL OF AFFECTIVE DISORDERS Hooshmand, F., Miller, S., Dore, J., Wang, P. W., Hill, S. J., Portillo, N., Ketter, T. A. 2014; 155: 283-287

  Abstract

  To assess mood stabilizer (MS) and second-generation antipsychotic (SGA) prescribing trends in bipolar disorder (BD) outpatients referred to a bipolar disorder specialty clinic over the past 12 years.BD outpatients referred to the Stanford University Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prescription rates for MSs and SGAs were compared during the first (2000-2005) and second (2006-2011) six years.Among 597 BD patients (mean±SD age 35.4±8.6 years; 58.1% female; 40.7% Type I, 43.6% Type II, and 15.7% Type Not Otherwise Specified; taking 2.6±1.7 prescription psychotropic medications), lamotrigine, quetiapine, and aripiprazole usage more than doubled, from 14.7% to 37.2% (p<0.0001), 7.2% to 19.7% (p<0.0001), and 3.1% to 10.9% (p=0.0003), respectively, while olanzapine and risperidone use decreased by more than half from 15.0% to 6.6% (p=0.0043), and from 8.7% to 3.8% (p=0.039), respectively. SGA use increased from 34.1% to 44.8% (p=0.013), although MS use continued to be more common (in 65.2% for 2006-2011). Use of other individual MSs and SGAs and MSs as a class did not change significantly.Over 12 years, in patients referred to a BD specialty clinic, lamotrigine, quetiapine, and aripiprazole use more than doubled, and olanzapine and risperidone use decreased by more than half. Tolerability (for lamotrigine, aripiprazole, olanzapine, and risperidone) more than efficacy (for quetiapine) differences may have driven these findings. Additional studies are needed to explore the relative influences of enhanced tolerability versus efficacy upon prescribing practices in BD patients.

  View details for DOI 10.1016/j.jad.2013.10.054

  View details for Web of Science ID 000329574500041

  View details for PubMedID 24314912

• Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): A pragmatic trial of complex treatment for a complex disorder. Clinical trials Nierenberg, A. A., Sylvia, L. G., Leon, A. C., Reilly-Harrington, N. A., Shesler, L. W., McElroy, S. L., Friedman, E. S., Thase, M. E., Shelton, R. C., Bowden, C. L., Tohen, M., Singh, V., Deckersbach, T., Ketter, T. A., Kocsis, J. H., McInnis, M. G., Schoenfeld, D., Bobo, W. V., Calabrese, J. R. 2014; 11 (1): 114-127

  Abstract

  Classic and second-generation antipsychotic mood stabilizers are recommended for treatment of bipolar disorder, yet there are no randomized comparative effectiveness studies that have examined the 'real-world' advantages and disadvantages of these medications.We describe the strategic decisions in the design of the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE). This article outlines the key issues and solutions the investigators faced in designing a clinical trial that would maximize generalizability and inform real-world clinical treatment of bipolar disorder.Bipolar CHOICE was a 6-month, multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. This study compares the effectiveness of quetiapine versus lithium, each with adjunctive personalized treatments (APTs). The co-primary outcomes selected are the overall benefits and harms of the study medications (as measured by the Clinical Global Impression-Efficacy Index) and the Necessary Clinical Adjustments (a measure of the number of medication changes). Secondary outcomes are continuous measures of mood, the Framingham General Cardiovascular Risk Score, and the Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT).The final study design consisted of a single-blind, randomized comparative effectiveness trial of quetiapine versus lithium, plus APT, across 10 sites. Other important study considerations included limited exclusion criteria to maximize generalizability, flexible dosing of APT medications to mimic real-world treatment, and an intent-to-treat analysis plan. In all, 482 participants were randomized to the study, and 364 completed the study.The potential limitations of the study include the heterogeneity of APT, selection of study medications, lack of a placebo-control group, and participants' ability to pay for study medications.We expect that this study will inform our understanding of the benefits and harms of lithium, a classic mood stabilizer, compared to quetiapine, a second-generation antipsychotic with broad-spectrum activity in bipolar disorder, and will provide an example of a well-designed and well-conducted randomized comparative effectiveness clinical trial.

  View details for DOI 10.1177/1740774513512184

  View details for PubMedID 24346608

• Acute and Maintenance Treatment of Bipolar and Related Disorders GABBARD'S TREATMENTS OF PSYCHIATRIC DISORDERS, 5TH EDITION Ketter, T. A., Miller, S., Goldberg, J. F., Gabbard, G. 2014: 249–74

  View details for Web of Science ID 000364632600017

• Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire Thai version NEUROPSYCHIATRIC DISEASE AND TREATMENT Waleeprakhon, P., Ittasakul, P., Lotrakul, M., Wisajun, P., Jullagate, S., Ketter, T. A. 2014; 10: 1497-1502

  Abstract

  The Mood Disorder Questionnaire (MDQ) has been translated to many languages and has been used in many countries as a screening instrument for bipolar disorder. The main objective of this study was to evaluate validity of the Thai version of the MDQ as a screening instrument for bipolar disorder in a psychiatric outpatient sample, and to determine its optimum question #1 item threshold value for bipolar disorder.The English language Mood Disorder Questionnaire (MDQ) was translated into Thai. The process involved back-translation, cross-cultural adaptation, field testing of the prefinal version, as well as final adjustments. Two hundred and fifty major depressive disorder outpatients were further assessed by the Thai version of the MDQ and the Thai version of the Mini International Neuropsychiatric Interview (MINI). During the assessment, reliability and validity analyses, and receiver operating characteristic curve (ROC) analysis were performed.The Thai version of the MDQ screening had adequate internal consistency (Cronbach's alpha =0.791, omega total =0.68, and omega hierarchical =0.69). The optimal question #1 item threshold value was at least five positive items, which yielded adequate sensitivity (76.5%), specificity (72.7%), positive predictive value (74.3%), and negative predictive value (75.0%). The ROC area under the curve (AUC) for this study was 0.82 (95% confidence interval: 0.70 to 0.90).The Thai version of the MDQ had some useful psychometric properties for screening for bipolar disorder in a mood disorder clinic setting, with a recommended question #1 item threshold value of at least five positive items.

  View details for DOI 10.2147/NDT.S67842

  View details for Web of Science ID 000340618100001

  View details for PubMedID 25170269

  View details for PubMedCentralID PMC4144938

• General medical burden in bipolar disorder: findings from the LiTMUS comparative effectiveness trial ACTA PSYCHIATRICA SCANDINAVICA Kemp, D. E., Sylvia, L. G., Calabrese, J. R., Nierenberg, A. A., Thase, M. E., Reilly-Harrington, N. A., Ostacher, M. J., Leon, A. C., Ketter, T. A., Friedman, E. S., Bowden, C. L., Rabideau, D. J., Pencina, M., Iosifescu, D. V. 2014; 129 (1): 24-34

  Abstract

  This study examined general medical illnesses and their association with clinical features of bipolar disorder.Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively.The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14).The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.

  View details for DOI 10.1111/acps.12101

  View details for Web of Science ID 000328209400004

  View details for PubMedID 23465084

  View details for PubMedCentralID PMC3789858

• Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: Contrasting LiTMUS baseline data with pre-existing placebo controlled trials JOURNAL OF AFFECTIVE DISORDERS Friedman, E. S., Calabrese, J. R., Ketter, T. A., Leon, A. C., Thase, M. E., Bowden, C. L., Sylvia, L. G., Ostracher, M. J., Severe, J., Iosifescu, D. V., Nierenberg, A. A., Reilly-Harrington, N. A. 2014; 152: 97-104

  Abstract

  Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity.To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥ 3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies.As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity.LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes.Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.

  View details for DOI 10.1016/j.jad.2013.05.052

  View details for Web of Science ID 000327763600013

• Lurasidone in Bipolar I Depression: A 24 Week, Open-label Extension Study Ketter, T., Sarma, K., Silva, R., Xu, J., Cucchiaro, J., Loebel, A. NATURE PUBLISHING GROUP. 2013: S534–S535

  View details for Web of Science ID 000209477100823

• Association of exercise with quality of life and mood symptoms in a comparative effectiveness study of bipolar disorder. Journal of affective disorders Sylvia, L. G., Friedman, E. S., Kocsis, J. H., Bernstein, E. E., Brody, B. D., Kinrys, G., Kemp, D. E., Shelton, R. C., McElroy, S. L., Bobo, W. V., Kamali, M., McInnis, M. G., Tohen, M., Bowden, C. L., Ketter, T. A., Deckersbach, T., Calabrese, J. R., Thase, M. E., Reilly-Harrington, N. A., Singh, V., Rabideau, D. J., Nierenberg, A. A. 2013; 151 (2): 722-727

  Abstract

  Individuals with bipolar disorder lead a sedentary lifestyle associated with worse course of illness and recurrence of symptoms. Identifying potentially modifiable predictors of exercise frequency could lead to interventions with powerful consequences on the course of illness and overall health.The present study examines baseline reports of exercise frequency of bipolar patients in a multi-site comparative effectiveness study of a second generation antipsychotic (quetiapine) versus a classic mood stabilizer (lithium). Demographics, quality of life, functioning, and mood symptoms were assessed.Approximately 40% of participants reported not exercising regularly (at least once per week). Less frequent weekly exercise was associated with higher BMI, more time depressed, more depressive symptoms, and lower quality of life and functioning. In contrast, more frequent exercise was associated with experiencing more mania in the past year and more current manic symptoms.Exercise frequency was measured by self-report and details of the exercise were not collected. Analyses rely on baseline data, allowing only for association analyses. Directionality and predictive validity cannot be determined. Data were collected in the context of a clinical trial and thus, it is possible that the generalizability of the findings could be limited.There appears to be a mood-specific relationship between exercise frequency and polarity such that depression is associated with less exercise and mania with more exercise in individuals with bipolar disorder. This suggests that increasing or decreasing exercise could be a targeted intervention for patients with depressive or mood elevation symptoms, respectively.

  View details for DOI 10.1016/j.jad.2013.07.031

  View details for PubMedID 23993440

• Assessing efficacy/effectiveness and safety/tolerability profiles of adjunctive pramipexole in bipolar depression: acute versus long-term data INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Dell'Osso, B., Ketter, T. A. 2013; 28 (6): 297-304

  Abstract

  Bipolar depression represents the most difficult-to-treat phase of bipolar disorder, mood-stabilizing compounds and second-generation antipsychotics being only partially effective, whereas the use of antidepressants is highly controversial because of risks of inefficacy, switching, rapid cycling, and increased suicidality. Among various augmentative pharmacological treatments, compounds with dopamine-enhancing activity have been shown to be variably beneficial in the treatment of bipolar depression with drug-resistance features. In particular, pramipexole - a dopamine D2/D3 receptor agonist - showed antidepressant properties in bipolar depressed patients in both randomized-controlled trials and open acute and follow-up reports. The present review aims to provide an updated perspective on the use of adjunctive pramipexole in bipolar depression, taking into account randomized-controlled trials, as well as open naturalistic studies, with a specific focus on the evaluation of acute versus long-term data in terms of effectiveness and tolerability. Despite methodological differences, short-term studies support the acute efficacy and tolerability/safety of adjunctive pramipexole, whereas open extended observations seem to confirm the effectiveness of the compound, with some additional concern in terms of safety and tolerability issues. Adjunctive pramipexole may be a valid option in both the acute and the long-term treatment of drug-resistant bipolar depression, with possible superior tolerability in the short term.

  View details for DOI 10.1097/YIC.0b013e3283639015

  View details for Web of Science ID 000325651700002

  View details for PubMedID 24081199

• Number needed to treat can be helpful: a response to Alphs et al. European neuropsychopharmacology Citrome, L., Ketter, T. A. 2013; 23 (11): 1656-1657

  View details for DOI 10.1016/j.euroneuro.2013.02.008

  View details for PubMedID 23712091

• Use of treatment services in a comparative effectiveness study of bipolar disorder. Psychiatric services Sylvia, L. G., Iosifescu, D., Friedman, E. S., Bernstein, E. E., Bowden, C. L., Ketter, T. A., Reilly-Harrington, N. A., Leon, A. C., Calabrese, J. R., Ostacher, M. J., Rabideau, D. J., Thase, M. E., Nierenberg, A. A. 2013; 64 (11): 1119-1126

  Abstract

  OBJECTIVE Bipolar disorder is a severe, chronic mental illness with a high incidence of medical and psychological comorbidities that make treatment and prevention of future episodes challenging. This study investigated the use of services among outpatients with bipolar disorder to further understanding of how to maximize and optimize personalization and accessibility of services for this difficult-to-treat population. METHODS The Lithium Treatment-Moderate Dose Use Study (LiTMUS) was a six-month multisite, comparative effectiveness trial that randomly assigned 283 individuals to receive lithium plus optimized care-defined as personalized, guideline-informed care-or optimized care without lithium. Relationships between treatment service utilization, captured by the Cornell Service Index, and demographic and illness characteristics were examined with generalized linear marginal models. RESULTS Analyses with complete data (week 12, N=246; week 24, N=236) showed that increased service utilization was related to more severe bipolar disorder symptoms, physical side effects, and psychiatric and general medical comorbidities. Middle-aged individuals and those living in the United States longer tended to use more services than younger individuals or recent immigrants, respectively. CONCLUSIONS These data suggest that not all individuals with bipolar disorder seek treatment services at the same rate. Instead, specific clinical or demographic features may affect the degree to which one seeks treatment, conveying clinical and public health implications and highlighting the need for specific approaches to correct such discrepancies. Future research is needed to elucidate potential moderators of service utilization in bipolar disorder to ensure that those most in need of additional services utilize them.

  View details for DOI 10.1176/appi.ps.201200479

  View details for PubMedID 23945956

• The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders AMERICAN JOURNAL OF PSYCHIATRY Pacchiarotti, I., Bond, D. J., Baldessarini, R. J., Nolen, W. A., Grunze, H., Licht, R. W., Post, R. M., Berk, M., Goodwin, G. M., Sachs, G. S., Tondo, L., Findling, R. L., Youngstrom, E. A., Tohen, M., Undurraga, J., Gonzalez-Pinto, A., Goldberg, J. F., Yildiz, A., Altshuler, L. L., Calabrese, J. R., Mitchell, P. B., Thase, M. E., Koukopoulos, A., Colom, F., Frye, M. A., Malhi, G. S., Fountoulakis, K. N., Vazquez, G., Perlis, R. H., Ketter, T. A., Cassidy, F., Akiskal, H., Azorin, J., Valenti, M., Mazzei, D. H., Lafer, B., Kato, T., Mazzarini, L., Martinez-Aran, A., Parker, G., Souery, D., Ozerdem, A., McElroy, S. L., Girardi, P., Bauer, M., Yatham, L. N., Zarate, C. A., Nierenberg, A. A., Birmaher, B., Kanba, S., El-Mallakh, R. S., Serretti, A., Rihmer, Z., Young, A. H., Kotzalidis, G. D., MacQueen, G. M., Bowden, C. L., Ghaemi, S. N., Lopez-Jaramillo, C., Rybakowski, J., Ha, K., Perugi, G., Kasper, S., Amsterdam, J. D., Hirschfeld, R. M., Kapczinski, F., Vieta, E. 2013; 170 (11): 1249-1262

  Abstract

  The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

  View details for DOI 10.1176/appi.ajp.2013.13020185

  View details for Web of Science ID 000326724300008

  View details for PubMedID 24030475

• Number needed to harm can be clinically useful: a response to Safer and Zito. journal of nervous and mental disease Citrome, L., Ketter, T. A. 2013; 201 (11): 1001-1002

  View details for DOI 10.1097/NMD.0000000000000042

  View details for PubMedID 24177490

• The Medication Recommendation Tracking Form: A novel tool for tracking changes in prescribed medication, clinical decision making, and use in comparative effectiveness research. Journal of psychiatric research Reilly-Harrington, N. A., Sylvia, L. G., Leon, A. C., Shesler, L. W., Ketter, T. A., Bowden, C. L., Calabrese, J. R., Friedman, E. S., Ostacher, M. J., Iosifescu, D. V., Rabideau, D. J., Thase, M. E., Nierenberg, A. A. 2013; 47 (11): 1686-1693

  Abstract

  This paper describes the development and use of the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. The Bipolar Trials Network developed and implemented the MRTF in a comparative effectiveness study for bipolar disorder (LiTMUS). The MRTF was used to assess the frequency, types, and reasons for medication adjustments. Changes in treatment were operationalized by the metric Necessary Clinical Adjustments (NCA), defined as medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. Randomized treatment groups did not differ in rates of NCAs, however, responders had significantly fewer NCAs than non-responders. Patients who had more NCAs during their previous visit had significantly lower odds of responding at the current visit. For each one-unit increase in previous CGI-BP depression score and CGI-BP overall severity score, patients had an increased NCA rate of 13% and 15%, respectively at the present visit. Ten-unit increases in previous Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores resulted in an 18% and 14% increase in rates of NCAs, respectively. Patients with fewer NCAs had increased quality of life and decreased functional impairment. The MRTF standardizes the reporting and rationale for medication adjustments and provides an innovative metric for clinical effectiveness. As the first tool in psychiatry to track the types and reasons for medication changes, it has important implications for training new clinicians and examining clinical decision making. (ClinicalTrials.gov number NCT00667745).

  View details for DOI 10.1016/j.jpsychires.2013.07.009

  View details for PubMedID 23911057

• First controlled treatment trial of bipolar II hypomania with mixed symptoms: Quetiapine versus placebo. Journal of affective disorders Suppes, T., Ketter, T. A., Gwizdowski, I. S., Dennehy, E. B., Hill, S. J., Fischer, E. G., Snow, D. E., Gonzalez, R., Sureddi, S., Shivakumar, G., Cosgrove, V. E. 2013; 150 (1): 37-43

  Abstract

  OBJECTIVES: To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS: Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS: Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS: While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

  View details for DOI 10.1016/j.jad.2013.02.031

  View details for PubMedID 23521871

• Superior chronic tolerability of adjunctive modafinil compared to pramipexole in treatment-resistant bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Dell'Osso, B., Timtim, S., Hooshmand, F., Miller, S., Wang, P. W., Hill, S. J., Portillo, N., Ketter, T. A. 2013; 150 (1): 130-135

  Abstract

  Suboptimal outcomes are common in bipolar disorder (BD) pharmacotherapy, and may be mitigated with novel adjunctive agents such as modafinil (a low-affinity dopamine transport inhibitor) and pramipexole (a dopamine D2/D3 receptor agonist). While uncontrolled long-term effectiveness data have been reported for these treatments, reports specifically assessing their comparative acute versus chronic tolerability in BD are lacking. Such information, particularly in relation to discontinuation causes, has substantial relevance, providing initial indications to clinicians which treatment may be better tolerated, and to researchers which agent ought to be assessed in longer-term controlled trials.BD outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Affective Disorders Evaluation, and followed with the STEP-BD Clinical Monitoring Form, were naturalistically prescribed adjunctive modafinil or pramipexole, and somatic/psychiatric intolerability discontinuation rates were compared.Among 63 BD outpatients (mean±SD age 43.5±14.3 years, 60.3% female, 42.9% type I, 44.4% type II, 12.7% type not otherwise specified), taking 3.5±1.5 (median 3) concurrent prescription psychotropics, adjunctive modafinil (n=24) for 626.9±863.9 (286) days versus pramipexole (n=39) for 473.7±613.4 (214; p=0.51) days yielded a 26.0% lower somatic/psychiatric intolerability discontinuation rate (12.5% vs. 38.5%; p<0.05), with most of the difference accounted for by more pramipexole somatic intolerability discontinuations, due to nausea and sedation, after the first 12 weeks of treatment.No placebo comparison group. Small sample of predominantly female Caucasian insured outpatients, taking complex concurrent medication regimens.Further studies are warranted to assess our preliminary observation that modafinil, compared to pramipexole, may be better tolerated for longer-term BD treatment.

  View details for DOI 10.1016/j.jad.2012.11.030

  View details for Web of Science ID 000322762600019

  View details for PubMedID 23261131

• Long-term aripiprazole effectiveness in bipolar disorder patients decreases with pharmacotherapeutic complexity and degree of baseline mood disturbance ASIAN BIOMEDICINE Ittasakul, P., Miller, S., Wang, P. W., Hill, S. J., Childers, M. E., Ketter, T. A. 2013; 7 (4): 537-544

  View details for DOI 10.5372/1905-7415.0704.209

  View details for Web of Science ID 000341273400010

• Assessing the Roles of Stimulants/Stimulant-like Drugs and Dopamine-agonists in the Treatment of Bipolar Depression CURRENT PSYCHIATRY REPORTS Dell'Osso, B., Ketter, T. A., Cremaschi, L., Spagnolin, G., Altamura, A. C. 2013; 15 (8)

  Abstract

  Bipolar depression is considered the most difficult-to-treat phase of bipolar disorder, in relation to its pervasiveness and efficacy and/or tolerability limitations of available treatments. Indeed, most mood stabilizers and atypical antipsychotics are not as effective in ameliorating depressive compared with manic symptoms, and entail substantial tolerability limitations. However, the use of antidepressants is highly controversial, as their efficacy appears less robust in bipolar compared with unipolar depression. In addition, antidepressants, in spite of generally having adequate somatic tolerability, in BD may be associated with a higher risk of manic/hypomanic switch, suicidality and rapid cycling. Among alternative pharmacological strategies, compounds with stimulant and pro-dopaminergic effects, such as methylphenidate, modafinil, armodafinil and pramipexole, have showed potential antidepressant activity, even though their use in clinical practice has been limited by the paucity of controlled evidence. This article seeks to review available evidence about the use of the aforementioned compounds in the treatment of bipolar depression. Findings from reviewed studies suggested that pro-dopaminergic compounds, such as pramipexole and stimulants/stimulant-like agents, deserve consideration as adjunctive therapies in bipolar depressed patients, at least in some subgroups of patients. Nevertheless, caution regarding their use is recommended as further clinical trials with larger samples and longer follow-up periods are necessary to clarify the roles of these medications in bipolar depression.

  View details for DOI 10.1007/s11920-013-0378-z

  View details for Web of Science ID 000323248300004

  View details for PubMedID 23881710

• Bipolar disorder and attention-deficit/hyperactivity disorder comorbidity in children and adolescents: evidence-based approach to diagnosis and treatment. journal of clinical psychiatry Miller, S., Chang, K. D., Ketter, T. A. 2013; 74 (6): 628-629

  View details for DOI 10.4088/JCP.13ac08565

  View details for PubMedID 23842014

• Lurasidone treatment for bipolar I depression: effects on quality of life and patient's functioning 10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders Ketter, T. A., Cucchiaro, J., Silva, R., Pikalov, A., Sarma, K., Kroger, H., Loebel, A. WILEY-BLACKWELL. 2013: 91–91

  View details for Web of Science ID 000319826800207

• A double-blind, placebo-controlled, multicenter trial of adjunctive armodafinil for the treatment of major depression associated with bipolar I disorder 10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders Ketter, T. A., Calabrese, J. R., Yang, R., Frye, M. A. WILEY-BLACKWELL. 2013: 88–88

  View details for Web of Science ID 000319826800199

• Novel Compounds for Acute Management of Bipolar Depression 10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders Frye, M. A., Calabrese, J. R., Yang, R., Ketter, T. WILEY-BLACKWELL. 2013: 13–13

  View details for Web of Science ID 000319826800016

• Efficacy and safety of armodafinil as an adjunctive therapy for the treatment of a major depressive episode associated with bipolar I disorder 10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders Frye, M. A., Ketter, T. A., Yang, R. WILEY-BLACKWELL. 2013: 126–127

  View details for Web of Science ID 000319826800295

• Use of a novel adjunctive clinical trial design to examine efficacy, safety, and improved generalizability of armodafinil for the treatment of bipolar I depression 10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders Calabrese, J. R., Frye, M. A., Yang, R., Ketter, T. A. WILEY-BLACKWELL. 2013: 59–59

  View details for Web of Science ID 000319826800129

• When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed INTERNATIONAL JOURNAL OF CLINICAL PRACTICE Citrome, L., Ketter, T. A. 2013; 67 (5): 407-411

  Abstract

  Although great effort is made in clinical trials to demonstrate statistical superiority of one intervention vs. another, insufficient attention is paid regarding the clinical relevance or clinical significance of the observed outcomes. Effect sizes are not always reported. Available absolute effect size measures include Cohen's d, area under the curve, success rate difference, attributable risk and number needed to treat (NNT). Of all of these measures, NNT is arguably the most clinically intuitive and helps relate effect size difference back to real-world concerns of clinical practice. This commentary reviews the formula for NNT, and proposes acceptable values for NNT and its analogue, number needed to harm (NNH), using examples from the medical literature. The concept of likelihood to be helped or harmed (LHH), calculated as the ratio of NNH to NNT, is used to illustrate trade-offs between benefits and harms. Additional considerations in interpreting NNT are discussed, including the importance of defining acceptable response, adverse outcomes of interest, the effect of time, and the importance of individual baseline characteristics.

  View details for DOI 10.1111/ijcp.12142

  View details for Web of Science ID 000317604500005

  View details for PubMedID 23574101

• Brain-Derived Neurotrophic Factor VAL66MET Met Allele Carrier Genotype Associated with Lower Body Mass Index and Overweight/Obesity Rate Among Bipolar Disorder Patients Miller, S., Hallmayer, J., Hooshmand, F., Wang, P. W., Hill, S. J., Ketter, T. A. ELSEVIER SCIENCE INC. 2013: 176S

  View details for Web of Science ID 000318671800544

• USE OF A NOVEL ADJUNCTIVE CLINICAL TRIAL DESIGN TO EXAMINE EFFICACY, SAFETY OF ARMODAFINIL FOR THE TREATMENT OF BIPOLAR I DEPRESSION Calabrese, J. R., Ketter, T. A., Yang, R., Frye, M. A. ELSEVIER SCIENCE INC. 2013: A51–A52

  View details for Web of Science ID 000318916400265

• A DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER TRIAL OF ADJUNCTIVE ARMODAFINIL FOR THE TREATMENT OF MAJOR DEPRESSION ASSOCIATED WITH BIPOLAR I DISORDER Frye, M. A., Ketter, T. A., Yang, R., Calabrese, J. R. ELSEVIER SCIENCE INC. 2013: A55–A56

  View details for Web of Science ID 000318916400286

• Brain-derived neurotrophic factor val66met genotype and early life stress effects upon bipolar course JOURNAL OF PSYCHIATRIC RESEARCH Miller, S., Hallmayer, J., Wang, P. W., Hill, S. J., Johnson, S. L., Ketter, T. A. 2013; 47 (2): 252-258

  Abstract

  Gene-environment interactions may contribute to bipolar disorder (BD) clinical course variability. We examined effects of brain-derived neurotrophic factor (BDNF) val66met genotype and early life stress (ELS) upon illness severity and chronicity in adult BD patients.80 patients (43 BD I, 33 BD II, 4 BD not otherwise specified, mean ± SD age 46.4 ± 14.0 years, 63.7% female) receiving open evidence-based and measurement-based care in the Stanford Bipolar Disorders Clinic for at least 12 months underwent BDNF val66met genotyping and completed the Childhood Trauma Questionnaire. BDNF met allele carrier genotype and history of childhood sexual and physical abuse were evaluated in relation to mean prior-year Clinical Global Impressions-Bipolar Version-Overall Severity of Illness (MPY-CGI-BP-OS) score and clinical and demographic characteristics.BDNF met allele carriers (but not non-met allele carriers) with compared to without childhood sexual abuse had 21% higher MPY-CGI-BP-OS scores (3.5 ± 0.7 versus 2.9 ± 0.7, respectively, t = -2.4, df = 28, p = 0.025) and 35% earlier BD onset age (14.6 ± 5.7 versus 22.8 ± 7.9 years, respectively, t = 3.0, df = 27, p = 0.006). Regression analysis, however, was non-significant for a BDNF-childhood sexual abuse interaction.small sample of predominantly female Caucasian insured outpatients taking complex medication regimens; only one gene polymorphism considered.Between group comparisons suggested BDNF met allele carrier genotype might amplify negative effects of ELS upon BD illness severity/chronicity, although with regression analysis, there was not a significant gene-environment interaction. Further studies with larger samples are warranted to assess whether BDNF met allele carriers with ELS are at risk for more severe/chronic BD illness course.

  View details for DOI 10.1016/j.jpsychires.2012.10.015

  View details for Web of Science ID 000314330100016

  View details for PubMedID 23182421

  View details for PubMedCentralID PMC3529984

• PILOT RANDOMIZED TRIAL OF A CROSS-DIAGNOSIS COLLABORATIVE CARE PROGRAM FOR PATIENTS WITH MOOD DISORDERS DEPRESSION AND ANXIETY Kilbourne, A. M., Li, D., Lai, Z., Waxmonsky, J., Ketter, T. 2013; 30 (2): 116-122

  Abstract

  Chronic care models improved outcomes for persons with mental disorders but to date have primarily been tested for single diagnoses (e.g. unipolar depression). We report findings from a pilot multisite randomized controlled trial of a cross-diagnosis care model for patients with mood disorders.Patients (N = 60) seen in one of four primary care or mental health clinics affiliated with the National Network of Depression Centers were randomized to receive a mood disorder care model, Life Goals Collaborative Care (LGCC, N = 29) or usual care (N = 31). LGCC consisted of five group self-management sessions focused on mood symptom coping and health behavior change strategies followed by monthly patient and provider care management contacts for up to 6 months. Outcomes at 3 and 6 months included mood symptoms (Patient Health Questionnaire-PHQ-9, Internal State Scale-well-being, Generalized Anxiety Disorder scale) and health-related quality of life.Of the 60 enrolled, the mean age was 46.2 (SD = 13.2), 73.3% were female, 16.7% were non-white, and 36.8% had a bipolar disorder diagnosis. LGCC was associated with greater likelihood of depressive symptom remission in 6 months (respectively, 50% versus 19% had a PHQ-9 score ≤9 and 50% reduction in PHQ-9 score, P = .04) and improved well-being (β = 2.66, P ≤ .01, Cohen's D = 0.43).LGCC may improve outcomes for patients regardless of mood diagnosis, potentially providing a feasible and generalizable chronic care model for routine practice settings.

  View details for DOI 10.1002/da.22003

  View details for Web of Science ID 000314113300003

  View details for PubMedID 23077119

• Use of adjunctive stimulants in adult bipolar depression INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Dell'Osso, B., Ketter, T. A. 2013; 16 (1): 55-68

  Abstract

  Bipolar depression represents a high priority research field, due to its pervasiveness, and high economic and personal (suicidality, impaired function, quality of life) costs, and the limited evidence base to inform therapeutics. Mood stabilizers and second-generation antipsychotics for bipolar depression are commonly only partially effective, and their side-effects may overlap with depressive symptoms such as hypersomnia, daytime drowsiness, fatigue, psychomotor retardation, and weight gain. Moreover, the use of antidepressants in bipolar depression is controversial due to concerns regarding the risks of inefficacy or switching to mood elevation. Stimulants and related compounds such as modafinil and armodafinil have on occasion been used as adjuncts in bipolar depressed patients with encouraging results, but their use is limited by the paucity of systematic evidence of efficacy and safety. The present review aims to provide an updated perspective on the use of stimulants and stimulant-like medications in adult bipolar depression, considering not only recent randomized controlled trials, but also open naturalistic studies, in order to clarify the strengths and limitations of using these agents.

  View details for DOI 10.1017/S1461145712000326

  View details for Web of Science ID 000312658300006

  View details for PubMedID 22717304

• Lithium Treatment Moderate-Dose Use Study (LiTMUS) for Bipolar Disorder: A Randomized Comparative Effectiveness Trial of Optimized Personalized Treatment With and Without Lithium AMERICAN JOURNAL OF PSYCHIATRY Nierenberg, A. A., Friedman, E. S., Bowden, C. L., Sylvia, L. G., Thase, M. E., Ketter, T., Ostacher, M. J., Leon, A. C., Reilly-Harrington, N., Iosifescu, D. V., Pencina, M., Severe, J. B., Calabrese, J. R. 2013; 170 (1): 102-110

  Abstract

  Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT).The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder-Severity (CGI-BP-S) and "necessary clinical adjustments" (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score ≤2 for 2 months) and treatment with second-generation antipsychotics. The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.The authors observed no statistically significant advantage of lithium plus OPT on CGI-BP-S scores, necessary clinical adjustments, or proportion with sustained remission. Both groups had similar outcomes across secondary clinical and functional measures. Fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively).In this pragmatic comparative effectiveness study, a moderate but tolerated dosage of lithium plus OPT conferred no symptomatic advantage when compared with OPT alone, but the lithium-plus-OPT group had less exposure to second-generation antipsychotics. Only about one-quarter of patients in both groups achieved sustained remission of symptoms. These findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.

  View details for DOI 10.1176/appi.ajp.2012.12060751

  View details for Web of Science ID 000313086200013

  View details for PubMedID 23288387

• Enhanced Ziprasidone Combination Therapy Effectiveness in Obese Compared to Nonobese Patients With Bipolar Disorder JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Miller, S., Ittasakul, P., Wang, P. W., Hill, S. J., Childers, M. E., Rasgon, N., Ketter, T. A. 2012; 32 (6): 814-819

  Abstract

  To assess longer-term ziprasidone effectiveness in obese and non-obese patients with bipolar disorder (BD).Outpatients assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation and monitored with the Systematic Treatment Enhancement Program for BD Clinical Monitoring Form received open ziprasidone.Eighty-two patients (39 patients with BD I, 39 patients with BD II, and 4 patients with BD not otherwise specified; mean age, 41.1 years; females, 78.0%; obese, 48.8%) received ziprasidone combined with an average of 3.6 (in 74.4% at least 3) other prescription psychotropics and 1.2 prescription nonpsychotropics. Mean (median) ziprasidone final dose and duration were 134.3 (150) mg/d and 489 (199.5) days, respectively. Ziprasidone yielded in obese compared to nonobese patients less discontinuation (42.5% vs 71.4%, P = 0.01), albeit with a higher rate of addition of subsequent psychotropic medication (62.5% vs 35.7%, P = 0.03). Moreover, obese compared to nonobese patients had a higher rate of shift to final-visit euthymia (27.5% vs 0.0%, P = 0.0002), and more weight loss (-20.7 lbs vs -0.6 lbs, P = 0.001), and obese (but not nonobese) patients had significant improvements in mean Clinical Global Impression-Severity of Illness (decreased 0.6 points; P = 0.03) and Global Assessment of Functioning (increased 3.3 points, P = 0.01) scores. Weight change correlated significantly with Global Assessment of Functioning change (P = 0.047) but not with Clinical Global Impression-Severity of Illness change. Limitations are small sample size and open-label, uncontrolled, observational design.Controlled and additional observational studies seem warranted to confirm our preliminary findings suggesting ziprasidone may be more effective in obese compared to nonobese patients with BD already receiving combination pharmacotherapy.

  View details for DOI 10.1097/JCP.0b013e318270dea9

  View details for Web of Science ID 000310923500014

  View details for PubMedID 23131875

• Torticollis after low-dose aripiprazole administration in a Thai schizophrenia patient. Asian journal of psychiatry Ittasakul, P., Srivastava, S., Hiranyatheb, T., Ketter, T. A. 2012; 5 (4): 365-366

  View details for DOI 10.1016/j.ajp.2012.02.002

  View details for PubMedID 23174451

• Addressing challenges in bipolar diagnosis: what do good clinicians already do? An editorial comment to Phelps J, Ghaemi SN 'The mistaken claim of bipolar 'overdiagnosis': solving the false positives problem for DSM-5/ICD-11'. Acta psychiatrica Scandinavica Ketter, T. A., Citrome, L. 2012; 126 (6): 393-394

  View details for DOI 10.1111/j.1600-0447.2012.01914.x

  View details for PubMedID 23134536

• Effectiveness of quetiapine plus lamotrigine maintenance therapy in challenging bipolar disorder patients Ittasakul, P., Johnson, K., Srivastava, S., Childers, M., Brook, J., Hoblyn, J., Ketter, T. WILEY-BLACKWELL. 2012: 117–118

  View details for Web of Science ID 000310467000248

• Progression of female reproductive stages associated with bipolar illness exacerbation BIPOLAR DISORDERS Marsh, W. K., Ketter, T. A., Crawford, S. L., Johnson, J. V., Kroll-Desrosiers, A. R., Rothschild, A. J. 2012; 14 (5): 515-526

  Abstract

  Late perimenopause and early postmenopause confer an increased risk of depression in the population, yet bipolar disorder mood course during these times remains unclear.Clinic visits in 519 premenopausal, 116 perimenopausal (including 13 women transitioning from perimenopause to postmenopause), and 133 postmenopausal women with bipolar disorder who received naturalistic treatment in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study over 19.8 ± 15.5 months were analyzed for mood state. History of postpartum and perimenstrual mood exacerbation and current hormone therapy were evaluated as potential mood predictors.A progression in female reproductive stage (premenopause, perimenopause, and postmenopause) was significantly associated with percent of visits decreasing in euthymia (29.3%, 27.0%, 25.0%, respectively, p < 0.05), decreasing in syndromal mood elevation (5.3%, 4.1%, and 3.0%, respectively, p < 0.001), and increasing in subsyndromal symptoms (47.3%, 50.7%, and 52.7%, respectively, p = 0.05). Thirteen women transitioning from peri- to postmenopause had a significantly greater proportion of visits in syndromal depression (24.4%, p < 0.0005) compared to premenopausal, perimenopausal, and postmenopausal women, while depression in the latter three groups (18.1%, 18.1%, and 19.3%, respectively) did not differ. Perimenstrual and/or postpartum mood exacerbation, or hormone therapy did not significantly alter depression during perimenopause.A progression in female reproductive stages was associated with bipolar illness exacerbation. A small number of women transitioning from perimenopause to postmenopause had significantly greater depression than other female reproductive groups. Euthymia and mood elevation decreased with progressing female reproductive stage. Menstrual cycle or postpartum mood exacerbation, or current hormone therapy use, was not associated with perimenopausal depression. Future studies, which include hormonal assessments, are needed to confirm these preliminary findings.

  View details for DOI 10.1111/j.1399-5618.2012.01026.x

  View details for Web of Science ID 000306805000007

  View details for PubMedID 22650986

  View details for PubMedCentralID PMC3407285

• Pilot study of the efficacy of double-blind, placebo-controlled one-week olanzapine stabilization therapy in heterogeneous symptomatic bipolar disorder patients JOURNAL OF PSYCHIATRIC RESEARCH Srivastava, S., Wang, P. W., Hill, S. J., Childers, M. E., Keller, K. L., Ketter, T. A. 2012; 46 (7): 920-926

  Abstract

  Olanzapine has demonstrated efficacy in acute mania and bipolar I disorder (BDI) maintenance, but efficacy in brief therapy in more diverse populations, including patients with bipolar II disorder (BDII)/bipolar disorder not otherwise specified (BDNOS) with syndromal/subsyndromal depressive/mood elevation symptoms and taking/not taking concurrent medications remains to be established.Fifty adult outpatients (24 BD1, 22 BDII, 4 BDNOS, mean ± SD age 40.8 ± 11.5 years, 28.1% female, already taking 1.1 ± 1.2 [median 1] prescription psychotropics) with 17-item Hamilton Depression Rating Scale (HDRS) ≥10 and/or Young Mania Rating Scale (YMRS) ≥10 and ≤24, were randomized to double-blind olanzapine (2.5-20 mg/day) versus placebo for one week.Among 45 patients with post-baseline ratings, olanzapine (9.0 ± 5.8 mg/day, n = 23) compared to placebo (n = 22) tended to yield greater Clinical Global Impressions-Bipolar Version-Overall Severity of Illness (-1.4 ± 0.9 versus -0.8 ± 1.1, p = 0.08) and Hamilton Anxiety Scale (-7.9 ± 6.3 versus -3.8 ± 6.1, p = 0.07) improvements, and YMRS/HDRS remission rate (47.8% versus 22.7%, p = 0.08), but significantly increased median weight (+2 versus -1 lbs, p = 0.001), and rates of excessive appetite (54.2% versus 22.7%, p = 0.04) and tremor (50.0% versus 9.1% p = 0.004). Number Needed to Treat and 95% Confidence Interval for YMRS/HDRS remission were 4 (1-∞). Numbers Needed to Harm for excessive appetite and tremor were 4 (1-21) and 3 (1-6), respectively.Olanzapine tended to yield affective improvement and significantly increased weight, appetite, and tremor. Larger controlled studies appear feasible and warranted to assess brief olanzapine therapy in heterogeneous symptomatic bipolar disorder patients.

  View details for DOI 10.1016/j.jpsychires.2012.04.004

  View details for Web of Science ID 000306536100012

  View details for PubMedID 22579071

• Effectiveness of quetiapine plus lamotrigine maintenance therapy in challenging bipolar disorder patients JOURNAL OF AFFECTIVE DISORDERS Ittasakul, P., Johnson, K. R., Srivastava, S., Childers, M. E., Brooks, J. O., Hoblyn, J. C., Ketter, T. A. 2012; 137 (1-3): 139-145

  Abstract

  Assess quetiapine plus lamotrigine (QTP+LTG) combination maintenance therapy effectiveness in challenging bipolar disorder (BD).Outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form were naturalistically prescribed QTP+LTG.Fifty-four outpatients with challenging BD, taking in addition to QTP+LTG, a mean±SD of 2.1±1.6 (in 63.0% at least 2) other psychotropic and 2.3±1.9 non-psychotropic prescription medications, had QTP+LTG maintenance trials. Median(mean±SD) QTP+LTG duration was 401(730±756) days. Final QTP and LTG doses were 87.5(188±211) and 300(287±108) mg/day, respectively. Half (27/54) of patients discontinued QTP (in 19), LTG (in 6), or QTP+LTG (in 2), after 294(415±414) days - due to side-effects in 10, inefficacy in seven, non-adherence in five, and other reasons in five. 42.6%(23/54) had additional pharmacotherapy intervention for emergent mood symptoms, after 175(261±237) days, with at least one psychotropic added (in 16/54) or substantively (by ≥50%) increased (in 7/54). 55.6%(30/54) had recurrent mood episodes, after 126(187±158) days, most often depressive (in 35.2%), although 64.8%(35/54) were euthymic at final visit taking QTP+LTG. Sedation increased significantly during treatment among those with side-effect discontinuations, and 19.2%(10/52, all having QTP added to LTG) had clinically significant (≥7%) weight gain.No placebo comparison group. Small sample of predominantly female Caucasian insured outpatients taking complex concurrent medication regimens.Additional studies are warranted to confirm our preliminary observation that QTP+LTG maintenance may be effective in patients with challenging BD.

  View details for DOI 10.1016/j.jad.2011.12.024

  View details for Web of Science ID 000301759900018

  View details for PubMedID 22240084

• Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392) BIPOLAR DISORDERS Carlson, B. X., Ketter, T. A., Sun, W., Timko, K., McQuade, R. D., Sanchez, R., Vester-Blokland, E., Marcus, R. 2012; 14 (1): 41-53

  Abstract

  To evaluate the efficacy and safety of aripiprazole (ARI) plus lamotrigine (LTG) compared with placebo (PBO) plus LTG, for long-term treatment in bipolar I disorder patients with a recent manic/mixed episode.After a 9-24 week stabilization phase receiving single-blind ARI (10-30 mg/day) plus open-label LTG (100 or 200 mg/day), patients maintaining stability (Young Mania Rating Scale/Montgomery-Åsberg Depression Rating Scale total scores ≤ 12) with ARI+LTG for eight consecutive weeks were randomized to continue on double-blind ARI + LTG or to receive PBO + LTG, after removing ARI from ARI + LTG treatment, and followed up for 52 weeks. The primary outcome measure was time from randomization to relapse into a manic/mixed episode. A total of 787 patients entered the stabilization phase, and 351 were randomized to ARI + LTG (n = 178) or PBO + LTG (n = 173). ARI + LTG yielded a numerically longer time to manic/mixed relapse than PBO + LTG, but it was not statistically significant [hazard ratio (HR) = 0.55; 95% confidence interval (CI): 0.30-1.03; p = 0.058]. The estimated relapse rates at Week 52 were 11% for ARI + LTG and 23% for PBO + LTG, yielding a number needed-to-treat of nine (95% CI: 5-121). The three most common adverse events were akathisia [10.8%, 6.1% for ARI + LTG and PBO + LTG, respectively; number needed-to-harm (NNH) = 22], insomnia (7.4%, 11.5%), and anxiety (7.4%, 3.6%). Mean weight change was 0.43 kg and -1.81 kg, respectively (last observation carried forward, p = 0.001). Rates of ≥ 7% weight gain with ARI + LTG and PBO + LTG were 11.9% and 3.5%, respectively (NNH = 12). ARI + LTG delayed the time to manic/mixed relapse but did not reach statistical significance. Safety and tolerability results revealed no unexpected adverse events for ARI combination with LTG.

  View details for DOI 10.1111/j.1399-5618.2011.00974.x

  View details for Web of Science ID 000300448000005

  View details for PubMedID 22329471

• Methods to limit attrition in longitudinal comparative effectiveness trials: lessons from the Lithium Treatment - Moderate dose Use Study (LiTMUS) for bipolar disorder CLINICAL TRIALS Sylvia, L. G., Reilly-Harrington, N. A., Leon, A. C., Kansky, C. I., Ketter, T. A., Calabrese, J. R., Thase, M. E., Bowden, C. L., Friedman, E. S., Ostacher, M. J., Iosifescu, D. V., Severe, J., Keyes, M., Nierenberg, A. A. 2012; 9 (1): 94-101

  Abstract

  High attrition rates, which occur frequently in longitudinal clinical trials of interventions for bipolar disorder, limit the interpretation of results.The aim of this article is to present design approaches that limited attrition in the Lithium Treatment - Moderate dose Use Study (LiTMUS) for bipolar disorder.LiTMUS was a 6-month randomized, longitudinal multisite comparative effectiveness trial that enrolled bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium; other treatments needed for mood stabilization were administered in a guideline-informed, empirically supported, and personalized fashion to participants in both treatment arms.Components of the study design that may have contributed to low attrition (16%) among 283 participants randomized included the use of (1) an intent-to-treat design, (2) a randomized adjunctive single-blind design, (3) participant reimbursement, (4) assessment of intent to attend the next study visit (included a discussion of attendance obstacles when intention was low), (5) quality care with limited participant burden, and (6) target windows for study visits.The relationships between attrition and effectiveness and tolerability of treatment have not been analyzed yet.These components of the LiTMUS design may have limited attrition and may inform the design of future randomized comparative effectiveness trials among similar patients and those from other difficult-to-follow populations.

  View details for DOI 10.1177/1740774511427324

  View details for Web of Science ID 000300380200013

  View details for PubMedID 22076437

• Aims and Results of the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) CNS NEUROSCIENCE & THERAPEUTICS Bowden, C. L., Perlis, R. H., Thase, M. E., Ketter, T. A., Ostacher, M. M., Calabrese, J. R., Reilly-Harrington, N. A., Gonzalez, J. M., Singh, V., Nierenberg, A. A., Sachs, G. S. 2012; 18 (3): 243-249

  Abstract

  The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.

  View details for DOI 10.1111/j.1755-5949.2011.00257.x

  View details for Web of Science ID 000301343800010

  View details for PubMedID 22070541

• Clinical models for managing Bipolar II disorder: model 2 BIPOLAR II DISORDER: MODELLING, MEASURING AND MANAGING, 2ND EDITION Ketter, T. A., Wang, P. W., Parker, G. 2012: 192–213

  View details for Web of Science ID 000315688800019

• Clinical Relevance of Treatments for Acute Bipolar Disorder: Balancing Therapeutic and Adverse Effects CLINICAL THERAPEUTICS Srivastava, S., Ketter, T. A. 2011; 33 (12): B40-B48

  Abstract

  The US Food and Drug Administration (FDA) has approved 10 treatments for acute mania, but only 2 for acute bipolar depression. These agents differ from one another with respect to their efficacy and tolerability profiles, such that certain medications may be optimal for some patients but not others.Our aim was to compare the therapeutic and adverse effects of treatments for acute mania and acute bipolar depression to inform clinical decision making.Using data from large, randomized, double-blind, placebo-controlled acute mania and acute bipolar depression trials, we assessed number needed to treat (NNT) for response, number needed to harm (NNH) for sedation/weight gain, and likelihood to help or harm (LHH = NNH ÷ NNT) compared with placebo.For acute mania, lithium compared with other FDA-approved agents yielded substantively less sedation (NNH, 27 vs 5-17) yet broadly similar efficacy (NNT, 4 vs 4-8), and thus a more favorable efficacy:sedation likelihood (LHH, 6.8 vs 0.7-3.4). For acute bipolar depression, lamotrigine compared with FDA-approved treatments yielded substantively less sedation (NNH, 42 vs 6-12), weight gain (NNH, -34 vs 6-19), and efficacy (NNT, 12 vs 4-6), but still more favorable efficacy:sedation likelihood (LHH, 3.5) than quetiapine (LHH, 1.0) and efficacy:weight gain likelihood (LHH, -2.8) than the olanzapine plus fluoxetine combination (LHH, 1.5).For acute mania, lithium compared with other FDA-approved agents yielded less sedation yet similar efficacy, indicating utility for patients sensitive to sedation. For acute bipolar depression, lamotrigine compared with FDA-approved treatments yielded better tolerability but poorer efficacy, suggesting utility in patients sensitive to sedation/weight gain with milder episodes, whereas the FDA-approved treatments might have utility in patients with more severe episodes.

  View details for DOI 10.1016/j.clinthera.2011.11.020

  View details for Web of Science ID 000298831400034

  View details for PubMedID 22177379

• Sleep matters: Sleep functioning and course of illness in bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Gruber, J., Miklowitz, D. J., Harvey, A. G., Frank, E., Kupfer, D., Thase, M. E., Sachs, G. S., Ketter, T. A. 2011; 134 (1-3): 416-420

  Abstract

  Few studies have prospectively examined the relationships of sleep with symptoms and functioning in bipolar disorder.The present study examined concurrent and prospective associations between total sleep time (TST) and sleep variability (SV) with symptom severity and functioning in a cohort of DSM-IV bipolar patients (N = 468) participating in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), all of whom were recovered at study entry.Concurrent associations at study entry indicated that shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity. Mixed-effects regression modeling was used to examine prospective associations in the 196 patients for whom follow-up data were available. Consistent with findings at study entry, shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity over 12 months.These findings highlight the importance of disrupted sleep patterns in the course of bipolar illness.

  View details for DOI 10.1016/j.jad.2011.05.016

  View details for Web of Science ID 000295753400053

  View details for PubMedID 21683450

  View details for PubMedCentralID PMC3387668

• Gender-specific lipid profiles in patients with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Vemuri, M., Kenna, H. A., Wang, P. W., Ketter, T. A., Rasgon, N. L. 2011; 45 (8): 1036-1041

  Abstract

  High rates of dyslipidemia and insulin resistance (IR) are reported in patients with bipolar disorder (BD). We assessed gender effects upon rates of dyslipidemia/IR in outpatients with BD.Data from 491 outpatients (ages 18-88) seen in the Stanford Bipolar Disorders clinic between 2000 and 2007 were evaluated. Patients were followed longitudinally and received naturalistic treatment. BD patients (n = 234; 61% female; 42% Type I, 47% Type II, 11% NOS) with a mean age of 40.3 ± 14.0 years, mean BMI 26.8 ± 6.4, and 81% Caucasian, who had one of four lipid measures (total cholesterol, LDL, HDL, TG) at clinicians' discretion, a psychiatry clinic visit within 2 months of laboratory, and were not medicated for dyslipidemia were included. IR was imputed from TG/HDL ratio.Women, compared with men, had significantly lower mean triglycerides (105.58 ± 64.12 vs. 137.99 ± 105.14, p = 0.009), higher mean HDL cholesterol (60.17 ± 17.56 vs. 46.07 ± 11.91 mg/dl, p < 0.001), lower mean LDL cholesterol (109.84 ± 33.47 vs. 123.79 ± 35.96 mg/dl, p = 0.004), and lower TG/HDL ratio (1.98 ± 1.73 vs. 3.59 ± 3.14 p < 0.001). Compared to men, women had a significantly lower prevalence of abnormal total cholesterol, LDL, TG, HDL, and TG/HDL ratio. No significant differences were found between men and women with regard to age, BMI, ethnicity, educational attainment, smoking habits, bipolar illness type, illness severity or duration, or weight-liable medication exposure.In outpatients with BD, women had more favorable lipid profiles than men despite similar demographic variables. This sample of primarily Caucasian and educated patients, receiving vigilant clinical monitoring, may represent a relatively healthy psychiatric population demonstrating gender differences similar to those in the general population.

  View details for DOI 10.1016/j.jpsychires.2011.02.002

  View details for Web of Science ID 000293938900006

  View details for PubMedID 21377167

• Open adjunctive ziprasidone associated with weight loss in obese and overweight bipolar disorder patients JOURNAL OF PSYCHIATRIC RESEARCH Wang, P. W., Hill, S. J., Childers, M. E., Chandler, R. A., Rasgon, N. L., Ketter, T. A. 2011; 45 (8): 1128-1132

  Abstract

  To assess effectiveness and tolerability of open adjunctive ziprasidone for weight loss in obese/overweight patients with bipolar disorders (BD) in diverse mood states, taking weight gain-implicated psychotropic medications.22 obese and three overweight BD patients (20 female; 10 BD-I, 14 BD-II, 1 BD-NOS) with mean ± SD baseline body mass index (BMI) of 31.8 ± 2.5 kg/m2 received ZIP (mean final dose 190 ± 92 mg/day) for mean of 79.2 ± 23.2 days. Weight was assessed at six weekly and three biweekly visits. Subjects entered the study in diverse mood states. At baseline, 21 were taking second-generation antipsychotics, 7 lithium, and 1 valproate, which could be reduced/discontinued at investigators' discretion.Weight and BMI decreased from baseline to endpoint by 4.5 ± 3.4 kg and 1.6 ± 1.2 kg/m2, respectively, at weekly rates of 0.37 kg and 0.13 kg/m2, respectively (all p < 0.00001). 48% of patients had at least 5% weight loss. Obesity rate decreased from 88% to 35% (p < 0.0001). Waist circumference decreased 1.6 inches (p = 0.0001). Overall, mood did not change. Patients with at least moderate baseline mood symptoms experienced significant mood improvement, despite 72% patients decreasing/discontinuing weight gain-implicated psychotropic medications. Seven patients discontinued ZIP early: 3 for weight loss inefficacy, and 1 each for viral gastroenteritis, loss of consciousness, pneumonia with hypomania, and lost to follow up.Open adjunctive ziprasidone may be effective for weight loss in obese/overweight BD patients taking weight gain-implicated psychotropic medications. These preliminary data should be considered with caution due to the open uncontrolled design, small sample size, and brief duration.

  View details for DOI 10.1016/j.jpsychires.2011.01.019

  View details for Web of Science ID 000293938900019

  View details for PubMedID 21371718

• Strategies for the early recognition of bipolar disorder. journal of clinical psychiatry Ketter, T. A. 2011; 72 (7)

  Abstract

  Bipolar disorder often exists for 10 or more years without being correctly diagnosed or treated. Early-onset bipolar disorder is associated with longer treatment delay and a worse outcome than adult-onset bipolar disorder. This activity describes various risk factors for the development of bipolar disorder and discusses possible solutions to the challenges surrounding timely diagnosis.

  View details for DOI 10.4088/JCP.9075tx1c

  View details for PubMedID 21824451

• DSM-5 mixed features specifier may increase complexity without enhancing milder mixed symptom detection in bipolar disorder patients: a 36 case series 9th International Conference on Bipolar Disorder (ICBD) Ketter, T. A., Srivastava, S., Wang, P. W., Childers, M. E., Hill, S. J., Keller, K. L. WILEY-BLACKWELL. 2011: 62–62

  View details for Web of Science ID 000300102400142

• Pilot study of the effectiveness of double-blind, placebo-controlled brief olanzapine therapy in heterogeneous symptomatic bipolar disorder patients 9th International Conference on Bipolar Disorder (ICBD) Srivastava, S., Wang, P. W., Childers, M. E., Hill, S. J., Keller, K. L., Ketter, T. A. WILEY-BLACKWELL. 2011: 93–94

  View details for Web of Science ID 000300102400232

• Effectiveness of Aripiprazole in Bipolar Disorder Patients Primarily Taking Complex Pharmacotherapy 66th Annual Meeting of the Society-of-Biological-Psychiatry Ittasakul, P., Srivastava, S., Wang, P. W., Hill, S. J., Childers, M. E., Ketter, T. A. ELSEVIER SCIENCE INC. 2011: 92S–92S

  View details for Web of Science ID 000290641800295

• Sleep Quality Disturbance Predicts Depressive Recurrence in Bipolar Disorder Selig, B., Gruber, J., Wang, P. W., Culver, J. L., Ketter, T. A. ELSEVIER SCIENCE INC. 2011: 135S

  View details for Web of Science ID 000290641800429

• Pilot Study of the Effectiveness of Double-Blind, Placebo-Controlled Brief Olanzapine Therapy in Heterogeneous Symptomatic Bipolar Disorder Patients Srivastava, S., Wang, P. W., Childers, M. E., Hill, S. J., Keller, K. L., Ketter, T. A. ELSEVIER SCIENCE INC. 2011: 135S

  View details for Web of Science ID 000290641800430

• Treatments for bipolar disorder: can number needed to treat/harm help inform clinical decisions? ACTA PSYCHIATRICA SCANDINAVICA Ketter, T. A., Citrome, L., Wang, P. W., Culver, J. L., Srivastava, S. 2011; 123 (3): 175-189

  Abstract

  To compare bipolar treatment interventions, using number needed to treat (NNT) and number needed to harm (NNH).Results of randomized controlled clinical trials were used to assess efficacy (NNT for response and relapse/recurrence prevention vs. placebo) and tolerability (e.g. NNH for weight gain and sedation vs. placebo).United States Food and Drug Administration-approved bipolar disorder pharmacotherapies all have single-digit NNTs (i.e. > 10% advantage over placebo), but NNHs for adverse effects that vary widely. Some highly efficacious agents are as likely to yield adverse effects as therapeutic benefit, but may be interventions of choice in more acute severe illness. In contrast, some less efficacious agents with better tolerability may be interventions of choice in more chronic mild-moderate illness.Clinical trials can help inform clinical decision making by quantifying the likelihood of benefit vs. harm. Integrating such data with individual patient circumstances, values, and preferences can help optimize treatment choices.

  View details for DOI 10.1111/j.1600-0447.2010.01645.x

  View details for Web of Science ID 000286890300002

  View details for PubMedID 21133854

• Lamotrigine plus quetiapine combination therapy in treatment-resistant bipolar depression ANNALS OF CLINICAL PSYCHIATRY Ahn, Y. M., Nam, J. Y., Culver, J. L., Marsh, W. K., Bonner, J. C., Ketter, T. A. 2011; 23 (1): 17-24

  Abstract

  Lamotrigine and quetiapine are commonly used in bipolar disorder, but there are no published systematic studies of their use in combination for treatment-resistant bipolar depression.We studied 39 trials in outpatients (15 with bipolar I disorder, 22 with bipolar II disorder, and 1 with bipolar disorder not otherwise specified; 1 patient had 2 trials) with depression resistant to quetiapine or lamotrigine who were taking a mean of 1.7 other prescription psychotropic medications. Patients were given either open-label lamotrigine or quetiapine naturalistically, for up to 12 weeks of combination therapy.Lamotrigine (mean dose, 204.2 mg/d) plus quetiapine (mean dose, 188.5 mg/d) increased the euthymia rate (0.0% to 46.2%), decreased syndromal (79.5% to 30.8%) and subsyndromal (20.5% to 15.4%) depression rates, and improved Clinical Global Impression-Severity (mean change, -1.0) and Global Assessment of Functioning (mean change, +5.9) scores. Approximately one-fifth of patients discontinued therapy (20.5%) or required subsequent additional pharmacotherapy (20.5%). Only 10.3% discontinued due to adverse effects, and there was no significant change in mean body weight.The findings of this uncontrolled open pilot study must be viewed with caution. However, randomized, double-blind, placebo-controlled studies are warranted to confirm the possibility that combination therapy with lamotrigine and quetiapine is effective and well tolerated in patients with treatment-resistant bipolar depression.

  View details for Web of Science ID 000287616500004

  View details for PubMedID 21318192

• Early symptom change and prediction of subsequent remission with olanzapine augmentation in divalproex-resistant bipolar mixed episodes JOURNAL OF PSYCHIATRIC RESEARCH Houston, J. P., Ketter, T. A., Case, M., Bowden, C., Degenhardt, E. K., Jamal, H. H., Tohen, M. 2011; 45 (2): 169-173

  Abstract

  Potential predictors of remission in mixed bipolar I disorder were identified using early Clinical Global Impression-Severity (CGI-S) improvement criteria in divalproex-resistant patients randomized to olanzapine augmentation (olanzapine + divalproex; N = 101) in a 6-week, double-blind, placebo-controlled trial. In a post-hoc analysis, receiver operating characteristics of 1-point decreases in the CGI-S total score after 2, 4, 7, and 14 days were examined as predictors of endpoint (Week 6 or last observation) remission of depression and/or mania as defined by 21-item Hamilton Depression Rating Scale (HDRS-21) and Young Mania Rating Scale (YMRS) total score ≤8. Based on a 1-point improvement in CGI-S as a predictor of remission, all odds ratios (ORs) and 95% confidence intervals (CIs) were statistically significant for depression or mania remission criteria. ORs for mixed symptom remission with a decrease ≥1 in CGI-S scores at Day 2 for olanzapine augmentation were (6.727; CI: 2.382, 18.997; p < .001) with negative predictive value = 89.5% and positive predictive value = 44.2%. Changes in HDRS-21 and YMRS individual item scores after 2 days of augmentation as predictors of endpoint remission identified that decreases in HDRS-21 symptom item scores (early, middle, and/or late insomnia; paranoid; agitation; and somatic/gastrointestinal) predicted depressive symptom remission at endpoint, and decreases in YMRS item scores (language-thought disorder and irritability) were associated with manic symptom remission at endpoint. Because remission with augmentation therapy may occur in as few as one in ten individuals who lack very early symptom reduction, lack of early improvement may indicate a need to expediently reassess treatment strategy.

  View details for DOI 10.1016/j.jpsychires.2010.05.016

  View details for Web of Science ID 000287906500005

  View details for PubMedID 20541220

• Safety and Tolerability Associated With Second-Generation Antipsychotic Polytherapy in Bipolar Disorder: Findings From the Systematic Treatment Enhancement Program for Bipolar Disorder JOURNAL OF CLINICAL PSYCHIATRY Brooks, J. O., Goldberg, J. F., Ketter, T. A., Miklowitz, D. J., Calabrese, J. R., Bowden, C. L., Thase, M. E. 2011; 72 (2): 240-247

  Abstract

  Practitioners often combine 2 or more second-generation antipsychotics (SGAs) in patients with bipolar disorder, despite an absence of data to support their safety, tolerability, or efficacy.This study sought to evaluate the safety and tolerability of SGA polytherapy compared to SGA monotherapy in bipolar disorder patients receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).A longitudinal cohort of 1,958 patients who were prescribed at least 1 SGA was drawn from 4,035 bipolar patients in STEP-BD recruited between November 1999 and July 2005 and assessed at least quarterly for a mean duration of 21 months. Main outcome measures were the mean quarterly prevalence of adverse events, medical and psychiatric service usage, Global Assessment of Functioning ratings, and percentage of days spent well.Almost 10% of patients taking SGAs were prescribed SGA polytherapy. After controlling for illness onset, age, baseline illness severity, and medication load, patients prescribed SGA polytherapy, compared to monotherapy, exhibited more dry mouth (number needed to harm [NNH] = 4), tremor (NNH = 6), sedation (NNH = 8), sexual dysfunction (NNH = 8), and constipation (NNH = 11) and were almost 3 times as likely to incur more psychiatric and medical care; there was no association with greater global functioning scores or percentage of days spent well.Although SGA polytherapy was fairly common in bipolar disorder, it was associated with increased side effects and health service use but not with improved clinical status or function. Thus, SGA polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.

  View details for DOI 10.4088/JCP.09m05214yel

  View details for Web of Science ID 000287985400014

  View details for PubMedID 20868629

• Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder BIPOLAR DISORDERS Brooks, J. O., Bearden, C. E., Hoblyn, J. C., Woodard, S. A., Ketter, T. A. 2010; 12 (8): 866-874

  Abstract

    Reports of sustained attention deficits in the euthymic phase of bipolar disorder have been variable, and have yet to be related to cerebral metabolism. In the present study, we evaluated relationships between cognitive performance deficits and resting cerebral metabolism in euthymic older adults with bipolar disorder.  Sixteen older (mean age 58.7 years) euthymic outpatients with bipolar disorder (10 type I, 6 type II; 44% female) and 11 age-matched healthy controls received resting positron emission tomography with (18) fluorodeoxyglucose and, within 10 days, the Conners' Continuous Performance Test-II, a commonly used measure of sustained attention and inhibitory control.  Bipolar disorder patients had significantly more omission errors (z = 2.53, p = 0.01) and a trend toward more commission errors (z = 1.83, p < 0.07) than healthy controls. Relative to healthy controls, among bipolar disorder subjects commission errors were more strongly related to inferior frontal gyrus [Brodmann area (BA) 45/47] hypometabolism and paralimbic hypermetabolism. In bipolar disorder subjects, relative to controls, omission errors were more strongly related to dorsolateral prefrontal (BA 9/10) hypometabolism and greater paralimbic, insula, and cingulate hypermetabolism.  In older adults with bipolar disorder, even during euthymia, resting-state corticolimbic dysregulation was related to sustained attention deficits and inhibitory control, which could reflect the cumulative impact of repeated affective episodes upon cerebral metabolism and neurocognitive performance. The relative contributions of aging and recurrent affective episodes to these differences in bipolar disorder patients remain to be established.

  View details for DOI 10.1111/j.1399-5618.2010.00881.x

  View details for Web of Science ID 000285751400013

  View details for PubMedID 21176034

• In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005 EUROPEAN PSYCHIATRY Severus, W. E., Lipkovich, I. A., Licht, R. W., Young, A. H., Greil, W., Ketter, T., Deberdt, W., Tohen, M. 2010; 25 (8): 443-449

  Abstract

  The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder.A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment.The LoLi group (<0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR]=1.96, p=0.042), but not depressive (HR=2.11, p=0.272) episodes, compared to the combined medium (0.6-0.79 mmol/L) and high lithium level (≥0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥0.8 mmol/L) for new manic/mixed (HR=0.96, p=0.893) or depressive (HR=0.95, p=0.922) episodes. The LoOL group (<10mg/day) showed a significantly increased risk of depressive (HR=2.24, p=0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10-20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR=0.94, p=0.895).Lithium levels≥0.6 mmol/L and olanzapine doses≥10mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.

  View details for DOI 10.1016/j.eurpsy.2009.10.009

  View details for Web of Science ID 000286037800002

  View details for PubMedID 20430594

• The Link Between Bipolar Disorders and Creativity: Evidence from Personality and Temperament Studies CURRENT PSYCHIATRY REPORTS Srivastava, S., Ketter, T. A. 2010; 12 (6): 522-530

  Abstract

  Although extensive literature supports connections between bipolar disorder and creativity, possible mechanisms underlying such relationships are only beginning to emerge. Herein we review evidence supporting one such possible mechanism, namely that personality/temperament contribute to enhanced creativity in individuals with bipolar disorder, a theory supported by studies showing that certain personality/temperamental traits are not only common to bipolar disorder patients and creative individuals but also correlate with measures of creativity. Thus, we suggest based on studies using three important personality/temperament measures-the Neuroticism, Extraversion, and Openness Personality Inventory (NEO); the Myers-Briggs Type Indicator (MBTI); and the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A)-that changeable (increased TEMPS-A-cyclothymia) and at times negative (increased NEO-neuroticism) affect and open-minded (increased NEO-openness) and intuitive (increased MBTI-intuition) cognition may contribute importantly to enhanced creativity in individuals with bipolar disorder.

  View details for DOI 10.1007/s11920-010-0159-x

  View details for Web of Science ID 000289733500006

  View details for PubMedID 20936438

• What Have We Learned about Trial Design From NIMH-Funded Pragmatic Trials? NEUROPSYCHOPHARMACOLOGY March, J., Kraemer, H. C., Trivedi, M., Csernansky, J., Davis, J., Ketter, T. A., Glick, I. D. 2010; 35 (13): 2491-2501

  Abstract

  At the 2008 annual meeting of the American College of Neuropsychopharmacology (ACNP), a symposium was devoted to the following question: 'what have we learned about the design of pragmatic clinical trials (PCTs) from the recent costly long-term, large-scale trials of psychiatric treatments?' in order to inform the design of future trials. In all, 10 recommendations were generated placing emphasis on (1) appropriate conduct of pragmatic trials; (2) clinical, rather than, merely statistical significance; (3) sampling from the population clinicians are called upon to treat; (4) clinical outcomes of patients, rather than, on outcome measures; (5) use of stratification, controlling, or adjusting when necessary and not otherwise; (6) appropriate consideration of site differences in multisite studies; (7) encouragement of 'post hoc' exploration to generate (not test) hypotheses; (8) precise articulation of the treatment strategy to be tested and use of the corresponding appropriate design; (9) expanded opportunity for training of researchers and reviewers in RCT principles; and (10) greater emphasis on data sharing.

  View details for DOI 10.1038/npp.2010.115

  View details for Web of Science ID 000284104400002

  View details for PubMedID 20736990

  View details for PubMedCentralID PMC3055577

• Higher prevalence of bipolar I disorder among Asian and Latino compared to Caucasian patients receiving treatment ASIA-PACIFIC PSYCHIATRY Hwang, S. H., Childers, M. E., Wang, P. W., Nam, J. Y., Keller, K. L., Hill, S. J., Ketter, T. A. 2010; 2 (3): 156-165

  View details for DOI 10.1111/j.1758-5872.2010.00080.x

  View details for Web of Science ID 000282375900079

• Adjunctive Armodafinil for Major Depressive Episodes Associated With Bipolar I Disorder: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Proof-of-Concept Study JOURNAL OF CLINICAL PSYCHIATRY Calabrese, J. R., Ketter, T. A., Youakim, J. M., Tiller, J. M., Yang, R., Frye, M. A. 2010; 71 (10): 1363-1370

  Abstract

  To evaluate the efficacy and safety of armodafinil, the longer-lasting isomer of modafinil, when used adjunctively in patients with bipolar depression.In this 8-week, multicenter, randomized, double-blind, placebo-controlled study conducted between June 2007 and December 2008, patients who were experiencing a major depressive episode associated with bipolar I disorder (according to DSM-IV-TR criteria) despite treatment with lithium, olanzapine, or valproic acid were randomly assigned to adjunctive armodafinil 150 mg/d (n = 128) or placebo (n = 129) administered once daily in the morning. The primary outcome measure was change from baseline in the total 30-item Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C₃₀) score. Secondary outcomes included changes from baseline in scores on the Montgomery-Åsberg Depression Rating Scale, among other psychological symptom scales. Statistical analyses were performed using analysis of covariance (ANCOVA), with study drug and concurrent mood stabilizer treatment for bipolar disorder as factors and the corresponding baseline value as a covariate. A prespecified sensitivity analysis was done using analysis of variance (ANOVA) if a statistically significant treatment-by-baseline interaction was found. Tolerability was also assessed.A significant baseline-by-treatment interaction in the total IDS-C₃₀ score (P = .08) was found. Patients administered adjunctive armodafinil showed greater improvement in depressive symptoms as seen in the greater mean ± SD change on the total IDS-C₃₀ score (-15.8 ± 11.57) compared with the placebo group (-12.8 ± 12.54) (ANOVA: P = .044; ANCOVA: P = .074). No differences between treatment groups were observed in secondary outcomes. Adverse events reported more frequently in patients receiving adjunctive armodafinil were headache, diarrhea, and insomnia. Armodafinil was not associated with an increased incidence and/or severity of suicidality, depression, or mania or with changes in metabolic profile measurements.In this proof-of-concept study, adjunctive armodafinil 150 mg/d appeared to improve depressive symptoms according to some, but not all, measures and was generally well tolerated in patients with bipolar depression.clinicaltrials.gov Identifier: NCT00481195.

  View details for DOI 10.4088/JCP.09m05900gry

  View details for Web of Science ID 000285444100013

  View details for PubMedID 20673554

• Long-term effectiveness of quetiapine in bipolar disorder in a clinical setting 45th Annual Meeting of the American-College-of-Neuropsychopharmacology Ketter, T. A., Brooks, J. O., Hoblyn, J. C., Holland, A. A., Nam, J. Y., Culver, J. L., Marsh, W. K., Bonner, J. C. PERGAMON-ELSEVIER SCIENCE LTD. 2010: 921–29

  Abstract

  To assess quetiapine effectiveness in bipolar disorder (BD) patients in a clinical setting.We naturalistically administered open quetiapine to outpatients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.96 patients (36 BD I, 50 BD II, 9 BD NOS, 1 Schizoaffective Bipolar Type, mean ± SD age 42.3 ± 13.8 years, 66.7% female) received quetiapine, combined with an average of 2.5 (in 66.7% of patients at least 2) other psychotropic medications and 0.9 non-psychotropic medications, started most often during depressive symptoms (53.1%) or euthymia (37.5%). Mean quetiapine duration and final dose were 385 days and 196 mg/day (50.0% of patients took ≤75 mg/day). Quetiapine was discontinued in 38.5% of trials, after on average 307 days, most often (in 19.8%) due to CNS adverse effects (primarily sedation). In 38.5% of trials quetiapine was continued on average 328 days with no subsequent psychotropic added. In 22.9% quetiapine was continued on average 613 days, but had subsequent psychotropic added after on average 113 days, most often for depressive symptoms. In 67 trials started at Stanford, quetiapine tended to primarily maintain euthymia and relieve depressive symptoms. In 29 trials started prior to Stanford, continuing quetiapine tended to primarily maintain euthymia and relieve mood elevation symptoms. Aside from sedation, quetiapine was generally well tolerated.In bipolar disorder outpatients quetiapine had a moderate (38.5%, with 385-day mean duration) discontinuation rate, and commonly did not require subsequent additional pharmacotherapy, suggesting effectiveness in a clinical setting.

  View details for DOI 10.1016/j.jpsychires.2010.02.005

  View details for Web of Science ID 000283903700009

  View details for PubMedID 20378127

• Nosology, diagnostic challenges, and unmet needs in managing bipolar disorder. journal of clinical psychiatry Ketter, T. A. 2010; 71 (10)

  Abstract

  The spectrum of bipolar disorders includes the subtypes of bipolar I disorder, bipolar II disorder, cyclothymic disorder, and bipolar disorder not otherwise specified (NOS). Because depression is the most pervasive symptom of bipolar disorder, this condition is frequently misdiagnosed as unipolar major depressive disorder. As a result, patients often experience substantive delays in receiving the correct diagnosis and appropriate treatment. To help meet this important diagnostic challenge, various markers have been identified that have predictive value for a bipolar outcome, including early onset of depression, family history of bipolar disorder, atypical depressive symptoms, and the presence of psychosis. Unmet needs in the management of bipolar disorder include an enhanced diagnostic process, more options for treating bipolar depressive episodes, and safer, more tolerable medications for long-term maintenance treatment.

  View details for DOI 10.4088/JCP.8125tx12c

  View details for PubMedID 21062613

• Toward interaction of affective and cognitive contributors to creativity in bipolar disorders: A controlled study JOURNAL OF AFFECTIVE DISORDERS Srivastava, S., Childers, M. E., Baek, J. H., Strong, C. M., Hill, S. J., Warsett, K. S., Wang, P. W., Akiskal, H. S., Akiskal, K. K., Ketter, T. A. 2010; 125 (1-3): 27-34

  Abstract

  Enhanced creativity in bipolar disorder patients may be related to affective and cognitive phenomena.32 bipolar disorder patients (BP), 21 unipolar major depressive disorder patients (MDD), 22 creative controls (CC), and 42 healthy controls (HC) (all euthymic) completed the Revised Neuroticism Extraversion Openness Personality Inventory (NEO), the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A), the Myers-Briggs Type Inventory (MBTI); the Barron-Welsh Art Scale (BWAS), the Adjective Check List Creative Personality Scale, and the Figural and Verbal Torrance Tests of Creative Thinking. Mean scores were compared across groups, and relationships between temperament/personality and creativity were assessed with bivariate correlation and hierarchical multiple linear regression.BP and CC (but not MDD) compared to HC had higher BWAS-Total (46% and 42% higher, respectively, p<0.05) and BWAS-Dislike (83% and 93% higher, p<0.02) scores, and higher MBTI-Intuition preference type rates (78% vs. 50% and 96% vs. 50%, p<0.05). BP, MDD, and CC, compared to HC, had increased TEMPS-A-Cyclothymia scores (666%, 451% and 434% higher, respectively, p<0.0001), and NEO-Neuroticism scores (60%, 57% and 51% higher, p<0.0001). NEO-Neuroticism and TEMPS-A Cyclothymia correlated with BWAS-Dislike (and BWAS-Total), while MBTI-Intuition continuous scores and NEO-Openness correlated with BWAS-Like (and BWAS-Total).Relatively small sample size.We replicate the role of cyclothymic and related temperaments in creativity, as well as that of intuitive processes. Further studies are needed to clarify relationships between creativity and affective and cognitive processes in bipolar disorder patients.

  View details for DOI 10.1016/j.jad.2009.12.018

  View details for Web of Science ID 000281377100004

  View details for PubMedID 20085848

• Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus BIPOLAR DISORDERS Rasgon, N. L., Kenna, H. A., Reynolds-May, M. F., Stemmle, P. G., Vemuri, M., Marsh, W., Wang, P., Ketter, T. A. 2010; 12 (5): 504-513

  Abstract

  Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD.Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women.As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity.Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

  View details for DOI 10.1111/j.1399-5618.2010.00839.x

  View details for Web of Science ID 000280987800005

  View details for PubMedID 20712751

  View details for PubMedCentralID PMC2941396

• Divalproex extended-release in acute bipolar II depression JOURNAL OF AFFECTIVE DISORDERS Wang, P. W., Nowakowska, C., Chandler, R. A., Hill, S. J., Nam, J. Y., Culver, J. L., Keller, K. L., Ketter, T. A. 2010; 124 (1-2): 170-173

  Abstract

  Divalproex extended-release (divalproex-ER) is effective in acute mania, and limited data suggest divalproex may have efficacy in acute bipolar depression.A 7-week, open-label trial of divalproex-ER monotherapy or adjunctive therapy was conducted in 28 outpatients (15 female, mean age 36.7+/-9.1, and mean duration of illness 22.1+/-11.1 years) with bipolar II depression (39% with rapid cycling course of illness within the prior year). Divalproex-ER was generally given as a single dose at bedtime, starting at 250mg and increased by 250mg every 4 days to symptom relief or adverse effects. Efficacy was assessed using weekly prospective Montgomery Asberg Depression Rating Scale (MADRS) scores.Overall, mean divalproex-ER final doses and serum concentrations were 1469mg/day and 80.1microg/mL, respectively. Mean MADRS scores (last observation carried forward) decreased significantly from baseline in patients in the overall group (from 30.1 to 15.2, p<.00001). The overall response rate was 54%. Divalproex-ER therapy was generally well tolerated, with no early discontinuations due to adverse events.This study is limited by a small sample size and an open-label study design with no placebo control.Divalproex-ER as monotherapy and adjunctive therapy was well tolerated and yielded an overall response rate of 54% in bipolar II depression. Based on the results of this pilot study, randomized, double-blind, placebo-controlled studies of divalproex-ER in bipolar II depression are warranted.

  View details for DOI 10.1016/j.jad.2009.10.021

  View details for Web of Science ID 000278787400022

  View details for PubMedID 19923006

• Pharmacokinetic Drug-Drug Interactions Between Olanzapine and Valproate Need to Be Better Studied Reply JOURNAL OF CLINICAL PSYCHIATRY Houston, J. P., Ketter, T. A., Tohen, M., Case, M. G., Degenhardt, E. K., Jamal, H. H. 2010; 71 (7): 958–59

  View details for DOI 10.9088/JCP.09lr05902ayel

  View details for Web of Science ID 000280470700021

• Diagnostic features, prevalence, and impact of bipolar disorder. journal of clinical psychiatry Ketter, T. A. 2010; 71 (6)

  Abstract

  Bipolar disorder shares depressive symptoms with unipolar major depressive disorder but is defined by episodes of mania or hypomania. Bipolar disorder in its broadest sense has a community lifetime prevalence of 4% and is a severely impairing illness that impacts several aspects of patients' lives. Race, ethnicity, and gender have no effect on prevalence rates, but women are more likely to experience rapid cycling, mixed states, depressive episodes, and bipolar II disorder than men. Patients with bipolar disorder have high rates of disability and higher rates of mortality than individuals without bipolar disorder. Natural causes such as cardiovascular disease and diabetes, as well as suicide and other "unnatural" causes are key contributors to the high mortality rate. The costs associated with bipolar disorder include not only the direct costs of treatment, but also the much greater indirect costs of decreased productivity, excess unemployment, and excess mortality.

  View details for DOI 10.4088/JCP.8125tx11c

  View details for PubMedID 20573324

• Metabolic evidence of corticolimbic dysregulation in bipolar mania PSYCHIATRY RESEARCH-NEUROIMAGING Brooks, J. O., Hoblyn, J. C., Ketter, T. A. 2010; 181 (2): 136-140

  Abstract

  Findings from previous research on the neural substrates of mania have been variable, in part because of heterogeneity of techniques and patients. Though some findings have been replicated, the constellation of neurophysiological changes has not been demonstrated simultaneously. We sought to determine resting state cerebral metabolic changes associated with relatively severe acute mania. Resting positron emission tomography with (18)fluorodeoxyglucose was performed in bipolar disorder patients with severe mania and in healthy controls. Statistical parametric mapping was used to determine regions of differential metabolism. Relative to controls, bipolar disorder patients with mania exhibited significantly decreased cerebral metabolism in both the dorsolateral prefrontal regions and the precuneus. Conversely, manic patients exhibited significant hypermetabolism in the parahippocampal complex, temporal lobe, anterior cingulate, and subgenual prefrontal cortex compared with controls. These results demonstrate simultaneous resting limbic/paralimbic hypermetabolism and prefrontal hypometabolism during mania. The findings support the hypothesis of corticolimbic dysregulation as a crucial contributor to the pathophysiology of bipolar disorder.

  View details for DOI 10.1016/j.pscychresns.2009.08.006

  View details for Web of Science ID 000275009200009

  View details for PubMedID 20080037

• Strategies for monitoring outcomes in patients with bipolar disorder. Primary care companion to the Journal of clinical psychiatry Ketter, T. A. 2010; 12: 10-16

  Abstract

  Practical strategies are available for primary care physicians to monitor psychiatric and medical outcomes as well as treatment adherence in patients with bipolar disorder. Current depressive symptoms can be assessed with tools like the 9-item Patient Health Questionnaire or Beck Depression Inventory. Lifetime presence or absence of manic or hypomanic symptoms can be assessed using the Mood Disorder Questionnaire (MDQ). These measures can be completed quickly by patients prior to appointments. Sensitivity of such ratings, particularly the MDQ, can be increased by having a significant other also rate the patient. Clinicians should also screen mood disorder patients for psychiatric comorbidities that are common in this population such as anxiety and substance use disorders. While patients with bipolar disorder may commonly be nonadherent with prescribed medication regimens, strategies that can help include having frank discussions with the patient, selecting medication collaboratively, adding psychotherapy with a psychoeducation element, monitoring appointment-keeping, using patient self-reports of medication-taking, enlisting the aid of significant others, and measuring plasma drug levels. Medical monitoring is needed to assess the safety and tolerability of psychotropic medications. All of the approved medications for bipolar disorder have at least 1 boxed warning for serious side effects, but are also associated with other common management-limiting side effects such as sedation, tremor, unsteadiness, restlessness, nausea, vomiting, diarrhea, constipation, weight gain, and metabolic problems. Routine monitoring is particularly needed for obesity, metabolic syndrome, and cardiovascular disorders, which lead to high rates of medical morbidity and mortality in patients with bipolar disorder. Monitoring protocols such as the one recommended by the American Diabetes Association for patients taking second-generation antipsychotics can be used for regular assessment.

  View details for DOI 10.4088/PCC.9064su1c.02

  View details for PubMedID 20628501

  View details for PubMedCentralID PMC2902193

• Principles of Assessment and Treatment of Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Ketter, T. A. 2010: 1–9

  View details for Web of Science ID 000294220800002

• Handbook of Diagnosis and Treatment of BIPOLAR DISORDERS Preface HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Ketter, T. A. 2010: XIII-XIV

  View details for Web of Science ID 000294220800001

• Management of Rapid-Cycling Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 331–87

  View details for Web of Science ID 000294220800010

• Florida Best Practice Medication Guidelines for Bipolar Disorder HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 677–83

  View details for Web of Science ID 000294220800017

• Management of Acute Manic and Mixed Episodes in Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 107–64

  View details for Web of Science ID 000294220800007

• Addressing Clinical Diagnostic Challenges in Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 39–68

  View details for Web of Science ID 000294220800004

• Multiphase Treatment Strategy for Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Culver, J. L., Ketter, T. A. 2010: 69–81

  View details for Web of Science ID 000294220800005

• Overview of Pharmacotherapy for Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 83–106

  View details for Web of Science ID 000294220800006

• Antidepressants, Anxiolytics/Hypnotics, and Other Medications Pharmacokinetics, Drug Interactions, Adverse Effects, and Administration HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 611–60

  View details for Web of Science ID 000294220800015

• DSM-IV-TR Diagnosis of Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 11–37

  View details for Web of Science ID 000294220800003

• Longer-Term Management of Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 251–330

  View details for Web of Science ID 000294220800009

• Management of Acute Major Depressive Episodes in Bipolar Disorders HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Wang, P. W., Ketter, T. A., Ketter, T. A. 2010: 165–250

  View details for Web of Science ID 000294220800008

• Mood Stabilizers and Antipsychotics Pharmacokinetics, Drug Interactions, Adverse Effects, and Administration HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Ketter, T. A., Wang, P. W., Ketter, T. A. 2010: 499–609

  View details for Web of Science ID 000294220800014

• Management of Bipolar Disorders in Older Adults HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Brooks, J. O., Sommer, B. R., Ketter, T. A., Ketter, T. A. 2010: 453–97

  View details for Web of Science ID 000294220800013

• Linkage Disequilibrium Mapping of The Chromosome 6q21-22.31 Bipolar I Disorder Susceptibility Locus AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Fan, J., Ionita-Laza, I., McQueen, M. B., Devlin, B., Purcell, S., Faraone, S. V., Allen, M. H., Bowden, C. L., Calabrese, J. R., Fossey, M. D., Friedman, E. S., Gyulai, L., Hauser, P., Ketter, T. B., Marangell, L. B., Miklowitz, D. J., Nierenberg, A. A., Patel, J. K., Sachs, G. S., Thase, M. E., Molay, F. B., Escamilla, M. A., Nimgaonkar, V. L., Sklar, P., Laird, N. M., Smoller, J. W. 2010; 153B (1): 29-37

  Abstract

  We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

  View details for DOI 10.1002/ajmg.b.30942

  View details for Web of Science ID 000273440500004

  View details for PubMedID 19308960

• Rapid antipsychotic response with ziprasidone predicts subsequent acute manic/mixed episode remission JOURNAL OF PSYCHIATRIC RESEARCH Ketter, T. A., Agid, O., Kapur, S., Loebel, A., Siu, C. O., Romano, S. J. 2010; 44 (1): 8-14

  Abstract

  To assess rapid antipsychotic efficacy with oral ziprasidone monotherapy in bipolar acute manic/mixed episodes with psychotic features, and predictive value of rapid antipsychotic response for subsequent acute manic/mixed episode remission.Pooled analysis of two 3-week, randomized, double-blind, placebo-controlled trials of ziprasidone (40-160mg/d) in inpatients with bipolar I disorder, and a current manic or mixed episode, with (n=152) or without (n=246) psychotic features. Psychosis improvement was evaluated by change in SADS-C psychosis score (sum of delusions, hallucinations, and suspiciousness items). Rapid antipsychotic response (>or=50% decrease in SADS-C psychosis score by Day 4) and acute manic episode response and remission (endpoint >or=50% MRS decrease, and a MRS score

  View details for DOI 10.1016/j.jpsychires.2009.07.006

  View details for Web of Science ID 000274499100002

  View details for PubMedID 19699488

• Atypical Antipsychotics for Acute Manic and Mixed Episodes in Children and Adolescents with Bipolar Disorder Efficacy and Tolerability DRUGS Singh, M. K., Ketter, T. A., Chang, K. D. 2010; 70 (4): 433-442

  Abstract

  The diagnosis of bipolar disorder (BD) in children is increasing, and often requires a comprehensive treatment plan to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for the treatment and stabilization of disrupted mood. Current evidence collectively demonstrates, by randomized controlled design, that atypical antipsychotics have efficacy for the treatment of acute manic or mixed symptoms in children and adolescents with BD. Additional longitudinal and biological studies are warranted to characterize the effects of atypical antipsychotics on all phases and stages of bipolar illness development in children and adolescents.

  View details for PubMedID 20205485

• Resting Prefrontal Hypometabolism and Paralimbic Hypermetabolism Related to Verbal Recall Deficits in Euthymic Older Adults With Bipolar Disorder 62nd Annual Meeting of the Society-of-Biological-Psychiatry Brooks, J. O., Rosen, A. C., Hoblyn, J. C., Woodard, S. A., Krasnykh, O., Ketter, T. A. LIPPINCOTT WILLIAMS & WILKINS. 2009: 1022–29

  Abstract

  To evaluate deficits of delayed free recall in euthymic older patients with bipolar disorder and relate deficits to resting cerebral metabolism.Two group, between subjects.Outpatient.Participants included 16 older adult (mean age, 58.7 years; SD = 7.5) euthymic outpatients with bipolar disorder (10 Type I and 6 Type II) and 11 healthy comparison subjects (mean age, 58.3 years; SD = 5.2).All participants received resting positron emission tomography with (18)flurodeoxyglucose and, within 10 days, delayed free verbal recall testing with the California Verbal Learning Test II.Patients with bipolar disorder, relative to healthy comparison subjects, had significantly poorer delayed free verbal recall. In patients with bipolar disorder, relative to healthy comparison subjects, prefrontal hypometabolism (dorsolateral prefrontal cortex) and paralimbic hypermetabolism (hippocampus, parahippocampal gyrus, and superior temporal gyrus) was associated with recall deficits in patients with bipolar disorder. Prefrontal and limbic metabolism were inversely related.Our findings demonstrate an association between prefrontal hypometabolism and paralimbic hypermetabolism and verbal memory deficits in euthymic older patients with bipolar disorder. Verbal memory deficits may be a clinical consequence of corticolimbic dysregulation in bipolar disorder, even during euthymia. This suggests that such dysregulation and related deficits could be bipolar disorder traits.

  View details for DOI 10.1097/JGP.0b013e3181ad4d47

  View details for Web of Science ID 000272459700004

  View details for PubMedID 20104059

• Lithium treatment-moderate dose use study (LiTMUS) for bipolar disorder: rationale and design CLINICAL TRIALS Nierenberg, A. A., Sylvia, L. G., Leon, A. C., Reilly-Harrington, N. A., Ketter, T. A., Calabrese, J. R., Thase, M. E., Bowden, C. L., Friedman, E. S., Ostacher, M. J., Novak, L., Iosifescu, D. V. 2009; 6 (6): 637-648

  Abstract

  Recent data indicate that lithium use for bipolar disorder has declined over the last decade and that lithium largely has been replaced with alternate, commercially promoted medications that may or may not result in better outcomes.This article describes the rationale and study design of LiTMUS, a multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. LiTMUS seeks to address whether initiating therapy at lower doses of lithium as part of optimized treatment (OPT, guideline-informed, evidence-based, and personalized pharmacotherapy) improves outcomes and decreases the need for other medication changes across 6 months of therapy.LiTMUS will randomize 284 adults with bipolar disorder (Type I or II) across 6 study sites. The co-primary outcomes are overall illness severity on clinical global improvement scale for bipolar disorder and a novel measure, necessary clinical adjustments. This metric provides a composite that reflects both clinical response and tolerability. Other relevant outcomes include full symptomatic recovery, quality of life, suicidal behaviors, and moderators of suicidality.As of August 28th, 2009, we have consented 338 patients and randomized 281 for this study.The potential limitations of the study include an arbitrary definition of 'low, but effective' doses of lithium, lack of a placebo-controlled group, open treatment, and use of a new outcome measure (i.e., necessary clinical adjustments).We expect that this study will inform our understanding of the effectiveness of low to moderate doses of lithium therapy for individuals with bipolar disorder.

  View details for DOI 10.1177/1740774509347399

  View details for Web of Science ID 000272678800008

  View details for PubMedID 19933719

• Olanzapine-Divalproex Combination Versus Divalproex Monotherapy in the Treatment of Bipolar Mixed Episodes: A Double-Blind, Placebo-Controlled Study JOURNAL OF CLINICAL PSYCHIATRY Houston, J. P., Tohen, M., Degenhardt, E. K., Jamal, H. H., Liu, L. L., Ketter, T. A. 2009; 70 (11): 1540-1547

  Abstract

  This 6-week, randomized, double-blind, placebo-controlled trial used simultaneous depression and mania criteria to compare a single mood stabilizer, divalproex, with and without adjunctive olanzapine in patients with bipolar I disorder experiencing acute mixed episodes.Two hundred two adults, aged 18 to 60 years, who met DSM-IV-TR criteria for bipolar disorder with a current mixed episode and had been taking divalproex for >or=14 days at levels of 75 to 125 microg/mL with inadequate efficacy (21-item Hamilton Depression Rating Scale [HDRS-21] and Young Mania Rating Scale [YMRS] scores >or=16) were randomly assigned to olanzapine 5 to 20 mg/d versus placebo augmentation. HDRS-21, YMRS, Clinical Global Impressions for Bipolar Disorder (CGI-BP), hospitalizations, concomitant medications, and adverse events were assessed. Comparisons included changes in both HDRS-21 and YMRS (primary outcome measure), time to partial response and time to response, CGI-BP improvement, hospitalizations, and safety (secondary outcome measures). The study was conducted from December 2006 to February 2008.Mean (SD) baseline HDRS-21 and YMRS scores were 22.2 (4.5) and 20.9 (4.4), respectively, with 59% female and 51% white subjects. Mean +/- SE score changes from baseline across the 6-week treatment period for adjunctive olanzapine (n = 100) versus adjunctive placebo (n = 101) arms, respectively, were -9.37 +/- 0.55 versus -7.69 +/- 0.54, P = .022, on the HDRS-21 and -10.15 +/- 0.44 versus -7.68 +/- 0.44 P < .001, on the YMRS. Mean +/- SE score changes from baseline to last observation carried forward for CGI-BP measures were -1.34 +/- 0.11 for adjunctive olanzapine versus -1.06 +/- 0.11 for adjunctive placebo, P = .056. Time to partial response (>or=25% HDRS-21 and YMRS decreases, median 7 versus 14 days) and time to response (>or=50% HDRS-21 and YMRS decreases, median 25 versus 49 days) were significantly shorter with adjunctive olanzapine. Increases in weight (total and >or=7%) and fasting blood glucose were significantly greater with adjunctive olanzapine.Adjunctive olanzapine yielded greater and earlier reduction of manic and depressive symptoms in mixed-episode patients with inadequate response to at least 2 weeks of divalproex.clinicaltrials.gov Identifier: NCT00402324.

  View details for DOI 10.4088/JCP.08m04895yel

  View details for Web of Science ID 000272206200009

  View details for PubMedID 19778495

• Teaching the philosophy and tools of evidence-based medicine: misunderstandings and solutions. Journal of evidence-based medicine Citrome, L., Ketter, T. A. 2009; 2 (4): 220-225

  View details for DOI 10.1111/j.1756-5391.2009.01041.x

  View details for PubMedID 21349020

• Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia BIPOLAR DISORDERS Mansour, H. A., Talkowski, M. E., Wood, J., Chowdari, K., McClain, L., Prasad, K., Montrose, D., Fagiolini, A., Friedman, E. S., Allen, M. H., Bowden, C. L., Calabrese, J., El-Mallakh, R. S., Escamilla, M., Faraone, S. V., Fossey, M. D., Gyulai, L., Loftis, J. M., Hauser, P., Ketter, T. A., Marangell, L. B., Miklowitz, D. J., Nierenberg, A. A., Patel, J., Sachs, G. S., Sklar, P., Smoller, J. W., Laird, N., Keshavan, M., Thase, M. E., Axelson, D., Birmaher, B., Lewis, D., Monk, T., Frank, E., Kupfer, D. J., Devlin, B., Nimgaonkar, V. L. 2009; 11 (7): 701-710

  Abstract

  Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL.Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.

  View details for Web of Science ID 000270826100003

  View details for PubMedID 19839995

  View details for PubMedCentralID PMC3401899

• Mood Stabilization and Destabilization During Acute and Continuation Phase Treatment for Bipolar I Disorder With Lamotrigine or Placebo JOURNAL OF CLINICAL PSYCHIATRY Goldberg, J. F., Calabrese, J. R., Saville, B. R., Frye, M. A., Ketter, T. A., Suppes, T., Post, R. M., Goodwin, F. K. 2009; 70 (9): 1273-1280

  Abstract

  During post-acute phase pharmacotherapy for bipolar disorder, there has been little empirical study to establish when emerging mania symptoms (1) are of clinical significance and (2) reflect iatrogenic events versus the natural course of illness.Secondary analyses were conducted in a previously studied group of bipolar I disorder (DSM-IV) outpatients randomly assigned to lamotrigine monotherapy (n=171) or placebo (n=121), and a larger prerandomization group (N=966) during open-label titration of lamotrigine, following an index depressive episode. Time until the emergence of mania symptoms, at varying severity thresholds, was examined over 6 months for lamotrigine versus placebo, while controlling for potential confounding factors in Cox proportional hazard models. Subject enrollment occurred between July 1997 and August 2001.Rates of mood elevation during both acute open-label and randomized continuation phases of lamotrigine treatment were comparable to those seen with placebo during the randomized phase. The hazard ratio for the emergence of mania symptoms with lamotrigine was not significantly different from placebo (hazard ratio=0.79; 95% CI, 0.53 to 1.16), with an upper bound that suggests no meaningful increase in susceptibility toward mania with lamotrigine. By contrast, clinically meaningful rises in mania symptom severity were predicted by baseline residual manic symptoms prerandomization and by the number of manic, hypomanic, or mixed episodes in the past year.Based on a composite definition of mood destabilization involving a range of severity thresholds for emerging signs of mania, lamotrigine confers no meaningful elevated risk relative to placebo for mood destabilization in bipolar I disorder. Rather, illness burden related to residual or lifetime mania features may hold greater importance for explaining mania relapses or breakthrough manic features during lamotrigine continuation pharmacotherapy.

  View details for DOI 10.4088/JCP.08m04381

  View details for Web of Science ID 000270246700010

  View details for PubMedID 19689918

• Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies ACTA PSYCHIATRICA SCANDINAVICA Frye, M. A., Yatham, L., Ketter, T. A., Goldberg, J., Suppes, T., Calabrese, J. R., Bowden, C. L., Bourne, E., Bahn, R. S., Adams, B. 2009; 120 (1): 10-13

  Abstract

  To assess the relationship between depressive relapse and change in thyroid function in an exploratory post hoc analysis from a controlled maintenance evaluation of bipolar I disorder.Mean thyroid-stimulating hormone (TSH) and outcome data were pooled from two 18-month, double-blind, placebo-controlled, maintenance studies of lamotrigine and lithium monotherapy. A post hoc analysis of 109 subjects (n = 55 lamotrigine, n = 32 lithium, n = 22 placebo) with serum TSH values at screening and either week 52 (+/-14 days) or study drop-out was conducted.Lithium-treated subjects who required an intervention for a depressive episode had a significantly higher adjusted mean TSH level (4.4 microIU/ml) compared with lithium-treated subjects who did not require intervention for a depressive episode (2.4 microIU/ml).Lithium-related changes in thyroid function are clinically relevant and should be carefully monitored in the maintenance phase of bipolar disorder to maximize mood stability and minimize the risk of subsyndromal or syndromal depressive relapse.

  View details for DOI 10.1111/j.1600-0447.2008.01343.x

  View details for Web of Science ID 000266636100002

  View details for PubMedID 19183414

• Dorsolateral and dorsomedial prefrontal gray matter density changes associated with bipolar depression PSYCHIATRY RESEARCH-NEUROIMAGING Brooks, J. O., Bonner, J. C., Rosen, A. C., Wang, P. W., Hoblyn, J. C., Hill, S. J., Ketter, T. A. 2009; 172 (3): 200-204

  Abstract

  Mood states are associated with alterations in cerebral blood flow and metabolism, yet changes in cerebral structure are typically viewed in the context of enduring traits, genetic predispositions, or the outcome of chronic psychiatric illness. Magnetic resonance imaging (MRI) scans were obtained from two groups of patients with bipolar disorder. In one group, patients met criteria for a current major depressive episode whereas in the other no patient did. No patient in either group met criteria for a current manic, hypomanic, or mixed episode. Groups were matched with respect to age and illness severity. Analyses of gray matter density were performed with Statistical Parametric Mapping software (SPM5). Compared with non-depressed bipolar subjects, depressed bipolar subjects exhibited lower gray matter density in the right dorsolateral and bilateral dorsomedial prefrontal cortices and portions of the left parietal lobe. In addition, gray matter density was greater in the left temporal lobe and right posterior cingulate cortex/parahippocampal gyrus in depressed than in non-depressed subjects. Our findings highlight the importance of mood state in structural studies of the brain-an issue that has received insufficient attention to date. Moreover, our observed differences in gray matter density overlap metabolic areas of change and thus have implications for the conceptualization and treatment of affective disorders.

  View details for DOI 10.1016/j.pscychresns.2008.06.007

  View details for Web of Science ID 000266580800005

  View details for PubMedID 19351579

  View details for PubMedCentralID PMC3265395

• The long term effectiveness of quetiapine plus lamotrigine therapy in bipolar patients 8th International Conference on Bipolar Disorder Ketter, T. A., Johnson, K., Childers, M., Srivastava, S., Brooks, J. O., Hoblyn, J. C. WILEY-BLACKWELL. 2009: 53–53

  View details for Web of Science ID 000268963500144

• Adjunctive armodafinil for major depression associated with bipolar I disorder: a randomized, double-blind, placebo-controlled study 8th International Conference on Bipolar Disorder Calabrese, J. R., Ketter, T. A., Youakim, J. M., Tiller, J., Yang, R., Frye, M. A. WILEY-BLACKWELL. 2009: 26–26

  View details for Web of Science ID 000268963500069

• Increased depressive symptoms in menopausal age women with bipolar disorder: Age and gender comparison JOURNAL OF PSYCHIATRIC RESEARCH Marsh, W. K., Ketter, T. A., Rasgon, N. L. 2009; 43 (8): 798-802

  Abstract

  Emerging data suggest the menopausal transition may be a time of increased risk for depression. This study examines the course of bipolar disorder focusing on depressive symptoms in menopausal transition age women, compared to similar-aged men as well as younger adult women and men.Outpatients with bipolar disorder were assessed with the systematic treatment enhancement program for bipolar disorder (STEP-BD) affective disorders evaluation and longitudinally monitored during naturalistic treatment with the STEP-BD clinical monitoring form. Clinical status (syndromal/subsyndromal depressive symptoms, syndromal/subsyndromal elevation or mixed symptoms, and euthymia) was compared between menopausal transition age women (n=47) and pooled similar-aged men (n=30) 45-55 years old, younger women (n=48) and men (n=39) 30-40 years old.Subjects included 164 bipolar disorder patients (67 type I, 82 type II, and 15 not otherwise specified), 34% were rapid cycling and 58% women. Bipolar II disorder/bipolar NOS was more common in women. Monitoring averaged 30+/-22 months, with an average of 0.9+/-0.5 clinic visits/month. Menopausal age women had a significantly greater proportion of visits with depressive symptoms (p<0.05), significantly fewer euthymic visits (p<0.05) and no difference in proportion of visits with elevated/mixed symptoms compared to pooled comparison group.Menopausal transition age women with bipolar disorder experience a greater proportion of clinic visits with depressive symptoms compared to similarly aged men, and younger women and men with bipolar disorder. Further systematic assessment on the influence of the menopausal transition and reproductive hormones upon mood is needed to better inform clinical practice in treating women with bipolar disorder.

  View details for DOI 10.1016/j.jpsychires.2008.11.003

  View details for Web of Science ID 000266177600008

  View details for PubMedID 19155021

• Do positive emotions predict symptomatic change in bipolar disorder? BIPOLAR DISORDERS Gruber, J., Culver, J. L., Johnson, S. L., Nam, J. Y., Keller, K. L., Ketter, T. A. 2009; 11 (3): 330-336

  Abstract

  Bipolar disorder is associated with positive emotion disturbance, though it is less clear which specific positive emotions are affected.The present study examined differences among distinct positive emotions in recovered bipolar disorder (BD) patients (n = 55) and nonclinical controls (NC) (n = 32) and whether they prospectively predicted symptom severity in patients with BD. At baseline, participants completed self-report measures of several distinct trait positive emotions. Structured assessments of diagnosis and current mood symptoms were obtained for BD participants. At a six-month follow-up, a subset of BD participants' (n = 39) symptoms were reassessed.BD participants reported lower joy, compassion, love, awe, and contentment compared to NC participants. BD and NC participants did not differ in pride or amusement. For BD participants, after controlling for baseline symptom severity, joy and amusement predicted increased mania severity, and compassion predicted decreased mania severity at the six-month follow-up. Furthermore, amusement predicted increased depression severity and pride predicted decreased severity of depression. Awe, love, and contentment did not predict symptom severity.These results are consistent with a growing literature highlighting the importance of positive emotion in the course of bipolar disorder.

  View details for DOI 10.1111/j.1399-5618.2009.00679.x

  View details for Web of Science ID 000265185000010

  View details for PubMedID 19419390

  View details for PubMedCentralID PMC2850607

• A Double-Blind, Placebo-Controlled Trial of Olanzapine Augmentation in Bipolar I Disorder, Mixed Episode 64th Annual Convention of the Society-of-Biological-Psychiatry Houston, J. P., Tohen, M., Degenhardt, E., Jamal, H. H., Liu, L., Ketter, T. A. ELSEVIER SCIENCE INC. 2009: 131S–131S

  View details for Web of Science ID 000265144200424

• Safety and Tolerability Associated with Second Generation Antipsychotic Polytherapy in Bipolar Disorder: Findings from STEP-BD Brooks, J., Goldberg, J. F., Ketter, T. A., Miklowitz, D. J., Calabrese, J. R., Bowden, C. L., Thase, M. E. ELSEVIER SCIENCE INC. 2009: 138S

  View details for Web of Science ID 000265144200445

• Sleep functioning in relation to mood, function, and quality of life at entry to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) JOURNAL OF AFFECTIVE DISORDERS Gruber, J., Harvey, A. G., Wang, P. W., Brooks, J. O., Thase, M. E., Sachs, G. S., Ketter, T. A. 2009; 114 (1-3): 41-49

  Abstract

  Sleep disturbance in bipolar disorder can be both a risk factor and symptom of mood episodes. However, the associations among sleep and clinical characteristics, function, and quality of life in bipolar disorder have not been fully investigated.The prevalence of sleep disturbance, duration, and variability, as well as their associations with mood, function, and quality of life, was determined from 2024 bipolar patients enrolled in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).Analyses indicated that 32% of patients were classified as short sleepers, 38% normal sleepers, and 23% long sleepers. Overall, short sleepers demonstrated greater mood elevation, earlier age at onset, and longer illness duration compared to both normal and long sleepers. Both short and long sleepers had greater depressive symptoms, poorer life functioning, and quality of life compared to normal sleepers.Short sleep duration in bipolar disorder was associated with a more severe symptom presentation, whereas both short and long sleep duration are associated with poorer function and quality of life compared to normal sleep duration. Sleep disturbance could be a trait marker of bipolar disorder, though longitudinal assessments are warranted to assess potential causal relations and the longer-term implications of sleep disturbance in bipolar disorder.

  View details for DOI 10.1016/j.jad.2008.06.028

  View details for Web of Science ID 000264223900004

  View details for PubMedID 18707765

  View details for PubMedCentralID PMC2677624

• Teaching the philosophy and tools of evidence-based medicine: misunderstandings and solutions INTERNATIONAL JOURNAL OF CLINICAL PRACTICE Citrome, L., Ketter, T. A. 2009; 63 (3): 353-359

  View details for DOI 10.1111/j.1742-1241.2009.02014.x

  View details for Web of Science ID 000262953500004

  View details for PubMedID 19222621

• Treating bipolar disorder: monotherapy versus combination therapy. journal of clinical psychiatry Ketter, T. A. 2009; 70 (2)

  Abstract

  Combination treatments for patients with bipolar disorder can be potentially advantageous for patients due to the therapeutic synergy. However, combining treatments can also increase the possibility of drug interactions and adverse effects. When considering using combination therapy, clinicians should evaluate the efficacy, tolerability, and safety of the combination for each individual patient. Physicians should exercise caution when treating patients with a combination of medications and strive to use monotherapy when feasible.

  View details for PubMedID 19265641

• Depressive Illness Burden Associated With Complex Polypharmacy in Patients With Bipolar Disorder: Findings From the STEP-BD JOURNAL OF CLINICAL PSYCHIATRY Goldberg, J. F., Brooks, J. O., Kurita, K., Hoblyn, J. C., Ghaemi, N., Perlis, R. H., Miklowitz, D. J., Ketter, T. A., Sachs, G. S., Thase, M. E. 2009; 70 (2): 155-162

  Abstract

  Many patients with bipolar disorder receive multi-drug treatment regimens, but the distinguishing profiles of patients who receive complex pharmacologies have not been established.Prescribing patterns of lithium, anticonvulsants, antidepressants, and antipsychotics were examined for 4,035 subjects with bipolar disorder (DSM-IV) immediately prior to entering the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Subjects were recruited for participation across 22 centers in the United States between November 1999 and July 2005. The quality receiver operating characteristic (ROC) method was used to develop composite profiles of patients receiving complex regimens (p < .01 for all iterations).Use of 3 or more medications occurred in 40% of subjects, while 18% received 4 or more agents. Quality ROC analyses revealed that subjects had a 64% risk for receiving a complex regimen (> or = 4 medications) if they had (1) ever taken an atypical antipsychotic, (2) > or = 6 lifetime depressive episodes, (3) attempted suicide, and (4) an annual income > or = $75,000. Complex polypharmacy was least often associated with lithium, divalproex, or carbamazepine and most often associated with atypical antipsychotics or antidepressants. Contrary to expectations, a history of psychosis, age at onset, bipolar I versus II subtype, history of rapid cycling, prior hospitalizations, current illness state, and history of alcohol or substance use disorders did not significantly alter the risk profiles for receiving complex regimens.Complex polypharmacy involving at least 4 medications occurs in approximately 1 in 5 individuals with bipolar disorder. Use of traditional mood stabilizers is associated with fewer cotherapies. Complex regimens are especially common in patients with substantial depressive illness burden and suicidality, for whom simpler drug regimens may fail to produce acceptable levels of response.clinicaltrials.gov Identifier: NCT00012558.

  View details for Web of Science ID 000263627300001

  View details for PubMedID 19210946

• Corticolimbic metabolic dysregulation in euthymic older adults with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Brooks, J. O., Hoblyn, J. C., Woodard, S. A., Rosen, A. C., Ketter, T. A. 2009; 43 (5): 497-502

  Abstract

  The corticolimbic dysregulation hypothesis of bipolar disorder suggests that depressive symptoms are related to dysregulation of components of an anterior paralimbic network (anterior cingulate, anterior temporal cortex, dorsolateral prefrontal cortex, parahippocampal gyrus, and amygdala) with excessive anterior limbic activity accompanied by diminished prefrontal activity. In younger patients, such abnormalities tend to resolve with remission of depression, but it remains to be established whether the same is true for older patients. This was a cross-sectional, between-subjects design conducted with 16 euthymic, medicated patients with bipolar disorder (10 type I, six type II) and 11 age-matched healthy controls. All participants were over age 50. Our main outcome measures were relative rates of cerebral metabolism derived from a resting (18)flourodeoxyglucose positron emission tomography scan in specified regions of interest in the corticolimbic network. Resting metabolic rates in bipolar patients were significantly greater than in controls in bilateral amygdalae, bilateral parahippocampal gyri, and right anterior temporal cortex (BA 20, 38); they were significantly lower in bipolar patients than in controls in the bilateral dorsolateral prefrontal cortices (BA 9, 10, 46). The evidence of corticolimbic dysregulation observed is consistent with the hypothesis that bipolar disorder entails progressive, pernicious neurobiological disruptions that may eventually persist during euthymia. Persistent corticolimbic dysregulation may be related to residual affective, behavioral, and cognitive symptoms in older patients with bipolar disorder, even when not experiencing syndromal mood disturbance.

  View details for DOI 10.1016/j.jpsychires.2008.08.001

  View details for Web of Science ID 000264224700001

  View details for PubMedID 18947837

  View details for PubMedCentralID PMC2693401

• Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder. Journal of psychiatric research Brooks, J. O., Wang, P. W., Bonner, J. C., Rosen, A. C., Hoblyn, J. C., Hill, S. J., Ketter, T. A. 2009; 43 (3): 181-188

  Abstract

  This study explored whether cerebral metabolic changes seen in treatment resistant and rapid cycling bipolar depression inpatients are also found in an outpatient sample not specifically selected for treatment resistance or rapid cycling. We assessed 15 depressed outpatients with bipolar disorder (six type I and nine type II) who were medication-free for at least 2 weeks and were not predominantly rapid cycling. The average 28-item Hamilton Depression Scale (HAM-D) total score was 33.9. The healthy control group comprised 19 age-matched subjects. All participants received a resting quantitative 18F-fluoro-deoxyglucose positron emission tomography scan. Data analyses were performed with Statistical Parametric Mapping (SPM5). Analyses revealed that depressed patients exhibited similar global metabolism, but decreased absolute regional metabolism in the left much more than right dorsolateral prefrontal cortex, bilateral (left greater than right) insula, bilateral subgenual prefrontal cortex, anterior cingulate, medial prefrontal cortex, ventral striatum, and right precuneus. No region exhibited absolute hypermetabolism. Moreover, HAM-D scores inversely correlated with absolute global metabolism and regional metabolism in the bilateral medial prefrontal gyrus, postcentral gyrus, and middle temporal gyrus. Analysis of relative cerebral metabolism yielded a similar, but less robust pattern of findings. Our findings confirm prefrontal and anterior paralimbic metabolic decreases in cerebral metabolism outside of inpatients specifically selected for treatment resistant and rapid cycling bipolar disorder. Prefrontal metabolic rates were inversely related to severity of depression. There was no evidence of regional hypermetabolism, perhaps because this phenomenon is less robust or more variable than prefrontal hypometabolism.

  View details for DOI 10.1016/j.jpsychires.2008.04.015

  View details for PubMedID 18582900

• Psychotropic medications in bipolar disorder: Pharmacodynamics, pharmacokinetics, drug interactions, adverse effects and their management BIPOLAR DISORDER: A CLINICIAN'S GUIDE TO TREATMENT MANAGEMENT, 2ND EDITION Ketter, T. A., Wang, P. W., Yatham, L. N., Kusumakar 2009: 437–550

  View details for Web of Science ID 000305974800017

• Carbamazepine and Oxcarbazepine AMERICAN PSYCHIATRIC PUBLISHING TEXTBOOK OF PSYCHOPHARMACOLOGY, 4TH EDITION Ketter, T. A., Wang, P. W., Post, R. M., Schatzberg, A. F., Nemeroff, C. B. 2009: 735–65

  View details for Web of Science ID 000310050700038

• Insulin resistance and hyperlipidemia in women with bipolar disorder. Journal of psychiatric research Stemmle, P. G., Kenna, H. A., Wang, P. W., Hill, S. J., Ketter, T. A., Rasgon, N. L. 2009; 43 (3): 341-343

  View details for DOI 10.1016/j.jpsychires.2008.04.003

  View details for PubMedID 18490029

• Combination therapy versus monotherapy in bipolar disorder. journal of clinical psychiatry Ketter, T. A. 2008; 69 (12)

  Abstract

  Patients experiencing breakthrough manic or mixed episodes during maintenance therapy for bipolar disorder should first be assessed to ensure they are receiving an optimal dose of the first-line medication. If further intervention is needed, one option is to combine an atypical antipsychotic and a mood stabilizer. The decision to use a particular combination should be made on the basis of the efficacy, tolerability, and safety of each medication for individual patients. Psychosocial therapy as an adjunct to medication is also useful in delaying relapse.

  View details for PubMedID 19203484

• Effectiveness of lamotrigine in bipolar disorder in a clinical setting JOURNAL OF PSYCHIATRIC RESEARCH Ketter, T. A., Brooks, J. O., Hoblyn, J. C., Champion, L. M., Nam, J. Y., Culver, J. L., Marsh, W. K., Bonner, J. C. 2008; 43 (1): 13-23

  Abstract

  To assess lamotrigine effectiveness in bipolar disorder (BD) patients in a clinical setting.Open lamotrigine was naturalistically administered to outpatients at the Stanford University BD Clinic assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form.One hundred and ninety-seven patients (64 BD I, 110 BD II, 21 BD NOS, 2 Schizoaffective Bipolar Type, mean+/-SD age 42.2+/-14.4 years, 62% female) had 200 trials of lamotrigine. Lamotrigine was combined with a mean of 2.1+/-1.5 other psychotropic medications, most often during euthymia or depressive symptoms. Mean lamotrigine duration was 434+/-444 days, and mean final dose was 236+/-132mg/day without valproate, and 169+/-137mg/day with valproate. Lamotrigine was discontinued in only 26.5% of trials at 255+/-242 days, most often due to inefficacy, and seldom due to adverse effects. In 31.5% of trials lamotrigine was continued 264+/-375 days with no subsequent psychotropic added. In 42.0% of trials lamotrigine was continued 674+/-479 days, but had subsequent psychotropic added at 146+/-150 days, most often for anxiety/insomnia and depressive symptoms. In 145 trials started at Stanford, lamotrigine primarily yielded relief of depressive symptoms or maintained euthymia. In 55 trials in which lamotrigine was started prior to Stanford, lamotrigine primarily maintained euthymia. Lamotrigine was generally well tolerated, with no serious rash, and only 3.5% discontinuing due to benign rash.In a cohort of bipolar disorder outpatients commonly with comorbid conditions, and most often receiving complex combination therapy, lamotrigine had a low (26.5%, with an overall mean duration of treatment of 434 days) discontinuation rate, suggesting effectiveness in BD in a clinical setting.

  View details for DOI 10.1016/j.jpsychires.2008.02.007

  View details for Web of Science ID 000261276000003

  View details for PubMedID 18423667

• Interregional cerebral metabolic associativity during a continuous performance task (Part II) : Differential alterations in bipolar and unipolar disorders PSYCHIATRY RESEARCH-NEUROIMAGING Benson, B. E., Willis, M. W., Ketter, T. A., Speer, A., Kimbrell, T. A., George, M. S., Herscovitch, P., Post, R. M. 2008; 164 (1): 30-47

  Abstract

  Unipolar and bipolar disorders have often been reported to exhibit abnormal regional brain activity in prefrontal cortex and paralimbic structures compared with healthy controls. We sought to ascertain how regions postulated to be abnormal in bipolar and unipolar disorders were functionally connected to the rest of the brain, and how this associativity differed from healthy controls. Thirty patients with bipolar disorder (BPs), 34 patients with unipolar disorder (UPs), and 66 healthy volunteers (Willis, M.W., Benson, B.E., Ketter, T.A., Kimbrell, T.A., George, M.S., Speer, A.M., Herscovitch, P., Post, R.M., 2008. Interregional cerebral metabolic associativity during a continuous performance task in healthy adults. Psychiatry Research: Neuroimaging 164 (1)) were imaged using F-18-fluorodeoxyglucose and positron emission tomography (FDG-PET) while performing an auditory continuous performance task (CPT). Five bilateral regions of interest (ROIs), namely dorsolateral prefrontal cortex (DLPFC), insula, inferior parietal cortex (INFP), thalamus and cerebellum, were correlated with normalized cerebral metabolism in the rest of the brain while covarying out Hamilton Depression Rating Scale Scores. In bipolar patients compared with controls, metabolism in the left DLPFC and INFP, and bilateral thalamus and insula had more positive and fewer negative metabolic correlations with other brain regions. In contrast, compared with controls, unipolar patients had fewer significant correlative relationships, either positive or negative. In common, bipolar and unipolar patients lacked the normal inverse relationships between the DLPFC and cerebellum, as well as relationships between the primary ROIs and other limbic regions (medial prefrontal cortex, anterior cingulate, and temporal lobes) compared with controls. Associations of DLPFC and INFP with other brain areas were different in each hemisphere in patients and controls. Bipolar patients exhibited exaggerated positive coherence of activity throughout the brain, while unipolar patients showed a paucity of normal interrelationships compared with controls. These abnormal patterns of metabolic associativity suggest marked interregional neuronal dysregulation in bipolar and unipolar illness exists beyond that of mere absolute regional differences from control levels, and provides rationale for using acute and long-term therapies that may re-establish and maintain normal associativity in these devastating illnesses.

  View details for DOI 10.1016/j.pscychresns.2007.12.016

  View details for Web of Science ID 000261023800003

  View details for PubMedID 18801648

• Interregional cerebral metabolic associativity during a continuous performance task (Part I): Healthy adults PSYCHIATRY RESEARCH-NEUROIMAGING Willis, M. W., Benson, B. E., Ketter, T. A., Kimbrell, T. A., George, M. S., Speer, A. M., Herscovitch, P., Post, R. M. 2008; 164 (1): 16-29

  Abstract

  One emerging hypothesis regarding psychiatric illnesses is that they arise from the dysregulation of normal circuits or neuroanatomical patterns. In order to study mood disorders within this framework, we explored normal metabolic associativity patterns in healthy volunteers as a prelude to examining the same relationships in affectively ill patients (Part II). We applied correlational analyses to regional brain activity as measured with FDG-PET during an auditory continuous performance task (CPT) in 66 healthy volunteers. This simple attention task controlled for brain activity that otherwise might vary amongst affective and cognitive states. There were highly significant positive correlations between homologous regions in the two hemispheres in thalamic, extrapyramidal, orbital frontal, medial temporal and cerebellar areas. Dorsal frontal, lateral temporal, cingulate, and especially insula, and inferior parietal areas showed less significant homologous associativity, suggesting more specific lateralized function. The medulla and bilateral thalami exhibited the most diverse interregional associations. A general pattern emerged of cortical regions covarying inversely with subcortical structures, particularly the frontal cortex with cerebellum, amygdala and thalamus. These analytical data may help to confirm known functional and neuroanatomical relationships, elucidate others as yet unreported, and serve as a basis for comparison to patients with psychiatric illness.

  View details for DOI 10.1016/j.pscychresns.2007.12.015

  View details for Web of Science ID 000261023800002

  View details for PubMedID 18799294

  View details for PubMedCentralID PMC2779116

• A new US-UK diagnostic project: mood elevation and depression in first-year undergraduates at Oxford and Stanford universities ACTA PSYCHIATRICA SCANDINAVICA Chandler, R. A., Wang, P. W., Ketter, T. A., Goodwin, G. M. 2008; 118 (1): 81-85

  Abstract

  To investigate differences in prevalence of mood elevation, distress and depression among first-year undergraduates at Oxford and Stanford universities.An online survey was sent to Oxford and Stanford first-year undergraduate students for two consecutive years in the winter of 2005 and 2006. Students completed a survey that assessed mood symptoms and medication use.Both universities had similar rates of distress by General Health Questionnaire (Oxford - 42.4%; Stanford - 38.3%), depression by Primary Care Evaluation of Mental Disorders (Oxford - 6.2%; Stanford - 6.6%), and psychotropic and non-psychotropic medication usage (psychotropic: Oxford - 1.5%; Stanford 3.5%; nonpsychotropic: Oxford - 13.3%; Stanford - 18%). Oxford had higher rates of mood elevation by Mood Disorder Questionnaire (MDQ) (Oxford - 4%; Stanford - 1.7%).Oxford and Stanford students have similar rates of mood distress, depression and general medication usage. Students at Oxford have a higher prevalence of MDQ scores that possibly indicate a bipolar disorder, while Stanford students are prescribed more psychotropics.

  View details for DOI 10.1111/j.1600-0447.2008.01193.x

  View details for Web of Science ID 000256684000011

  View details for PubMedID 18595178

• Incorporating trial data into bipolar disorder management. journal of clinical psychiatry Ketter, T. A. 2008; 69 (7)

  Abstract

  Evidence-based medicine integrates data from clinical trials into clinical care while efficacy studies assess simplified interventions in simplified populations. The findings of such studies are useful in obtaining Food and Drug Administration approval of medications but often fail to generalize to the more complex populations and interventions commonly seen in clinical practice. Recently, an increased emphasis has been placed on effectiveness studies (also referred to as pragmatic or practical studies) designed to yield findings that can be generalized to the clinical management of patients with bipolar disorder. Mood stabilizers and increasingly second-generation antipsychotics are considered the foundation of treatment for bipolar disorder. In contrast, adjunctive antidepressants should be avoided when patients present with manic and mixed episodes. Additional interventions--such as psychoeducation and care coordination--when combined with pharmacotherapy, can lessen the frequency and severity of mood episodes, especially mania. These interventions, combined with judicious pharmacotherapy, can help minimize the impact of adverse effects and related nonadherence so that patients can achieve affective stability, regain psychosocial function, and maintain health.

  View details for PubMedID 18687016

• Caregiver burden and health in bipolar disorder - A cluster analytic approach JOURNAL OF NERVOUS AND MENTAL DISEASE Perlick, D. A., Rosenheck, R. A., Miklowitz, D. J., Kaczynski, R., Link, B., Ketter, T., Wisniewski, S., Wolff, N., Sachs, G. 2008; 196 (6): 484-491

  Abstract

  To identify caregivers at risk for adverse health effects associated with caregiving, the stress, coping, health and service use of 500 primary caregivers of patients with bipolar disorder were assessed at baseline, 6, and 12 months. K-means cluster analysis and ANOVA identified and characterized groups with differing baseline stress/coping profiles. Mixed effects models examined the effects of cluster, time, and covariates on health outcomes. Three groups were identified. Burdened caregivers had higher burden and avoidance coping levels, and lower mastery and social support than effective and stigmatized caregivers; stigmatized caregivers reported the highest perceived stigma (p < 0.05). Effective and stigmatized groups had better health outcomes and less service use than the burdened group over time; stigmatized caregivers had poorer self-care than effective caregivers. Cluster analysis is a promising method for identifying subgroups of caregivers with different stress and coping profiles associated with different health-related outcomes.

  View details for DOI 10.1097/NMD.0b013e3181773927

  View details for Web of Science ID 000256655700007

  View details for PubMedID 18552626

• Adjunctive zonisamide for weight loss in euthymic bipolar disorder patients: A pilot study JOURNAL OF PSYCHIATRIC RESEARCH Wang, P. W., Yang, Y., Chandler, R. A., Nowakowska, C., Alarcon, A. M., Culver, J., Ketter, T. A. 2008; 42 (6): 451-457

  Abstract

  To assess the effectiveness and tolerability of open adjunctive zonisamide in treatment of obesity in euthymic bipolar disorder (BD) patients.Zonisamide was administered to recovered, overweight BD outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorders (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form. Weight changes (Body Mass Index (BMI) and BMI percentage changes) were assessed prospectively at four weekly visits, one bi-weekly visit, and then five monthly visits, for a maximal duration of six months. Weight loss was assessed with random effects modeling to maximize all available data for analysis.Twenty-five BD (10 BD-type I, 15 BD-type II) patients (mean age 41.0+/-10.4 years, 64% female, 96% Caucasian) on a mean of 2.8+/-1.5 prescription psychotropic and 1.3+/-1.4 prescription non-psychotropic medications received zonisamide for a mean duration of 14.2+/-8.5 weeks, with a mean final dose of 375+/-206 (range 75-800) mg/day. Slope of weight loss was 0.078 BMI points per week, and non-zero (p<0.0005). Mean weight loss was 1.2+/-1.9 BMI points (baseline BMI 34.2+/-3.1 to final BMI 33.0+/-3.5, p<0.003). Eighteen patients (72%) discontinued study participation early, 11/25 (44%) due to emergent mood symptoms (eight depression, two mania, one subsyndromal mixed symptoms) requiring treatment intervention, 5/25 (20%) due to adverse physical events, and 2/25 (8%) due to patient choice, but none due to weight loss inefficacy.Adjunctive zonisamide appeared effective and generally physically tolerated, but had high rates of mood adverse events, in obese BD patients. Controlled trials are warranted to systematically explore these preliminary naturalistic observations.

  View details for DOI 10.1016/j.jpsychires.2007.05.005

  View details for Web of Science ID 000254720300004

  View details for PubMedID 17628595

• Increased rate of non-right-handedness in patients with bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Nowakowska, C., Sachs, G. S., Zarate, C. A., Marangell, L. B., Calabrese, J. R., Goldberg, J. F., Ketter, T. A. 2008; 69 (5): 866–67

  View details for DOI 10.4088/JCP.v69n0522g

  View details for Web of Science ID 000256279600028

  View details for PubMedID 18681768

  View details for PubMedCentralID PMC2713190

• Insulin resistance and hyperlipidemia in women with bipolar disorder Rasgon, N. L., Stemmle, P. G., Kenna, H. A., Wong, P. W., Hill, S. J., Ketter, T. A. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 2008: S235–S235

  View details for Web of Science ID 000254987801089

• Effectiveness of open adjunctive ziprasidone in obese and overweight bipolar disorder patients Wang, P. W., Keller, K. L., Hill, S., Childers, M., Ketter, T. A. ELSEVIER SCIENCE INC. 2008: 192S–193S

  View details for Web of Science ID 000254163700616

• Corticolimbic metabolic dysregulation in euthymic older adults with bipolar disorder Brooks, J. O., Hoblyn, J. C., Woodard, S. A., Rosen, A. C., Ketter, T. A. ELSEVIER SCIENCE INC. 2008: 181S

  View details for Web of Science ID 000254163700577

• Increased frequency of depressive episodes during the menopausal transition in women with bipolar disorder: Preliminary report JOURNAL OF PSYCHIATRIC RESEARCH Marsh, W. K., Templeton, A., Ketter, T. A., Rasgon, N. L. 2008; 42 (3): 247-251

  Abstract

  Data are emerging in bipolar disorder regarding mood across phases of the female reproductive life, yet information about mood during the menopausal transition remains limited. The menopausal transition in women without mood disorders is associated with an increase in depression. This study assesses mood course during the menopausal transition in women with bipolar disorder.We monitored mood episodes in 47 women with bipolar disorder ages 45-55 for 17.0+/-14.0 months with systematic treatment enhancement program for bipolar disorder (STEP-BD) standardized evaluations. Charts were additionally reviewed for menstrual status and menstrual history, as well as mood episode type, duration, frequency and history.During the menopausal transition 68% of women with bipolar disorder experienced at least one depressive episode. Depression (but not mood elevation) episode frequency significantly increased during the menopausal transition compared to reported frequency during patients' reproductive years. History of pre-menstrual and or post-partum mood instability did not predict perimenopausal mood episodes.Women with bipolar disorder experience a high frequency of depressive episodes during perimenopausal years and this frequency appears greater than during prior reproductive years. Prospective controlled studies are needed to better understand the course of mood episodes and to enhance the effectiveness of managing bipolar disorder during the menopausal transition.

  View details for DOI 10.1016/j.jpsychires.2006.12.006

  View details for Web of Science ID 000253397900010

  View details for PubMedID 17266987

• Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder BIPOLAR DISORDERS Konarski, J. Z., McIntyre, R. S., Kennedy, S. H., Rafi-Tari, S., Soczynska, J. K., Ketter, T. A. 2008; 10 (1): 1-37

  Abstract

  As patients with mood disorders manifest heterogeneity in phenomenology, pathophysiology, etiology, and treatment response, a biological classification of mental disease is urgently needed to advance research. Patient and methodological variability complicates the comparison of neuroimaging study results and limits heuristic model development and a biologically-based diagnostic schema.We have critically reviewed and compared the magnetic resonance neuroimaging literature to determine the degree and directionality of volumetric changes in brain regions putatively implicated in the pathophysiology of major depressive disorder (MDD) versus bipolar disorder (BD).A total of 140 published magnetic resonance imaging investigations evaluating subjects with BD or MDD were selected to provide a summary and interpretation of volumetric neuroimaging results in MDD and BD. Further commentary on the pathophysiological implications, and putative cellular and pharmacological mechanisms, is also provided.While whole brain volumes of patients with mood disorders do not differ from those of healthy controls, regional deficits in the frontal lobe, particularly in the anterior cingulate and the orbitofrontal cortex, appear to consistently differentiate subjects with mood disorders from the general population. Preliminary findings also suggest that subcortical structures, particularly the striatum, amygdala, and hippocampus, may be differentially affected in MDD and BD.Structural neuroimaging studies have consistently identified regional abnormalities in subjects with mood disorders. Future studies should strive to definitively establish the influence of age and medication.

  View details for Web of Science ID 000252319300001

  View details for PubMedID 18199239

• Insulin resistance and hyperlipidemia in women with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Stemmle, P. G., Kenna, H. A., Wang, P. W., Hill, S. J., Ketter, T. A., Rasgon, N. L. 2008; 43 (3): 341-343

  View details for DOI 10.1016/j.jpsychires.2008.04.003

  View details for Web of Science ID 000262747100018

• Management commentary BIPOLAR II DISORDER: MODELLING, MEASURING AND MANAGING Ketter, T. A., Wang, P. W., Parker, G. 2008: 217–31

  View details for Web of Science ID 000304414100018

• Switching from Other Agents to Extended-Release Carbamazepine in Acute Mania PSYCHOPHARMACOLOGY BULLETIN El-Mallakh, R. S., Ketter, T. A., Weisler, R. H., Hirschfeld, R., Cutler, A. J., Gazda, T., Keck, P., Swann, A. C., Kalali, A. H. 2008; 41 (1): 52-58

  Abstract

  There is a dearth of available knowledge relating to the efficacy of switching from one psychotropic agent to another in treating patients with acute mania.This is a post hoc analysis of data from two randomized, placebo-controlled trials of carbamazepine extended-release capsules (CBZ-ERC) in the treatment of mania, to evaluate the efficacy of CBZ-ERC in patients previously nonresponsive to lithium (n 5 40), olanzapine (n 5 38), or valproate (VPA, n 5 77).In patients previously on lithium, Young Mania Rating Scale (YMRS) scores improved significantly from baseline to end point (27.4 6 SD 3.5 vs. 15.8 6 11.1; P 5 .0002). In patients previously on VPA or olanzapine, YMRS scores significantly improved in both CBZ-ERC- and placebo-treated groups (VPA: CBZ-ERC, P , .0001; placebo, P 5 .0002; olanzapine: CBZ-ERC, P , .0001; placebo, P 5 .0054). Improvement in YMRS was significantly greater in CBZ-ERC-treated patients versus placebo in subjects previously nonresponsive to lithium (CBZ-ERC 11.6 6 10.3 vs. placebo 4.0 6 11.2, P 5 .03), or VPA (CBZ-ERC 10.8 6 11.9 vs. placebo 5.7 6 9.2; P 5 .04), and trending to be greater for those previously nonresponsive to olanzapine (olanzapine 13.2 6 9.3 vs. placebo 7.3 6 9.7, P 5 .06).CBZ-ERC is an effective therapy for bipolar patients previously nonresponsive to lithium or valproate. Medication switch is frequently associated with symptom improvement.

  View details for Web of Science ID 000207792400005

  View details for PubMedID 18362871

• Monotherapy Versus Combined Treatment With Second-Generation Antipsychotics in Bipolar Disorder JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A. 2008; 69: 9-15

  Abstract

  The American Psychiatric Association guidelines for treating bipolar disorder recommend combination therapies to treat patients experiencing severe acute manic or mixed episodes and breakthrough manic or mixed episodes during maintenance therapy. Combination therapies approved by the U.S. Food and Drug Administration for the treatment of acute manic states include the use of second-generation antipsychotics, such as olanzapine, risperidone, quetiapine, and aripiprazole in combination with lithium or divalproex; for the treatment of acute bipolar depression, the olanzapine plus fluoxetine combination; and for maintenance treatment, quetiapine combined with lithium or valproate. When combining medications for the management of patients with bipolar disorders, physicians face a potentially complex treatment strategy. Available agents have different mechanisms of action, routes of metabolism and excretion, therapeutic effects, and side effects. Combining treatments can be advantageous owing to therapeutic synergy; however, the liability is an increased possibility of adverse effects. The decision to use a combination therapy should be made on the basis of the efficacy, tolerability, and safety of each medication and their specific combination for individual patients.

  View details for Web of Science ID 000260983700002

  View details for PubMedID 19265635

• Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder 59th Annual Meeting of the Society-of-Biological-Psychiatry Goldberg, J. F., Bowden, C. L., Calabrese, J. R., Ketter, T. A., Dann, R. S., Frye, M. A., Suppes, T., Post, R. M. ELSEVIER SCIENCE INC. 2008: 125–30

  Abstract

  Fluctuations in mood are quintessential features of bipolar disorder; however, previous studies have seldom examined the extent to which pharmacotherapies for bipolar disorder may reduce or ameliorate daily or weekly mood variability. The anticonvulsant lamotrigine has demonstrated efficacy for relapse prevention in bipolar disorder, but its possible mood-stabilizing properties on a day-to-day or week-to-week basis have not previously been investigated.Weekly mood shifts were examined over 26 weeks using patients' self-reported prospective Life Chart Method (LCM) data obtained as part of a previously reported randomized relapse prevention comparison of lamotrigine monotherapy or placebo in 182 bipolar patients with DSM-IV rapid cycling. Generalized estimating equation (GEE) analyses were used to compare treatment arms for subjects who achieved euthymia across weeks.After adjusting for potential confounding factors, a final GEE model revealed that subjects taking lamotrigine were 1.8 times more likely than those taking placebo to achieve euthymia, as measured by LCM, at least once per week over 6 months (95% confidence interval [CI] = 1.03-3.13). Subjects taking lamotrigine had an increase of .69 more days per week euthymic as compared with those taking placebo (p = .014).Achievement of euthymia across weeks represents a novel paradigm shift in gauging the mood-stabilizing properties of a psychotropic agent. The present findings demonstrate the utility of the prospective Life Chart Method for assessing longitudinal mood stability during randomized clinical trials for bipolar disorder. The results lend support to the potential mood-stabilizing properties of lamotrigine monotherapy for bipolar disorder.

  View details for DOI 10.1016/j.biopsych.2006.12.031

  View details for Web of Science ID 000251864000020

  View details for PubMedID 17543894

• Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Brooks, J. O., Wang, P. W., Bonner, J. C., Rosen, A. C., Hoblyn, J. C., Hill, S. J., Ketter, T. A. 2008; 43 (3): 181-188

  View details for DOI 10.1016/j.jpsychires.2008.04.015

  View details for Web of Science ID 000262747100002

• Enhanced creativity in bipolar disorder patients: A controlled study JOURNAL OF AFFECTIVE DISORDERS Santosa, C. A., Strong, C. M., Nowakowska, C., Wang, P. W., Rennicke, C. M., Ketter, T. A. 2007; 100 (1-3): 31-39

  Abstract

  Associations between eminent creativity and bipolar disorders have been reported, but there are few data relating non-eminent creativity to bipolar disorders in clinical samples. We assessed non-eminent creativity in euthymic bipolar (BP) and unipolar major depressive disorder (MDD) patients, creative discipline controls (CC), and healthy controls (HC).49 BP, 25 MDD, 32 CC, and 47 HC (all euthymic) completed four creativity measures yielding six parameters: the Barron-Welsh Art Scale (BWAS-Total, and two subscales, BWAS-Dislike and BWAS-Like), the Adjective Check List Creative Personality Scale (ACL-CPS), and the Torrance Tests of Creative Thinking--Figural (TTCT-F) and Verbal (TTCT-V) versions. Mean scores on these instruments were compared across groups.BP and CC (but not MDD) compared to HC scored significantly higher on BWAS-Total (45% and 48% higher, respectively) and BWAS-Dislike (90% and 88% higher, respectively), but not on BWAS-Like. CC compared to MDD scored significantly higher (12% higher) on TTCT-F. For all other comparisons, creativity scores did not differ significantly between groups.We found BP and CC (but not MDD) had similarly enhanced creativity on the BWAS-Total (driven by an increase on the BWAS-Dislike) compared to HC. Further studies are needed to determine the mechanisms of enhanced creativity and how it relates to clinical (e.g. temperament, mood, and medication status) and preclinical (e.g. visual and affective processing substrates) parameters.

  View details for DOI 10.1016/j.jad.2006.10.013

  View details for Web of Science ID 000247704400005

  View details for PubMedID 17126406

• Is a lack of disgust something to fear? A functional magnetic resonance imaging facial emotion recognition study in euthymic bipolar disorder patients 6th International Conference on Bipolar Disorder Malhi, G. S., Lagopoulos, J., Sachdev, P. S., Ivanovski, B., Shnier, R., Ketter, T. WILEY-BLACKWELL. 2007: 345–57

  Abstract

  To determine the neural responses invoked in the recognition of facial fear and disgust in euthymic bipolar patients as compared with healthy subjects.This study examined 10 female euthymic bipolar patients, and 10 suitably matched healthy subjects using functional magnetic resonance imaging (fMRI) while subjects were engaged in an explicit facial emotion recognition task involving fear, disgust and neutral expressions. The activation paradigm involved nominating the facial expression using specified response keys. Behavioural data were collected and analysed and both within-group (Fear versus Neutral; Disgust versus Neutral) and random-effects between-group analyses were performed on fMRI data using BrainVoyager (Brain Innovations, Maastricht, the Netherlands).Patients were equally accurate in identifying facial expressions as healthy subjects but were slower to respond, especially with respect to fear and disgust. Responses to fear and disgust (within-group analyses) resulted in activation of anticipated brain regions such as amygdala and insula, respectively. However, between-group random effects analysis revealed differential responses to both disgust and fear in both healthy subjects and euthymic bipolar patients such that euthymic bipolar patients responded largely to fear and healthy subjects responded more so to disgust. This partitioning of responsiveness was reflected by differential activation involving the hippocampus and amygdala.Greater responsiveness to fear with hippocampal activation in patients perhaps reflects recollection of traumatic events associated with past experiences of illness or simply the use of a more mnemonic (hippocampal) as opposed to affective (amygdala) approach when performing the task. It is possible that in bipolar disorder, prefrontal-subcortical network dysfunction that relegates neural processing to limbic regions is impaired and that clinically euthymic bipolar patients, although able to accurately and effectively identify emotions such as fear and disgust, are limited in their ability to interpret their salience. The implications of these findings are discussed.

  View details for Web of Science ID 000247110600005

  View details for PubMedID 17547581

• Temperament-creativity relationships in mood disorder patients, healthy controls and highly creative individuals JOURNAL OF AFFECTIVE DISORDERS Strong, C. M., Nowakowska, C., Santosa, C. M., Wang, P. W., Kraemer, H. C., Ketter, T. A. 2007; 100 (1-3): 41-48

  Abstract

  To investigate temperament-creativity relationships in euthymic bipolar (BP) and unipolar major depressive (MDD) patients, creative discipline controls (CC), and healthy controls (HC).49 BP, 25 MDD, 32 CC, and 47 HC (all euthymic) completed three self-report temperament/personality measures: the Revised NEO Personality Inventory (NEO-PI-R), the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A), and the Temperament and Character Inventory (TCI); and four creativity measures yielding six parameters: the Barron-Welsh Art Scale (BWAS-Total, BWAS-Like, and BWAS-Dislike), the Adjective Check List Creative Personality Scale (ACL-CPS), and the Torrance Tests of Creative Thinking--Figural (TTCT-F) and Verbal (TTCT-V) versions. Factor analysis was used to consolidate the 16 subscales from the three temperament/personality measures, and the resulting factors were assessed in relationship to the creativity parameters.Five personality/temperament factors emerged. Two of these factors had prominent relationships with creativity measures. A Neuroticism/Cyclothymia/Dysthymia Factor, comprised mostly of NEO-PI-R-Neuroticism and TEMPS-A-Cyclothymia and TEMPS-A-Dysthymia, was related to BWAS-Total scores (r=0.36, p<0.0001) and BWAS-Dislike subscale scores (r=0.39, p<0.0001). An Openness Factor, comprised mostly of NEO-PI-R-Openness, was related to BWAS-Like subscale scores (r=0.28, p=0.0006), and to ACL-CPS scores (r=0.46, p<0.0001). No significant relationship was found between temperament/personality and TTCT-F and TTCT-V scores.Neuroticism/Cyclothymia/Dysthymia and Openness appear to have differential relationships with creativity. The former could provide affective (Neuroticism, i.e. access to negative affect, and Cyclothymia, i.e. changeability of affect) and the latter cognitive (flexibility) advantages to enhance creativity. Further studies are indicated to clarify mechanisms of creativity and its relationships to affective processes and bipolar disorders.

  View details for DOI 10.1016/j.jad.2006.10.015

  View details for Web of Science ID 000247704400006

  View details for PubMedID 17126408

• Effectiveness of adjunctive antidepressant treatment for bipolar depression NEW ENGLAND JOURNAL OF MEDICINE Sachs, G. S., Nierenberg, A. A., Calabrese, J. R., Marangell, L. B., Wisniewski, S. R., Gyulai, L., Friedman, E. S., Bowden, C. L., Fossey, M. D., Ostacher, M. J., Ketter, T. A., Patel, J., Hauser, P., Rapport, D., Martinez, J. M., Allen, M. H., Miklowitz, D. J., Otto, M. W., Dennehy, E. B., Thase, M. E. 2007; 356 (17): 1711-1722

  Abstract

  Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania.In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined.Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups.The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

  View details for DOI 10.1056/NEJMoa064135

  View details for Web of Science ID 000245942600006

  View details for PubMedID 17392295

• Regional cerebral gray matter density changes associated with creativity in healthy volunteers 62nd Annual Meeting of the Society-of-Biological-Psychiatry Bonner, J. C., Ketter, T. A., Wang, P. W., Garcia-Amador, M., Brooks, J. O. ELSEVIER SCIENCE INC. 2007: 113S–114S

  View details for Web of Science ID 000245698100361

• Circadian gene polymorphisms and liability to bipolar I disorder Mansour, H., Chowdari, K. V., Wood, J., Pless, L., McClendon, T., King, A. J., Allen, M., Bowden, C. L., Calabrese, J., El-Mallakh, R. S., Fagiolini, A., Faraone, S. V., Fossey, M. D., Friedman, E. S., Gyulai, L., Hauser, P., Ketter, T. A., Loftis, J. M., Marangell, L. B., Miklowitz, D. J., McQueen, M. B., Nierenberg, A. A., Patel, J., Sachs, G. S., Sklar, P. ELSEVIER SCIENCE INC. 2007: 7S

  View details for Web of Science ID 000245698100019

• Relations between delayed memory and cerebral metabolism in older euthymic adults with bipolar disorder 62nd Annual Meeting of the Society-of-Biological-Psychiatry Brooks, J. O., Hoblyn, J. C., Woodard, S., Rosen, A. C., Krasnykh, O., Ketter, T. A., Schatzberg, A. F. ELSEVIER SCIENCE INC. 2007: 114S–114S

  View details for Web of Science ID 000245698100363

• Cerebral metabolic correlates of attention in older euthymic adults with bipolar disorder Hoblyn, J. C., Brooks, J. O., Rosen, A. C., Woodard, S., Krasnykh, O., Ketter, T. A., Schatzberg, A. F. ELSEVIER SCIENCE INC. 2007: 116S

  View details for Web of Science ID 000245698100369

• Gray matter density changes associated with bipolar depression Brooks, J. O., Bonner, J. C., Rosen, A. C., Wang, P. W., Ketter, T. A. ELSEVIER SCIENCE INC. 2007: 56S

  View details for Web of Science ID 000245698100177

• Differential global cerebral metabolism changes with sadness induction between creative bipolar patients and healthy controls Wang, P. W., Sachs, N., Brooks, J. O., Bonner, J., Ketter, T. A. ELSEVIER SCIENCE INC. 2007: 230S

  View details for Web of Science ID 000245698100736

• Safety and efficacy of anticonvulsants in elderly patients with psychiatric disorders: oxcarbazepine, topiramate and gabapentin EXPERT OPINION ON DRUG SAFETY Sommer, B. R., Fenn, H. H., Ketter, T. A. 2007; 6 (2): 133-145

  Abstract

  Few controlled studies are available to guide the clinician in treating potentially assaultive elderly individuals with psychiatric disorders. Safety concerns limit the use of benzodiazepines and antipsychotic medications in the elderly individual, making anticonvulsants an attractive alternative. This paper reviews three specific anticonvulsants for this purpose: gabapentin, oxcarbazepine and topiramate, describing safety and efficacy in elderly patients with severe agitation from psychosis or dementia. Gabapentin, renally excreted, with a half-life of 6.5-10.5 h, may cause ataxia. Oxcarbazapine, hepatically reduced, may cause hyponatremia, and topiramate may cause significant cognitive impairment. Nonetheless, these are important medications to consider in the treatment of agitation.

  View details for DOI 10.1517/14740338.6.2.133

  View details for PubMedID 17367259

• Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Cookson, J., Keck, P. E., Ketterc, T. A., Macfadden, W. 2007; 22 (2): 93-100

  Abstract

  The objectives of this analysis are to elucidate the clinical significance of antidepressant effects with quetiapine by evaluating number needed to treat as well as time to response and remission with quetiapine monotherapy in patients with acute bipolar depression. A post-hoc analysis was conducted of 542 patients with bipolar I or II disorder, (moderate to severe depression), randomized to 8 weeks of double-blind treatment with quetiapine 600 mg/day (n=180), quetiapine 300 mg/day (n=181), or placebo (n=181). Number needed to treat, time to response (> or =50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score) and time to remission (Montgomery-Asberg Depression Rating Scale total score < or =12) were evaluated. Response rates at week 8 were 58.2 and 57.6% for quetiapine 600 and 300 mg/day, respectively, and 36.1% for placebo (P<0.001). Remission rates were 52.9% for both quetiapine groups and 28.4% for placebo (P<0.001). The number needed to treat was five for both response and remission for quetiapine (600 and 300 mg/day) compared with placebo. Median time to response and remission were significantly shorter with quetiapine 600 and 300 mg/day than placebo. No between-group difference was found in the incidence of treatment-emergent mania or hypomania (quetiapine 600 mg/day: 2.2%, quetiapine 300 mg/day: 3.9, and placebo: 3.9%). In conclusion, quetiapine compared with placebo significantly reduces time to response and remission compared with placebo, and has a favorable number needed to treat.

  View details for Web of Science ID 000244845100005

  View details for PubMedID 17293709

• Rates of remission/euthymia with quetiapine monotherapy compared with placebo in patients with acute mania JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A., Jones, M., Paulsson, B. 2007; 100: S45-S53

  Abstract

  To evaluate the effects of quetiapine monotherapy compared with placebo on acute (3-week) and more sustained (12-week) rates of response and remission/euthymia in bipolar disorder patients with acute mania.Two similar 12-week multicenter, double-blind, placebo-controlled, parallel-group studies were conducted, with an a priori decision to combine the data and analyze response and remission rates. Response was measured as a decrease of at least 50% in Young Mania Rating Scale (YMRS) scores from baseline to Day 21 and Day 84. Five remission/euthymia criteria were employed to determine efficacy at Day 21 and Day 84: (i) YMRS score < or = 12; (ii) YMRS score < or = 12 and Montgomery-Asberg Depression Rating Scale (MADRS) score < or = 10; (iii) YMRS score < or = 12 and MADRS score < or = 8; (iv) YMRS score < or = 8; and (v) YMRS score < or = 8 plus a score < or = 2 for the YMRS core items of Irritability, Speech, Content, and Disruptive/Aggressive Behavior.Patients treated with quetiapine (n=208) and placebo (n=195) had mean YMRS scores at entry of 33.3+/-6.3 and 33.5+/-6.7, respectively. Significantly higher response rates were observed with quetiapine compared with placebo, at Days 21 (48.1% versus 31.3%; p<0.001) and 84 (66.8% versus 40.0%; p<0.001). At Day 21, remission/euthymia rates with quetiapine monotherapy versus placebo were: 37.5% versus 23.1% (YMRS < or = 12), 35.6% versus 21.5% (YMRS < or = 12+MADRS < or = 10), 35.1% versus 20.0% (YMRS < or = 12+MADRS < or = 8), 25.0% versus 14.4% (YMRS < or = 8), and 21.6% versus 14.4% (YMRS < or = 8 plus core items < or = 2) (p<0.01 for all comparisons except YMRS < or = 8 plus core items < or = 2: p=0.06). By Day 84, these had increased to: 65.4% versus 35.9% (YMRS < or = 12), 60.1% versus 30.8% (YMRS < or = 12+MADRS < or = 10), 58.7% versus 29.7% (YMRS < or = 12+MADRS < or = 8), 60.1% versus 30.3% (YMRS < or = 8), and 56.7% versus 29.7% (YMRS < or = 8 plus core items < or = 2) (p<0.001 for all comparisons). The average daily dose of quetiapine in responders was 575 mg/day at Day 21 and 598 mg/day at Day 84. Quetiapine was generally well tolerated.Quetiapine was associated with significantly higher response and remission/euthymia rates compared with placebo with most criteria used, in patients with acute mania at the end of both 3 and 12 weeks.

  View details for DOI 10.1016/j.jad.2007.02.006

  View details for Web of Science ID 000247883900006

  View details for PubMedID 17383011

• Thirty years of clinical experience with carbamazepine in the treatment of bipolar illness - Principles and practice CNS DRUGS Post, R. M., Ketter, T. A., Uhde, T., Ballenger, J. C. 2007; 21 (1): 47-71

  Abstract

  Carbamazepine began to be studied in a systematic fashion in the 1970s and became more widely used in the treatment of bipolar disorder in the 1980s. Interest in carbamazepine has been renewed by (i) the recent US FDA approval of a long-acting preparation for the treatment of acute mania; (ii) studies suggesting some efficacy in bipolar depression; and (iii) evidence of prophylactic efficacy in some difficult-to-treat subtypes of bipolar illness. A series of double-blind controlled studies of the drug were conducted at the US National Institute of Mental Health from the mid-1970s to the mid-1990s. This review summarises our experience in the context of the current literature on the clinical efficacy, adverse effects and pharmacokinetic interactions of carbamazepine. Carbamazepine has an important and still evolving place in the treatment of acute mania and long-term prophylaxis. It may be useful in individuals with symptoms that are not responsive to other treatments and in some subtypes of bipolar disorder that are not typically responsive to a more traditional agent such as lithium. These subtypes might include those patients with bipolar II disorder, dysphoric mania, substance abuse co-morbidity, mood incongruent delusions, and a negative family history of bipolar illness in first-degree relatives. In addition, carbamazepine may be useful in patients who do not adequately tolerate other interventions as a result of adverse effects, such as weight gain, tremor, diabetes insipidus or polycystic ovarian syndrome. We review our clinical and research experience with carbamazepine alone and in combination with lithium, valproic acid and other agents in complex combination treatment of bipolar illness. More precise clinical and biological predictors and correlates of individual clinical responsiveness to carbamazepine and other mood stabilisers are eagerly awaited.

  View details for Web of Science ID 000244165700005

  View details for PubMedID 17190529

• Bipolar disorder: Improving diagnosis and optimizing integrated care JOURNAL OF CLINICAL PSYCHOLOGY Culver, J. L., Arnow, B. A., Ketter, T. A. 2007; 63 (1): 73-92

  Abstract

  Bipolar disorder is a chronic, severe condition commonly causing substantial mortality and psychosocial morbidity. Challenges in recognition can delay the institution of appropriate management, whereas misdiagnosis may initiate pharmacologic interventions that adversely affect the condition's course. Pharmacotherapy remains the foundation of treatment. In addition to efficacy, tolerability is an important consideration in medication choice, particularly for long-term maintenance because of its impact on adherence. Mood stabilizers are the classic treatments for bipolar disorder. Newer agents such as atypical antipsychotics may offer efficacy and/or tolerability advantages compared with other medications. The role of antidepressants in bipolar disorder remains controversial. Growing evidence indicates that adjunctive psychosocial interventions improve long-term functioning; consequently, psychologists are becoming increasingly involved in the long-term care of patients with bipolar disorder. This review seeks to update psychologists and related healthcare professionals on recent advances and the current limitations in the diagnosis and treatment of bipolar disorder.

  View details for DOI 10.1002/jclp.20333

  View details for Web of Science ID 000243044600005

  View details for PubMedID 17115430

• Introduction - Advancing understanding of the effectiveness of quetiapine in acute mania JOURNAL OF AFFECTIVE DISORDERS Ketter, T. A. 2007; 100: S1-S3

  View details for DOI 10.1016/j.jad.2007.02.003

  View details for Web of Science ID 000247883900001

  View details for PubMedID 17383012

• Overweight and obesity in bipolar disorders JOURNAL OF PSYCHIATRIC RESEARCH Wang, P. W., Sachs, G. S., Zarate, C. A., Marangell, L. B., Calabrese, J. R., Goldberg, J. F., Sagduyu, K., Miyahara, S., Ketter, T. A. 2006; 40 (8): 762-764

  View details for DOI 10.1016/j.jpyschires.2006.01.007

  View details for Web of Science ID 000241915500010

  View details for PubMedID 16516926

• Effectiveness of quetiapine in a clinical setting 45th Annual Meeting of the American-College-of-Neuropsychopharmacology Ketter, T. A., Holland, A. A., Nam, J. Y., Culver, J. L., Wang, P. W., Marsh, W. K., Bonner, J. C. NATURE PUBLISHING GROUP. 2006: S234–S234

  View details for Web of Science ID 000242215900616

• Perceptions of weight gain and bipolar pharmacotherapy: results of a 2005 survey of physicians in clinical practice CURRENT MEDICAL RESEARCH AND OPINION Ketter, T. A., Haupt, D. W. 2006; 22 (12): 2345-2353

  Abstract

  To assess the perceptions of clinicians in the psychiatric community about pharmacotherapy and its impact on weight gain and adverse metabolic effects in patients with bipolar disorder.In November 2005, self-administered questionnaires were sent to 7000 psychiatrists who treat bipolar disorder in their clinical practice. An additional mailing of these questionnaires was sent in January 2006 to a different group of 7000 psychiatrists who treat bipolar disorder in their clinical practice. The first 298 completed surveys were analyzed.Almost half of the respondents (48%) were psychiatrists in individual private practice and 32% were in community mental health centers. About two-thirds of respondents reported that 30-60% of their bipolar patients were overweight. Thirty-eight percent of respondents reported metabolic syndrome present in 20-40% of their patients. Almost all respondents (96%) reported a 20 lb increase in patients' weight as a troublesome potential adverse event associated with the use of some agents. After initiating a new medication, more than 80% of respondents monitored their patients' weight, fasting plasma glucose level, and fasting lipid profile at regular intervals. However, 80% did not monitor waist circumference. Overall, respondents viewed several agents (aripiprazole, ziprasidone, carbamazepine, and lamotrigine) as not (or minimally) problematic in terms of weight gain and adverse metabolic concerns. Clozapine and olanzapine were viewed as highly problematic due to their propensity to induce weight gain and negatively influence lipid and glucose metabolism. Other agents considered to be minimally to moderately problematic in terms of weight gain and metabolic issues were quetiapine, risperidone, lithium, and valproate. Respondents reported that the profile of a bipolar agent in terms of weight gain and adverse metabolic effects was an important consideration in the management of bipolar disorder.Although the study is limited by a low response rate and self-selection of respondents, clinicians who did respond were concerned about the risks of weight gain and metabolic disturbances in their patients treated with bipolar agents. For most parameters, such concerns were being integrated into clinical care. However, it appears that there is a need to increase clinicians' appreciation of the importance of abdominal obesity and the need to monitor waist circumference. A growing recognition of the differences in weight-gain potential and adverse metabolic effects among agents appears to have had a definite impact on prescribing patterns in the management of bipolar disorder.

  View details for DOI 10.1185/030079906X148616

  View details for Web of Science ID 000243238900004

  View details for PubMedID 17257449

• Incidence and time course of subsyndromal symptoms in patients with bipolar I disorder: An evaluation of 2 placebo-controlled maintenance trials JOURNAL OF CLINICAL PSYCHIATRY Frye, M. A., Yatham, L. N., Calabrese, J. R., Bowden, C. L., Ketter, T. A., Suppes, T., Adams, B. E., Thompson, T. R. 2006; 67 (11): 1721-1728

  Abstract

  Subsyndromal symptoms in bipolar disorder can cause significant functional impairment and are associated with relapse.In this post hoc analysis from 2 randomized, double-blind, 18-month, placebo-controlled maintenance trials for bipolar I disorder (both trials were conducted between August 1997 and August 2001 and used DSM-IV criteria), the incidence, time course, and impact of pharmacotherapy on subsyndromal symptoms were examined.Subsyndromal symptoms occurred in approximately 25% of all visits. Compared with placebo (54.8%), a significantly higher mean percentage of visits in remission were observed with lamotrigine treatment (63.0%, p = .020) but not with lithium treatment (60.0%, p = .165). The median time to onset of subsyndromal symptoms for lamotrigine (N = 223), lithium (N = 164), and placebo (N = 188) was 15, 15, and 9 days, respectively. Compared with placebo, both lamotrigine and lithium significantly delayed the time from randomization to onset of subsyndromal symptoms (p = .046, lamotrigine vs. placebo; p = .033, lithium vs. placebo; p = .763, lamotrigine vs. lithium) and the time from onset of subsyndromal symptoms to subsequent mood episode (p = .037, lamotrigine vs. placebo; p = .023, lithium vs. placebo; p = .845, lamotrigine vs. lithium). Agreement between the polarities of the first-observed subsyndromal symptom and subsequent intervention for mood episode was statistically significant (p < .001).Subsyndromal symptoms are common during maintenance treatment and appear to be associated with relapse into an episode of the same polarity. Both lithium and lamotrigine delayed the onset of subsyndromal symptoms and the time from onset of subsyndromal symptoms to subsequent relapse. Further study to assess whether treatment intervention can minimize subsyndromal symptoms or prevent relapse is encouraged.

  View details for Web of Science ID 000242432300008

  View details for PubMedID 17196051

• Omega-3 fatty acids in bipolar disorder: Clinical and research considerations PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS Marangell, L. B., Suppes, T., Ketter, T. A., Dennehy, E. B., Zboyan, H., Kertz, B., Nierenberg, A., Calabrese, J., Wisniewski, S. R., Sachs, G. 2006; 75 (4-5): 315-321

  Abstract

  Several lines of evidence suggest that omega-3 fatty acids may be important in the pathophysiology, treatment or prevention of bipolar disorder (BD). Electronic and manual searches were conducted in order to review the literature relevant to the etiology and treatment of BDs with omega-3 fatty acids. We also present data from a randomized, double-blind, placebo-controlled pilot study conducted at three sites (N = 10) comparing an omega-3 fatty acid (docosahexaenoic acid, DHA) versus placebo, added to psychosocial treatment for women with BD who chose to discontinue standard pharmacologic treatment while attempting to conceive. While some epidemiologic and preclinical data support the role of omega-3 fatty acids in BD, clinical trials to date have yielded conflicting results. In our pilot study of 10 Caucasian women taking DHA while attempting to conceive (BP1 = 9, BPII = 1), age 27-42 years, DHA was well tolerated and suggests that a larger study would be feasible. The elucidation of the potential role of omega-3 fatty acids as a treatment for BD requires further study. The current data are not sufficient to support a recommendation of monotherapy treatment as a substitute for standard pharmacologic treatments. However, judicious monotherapy in selected clinical situations, or adjunctive use, may be warranted pending further data from adequately powered controlled clinical trials. Our pilot trial of DHA in women who plan to stop conventional psychotropics in order to conceive suggests that such trials are feasible.

  View details for DOI 10.1016/j.plefa.2006.07.008

  View details for Web of Science ID 000241423400010

  View details for PubMedID 16928441

• The use of antiepileptic drugs in bipolar disorders. A review based on evidence from controlled trials CNS SPECTRUMS Weisler, R. H., Cutler, A. J., Ballenger, J. C., Post, R. M., Ketter, T. A. 2006; 11 (10): 788-799

  Abstract

  Antiepileptic drugs (AEDs) have diverse psychotropic profiles. Some AEDs have proven to be efficacious in the treatment of mood disorders, especially bipolar disorder. Others are ineffective as primary treatments but may be useful adjuncts for mood disorders or comorbid conditions. Valproate (acute mania and mixed episodes), carbamazepine (acute mania and mixed episodes), and lamotrigine (maintenance to delay recurrence) have United States Food and Drug Administration indications for the treatment of bipolar disorder. This article provides an overview of data on the use of AEDs in bipolar disorder, including acute mania and depression, prophylaxis, and rapid cycling.

  View details for Web of Science ID 000241447100021

  View details for PubMedID 17008822

• Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature JOURNAL OF AFFECTIVE DISORDERS Nasrallah, H. A., Ketter, T. A., Kalali, A. H. 2006; 95 (1-3): 69-78

  Abstract

  There are an increasing number of pharmacologic therapies for bipolar disorder. Two of these agents, the anticonvulsants carbamazepine (CBZ) and valproate (VPA), were first developed over 30 years ago for the treatment of epilepsy, and subsequent studies demonstrated that they are also effective in the treatment of acute mania and suggest efficacy as maintenance therapy in bipolar disorder. Because VPA and CBZ have been in use for many years, the psychiatric community is familiar with the adverse event profiles of these agents. A review of the clinical data evaluating VPA and CBZ monotherapy for the treatment of acute mania suggests that VPA and CBZ are similarly effective in acute mania. However, when their respective adverse event profiles are considered, VPA may be more tolerable than CBZ for short-term use, while CBZ may be better suited for long-term therapy. Controlled and direct comparative studies, both short and long term, are needed to further clarify the differences between VPA and CBZ.

  View details for DOI 10.1016/j.jad.2006.04.030

  View details for Web of Science ID 000241477700009

  View details for PubMedID 16780960

• Adjunctive aripiprazole in treatment-resistant bipolar depression. Annals of clinical psychiatry Ketter, T. A., Wang, P. W., Chandler, R. A., Culver, J. L., Alarcon, A. M. 2006; 18 (3): 169-172

  Abstract

  There are limited management options for treatment-resistant depression in bipolar disorder (BD) patients.Open adjunctive aripiprazole was administered to outpatients with treatment-resistant depression assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and followed with the STEP-BD Clinical Monitoring Form.Thirty BD (11 type I, 15 type II, 4 NOS) patients (mean age 44.4 +/- 17.0 years, 70% female) on a mean of 3.2 +/- 1.6 other psychotropic and 2.3 +/- 1.6 nonpsychotropic prescription medications received aripiprazole for a mean duration of 84 +/- 69 days, with a mean final dose of 15.3 +/- 11.2 (range 2.5-40) mg/day. Fourteen patients (47%) discontinued aripiprazole; due to inefficacy in 5/30 (17%), patient choice in 3/30 (10%), and adverse effects in 6/30 (20%). Aripiprazole yielded improvement in Clinical Global Impression-Severity (CGI-S, 4.4 +/- 1.1 to 3.8 +/- 1.2, p < 0.01), with 8/30 (27%) patients responding (CGI-S improvement > or = 2), including 4/30 (13%) who remitted (final CGI-S < or = 2). Global Assessment of Function, and depressed mood and suicidal ideation ratings also improved. Aripiprazole was generally well tolerated, with no significant change in mean adverse effect ratings or mean weight.Aripiprazole appeared effective and generally well tolerated in treatment-resistant bipolar depression. Controlled trials are warranted to systematically explore these preliminary naturalistic observations.

  View details for PubMedID 16923655

• Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder AMERICAN JOURNAL OF PSYCHIATRY Bowden, C. L., Calabrese, J. R., Ketter, T. A., Sachs, G. S., White, R. L., Thompson, T. R. 2006; 163 (7): 1199-1201

  Abstract

  This study assessed weight changes in a large cohort of patients with bipolar disorder who were treated with randomly assigned maintenance monotherapies.A post hoc analysis was conducted to assess the effects of lamotrigine, lithium, and placebo administration on body weight in obese and nonobese patients with bipolar disorder from two double-blind, placebo-controlled, 18-month studies.Mean changes in weight among obese patients (N=155) at week 52 were -4.2, +6.1, and -0.6 kg with lamotrigine, lithium, and placebo, respectively (lamotrigine versus lithium and lithium versus placebo). Among nonobese patients (N=399), mean changes in weight (kg) at week 52 were -0.5, +1.1, and +0.7 with lamotrigine, lithium, and placebo, respectively, with no significant differences among groups.Obese patients with bipolar I disorder lost weight while taking lamotrigine and gained weight while taking lithium.

  View details for Web of Science ID 000238712000016

  View details for PubMedID 16816224

• Preliminary evidence of differential relations between prefrontal cortex metabolism and sustained attention in depressed adults with bipolar disorder and healthy controls BIPOLAR DISORDERS Brooks, J. O., Wang, P. W., Strong, C., Sachs, N., Hoblyn, J. C., Fenn, R., Ketter, T. A. 2006; 8 (3): 248-254

  Abstract

  To assess the relations between sustained attention as assessed by the Continuous Performance Test (CPT) and subgenual and dorsolateral prefrontal cortex metabolism in depressed patients with bipolar disorders and healthy controls.Cross-sectional case-control design.Cerebral metabolic rates were assessed with 18F-fluoro-deoxyglucose and positron emission tomography (PET) in the regions of interest defined on co-registered structural magnetic resonance images in eight medication-free, depressed bipolar disorder patients and 27 healthy control participants. PET scans were obtained in a resting state and the CPT was administered within 1 week of the PET scan.Although there were no statistically significant differences in performance on the CPT or in cerebral metabolism between the two groups, our analyses revealed differential relations between the CPT and metabolism across the groups. Decreased subgenual prefrontal metabolism was associated with slower hit rate reaction time and more omission errors in the bipolar group, but not the control group. Decreased dorsolateral prefrontal metabolism in the bipolar group, but not the control group, was associated with more commission errors.This study extends previous neuroimaging findings of structural and functional relevance of the prefrontal region with attention to include depressed states in bipolar disorder. The results are consistent with interpretations that decreased prefrontal activity may represent failure to activate some areas of inhibitory control. Decreasing subgenual prefrontal cortex metabolism appears to relate to decreased attention whereas the decreased dorsolateral prefrontal cortex metabolism relates more to decreased inhibitory control.

  View details for Web of Science ID 000237515900005

  View details for PubMedID 16696826

• Recurrence in bipolar I disorder: A post hoc analysis excluding relapses in two double-blind maintenance studies BIOLOGICAL PSYCHIATRY Calabrese, J. R., Goldberg, J. F., Ketter, T. A., Suppes, T., Frye, M., White, R., DeVeaugh-Geiss, A., Thompson, T. R. 2006; 59 (11): 1061-1064

  Abstract

  To assess the efficacy of lamotrigine or lithium in preventing mood recurrence (i.e., a new mood episode) in bipolar disorder.Data from bipolar I patients with relapses (i.e., mood episodes having the same polarity as the index episode within 90 or 180 days of randomization) were excluded from post hoc efficacy analyses of two 18-month, placebo-controlled maintenance trials of lamotrigine and lithium.Both lamotrigine and lithium were more effective than placebo in delaying the time to intervention for any mood episode (depression, mania, hypomania, or mixed) when relapses that occurred in the first 90 days were excluded from the analyses (p = .002, lamotrigine vs. placebo; p = .010, lithium vs. placebo). Results were similar when patients with mood episodes within 180 days of randomization were excluded.Both lamotrigine and lithium maintenance therapy protected against mood episode recurrence in bipolar I disorder.

  View details for DOI 10.1016/j.biopsych.2006.02.034

  View details for Web of Science ID 000238416000011

  View details for PubMedID 16769295

• Safety and tolerability of mood-stabilising anticonvulsants in the elderly EXPERT OPINION ON DRUG SAFETY Fenn, H. H., Sommer, B. R., Ketter, T. A., Alldredge, B. 2006; 5 (3): 401-416

  Abstract

  The authors review current research on the safety and tolerability of anticonvulsant medications used for individuals over the age of 60 years with affective disorders, agitation and other psychiatric disorders. Three anticonvulsants currently approved in the US for treatment of bipolar affective disorder are reviewed: valproate, lamotrigine and extended-release carbamazepine. The authors discuss the pharmacokinetics, pharmacodynamics, drug-drug interactions and the impact of ageing for each drug. There are few studies of anticonvulsant medications in elderly patients with bipolar disorder or other psychiatric conditions. Therefore, the authors summarise adverse events of greatest prevalence and/or greatest severity based on data derived predominately from studies of geriatric patients with epilepsy and/or other non-psychiatric indications. Guidelines are offered for the safe use of these medications in the elderly, based on research literature.

  View details for DOI 10.1517/14740338.5.3.401

  View details for Web of Science ID 000239097500006

  View details for PubMedID 16610969

• REPRODUCTIVE HEALTH AND BIPOLAR DISORDER CNS SPECTRUMS Ketter, T. A., Suppes, T., Morrell, M. J., Rasgon, N., Cohen, L. S., Viguera, A. C. 2006; 11 (5): 1–16

  View details for Web of Science ID 000207075400001

• Commonalities and dissociations of cerebral metabolism with divalproex response in bipolar disorder Wang, P. W., Brooks, J. O., Bonner, J. C., Hill, S., Chandler, R. A., Ketter, T. A. ELSEVIER SCIENCE INC. 2006: 252S

  View details for Web of Science ID 000236767301396

• Effects of depression on cerebral metabolism in bipolar disorder Brooks, J. O., Wang, P. W., Bonner, J. C., Ketter, T. A. ELSEVIER SCIENCE INC. 2006: 168S

  View details for Web of Science ID 000236767301124

• Voxel-based morphometric analysis of gray matter in bipolar depression Bonner, J. C., Rosen, A. C., Wang, P. W., Ketter, T. A., Hill, S. J., Brooks, J. O. ELSEVIER SCIENCE INC. 2006: 174S

  View details for Web of Science ID 000236767301145

• Effects of lamotrigine and lithium on body weight during maintenance treatment of bipolar I disorder BIPOLAR DISORDERS Sachs, G., Bowden, C., Calabrese, J. R., Ketter, T., Thompson, T., White, R., Bentley, B. 2006; 8 (2): 175-181

  Abstract

  The effect of lamotrigine maintenance therapy on body weight was assessed retrospectively in analyses of data from two double-blind, placebo- and lithium-controlled, 18-month studies in patients with bipolar I disorder (n = 227 for lamotrigine, 190 for placebo, 166 for lithium).Endpoints included mean change in weight, the percentage of patients with > or = 7% change (increase, decrease, fluctuation) in weight, and the percentage of patients with weight-related adverse events during double-blind treatment.Mean weight remained stable during maintenance therapy with lamotrigine. In a mixed-model repeated-measures analysis, mean changes in weight (kg) at week 52 were -1.2 with lamotrigine, +0.2 with placebo, and +2.2 with lithium [estimated difference (95% CI) lamotrigine minus placebo = -1.3 (-3.6, 0.9), p = 0.237; lithium minus placebo = +2.0 (-0.3, 4.4), p = 0.094; lithium minus lamotrigine = +3.4 (1.4, 5.4), p < 0.001]. Analyses were truncated at week 52 because of the high incidence of missing data at later time points. The percentages of patients with a >/=7% weight gain, during randomized treatment, were 10.9%, 7.6% and 11.8% for the lamotrigine, placebo, and lithium groups, respectively. The percentages of patients with a > or = 7% weight loss, during randomized treatment, were 12.1%, 11.5%, and 5.1% for the lamotrigine, placebo, and lithium groups, respectively. The percentage of patients with a > or = 7% weight loss did not significantly differ between lamotrigine and placebo but was significantly higher with lamotrigine than lithium. The incidences of > or = 7% weight changes and of weight changes reported as adverse events were comparable between active treatments and placebo.Lamotrigine was associated with stable body weight during 1 year of treatment and was comparable to placebo in mean weight change, incidence of clinically significant weight change, and incidence of weight changes reported as adverse events in patients with bipolar disorder. Lithium was associated with weight gain, but the magnitude of lithium-associated weight gain was lower in the current analysis than in previous studies.

  View details for Web of Science ID 000236022400009

  View details for PubMedID 16542188

• Magnetic resonance spectroscopic measurement of cerebral gamma-aminobutyric acid concentrations in patients with bipolar disorders. Acta neuropsychiatrica Wang, P. W., Sailasuta, N., Chandler, R. A., Ketter, T. A. 2006; 18 (2): 120-6

  Abstract

  Animal models of depression and psychopharmacological mechanisms of action suggest the importance of the gamma-amino butyric acid (GABA) system in the pathophysiology of mood disorders. Mood stabilizers have overlapping effects on GABAergic neurotransmission, and antidepressant use has been associated with alterations in GABAB receptor function. Magnetic resonance spectroscopy (MRS) provides an opportunity to noninvasively assess cerebral GABA concentrations in anterior paralimbic circuits that have been implicated in mood disorders.In bipolar disorder patients and healthy control subjects, we used MRS with a modified GABA-edited point resolved spectroscopy sequence (TE 68 ms, TR 1500 ms, 512 averages, total scan time 26 min) to assess GABA in an 18-cm3 occipital voxel. In addition, in another cohort of bipolar disorder patients and healthy control subjects, we similarly assessed GABA in a 12.5-cm3 medial prefrontal/anterior cingulate (MPF/AC) voxel. The concentration of GABA was referenced to creatine (Cr) from unedited spectra.In bipolar patients and controls, we consistently detected 3.0 p.p.m. GABA peaks in occipital lobe and MPF/AC. In 16 bipolar (nine bipolar I and seven bipolar II) disorder patients, compared with six healthy control subjects, mean occipital GABA/Cr concentration was 61% higher. In addition, in 15 bipolar (five bipolar I, nine bipolar II, and one bipolar not otherwise specified) disorder patients, compared with six healthy control subjects, mean MPF/AC GABA/Cr concentration tended to be 41% higher.Patients with bipolar disorders may have increased cerebral GABA concentrations. Although this was more evident in the occipital lobe, MPC/AC GABA disturbance may be of greater potential interest in view the more established role of MPF/AC in affective processing. Additional studies are warranted to assess changes in GABAergic neurotransmission and the influences of diagnosis, mood state, and medication status in bipolar disorder patients.

  View details for DOI 10.1111/j.1601-5215.2006.00132.x

  View details for PubMedID 26989801

• Magnetic resonance spectroscopic measurement of cerebral gamma-aminobutyric acid concentrations in patients with bipolar disorders ACTA NEUROPSYCHIATRICA Wang, P. W., Sailasuta, N., Chandler, R. A., Ketter, T. A. 2006; 18 (2): 120-126

  Abstract

  Animal models of depression and psychopharmacological mechanisms of action suggest the importance of the gamma-amino butyric acid (GABA) system in the pathophysiology of mood disorders. Mood stabilizers have overlapping effects on GABAergic neurotransmission, and antidepressant use has been associated with alterations in GABAB receptor function. Magnetic resonance spectroscopy (MRS) provides an opportunity to noninvasively assess cerebral GABA concentrations in anterior paralimbic circuits that have been implicated in mood disorders.In bipolar disorder patients and healthy control subjects, we used MRS with a modified GABA-edited point resolved spectroscopy sequence (TE 68 ms, TR 1500 ms, 512 averages, total scan time 26 min) to assess GABA in an 18-cm3 occipital voxel. In addition, in another cohort of bipolar disorder patients and healthy control subjects, we similarly assessed GABA in a 12.5-cm3 medial prefrontal/anterior cingulate (MPF/AC) voxel. The concentration of GABA was referenced to creatine (Cr) from unedited spectra.In bipolar patients and controls, we consistently detected 3.0 p.p.m. GABA peaks in occipital lobe and MPF/AC. In 16 bipolar (nine bipolar I and seven bipolar II) disorder patients, compared with six healthy control subjects, mean occipital GABA/Cr concentration was 61% higher. In addition, in 15 bipolar (five bipolar I, nine bipolar II, and one bipolar not otherwise specified) disorder patients, compared with six healthy control subjects, mean MPF/AC GABA/Cr concentration tended to be 41% higher.Patients with bipolar disorders may have increased cerebral GABA concentrations. Although this was more evident in the occipital lobe, MPC/AC GABA disturbance may be of greater potential interest in view the more established role of MPF/AC in affective processing. Additional studies are warranted to assess changes in GABAergic neurotransmission and the influences of diagnosis, mood state, and medication status in bipolar disorder patients.

  View details for Web of Science ID 000237985900009

• The effect of dermatologic precautions on the incidence of rash with addition of lamotrigine in the treatment of bipolar I disorder: A randomized trial 59th Annual Meeting of the American-Epilepsy-Society/American-Clinical-Neurophysiology-Society Ketter, T. A., Greist, J. H., Graham, J. A., Roberts, J. N., Thompson, T. R., Nanry, K. P. PHYSICIANS POSTGRADUATE PRESS. 2006: 400–406

  Abstract

  Prescribing recommendations specify that lamotrigine should ordinarily be discontinued at the first sign of rash, regardless of its type and severity, unless the rash is clearly not drug related. This practice helps to ensure that lamotrigine is discontinued in instances of serious rash (an event occurring in up to 0.13% of cases in bipolar clinical trials) but may lead to unnecessary discontinuation of lamotrigine for cases of nonserious rash arising from nondrug causes. Measures aimed at reducing overall occurrence of dermatologic reactions might reduce the incidence of nonserious rash leading to premature lamotrigine discontinuation. This study assessed the impact of specific instructions designed to decrease risk of dermatologic reactions, including nonserious rash, during initiation of and early treatment with lamotrigine in patients with bipolar I disorder.Outpatients with DSM-IV-diagnosed bipolar I disorder >/= 13 years of age at 188 sites were randomly assigned to receive Usual Care Precautions (UCP; precautions from the patient instructions in the prescribing information for reducing risk of rash including nonserious rash) or Dermatologic Precautions (DP; precautions as above [UCP] plus additional precautions intended to decrease risk of any dermatologic reaction including nonserious rash) during 12 weeks of adding open-label lamotrigine to concomitant medications. Patients with comorbid medical and psychiatric problems were not excluded unless, in the opinion of the investigators, these problems were sufficiently severe to preclude participation. Investigators and patients were blinded to which precaution group patients were randomly assigned. The primary outcome measure was the rate of rash during the treatment period. Secondary outcome measures included clinical response to lamotrigine, assessed with the investigator- and self-rated Clinical Global Impressions-Bipolar version (CGI-BP) and the Clinical Global Impressions-Efficacy Index (CGI-EI). Data were collected from August 2003 to August 2004.867 (74%) of 1175 patients completed the study. Only 182 (15%) of 1175 patients had an adverse event leading to discontinuation of study medication or withdrawal, including 62 (5.3%) of 1175 due to non-serious rash. No serious rashes were reported during the study in either group. The incidence of nonserious rash was similarly low in patients with UCP and DP (8.8% and 8.6%, respectively). CGI-BP-Severity and -Improvement scores indicated mood improvement when lamotrigine was added to existing therapy, and CGI-EI scores at weeks 5 and 12 reflected a favorable balance between control of mood symptoms and tolerability. At both weeks 5 and 12, investigators reported that therapeutic effects of additional lamotrigine outweighed side effects in 74% of subjects.UCP and DP yielded low, similar non-serious rash rates, which were marginally lower than nonserious rash rates in prior clinical trials that did not utilize DP but marginally higher than that in a prior open case series using DP. Nevertheless, the results are encouraging: in this large study reflecting real-world use, lamotrigine was well tolerated with no serious rash and low incidences of nonserious rash and discontinuation due to rash, and lamotrigine therapy was associated with clinical improvement in a heterogeneous cohort of patients with bipolar I disorder.

  View details for Web of Science ID 000236721600009

  View details for PubMedID 16649826

• Predictors of recurrence in bipolar disorder: Primary outcomes from the systematic treatment enhancement program for bipolar disorder (STEP-BD) AMERICAN JOURNAL OF PSYCHIATRY Perlis, R. H., Ostacher, M. J., Patel, J. K., Marangell, L. B., Zhang, H. W., Wisniewski, S. R., Ketter, T. A., Miklowitz, D. J., Otto, M. W., Gyulai, L., Reilly-Harrington, N. A., Nierenberg, A. A., Sachs, G. S., Thase, M. E. 2006; 163 (2): 217-224

  Abstract

  Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence.The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression.Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence.Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence.

  View details for Web of Science ID 000235031000011

  View details for PubMedID 16449474

• Treatment-resistant bipolar depression: A STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone AMERICAN JOURNAL OF PSYCHIATRY Nierenberg, A. A., Ostacher, M. J., Calabrese, J. R., Ketter, T. A., Marangell, L. B., Miklowitz, D. J., Miyahara, S., Bauer, M. S., Thase, M. E., Wisniewski, S. R., Sachs, G. S. 2006; 163 (2): 210-216

  Abstract

  Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone.Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks.No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone.No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression.

  View details for Web of Science ID 000235031000010

  View details for PubMedID 16449473

• Mood stabilizers and atypical antipsychotics: bimodal treatments for bipolar disorder. Psychopharmacology bulletin Ketter, T. A., Nasrallah, H. A., Fagiolini, A. 2006; 39 (1): 120-146

  Abstract

  Treatment options for bipolar disorder have rapidly expanded over the last decade, but providing optimal management remains an elusive goal. The authors reviewed the literature on the efficacy of agents with the best clinical evidence supporting their use in bipolar disorder, including the mood stabilizers lithium, valproate, lamotrigine, and carbamazepine, as well as the atypical antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Most medications appear to be more effective for symptoms of mood elevation than for symptoms of depression. The efficacy, tolerability, and safety profiles of agents must be considered when making clinical decisions. Several agents, including lithium, valproate, olanzapine, quetiapine, and risperidone, can cause problematic weight gain. In addition, the use of atypical antipsychotics has been associated with an increased risk of metabolic abnormalities such as dyslipidemia, hypergylycemia, and diabetes mellitus. In most patients, monotherapy offers inadequate efficacy. Further investigation of combinations of agents such as mood stabilizers and atypical antipsychotics may yield valuable insights into the potential of combination therapies to enhance clinical outcomes in patients with bipolar disorder.

  View details for PubMedID 17065977

• Extended-release carbamazepine capsules as monotherapy in bipolar disorder - Pooled results from two randomised, double-blind, placebo-controlled trials CNS DRUGS Weisler, R. H., Hirschfeld, R., Cutler, A. J., Gazda, T., Ketter, T. A., Keck, P. E., Swann, A., Kalali, A. 2006; 20 (3): 219-231

  Abstract

  Recently, two large, 3-week, randomised, double-blind, placebo-controlled trials using nearly identical protocols demonstrated that monotherapy with carbamazepine extended-release capsules (CBZ-ERC) was effective for the treatment of acute mania in patients with bipolar I disorder. By pooling data from these two trials, a more highly powered analysis of the efficacy and safety of CBZ-ERC in bipolar I disorder could be conducted.Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Clinical Global Impression (CGI)-Severity (CGI-S) scale, the CGI-Improvement (CGI-I) scale and the Hamilton Depression Rating Scale (HDRS). A sub-analysis of the data based on manic versus mixed presentation was performed, as well as sub-analyses by age, sex and ethnicity.Of the 443 randomised patients in the pooled population, 240 completed the studies. Forty-two percent of CBZ-ERC-treated patients did not complete the studies, compared with 50% of placebo-treated patients (p=0.087). Ten percent of patients given CBZ-ERC withdrew because of lack of efficacy, compared with 22% of patients given placebo (p<0.001). At endpoint, CBZ-ERC compared with placebo was associated with significant improvements in mean YMRS total scores in patients experiencing both manic (p<0.0001) and mixed (p<0.01) episodes, using last-observation-carried-forward analyses. CGI-I and CGI-S scores also showed significant improvements from baseline for both manic and mixed patients at endpoint. In patients with mixed episodes, at endpoint there was a mean improvement in HDRS total score of 4.8 points with CBZ-ERC, compared with 2.3 points with placebo (p<0.05). Ninety percent of patients given CBZ-ERC experienced an adverse event, compared with 64% of those patients given placebo. Discontinuation because of adverse events occurred in 10.8% of patients taking CBZ-ERC, compared with 5.5% of patients taking placebo.These results confirm previous findings that CBZ-ERC is effective in the treatment of bipolar I disorder patients with either acute manic or mixed episodes. These data suggest that further randomised controlled studies are warranted to delineate the effect of CBZ-ERC on depressive symptoms in patients with bipolar disorder.

  View details for Web of Science ID 000237240000004

  View details for PubMedID 16529527

• Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Houston, J. P., Adams, D. H., Risser, R. C., Meyers, A. L., Williamson, D. J., Tohen, M. 2006; 67 (1): 95-101

  Abstract

  Bipolar disorder outcome worsens as number of manic episodes increases, suggesting that prevention of recurrent episodes early during the disorder could improve patient prognosis. We investigated treatment efficacy in prevention of mood episodes in patients subgrouped by number of prior manic episodes.This study was a post hoc analysis of data from a multicenter, double-blind, 12-month clinical trial of relapse/recurrence in 431 initially euthymic patients with at least 2 prior manic/ mixed episodes and a DSM-IV diagnosis of bipolar I disorder randomly assigned to olanzapine (5-20 mg/day) or lithium (serum concentration 0.6 to 1.2 mEq/L). Data were collected between August 1999 and June 2002. Patients were subcategorized by illness stage according to number of prior manic/mixed episodes-early stage: 2 prior episodes (N = 53, lithium; N = 48, olanzapine), intermediate stage: 3 to 5 prior episodes (N = 80, lithium; N = 98, olanzapine), and later stage: more than 5 prior episodes (N = 81, lithium; N = 71, olanzapine)-and were evaluated for rates of relapse/recurrence.There were significant effects for treatment (p < .001) and illness stage (p = .006) but no significant interaction (p = .107) on rate of manic/mixed relapse/recurrence. Rates of manic/ mixed relapse/recurrence for olanzapine versus lithium were 2.1% versus 26.4% (p = .008), 13.3% versus 23.8% (p = .073), and 23.9% versus 33.3% (p = .204) for early-, intermediate-, and later-stage groups, respectively. There was no significant effect for treatment (p = .096) or illness stage (p = .731) for depressive relapse/recurrence.Early-stage (but not intermediate-or later-stage) patients had a significantly lower rate of relapse/recurrence of manic/mixed episodes with olanzapine compared to lithium. Thus, olanzapine maintenance therapy may be particularly effective early in the course of bipolar illness.

  View details for Web of Science ID 000235151000014

  View details for PubMedID 16426094

• Clinical use of carbamazepine for bipolar disorders EXPERT OPINION ON PHARMACOTHERAPY Wang, P. W., Ketter, T. A. 2005; 6 (16): 2887-2902

  Abstract

  Two recently completed large, randomised, double-blind, placebo-controlled trials supporting the efficacy of carbamazepine (CBZ) extended-release capsules (ERC) for the treatment of acute manic and mixed episodes have resulted in US FDA approval of CBZ-ERC, and have reinvigorated the importance of understanding the role of CBZ in bipolar disorder (BD) pharmacotherapy. Additional data suggest that CBZ may have a use in BD maintenance treatment and possibly in acute BD depression. Optimal use of CBZ requires sound knowledge of adverse effects and pharmacokinetic interactions with this agent. Adverse effects commonly involve benign side effects but can rarely include serious haematological, dermatological and hepatic manifestations. On the other hand, metabolic adverse effects (thyroid, glucose, lipid disturbances and significant weight gain) can be less problematic with CBZ, compared with lithium, valproate and atypical antipsychotics. Pharmacokinetic considerations (cytochrome P450 3A3/4 metabolism, active epoxide metabolite and catabolic enzyme induction) can influence the clinical use of CBZ. Managing adverse effects and pharmacokinetic complexities is important for optimising pharmacotherapy with CBZ in patients with BD. This paper reviews the chemistry, pharmacodynamics and pharmacokinetics of CBZ, as well as reviews of the controlled trials of CBZ in acute bipolar mania, acute bipolar depression and bipolar maintenance treatment.

  View details for DOI 10.1517/14656566.6.16.2887

  View details for Web of Science ID 000233901000011

  View details for PubMedID 16318439

• Rapid cycling differentially exacerbates bipolar II compared to bipolar I disorder: Implications for adjunctive antidepressant therapy Ketter, T. A., Calabrese, J., Bowden, C., Marangell, L., Gyulai, L., Nierenberg, A., Wisniewski, S., Sachs, G. NATURE PUBLISHING GROUP. 2005: S176

  View details for Web of Science ID 000233442100461

• Preliminary findings of uncoupling of flow and metabolism in unipolar compared with bipolar affective illness and normal controls PSYCHIATRY RESEARCH-NEUROIMAGING Dunn, R. T., Willis, M. W., Benson, B. E., Repella, J. D., Kimbrell, T. A., Ketter, T. A., Speer, A. M., Osuch, E. A., Post, R. M. 2005; 140 (2): 181-198

  Abstract

  Cerebral metabolism (CMR for glucose or oxygen) and blood flow (CBF) have been reported to be closely correlated in healthy controls. Altered relationships between CMR and CBF have been reported in some brain disease states, but not others. This study examined relationships between global and regional CMRglu vs. CBF in controls and medication-free primary affective disorder patients. Nine bipolars, eight unipolars, and nine healthy controls had [15O]-water positron emission tomography (PET) scans at rest, and [18F]-fluorodeoxyglucose PET scans during an auditory continuous performance task. Patients had [15O]-water and FDG PET scans in tandem the same day; controls had an average of 45+/-27 days between scans. Maps of regional coupling were constructed for each subject group. In controls and bipolars, global and virtually all regional correlation coefficients for CMRglu and CBF were positive, albeit more robustly so in controls. However, correlative relationships in unipolars were qualitatively different, such that global and most regional measures of flow and metabolism were not positively related. Unipolars had significantly fewer positive regional correlation coefficients than healthy controls and bipolars. These were significantly different from controls in orbital cortex, anterior cingulate, posterior cingulate, and posterior temporal cortex, and different from bipolars in pregenual anterior cingulate. In unipolars, the degree of flow-metabolism uncoupling was inversely correlated with Hamilton depression scores, indicating the severity of uncoupling was directly related to the severity of depression. These preliminary data suggest abnormal relationships between cerebral metabolism and blood flow globally and regionally in patients with unipolar depression that warrant replication and extension to potential pathophysiological implications.

  View details for DOI 10.1016/j.pscychresns.2005.07.005

  View details for Web of Science ID 000233534500007

  View details for PubMedID 16257515

• Creativity in familial bipolar disorder 50th Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry Simeonova, D. I., Chang, K. D., Strong, C., Ketter, T. A. PERGAMON-ELSEVIER SCIENCE LTD. 2005: 623–31

  Abstract

  Studies have demonstrated relationships between creativity and bipolar disorder (BD) in individuals, and suggested familial transmission of both creativity and BD. However, to date, there have been no studies specifically examining creativity in offspring of bipolar parents and clarifying mechanisms of intergenerational transmission of creativity. We compared creativity in bipolar parents and their offspring with BD and bipolar offspring with attention-deficit/hyperactivity disorder (ADHD) with healthy control adults and their children. 40 adults with BD, 20 bipolar offspring with BD, 20 bipolar offspring with ADHD, and 18 healthy control parents and their healthy control children completed the Barron-Welsh Art Scale (BWAS), an objective measure of creativity. Adults with BD compared to controls scored significantly (120%) higher on the BWAS Dislike subscale, and non-significantly (32%) higher on the BWAS Total scale. Mean BWAS Dislike subscale scores were also significantly higher in offspring with BD (107% higher) and offspring with ADHD (91% higher) than in healthy control children. Compared to healthy control children, offspring with BD had 67% higher and offspring with ADHD had 40% higher BWAS Total scores, but these differences failed to reach statistical significance when adjusted for age. In the bipolar offspring with BD, BWAS Total scores were negatively correlated with duration of illness. The results of this study support an association between BD and creativity and contribute to a better understanding of possible mechanisms of transmission of creativity in families with genetic susceptibility for BD. This is the first study to show that children with and at high risk for BD have higher creativity than healthy control children. The finding in children and in adults was related to an enhanced ability to experience and express dislike of simple and symmetric images. This could reflect increased access to negative affect, which could yield both benefits with respect to providing affective energy for creative achievement, but also yield liabilities with respect to quality of interpersonal relationships or susceptibility to depression.

  View details for DOI 10.1016/j.jpsychires.2005.01.005

  View details for PubMedID 16157163

• Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder 58th Annual Convention of the Society-of-Biological-Psychiatry Chang, K., Barnea-Goraly, N., Karchemskiy, A., Simeonova, D. I., Barnes, P., Ketter, T., Reiss, A. L. ELSEVIER SCIENCE INC. 2005: 197–203

  Abstract

  Morphometric magnetic resonance imaging (MRI) studies of pediatric bipolar disorder (BD) have not reported on gray matter volumes but have reported increased lateral ventricular size and presence of white matter hyperintensities (WMH). We studied gray matter volume, ventricular-to-brain ratios (VBR), and number of WMH in patients with familial, pediatric BD compared with control subjects.Twenty subjects with BD (aged 14.6 +/- 2.8 years; 4 female) according to the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, each with a parent with BD, and 20 age-, gender-, and intelligence quotient-matched healthy control subjects (aged 14.1 +/- 2.8 years; 4 female) were scanned at 3 T. Most subjects were taking psychotropic medications. A high-resolution T1-weighted spoiled gradient echo three-dimensional MRI sequence was analyzed by BrainImage for volumetric measurements, and T2-weighted images were read by a neuroradiologist to determine presence of WMH.After covarying for age and total brain volume, there were no significant differences between subjects with BD and control subjects in volume of cerebral (p = .09) or prefrontal gray matter (p = .34). Subjects with BD did not have elevated numbers of WMH or greater VBR when compared with control subjects.Children and adolescents with familial BD do not seem to have decreased cerebral grey matter or increased numbers of WMH, dissimilar to findings in adults with BD. Gray matter decreases and development of WMH might be later sequelae of BD or unique to adult-onset BD.

  View details for DOI 10.1016/j.biopsych.2005.03.039

  View details for PubMedID 16084840

• Mood disorders in the medically ill: Scientific review and recommendations BIOLOGICAL PSYCHIATRY Evans, D. L., Charney, D. S., Lewis, L., Golden, R. N., Gorman, J. M., Krishnan, K. R., Nemeroff, C. B., Bremner, J. D., Carney, R. M., Coyne, J. C., DeLong, M. R., Frasure-Smith, N., Glassman, A. H., Gold, P. W., Grant, I., Gwyther, L., Ironson, G., Johnson, R. L., Kanner, A. M., Katon, W. J., Kaufmann, P. G., Keefe, F. J., Ketter, T., Laughren, T. P., Leserman, J., Lyketsos, C. G., McDonald, W. M., McEwen, B. S., Miller, A. H., Musselman, D., O'Connor, C., Petitto, J. M., Pollock, B. G., Robinson, R. G., Roose, S. P., Rowland, J., Sheline, Y., Sheps, D. S., Simon, G., Spiegel, D., Stunkard, A., Sunderland, T., Tibbits, P., Valvo, W. J. 2005; 58 (3): 175-189

  Abstract

  The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research.Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors.Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed.A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

  View details for DOI 10.1016/j.biopsych.2005.05.001

  View details for Web of Science ID 000231057100001

  View details for PubMedID 16084838

• The Texas Implementation of Medication Algorithms: Update to the algorithms for treatment of bipolar I disorder JOURNAL OF CLINICAL PSYCHIATRY Suppes, T., Dennehy, E. B., Hirschfeld, R. M., Altshuler, L. L., Bowden, C. L., Calabrese, J. R., Crismon, M. L., Ketter, T. A., Sachs, G. S., Swann, A. C. 2005; 66 (7): 870-886

  Abstract

  A panel consisting of academic psychiatrists and pharmacist administrators of the Texas Department of State Health Services (formerly Texas Department of Mental Health and Mental Retardation), community mental health physicians, advocates, and consumers met in May 2004 to review new evidence in the pharmacologic treatment of bipolar I disorder (BDI). The goal of the consensus conference was to update and revise the current treatment algorithm for BDI as part of the Texas Implementation of Medication Algorithms, a statewide quality assurance program for the treatment of major psychiatric illness. The guidelines for evaluating possible medications, the criteria for selection and ranking, and the updated algorithms are described.Principles from previous consensus conferences were reviewed and amended. Medication algorithms for the acute treatment of hypomanic/manic or mixed and depressive episodes in BDI were developed after examining recent efficacy and safety and tolerability data. Recommendations for maintenance treatments were developed.The panel updated the 2 primary algorithms (hypomanic/manic/mixed and depressive) based on clinical evidence for efficacy, tolerability, and safety developed since 2000. Expert consensus was utilized where clinical evidence was limited. Prevention of new episodes or prophylaxis treatment recommendations were developed based on recent data from longer-term trials. Maintenance recommendations are provided as levels versus a specified staged algorithm, as for acute treatment, due to the relatively limited database to inform treatment.These algorithms for the treatment of BDI represent the recommendations based on the most recent evidence available. These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.

  View details for Web of Science ID 000230663800010

  View details for PubMedID 16013903

• A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression AMERICAN JOURNAL OF PSYCHIATRY Calabrese, J. R., Keck, P. E., Macfadden, W., Minkwitz, M., Ketter, T. A., Weisler, R. H., Cutler, A. J., McCoy, R., Wilson, E., Mullen, J. 2005; 162 (7): 1351-1360

  Abstract

  There is a major unmet need for effective options in the treatment of bipolar depression.Five hundred forty-two outpatients with bipolar I (N=360) or II (N=182) disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks of quetiapine (600 or 300 mg/day) or placebo. The primary efficacy measure was mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score. Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global Impression of severity and improvement, Hamilton Anxiety Rating Scale, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire.Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week 1 onward. The proportions of patients meeting response criteria (> or =50% Montgomery-Asberg Depression Rating Scale score improvement) at the final assessment in the groups taking 600 and 300 mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for placebo. The proportions of patients meeting remission criteria (Montgomery-Asberg Depression Rating Scale < or =12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at 600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg Depression Rating Scale items, respectively, compared to placebo, including the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively).Quetiapine monotherapy is efficacious and well tolerated for the treatment of bipolar depression.

  View details for Web of Science ID 000230196500018

  View details for PubMedID 15994719

• Reassessing Carbamazepine in the Treatment of Bipolar Disorder Clinical Implications of New Data CNS SPECTRUMS Ketter, T. A., Akiskal, H. S., Keck, P. E., Fuller, M. A., Weisler, R. H., Hirschfeld, R. M. 2005: 1-13

  Abstract

  This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions. Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

  View details for Web of Science ID 000207075700001

  View details for PubMedID 16041864

• The impact of polarity of subyndromal symptoms in bipolar maintenance studies 6th International Conference on Bipolar Disorder Yatham, L. N., Bowden, C. L., Calabrese, J. R., Ketter, T. A., Adams, B. E., DeVeaugh-Geiss, A. M., Thompson, T. R. WILEY-BLACKWELL. 2005: 113–113

  View details for Web of Science ID 000229369500300

• A 12-week randomized open-label study of dermatological precautions with lamotrigine in bipolar disorder patients 6th International Conference on Bipolar Disorder Graham, J. A., Ketter, T. A., Roberts, J., DeVeaugh-Geiss, A. M., Thompson, T. R. WILEY-BLACKWELL. 2005: 62–62

  View details for Web of Science ID 000229369500134

• Olanzapine and lithium prophylaxis of bipolar disorder and episode history 6th International Conference on Bipolar Disorder Houston, J. P., Ketter, T. A., Risser, R. C., Adams, D. H., Meyers, A., Williamson, D. J., Tohen, M. WILEY-BLACKWELL. 2005: 66–66

  View details for Web of Science ID 000229369500145

• Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Wang, P. W., Chandler, R. A., Alarcon, A. M., Becker, O. V., Nowakowska, C., O'Keeffe, C. M., Schumacher, M. R. 2005; 66 (5): 642-645

  Abstract

  To assess treatment-emergent rash incidence when using dermatology precautions (limited antigen exposure) and slower titration during lamotrigine initiation.We assessed rash incidence in 100 patients with DSM-IV bipolar disorder instructed, for their first 3 months taking lamotrigine, to avoid other new medicines and new foods, cosmetics, conditioners, deodorants, detergents, and fabric softeners, as well as sunburn and exposure to poison ivy/oak. Lamotrigine was not started within 2 weeks of a rash, viral syndrome, or vaccination. In addition, lamotrigine was titrated more slowly than in the prescribing information. Patients were monitored for rash and clinical phenomena using the Systematic Treatment Enhancement Program for Bipolar Disorder Clinical Monitoring Form. Descriptive statistics were compiled.No patient had serious rash. Benign rash occurred in 5 patients (5%) and resolved uneventfully in 3 patients discontinuing and 2 patients continuing lamotrigine. Two patients with rash were found to be not adherent to dermatology precautions. Therefore, among the remaining patients, only 3/98 (3.1%) had benign rashes.The observed rate of benign rash was lower than the 10% incidence in other clinical studies. The design of this study confounds efforts to determine the relative contributions of slower titration versus dermatology precautions to the low rate of rash. Systematic studies are needed to confirm these preliminary findings, which suggest that adhering to dermatology precautions with slower titration may yield a low incidence of rash with lamotrigine.

  View details for Web of Science ID 000229302900016

  View details for PubMedID 15889953

• Analyses of treatment-emergent mania with olanzapine/fluoxetine combination in the treatment of bipolar depression 4th International Forum on Mood and Anxiety Disorders Keck, P. E., Corya, S. A., Altshuler, L. L., Ketter, T. A., McElroy, S. L., Case, M., Briggs, S. D., Tohen, M. PHYSICIANS POSTGRADUATE PRESS. 2005: 611–16

  Abstract

  Treatment-emergent mania is a potential risk when patients with bipolar disorder are treated with antidepressant agents. These subanalyses compare treatment-emergent mania rates in bipolar I depressed patients treated with olanzapine, placebo, or olanzapine/fluoxetine combination.In this 8-week, double-blind investigation, patients with bipolar I depression (DSM-IV criteria) (N = 833, baseline Montgomery-Asberg Depression Rating Scale total score > or = 20) were randomly assigned to olanzapine (5-20 mg/day, N = 370), placebo (N = 377), or olanzapine/fluoxetine combination (6/25, 6/50, or 12/50 mg/day; N = 86). Treatment-emergent mania was evaluated with the Young Mania Rating Scale (YMRS), the Clinical Global Impressions-Bipolar Edition (CGI-BP) Severity of Mania scale, and adverse events records.Overall rates of study discontinuation due to mania were low and not significantly different among the therapy groups (p = .358). Incidence of treatment-emergent mania (defined as a YMRS score < 15 at baseline and > or = 15 at any subsequent visit) did not differ significantly among therapy groups (olanzapine 5.7%, placebo 6.7%, olanzapine/fluoxetine combination 6.4%; p = .861). Subjects receiving olanzapine or olanzapine/fluoxetine combination had greater mean decreases in YMRS scores than those receiving placebo (p < .001 for both). Subjects receiving olanzapine or olanzapine/fluoxetine combination also had greater mean decreases in CGI-BP scores than those receiving placebo (p = .040 and p = .003, respectively).These results suggest that olanzapine/fluoxetine combination does not present a greater risk of treatment-emergent mania compared to olanzapine or placebo over 8 weeks of acute treatment for bipolar I depression. Due to the cyclical nature of bipolar disorder, patients taking olanzapine/fluoxetine combination for bipolar depression should still be monitored for signs or symptoms of emerging mania.

  View details for Web of Science ID 000229302900011

  View details for PubMedID 15889948

• Olanzapine and lithium prophylaxis of bipolar disorder and episode history 60th Annual Convention of the Society-of-Biological-Psychiatry Ketter, T., Houston, J. P., Risser, R. C., Adams, D. H., Meyers, A., Williamson, D., Tohen, M. ELSEVIER SCIENCE INC. 2005: 54S–54S

  View details for Web of Science ID 000228338600190

• Temperamental commonalities and differences in euthymic mood disorder patients, creative controls, and healthy controls JOURNAL OF AFFECTIVE DISORDERS Nowakowska, C., Strong, C. M., Santosa, C. M., Wang, P. W., Ketter, T. A. 2005; 85 (1-2): 207-215

  Abstract

  Understanding of mood disorders can be enhanced through assessment of temperamental traits. We explored temperamental commonalities and differences among euthymic bipolar (BP) and unipolar (MDD) mood disorder patients, creative discipline graduate student controls (CC), and healthy controls (HC).Forty-nine BP, 25 MDD, 32 CC, and 47 HC completed self-report temperament/personality measures including: The Affective Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A); the Revised NEO Personality Inventory (NEO-PI-R); and the Temperament and Character Inventory (TCI).Euthymic BP, MDD, and CC, compared to HC, had significantly increased cyclothymia, dysthymia and irritability scores on TEMPS-A; increased neuroticism and decreased conscientiousness on NEO-PI-R; and increased harm avoidance and novelty seeking as well as decreased self-directedness on TCI. TEMPS-A cyclothymia scores were significantly higher in BP than in MDD. NEO-PI-R openness was increased in BP and CC, compared to HC, and in CC compared to MDD. TCI self-transcendence scores in BP were significantly higher than in MDD, CC, and HC.Most of the subjects were not professional artists, and represented many fields; temperament might be different in different art fields.Euthymic BP, MDD, and CC compared to HC, had prominent temperamental commonalities. However, BP and CC had the additional commonality of increased openness compared to HC. BP had particularly high Cyclothymia scores that were significantly higher then those of MDD. The prominent BP-CC overlap suggests underlying neurobiological commonalities between people with mood disorders and individuals involved in creative disciplines, consistent with the notion of a temperamental contribution to enhanced creativity in individuals with bipolar disorders.

  View details for DOI 10.1016/j.jad.2003.11.012

  View details for Web of Science ID 000228409400022

  View details for PubMedID 15780691

• Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: A multicenter, randomized, double-blind, placebo-controlled trial JOURNAL OF CLINICAL PSYCHIATRY Weisler, R. H., Keck, P. E., Swann, A. C., Cutler, A. J., Ketter, T. A., Kalali, A. H. 2005; 66 (3): 323-330

  Abstract

  Although carbamazepine has long been used for the treatment of acute mania, only recently was its efficacy confirmed in a large, multicenter, parallel-group, placebo-controlled, randomized trial. In the present study, we further evaluated the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ) in patients with bipolar I disorder experiencing manic or mixed episodes.Hospitalized bipolar I disorder (DSM-IV criteria) patients (N = 239) with manic or mixed episodes were randomly assigned on a double-blind basis to receive ERC-CBZ or placebo for 3 weeks, following a single-blind placebo lead-in. Treatment with ERC-CBZ was initiated at 200 mg twice daily, and investigators were encouraged to increase doses, as necessary and tolerated, by 200 mg/day up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression. The study was conducted from July 23, 2002, to April 1, 2003.144 patients (60.3%) completed the study, with a significant number of placebo patients discontinuing due to lack of efficacy (p < .001). Extended-release carbamazepine treatment was associated with significant improvements in mean YMRS total and CGI total scores, using last-observation-carried-forward analyses, beginning at day 7 (p < .05). Adverse events occurring more frequently in the ERC-CBZ-treated group included dizziness (39.3%), somnolence (30.3%), and nausea (23.8%) [corrected] Patients taking ERC-CBZ experienced a significant increase in total cholesterol, composed of increases in both high-density and low-density lipoproteins.Extended-release carbamazepine monotherapy had significantly greater efficacy compared with placebo in the treatment of acute mania in this large, randomized, double-blind, placebo-controlled trial.

  View details for Web of Science ID 000227744700007

  View details for PubMedID 15766298

• Bupropion and venlafaxine responders differ in pretreatment regional cerebral metabolism in unipolar depression BIOLOGICAL PSYCHIATRY Little, J. T., Ketter, T. A., Kimbrell, T. A., Dunn, R. T., Benson, B. E., Willis, M. W., Luckenbaugh, D. A., Post, R. M. 2005; 57 (3): 220-228

  Abstract

  Pretreatment functional brain imaging was examined for never-hospitalized outpatients with unipolar depression compared with control subjects in a crossover treatment trial involving bupropion or venlafaxine monotherapy.Patients (n = 20) with unipolar depression received baseline (medication-free) fluorine-18 deoxyglucose (FDG) positron emission tomography (PET) scan and then at least 6 weeks of bupropion or venlafaxine monotherapy in a single-blind crossover trial. Age-matched healthy control subjects (n = 20) also received baseline FDG PET scans. For each medication PET data from patients compared with control subjects was analyzed as a function of treatment response (defined as moderate to marked improvement on the Clinical Global Impression Scale).Treatment response rates were similar for buproprion (32%) and venlafaxine (33%). Compared with control subjects, responders but not nonresponders, to both drugs demonstrated frontal and left temporal hypometabolism. Selectively, compared with control subjects bupropion responders (n = 6) also had cerebellar hypermetabolism, whereas venlafaxine responders (n = 7) showed bilateral temporal and basal ganglia hypometabolism.These data suggest that pretreatment frontal and left temporal hypometabolism in never-hospitalized depressed outpatients compared with control subjects is linked to positive antidepressant response and that additional alterations in regional metabolism may be linked to differential responsivity to bupropion and venlafaxine monotherapy.

  View details for DOI 10.1016/j.biopsysch.2004.10.033

  View details for Web of Science ID 000226886400003

  View details for PubMedID 15691522

• Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter ANNALS OF MEDICINE Mansour, H. A., Talkowski, M. E., Wood, J., Pless, L., Bamne, M., Chowdari, K. V., Allen, M., Bowden, C. L., Calabrese, J., El-Mallakh, R. S., Fagiolini, A., Faraone, S. V., Fossey, M. D., Friedman, E. S., Gyulai, L., Hauser, P., Ketter, T. A., Loftis, J. M., Marangell, L. B., Miklowitz, D. J., Nierenberg, A. A., Patel, J., Sachs, G. S., Sklar, P., Smoller, J. W., Thase, M. E., Frank, E., Kupfer, D. J., Nimgaonkar, V. L. 2005; 37 (8): 590-602

  Abstract

  The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n = 182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

  View details for DOI 10.1080/07853890500357428

  View details for Web of Science ID 000234258900005

  View details for PubMedID 16338761

• A US perspective of the CANMAT bipolar guidelines BIPOLAR DISORDERS Calabrese, Keck, P. E., Bowden, C. L., Ketter, T. A., Sachs, G., Findling, R. L., Sajatovic, M. A. 2005; 7: 70–72

  View details for DOI 10.1111/j.1399-5618.2005.00220.x

  View details for Web of Science ID 000231193600002

  View details for PubMedID 15952958

• A 12-week randomized open-label study of dermatological precautions with lamotrigine in bipolar disorder patients Ketter, T. A., Graham, J., Thompson, T., Nanry, K. BLACKWELL PUBLISHING. 2005: 176

  View details for Web of Science ID 000232540100518

• Demographic and diagnostic characteristics of the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) BIPOLAR DISORDERS Kogan, J. N., Otto, M. W., Bauer, M. S., Dennehy, E. B., Miklowitz, D. J., Zhang, H. W., Ketter, T., Rudorfer, M. V., Wisniewski, S. R., Thase, M. E., Calabrese, J., Sachs, G. S. 2004; 6 (6): 460-469

  Abstract

  Bipolar disorder is a severe, recurrent, and often highly impairing psychiatric disorder. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is a large-scale multicenter study funded by the National Institute of Mental Health (NIMH) to examine the longitudinal course of the disorder and the effectiveness of current treatments. The current report provides a context for interpreting studies resulting from STEP-BD by summarizing the baseline demographic and diagnostic characteristics of the first 1000 enrolled.The majority of the sample met DSM-IV criteria for bipolar I disorder (71%). Mean age of patients was 40.6 (+/-12.7) years and mean duration of bipolar illness was 23.1 (+/-12.9) years. Among the first 1000 subjects enrolled, 58.6% are females and 92.6% Caucasian. This report compares the STEP-BD sample with other large cohorts of bipolar patients (treatment and community samples).Compared with US population and community studies, the first 1000 STEP-BD patients were less racially diverse, more educated, had lower income, and a higher unemployment rate. Results are discussed in terms of the contributions of STEP-BD (and other large-scale treatment studies) in understanding the nature, treatments, and outcomes of bipolar disorder for patients seeking care at academic treatment centers.The current report provides a context for interpreting future studies resulting from STEP-BD. The comparison of demographic and clinical characteristics between the samples across clinic-based studies suggests broad similarities despite the substantial differences in geography, payer mix, and clinical entry point.

  View details for Web of Science ID 000225081000003

  View details for PubMedID 15541061

• Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania BRITISH JOURNAL OF PSYCHIATRY Baker, R. W., Brown, E., Akiskal, H. S., Calabrese, J. R., Ketter, T. A., Schuh, L. M., Trzepacz, P. T., Watkin, J. G., Tohen, M. 2004; 185: 472-478

  Abstract

  Few controlled studies examine the treatment of depressive features in mania.To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania.Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5-20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients.In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy.In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings.

  View details for Web of Science ID 000225675200006

  View details for PubMedID 15572737

• Lamotrigine therapy in treatment-resistant menstrually-related rapid cycling bipolar disorder: a case report BIPOLAR DISORDERS Becker, O. V., Rasgon, N. L., Marsh, W. K., Glenn, T., Ketter, T. A. 2004; 6 (5): 435-439

  Abstract

  To evaluate lamotrigine in a woman with a 30-year history of treatment-resistant menstrually-entrained rapid cycling bipolar II disorder with follicular phase depressive and luteal phase mood elevation symptoms.Lamotrigine was started at 5 mg/day and gradually increased up to 300 mg/day, while venlafaxine was tapered gradually and discontinued, and divalproex sodium 500 mg/day and levothyroxine 175 mcgm/day were continued. Daily self-reported mood ratings were obtained from the patient, using ChronoRecord software.As lamotrigine was increased gradually, mood cycle amplitude attenuated. There was notable decrease in the severity and duration of depressive symptoms specifically during the follicular phase of the menstrual cycle. At the time of submission of this paper, the subject had remained euthymic for a total of 12 months.This case suggests the potential utility of lamotrigine in treatment-resistant menstrually-related rapid cycling bipolar disorder, and raises the possibility that lamotrigine might be able to treat pathological entrainment of mood with the menstrual cycle. Both of these issues merit systematic assessment.

  View details for Web of Science ID 000223996200013

  View details for PubMedID 15383138

• Phenomenology of rapid-cycling bipolar disorder: Data from the first 500 participants in the systematic treatment enhancement program AMERICAN JOURNAL OF PSYCHIATRY Schneck, C. D., Miklowitz, D. J., Calabrese, J. R., Allen, M. H., Thomas, M. R., Wisniewski, S. R., Miyahara, S., Shelton, M. D., Ketter, T. A., Goldberg, J. F., Bowden, C. L., Sachs, G. S. 2004; 161 (10): 1902-1908

  Abstract

  This study compared demographic and phenomenological variables between bipolar patients with and without rapid cycling as a function of bipolar I versus bipolar II status.The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder.Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid-cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients.Patients with rapid-cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to refine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.

  View details for Web of Science ID 000224279000026

  View details for PubMedID 15465989

• A potential cholinergic mechanism of procaine's limbic activation NEUROPSYCHOPHARMACOLOGY Benson, B. E., Carson, R. E., Kiesewetter, D. O., Herscovitch, P., Eckelman, W. C., Post, R. M., Ketter, T. A. 2004; 29 (7): 1239-1250

  Abstract

  The local anesthetic procaine, when administered to humans intravenously (i.v.), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[18F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M(2)) receptors. On separate days each animal received six different doses of i.v. procaine in a randomized fashion. Procaine blocked up to approximately 90% of [18F]FP-TZTP specific binding globally in a dose-related manner. There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC50) for [18F]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC50 for average cortex. Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion.

  View details for DOI 10.1038/sj.npp.1300404

  View details for Web of Science ID 000222110700003

  View details for PubMedID 14997171

• Sustained remission/euthymia with quetiapine monotherapy for bipolar mania 24th CINP Congress Ketter, T. A., Paulsson, B., Jones, M. CAMBRIDGE UNIV PRESS. 2004: S330–S330

  View details for Web of Science ID 000224663002032

• Clinical predictors of response to olanzapine or olanzapine/fluoxetine combination for bipolar depression 24th CINP Congress Tohen, M., Vieta, E., Calabrese, J., Ketter, T., Mitchell, P., Briggs, S., Case, M. CAMBRIDGE UNIV PRESS. 2004: S331–S331

  View details for Web of Science ID 000224663002035

• A 6-month, multicenter, open-label evaluation of beaded, extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or mixed episodes JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Kalali, A. H., Weisler, R. H. 2004; 65 (5): 668-673

  Abstract

  Carbamazepine is frequently used for treating bipolar disorder, but few large trials have assessed its efficacy in preventing relapse. We evaluated open-label monotherapy with beaded extended-release carbamazepine capsules (ERC-CBZ; SPD417) as continuation and short-term maintenance therapy in bipolar disorder patients with manic and mixed episodes.A 6-month, open-label study enrolled 92 patients with DSM-IV bipolar disorder (most recent episode: 67% [N = 62] mixed, 33% [N = 30] manic) who had participated in 2 previous 3-week, double-blind, placebo-controlled studies. Subjects received beaded ERC-CBZ (200-1600 mg/day), titrated at investigators' discretion to a final mean dose of 938 mg/day and serum carbamazepine concentration of 6.6 microg/mL. The primary efficacy measure was time to relapse, and secondary efficacy measures included Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D) scores. Data were gathered from January 2000 to January 2002.Of 77 patients analyzed in the intent-to-treat population, 11 (14.3%) relapsed. Fifty-three patients (68.8%) discontinued early, including 18 (23.4%) due to adverse events. Observed mean time to relapse was 61.1 days, while estimated mean time to relapse based on the Kaplan-Meier model was 141.8 days. Improvements on the YMRS, CGI, and HAM-D from the beginning of prior double-blind treatment were maintained. The most common adverse events were headache, dizziness, and rash. No significant weight gain was noted.We noted a low relapse rate with beaded ERC-CBZ in this 6-month trial. Adverse events were generally mild to moderate and were typical of those associated with carbamazepine. Controlled studies are warranted to further explore the efficacy of beaded ERC-CBZ in preventing relapse in bipolar disorder.

  View details for Web of Science ID 000221887100011

  View details for PubMedID 15163253

• Clinical predictors of response to olanzapine or olanzapine/fluoxetine combination for bipolar depression 59th Annual Meeting of the Society-of-Biological-Psychiatry Tohen, M., Vieta, E., Calabrese, J. R., Ketter, T. A., Mitchell, P. B., Briggs, S. D., Case, M. ELSEVIER SCIENCE INC. 2004: 231S–231S

  View details for Web of Science ID 000220755300807

• A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes JOURNAL OF CLINICAL PSYCHIATRY Weisler, R. H., Kalali, A. H., Ketter, T. A. 2004; 65 (4): 478-484

  Abstract

  Carbamazepine has been used to treat mania for over 2 decades. Most evaluations of carbamazepine have had important limitations, such as absence of a parallel placebo group, small sample size, or the confounding influence of concomitant treatment. All studies have used conventional, immediate-release carbamazepine formulations. We assessed the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ; SPD417) in bipolar disorder patients with manic or mixed episodes.Following a single-blind placebo lead-in, DSM-IV-defined bipolar disorder patients with manic or mixed episodes were randomly assigned to receive ERC-CBZ (N = 101) or placebo (N = 103) for 3 weeks. Patients were hospitalized through the first 7 days of the double-blind period. ERC-CBZ was initiated at 400 mg/day and increased, as necessary and tolerated, up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D). Data were gathered from December 1999 to June 2001.Ninety-six (47.1%) of 204 patients completed the study. The mean +/- SD final ERC-CBZ dose was 756.44 +/- 413.38 mg/day with a mean plasma drug level of 8.9 microg/mL. Starting at week 2, ERC-CBZ was associated with significantly greater improvements in YMRS (p =.032) using last-observation-carried-forward analyses. At end point, the responder rate (patients with at least a 50% decrease in YMRS score) also favored ERC-CBZ (41.5% vs. 22.4%; p =.0074). In a post hoc analysis of mixed patients, HAM-D score was significantly improved in patients remaining on ERC-CBZ treatment on day 21 (p =.01). Adverse events occurring more frequently in the ERC-CBZ group than in the placebo group included dizziness, nausea, and somnolence.We found ERC-CBZ to be effective in the first large, randomized, double-blind, placebo-controlled parallel trial of carbamazepine monotherapy in acute mania. This trial provides important additional evidence supporting the use of carbamazepine in acute mania.

  View details for Web of Science ID 000222190600005

  View details for PubMedID 15119909

• Clinical predictors of response to olanzapine or olanzapine/fluoxetine combination for bipolar depression Tohen, M., Vieta, E., Calabrese, J. R., Ketter, T. A., Mitchell, P., Briggs, S. D., Case, M. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 2004: 204S–204S

  View details for Web of Science ID 000220948200685

• Lamotrigine treatment of bipolar disorder: data from the first 500 patients in STEP-BD BIPOLAR DISORDERS Marangell, L. B., Martinez, J. M., Ketter, T. A., Bowden, C. L., Goldberg, J. F., Calabrese, J. R., Miyahara, S., Miklowitz, D. J., Sachs, G. S., Thase, M. E. 2004; 6 (2): 139-143

  Abstract

  To describe the frequency and correlates of lamotrigine therapy among the first 500 patients enrolled into the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.Systematic recording of psychiatric history and medication data at intake into the STEP-BD project.Of the participants with bipolar disorder type I or II (n = 483), 77 (15.4%) were currently taking lamotrigine (mean dose: 258.12 mg/day) and 52 (10.4%) reported prior lamotrigine use. The groups were comparable with regard to duration of illness and mood state at study entry. Compared with participants who had never taken lamotrigine, those currently treated with lamotrigine were significantly more likely to have a prior history of rapid cycling (62.5% vs. 43.1%; p < 0.01) and an antidepressant-induced switch to (hypo)mania (49.3% vs. 33.3%; p < 0.01). In contrast, only 16.9% of lamotrigine-treated participants were taking an antidepressant at study intake, as compared with 29.1% of participants with no history of lamotrigine therapy (p < 0.03).While noting the limitations of a cross-sectional assessment, these data suggest that lamotrigine therapy was commonly used in these academic centers for patients with bipolar disorder several years before it was recommended in the American Psychiatric Association practice guidelines, particularly in patients with a history of rapid cycling or antidepressant-induced mania.

  View details for Web of Science ID 000220099300006

  View details for PubMedID 15005752

• Psychosocial service utilization by patients with bipolar disorders: data from the first 500 participants in the Systematic Treatment Enhancement Program. Journal of psychiatric practice Lembke, A., Miklowitz, D. J., Otto, M. W., Zhang, H., Wisniewski, S. R., Sachs, G. S., Thase, M. E., Ketter, T. A. 2004; 10 (2): 81-87

  Abstract

  Although patients with bipolar disorder have been shown to benefit from psychosocial interventions, the proportion that utilizes these interventions is unknown. We set out to clarify the determinants of psychosocial service utilization in adults with bipolar disorder.We investigated psychosocial service utilization among the first 500 patients admitted to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).In the 3 months prior to enrollment in STEP-BD, a majority of the patients (54%) were engaged in at least one psychosocial service modality in addition to pharmacotherapy. In order of decreasing frequency, these were therapy with a psychologist, self-help group, therapy with a social worker, and therapy with another type of provider. Bipolar patients with personality disorders (80% vs 20%, p = 0.0002), alcohol/drug abuse disorders (76% vs 24%, p = 0.0022), and anxiety disorders (60% vs 40%, p = 0.0043) received more psychosocial services than those without. Poorer global functioning also increased the likelihood of receiving services, whereas being married decreased service utilization.Psychosocial service utilization by outpatients with bipolar disorder is strongly linked to greater severity/complexity of illness. Potential moderators, such as insurance status and availability of care, should be examined in future studies.

  View details for PubMedID 15330403

• New medication treatment options for bipolar disorders ACTA PSYCHIATRICA SCANDINAVICA Ketter, T. A., Wang, P. W., Nowakowska, C., Marsh, W. K. 2004; 110: 18-33

  Abstract

  To assess new treatment options for bipolar disorders.Controlled studies of new treatments for bipolar disorders were identified by computerized searches and reviews of scientific meeting proceedings, and were compiled by drug category.Two main categories of medications, newer anticonvulsants and newer antipsychotics, are yielding emerging new treatment options for bipolar disorders. Newer anticonvulsants have diverse psychotropic profiles, and although not generally effective for acute mania, may have utility for other aspects of bipolar disorders (e.g. lamotrigine for maintenance or acute bipolar depression), or for comorbid conditions (e.g. gabapentin for anxiety or pain, topiramate for obesity, bulimia, alcohol dependence, or migraine, and zonisamide for obesity). In contrast, newer antipsychotics generally appear effective for acute mania, and some may ultimately prove effective in acute depression (e.g. olanzapine combined with fluoxetine, quetiapine) and maintenance (e.g. olanzapine).Emerging research is yielding new treatment options for bipolar disorders and comorbid conditions.

  View details for Web of Science ID 000224297000003

  View details for PubMedID 15330935

• Sustained remission/euthymia with quetiapine monotherapy for bipolar mania Ketter, T. A., Paulsson, B., Jones, M. WILEY-BLACKWELL. 2004: 31–31

  View details for Web of Science ID 000224297100078

• Psychotic bipolar disorders: dimensionally similar to or categorically different from schizophrenia? Conference on Non Schizophrenic Psychoses Ketter, T. A., Wang, P. W., Becker, O. V., Nowakowska, C., Yang, Y. S. PERGAMON-ELSEVIER SCIENCE LTD. 2004: 47–61

  Abstract

  For over a century, clinicians have struggled with how to conceptualize the primary psychoses, which include psychotic mood disorders and schizophrenia. Indeed, the nature of the relationship between mood disorders and schizophrenia is an area of ongoing controversy. Psychotic bipolar disorders have characteristics such as phenomenology, biology, therapeutic response, and brain imaging findings, suggesting both commonalities with and dissociations from schizophrenia. Taken together, these characteristics are in some instances most consistent with a dimensional view, with psychotic bipolar disorders being intermediate between non-psychotic bipolar disorders and schizophrenia spectrum disorders. However, in other instances, a categorical approach appears useful. Although more research is clearly necessary to address the dimensional versus categorical controversy, it is feasible that at least in the interim, a mixed dimensional/categorical approach could provide additional insights into pathophysiology and management options, which would not be available utilizing only one of these models.

  View details for DOI 10.1016/S0022-3956(03)00099-2

  View details for Web of Science ID 000220190700006

  View details for PubMedID 14690770

• New anticonvulsant medication uses in bipolar disorder CNS SPECTRUMS Wang, P. W., Ketter, T. A., Becker, O. V., Nowakowska, C. 2003; 8 (12): 930-?

  Abstract

  Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect g-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintenance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.

  View details for Web of Science ID 000226890300014

  View details for PubMedID 14978468

• Studies of offspring of parents with bipolar disorder AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Chang, K., Steiner, H., Ketter, T. 2003; 123C (1): 26-35

  Abstract

  Children and adolescents who are the biological offspring of individuals with bipolar disorder (BD) (bipolar offspring) represent a population rich in potential for revealing important aspects in the development of BD. Multiple cross-sectional assessments of psychopathology in bipolar offspring have confirmed high incidences of BD, as well as mood and behavioral disorders, and other psychopathology in this population. Longitudinal studies of offspring have begun to shed light on precursors of BD development. Other assessments of bipolar offspring have included dimensional reports of psychiatric and psychosocial functioning, temperament assessments, and descriptions of family environments and parenting styles. Neurobiological studies in bipolar offspring are just beginning to yield findings that may be related to the underlying neuropathophysiology of BD. The future holds promise for longitudinal studies of bipolar offspring incorporating all of these facets, including genetic analyses, to further elucidate the factors involved in the evolution of BD.

  View details for DOI 10.1002/ajmg.c.20011

  View details for PubMedID 14601034

• Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression 23rd Collegium-Internationale-Neuro-Psychopharmacologium Congress (CINP) Tohen, M., Vieta, E., Calabrese, J., Ketter, T. A., Sachs, G., Bowden, C., Mitchell, P. B., Centorrino, F., Risser, R., Baker, R. W., Evans, A. R., Beymer, K., Dube, S., Tollefson, G. D., Breier, A. AMER MEDICAL ASSOC. 2003: 1079–88

  Abstract

  Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression.To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.Double-blind, 8-week, randomized controlled trial.Eighty-four sites (inpatient and outpatient) in 13 countries. Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20. Intervention Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86).Changes in MADRS total scores using mixed-effects model repeated-measures analyses.During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (P<.001 for all). The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8. At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapine-fluoxetine groups, respectively. Remission criteria were met by 24.5% (87/355) of the placebo group, 32.8% (115/351) of the olanzapine group, and 48.8% (40/82) of the olanzapine-fluoxetine group. Treatment-emergent mania (Young Mania Rating Scale score <15 at baseline and > or =15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea.Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.

  View details for Web of Science ID 000186612300003

  View details for PubMedID 14609883

• Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission Zubieta, J. K., Ketter, T. A., Bueller, J. A., Xu, Y. J., Kilbourn, M. R., Young, E. A., Koeppe, R. A. AMER MEDICAL ASSOC. 2003: 1145–53

  Abstract

  Human affective responses appear to be regulated by limbic and paralimbic circuits. However, much less is known about the neurochemical systems engaged in this regulation. The mu-opioid neurotransmitter system is distributed in, and thought to regulate the function of, brain regions centrally implicated in affective processing.To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in healthy human volunteers.Measures of mu-opioid receptor availability in vivo were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer [11C]carfentanil during a neutral state and during a sustained sadness state. Subtraction analyses of the binding potential maps were then performed within subjects, between conditions, on a voxel-by-voxel basis.Imaging center at a university medical center.Fourteen healthy female volunteers. Intervention Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion.Changes in mu-opioid receptor availability and negative and positive affect ratings between conditions. Increases or reductions in the in vivo receptor measure reflect deactivation or activation of neurotransmitter release, respectively.The sustained sadness condition was associated with a statistically significant deactivation in mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, amygdala, and inferior temporal cortex. This deactivation was reflected by increases in mu-opioid receptor availability in vivo. The deactivation of mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, and amygdala was correlated with the increases in negative affect ratings and the reductions in positive affect ratings during the sustained sadness state.These data demonstrate dynamic changes in mu-opioid neurotransmission in response to an experimentally induced negative affective state. The direction and localization of these responses confirms the role of the mu-opioid receptor system in the physiological regulation of affective experiences in humans.

  View details for DOI 10.1001/archpsyc.60.11.1145

  View details for Web of Science ID 000186612300010

  View details for PubMedID 14609890

• Temperament characteristics of child and adolescent bipolar offspring JOURNAL OF AFFECTIVE DISORDERS Chang, K. D., Blasey, C. M., Ketter, T. A., Steiner, H. 2003; 77 (1): 11-19

  Abstract

  We wished to characterize temperament of children at high risk for bipolar disorder (BD).We collected data from the Dimensions of Temperament-Revised (DOTS-R) from 53 biological offspring of at least one parent with BD.Overall, our cohort differed from population means for the DOTS-R, having decreased Activity Level-General scores, and increased Approach, and Rhythmicity-Sleep scores. Offspring with psychiatric disorders differed from those without in having decreased Flexibility, Mood, and Task Orientation scores. Temperament profiles for diagnostic categories of BD and attention-deficit/hyperactivity disorder were performed in a descriptive manner.Self- or parent-report of temperament was used rather than clinical observation. Temperament characterization was cross-sectional and retrospective rather than prospective and may overlap with clinical diagnoses.Assessment of temperament may be useful in characterizing bipolar offspring. Decreased flexibility and task orientation, and presence of negative moods may be correlated with development of psychopathology.

  View details for DOI 10.1016/S0165-0327(02)00105-2

  View details for PubMedID 14550931

• Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Ketter, T. A., Manji, H. K., Post, R. M. 2003; 23 (5): 484-495

  Abstract

  Based on the mood-stabilizing properties of carbamazepine and valproate, new anticonvulsants have been explored for use in bipolar disorders. One such agent, lamotrigine, has a novel clinical profile in that it may "stabilize mood from below," as it appears to maximally impact depressive symptoms in bipolar disorders. In this paper, we review the mechanisms of action of lamotrigine in an effort to understand the basis of its distinctive clinical use in the management of bipolar disorders as well as its diverse antiseizure effects. We consider lamotrigine mechanisms, emphasizing commonalities and dissociations among actions of lamotrigine, older mood stabilizers, and other anticonvulsants. Although ion channel effects, especially sodium channel blockade, may importantly contribute to antiseizure effects, such actions may be less central to lamotrigine thymoleptic effects. Antiglutamatergic and neuroprotective actions are important candidate mechanisms for lamotrigine psychotropic effects. Lamotrigine has a variable profile in kindling and contingent tolerance experiments and does not appear to have robust gamma-aminobutyric acid or monoaminergic actions. Lamotrigine intracellular signaling effects warrant investigation. Although lamotrigine mechanisms overlap those of other mood-stabilizing anticonvulsants, important dissociations suggest candidate mechanisms, which could contribute to lamotrigine's distinctive psychotropic profile.

  View details for DOI 10.1097/01.jcp.0000088915.02635.e8

  View details for Web of Science ID 000185404300011

  View details for PubMedID 14520126

• Divalproex monotherapy in the treatment of bipolar offspring with mood and behavioral disorders and at least mild affective symptoms 41st Annual Meeting of the New-Clinical-Drug-Evaluation-Unit Chang, K. D., Dienes, K., Blasey, C., Adleman, N., Ketter, T., Steiner, H. PHYSICIANS POSTGRADUATE PRESS. 2003: 936–42

  Abstract

  Offspring of parents with bipolar disorder, by virtue of their high-risk status for developing bipolar disorder, merit an investigation of the efficacy of treatment with mood stabilizers. Behavioral and mood difficulties in this population may represent prodromal forms of bipolar disorder. We studied the efficacy of divalproex in treating child and adolescent bipolar offspring with mood or behavioral disorders who did not yet meet criteria for bipolar I or II disorder.We studied 24 children aged 6-18 years (mean = 11.3 years; 17 boys/7 girls) with at least 1 biological parent with bipolar disorder. Participants were diagnosed by the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia with at least 1 of the following DSM-IV disorders: major depressive disorder, dysthymic disorder, cyclothymic disorder, or attention-deficit/hyperactivity disorder. Subjects all had at least moderate affective symptoms (28-item Hamilton Rating Scale for Depression or Young Mania Rating Scale score > 12). After a 2-week washout period, subjects were treated with divalproex for 12 weeks, titrated to achieve serum levels of 50-120 micro g/mL (mean final dose = 821 mg/day; mean final serum level = 79.0 micro g/mL).One subject discontinued after 2 weeks due to continuation of symptoms. Of the remaining 23 subjects, 18 (78%) were considered responders by primary outcome criteria ("very much improved" or "much improved" on the Clinical Global Impressions-Improvement scale). Divalproex was well tolerated with no discontinuations due to adverse effects.Bipolar offspring with mood or behavioral disorders and at least mild affective symptoms may respond to divalproex treatment. Our study was limited by the open treatment, lack of a placebo group, and the heterogeneous nature of the sample. Controlled studies are warranted in the use of divalproex in symptomatic bipolar offspring.

  View details for Web of Science ID 000184920400012

  View details for PubMedID 12927009

• Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study AMERICAN JOURNAL OF PSYCHIATRY Tohen, M., Ketter, T. A., Zarate, C. A., Suppes, T., Frye, M., Altshuler, L., Zajecka, J., Schuh, L. M., Risser, R. C., Brown, E., Baker, R. W. 2003; 160 (7): 1263-1271

  Abstract

  Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex.This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest.Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness.In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.

  View details for Web of Science ID 000183957200010

  View details for PubMedID 12832240

• Bipolar offspring: A window into bipolar disorder evolution Conference on Pediatric Bipolar Disorder Chang, K., Steiner, H., Dienes, K., Adleman, N., Ketter, T. ELSEVIER SCIENCE INC. 2003: 945–51

  Abstract

  Children of parents with bipolar disorder (bipolar offspring) represent a rich cohort for study with potential for illumination of prodromal forms of bipolar disorder. Due to their high-risk nature, bipolar offspring may present phenomenological, temperamental, and biological clues to early presentations of bipolar disorder. This article reviews the evidence for establishing bipolar offspring as a high-risk cohort, the studies which point to possible prodromal states in bipolar offspring, biological findings in bipolar offspring which may be indicators of even higher risk for bipolar disorder, initial attempts at early intervention in prodromal pediatric bipolar disorder, and implications for future research.

  View details for DOI 10.1016/S0006-3223(03)00061-1

  View details for PubMedID 12788239

• Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD) Conference on Pediatric Bipolar Disorder Sachs, G. S., Thase, M. E., Otto, M. W., Bauer, M., Miklowitz, D., Wisniewski, S. R., Lavori, P., Lebowitz, B., Rudorfer, M., Frank, E., Nierenberg, A. A., Fava, M., Bowden, C., Ketter, T., Marangell, L., Calabrese, J., Kupfer, D., Rosenbaum, J. F. ELSEVIER SCIENCE INC. 2003: 1028–42

  Abstract

  The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.

  View details for DOI 10.1016/S0006-3223(03)00165-3

  View details for Web of Science ID 000183339900013

  View details for PubMedID 12788248

• Decreased N-acetylaspartate in children with familial bipolar disorder BIOLOGICAL PSYCHIATRY Chang, K., Adleman, N., Dienes, K., Barnea-Goraly, N., Reiss, A., Ketter, T. 2003; 53 (11): 1059-1065

  Abstract

  Relatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder.Subjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex.Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p <.02). No differences in myoinositol or choline levels were found.Children and adolescents with bipolar disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar to adults with BD, indicating a common neuropathophysiology. Longitudinal studies of at-risk children before the onset and during the early course of bipolar disorder are needed to determine the role of prefrontal N-acetylaspartate as a possible risk marker and/or indication of early bipolar illness progression.

  View details for DOI 10.1016/S0006-3223(02)01744-4

  View details for PubMedID 12788251

• The diverse roles of anticonvulsants in bipolar disorders. Annals of clinical psychiatry Ketter, T. A., Wang, P. W., Becker, O. V., Nowakowska, C., Yang, Y. 2003; 15 (2): 95-108

  Abstract

  Anticonvulsant drugs (ACs) have diverse antiseizure, psychotropic, and biochemical effects. Carbamazepine and valproate have mood-stabilizing actions, benzodiazepines and gabapentin have anxiolytic actions, lamotrigine is useful in rapid cycling and acute treatment and prophylaxis of bipolar depression, and topiramate and zonisamide can yield weight loss. Limited controlled data suggest the carbamazepine keto derivative oxcarbazepine has antimanic effects. A categorical approach to the diverse roles of ACs in bipolar disorders is proposed, using broad categories of ACs, on the basis of their predominant psychotropic profiles. Thus, some ACs have "sedating" profiles that may include sedation, cognitive difficulties, fatigue, weight gain, and possibly antimanic and/or anxiolytic effects. In contrast, some newer ACs have "activating" profiles that may include improved energy, weight loss, and possibly antidepressant and even anxiogenic effects. Still other newer ACs have novel "mixed" profiles, combining sedation and weight loss. A categorical-mechanistic extension of this approach is also presented, with hypotheses that "sedating" profiles might be related to prominent potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, "activating" profiles could be related to prominent attenuation of glutamate excitatory neurotransmission, and for "mixed" profiles, sedation and weight loss might be related to concurrent GABAergic and antiglutamatergic actions, respectively. The categorical approach may have utility as an aid to clinicians in reinforcing the heterogeneity ACs, and recalling psychotropic profiles of individual ACs, but is limited as it fails to address the etiology of the heterogeneity of AC psychotropic effects. The categorical-mechanistic extension strives to address this issue, but requires systematic clinical investigation of more precise relationships between psychotropic profiles and discrete mechanisms of action to assess its merits.

  View details for PubMedID 12938867

• The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders Conference on the Role of GABA in Neuropsychiatric Disorders Ketter, T. A., Wang, P. W. PHYSICIANS POSTGRADUATE PRESS. 2003: 15–20

  Abstract

  Treatment options to relieve the diverse symptoms encountered in patients with bipolar disorders include not only mood stabilizers, but also anxiolytics, new anticonvulsants, antidepressants, and antipsychotics. These agents have widely varying mechanisms of action, which could contribute to the heterogeneity of clinical effects seen in practice. Several of these medications, especially those with anticonvulsant effects, enhance gamma-aminobutyric acid (GABA) inhibitory neurotransmission and/or attenuate glutamate excitatory neurotransmission. We review the efficacy and tolerability of these diverse treatment options in bipolar disorders and explore possible relationships between clinical effects and GABAergic and antiglutamatergic mechanisms of action.

  View details for Web of Science ID 000181811400003

  View details for PubMedID 12662129

• The emerging role of olanzapine in bipolar disorders PSYCHIATRIC ANNALS Ketter, T. A., Wang, P. W., Janenawasin, S., Becker, O. V., Wang, A. 2002; 32 (12): 753-762

  View details for Web of Science ID 000179723500007

• Gabapentin augmentation therapy in bipolar depression BIPOLAR DISORDERS Wang, P. W., Santosa, C., Schumacher, M., Winsberg, M. E., Strong, C., Ketter, T. A. 2002; 4 (5): 296-301

  Abstract

  Gabapentin (GBP) may be useful in bipolar disorders, including as adjunctive therapy for bipolar depression, although controlled studies suggest inefficacy as primary treatment for mania or treatment-resistant rapid cycling.We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women, mean age 38.4 years) depressed (28-item Hamilton Depression Rating Scale (HDRS) > 18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness duration was 18.6 years, current depressive episode duration was 18.0 weeks. Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity (CGI-S) ratings were obtained.Overall, HDRS ratings decreased 53% from 32.5 +/- 7.7 at baseline to 16.5 +/- 12.8 at week 12 (p < 0.0001). Twelve of 22 (55%) patients had moderate to marked improvement (HDRS decrease = 50%) with HDRS decreasing 78% from 27.9 +/- 6.2 to 6.2 +/- 4.5 (p < 0.0001). Eight of 22 (36%) patients remitted (HDRS > or = 8). In non-responders, HDRS decreased from 38.0 +/- 5.4 to 28.9 +/- 6.7 (p = 0.005). Ten of 13 (77%) mild to moderately depressed (baseline HDRS > 18 and <35) patients responded, while only two of nine patients (22%) with severe depression (HDRS > or = 35) responded (p < 0.03). Both groups, however, had similar, statistically significant HDRS decreases. GBP was well tolerated.Open adjunctive GBP was effective and well tolerated in patients with mild to moderate bipolar depression. This open pilot study must be viewed with caution, and randomized controlled studies are warranted.

  View details for Web of Science ID 000178520500004

  View details for PubMedID 12479661

• Psychiatric uses of antiepileptic treatments. Epilepsy & behavior Boylan, L. S., Devinsky, O., Barry, J. J., Ketter, T. A. 2002; 3 (5S): 54-59

  Abstract

  Antiepileptic drugs (AEDs) possess potent negative or positive psychotropic effects. Clear evidence of benefit exists for valproate, carbamazepine, and lamotrigine in bipolar disorder. Reports of benefit from various AEDs in mood, anxiety, impulse control, and personality disorder are reviewed. Further research is needed to clarify which patients are likely to benefit. Clinicians must closely attend to the ongoing risk/benefit analysis and consider possible iatrogenic worsening of neuropsychiatric symptoms.

  View details for PubMedID 12609323

• Psychiatric uses of antiepileptic treatments EPILEPSY & BEHAVIOR Boylan, L. S., Devinsky, O., Barry, J. J., Ketter, T. A. 2002; 3 (5): S54-S59

  Abstract

  Antiepileptic drugs (AEDs) possess potent negative or positive psychotropic effects. Clear evidence of benefit exists for valproate, carbamazepine, and lamotrigine in bipolar disorder. Reports of benefit from various AEDs in mood, anxiety, impulse control, and personality disorder are reviewed. Further research is needed to clarify which patients are likely to benefit. Clinicians must closely attend to the ongoing risk/benefit analysis and consider possible iatrogenic worsening of neuropsychiatric symptoms.

  View details for Web of Science ID 000179698000012

• Olanzapine in diverse syndromal and subsyndromal exacerbations of bipolar disorders BIPOLAR DISORDERS Janenawasin, S., Wang, P. W., Lembke, A., Schumacher, M., Das, B., Santosa, C. M., Mongkolcheep, J., Ketter, T. A. 2002; 4 (5): 328-334

  Abstract

  To evaluate effects of olanzapine in diverse exacerbations of bipolar disorders.Twenty-five evaluable bipolar disorder [14 bipolar I (BPI), 10 bipolar II (BPII) and one bipolar disorder not otherwise specified (BP NOS)] outpatients received open olanzapine (15 adjunctive, 10 monotherapy). Thirteen had elevated (11 syndromal, two subsyndromal) and 12 depressed (four syndromal, eight subsyndromal) mood symptoms of at least mild severity, with Clinical Global Impression-Severity (CGI-S) scores of at least 3. Only one had psychotic symptoms.With open olanzapine (15 adjunctive, 10 monotherapy), overall symptom severity (CGI-S) as well as mood elevation (Young Mania Rating Scale), depression (Hamilton and Montgomery-Asberg Depression Rating Scales), and anxiety (Hamilton Anxiety Rating Scale), rapidly decreased (significantly by days 2-3). Patients with the greatest baseline severity (CGI-S) had the greatest improvement. Fifteen of 25 (60%) patients responded. Time to consistent response was bimodal, with five early (by 0.5 +/- 0.3 weeks) and 10 late (by 7.0 +/- 1.9 weeks) responders. Early compared with late responders had 51% lower final olanzapine doses. Olanzapine was generally well tolerated, with sedation and weight gain the most common adverse effects.Olanzapine was effective in diverse exacerbations of bipolar disorders. The bimodal distribution of time to response and different final doses are consistent with differential mechanisms mediating early compared with late responses. Controlled studies are warranted to further explore these preliminary observations.

  View details for Web of Science ID 000178520500009

  View details for PubMedID 12479666

• Automated cerebrum segmentation from three-dimensional sagittal brain MR images COMPUTERS IN BIOLOGY AND MEDICINE Huh, S., Ketter, T. A., Sohn, K. H., Lee, C. H. 2002; 32 (5): 311-328

  Abstract

  We present a fully automated cerebrum segmentation algorithm for full three-dimensional sagittal brain MR images. First, cerebrum segmentation from a midsagittal brain MR image is performed utilizing landmarks, anatomical information, and a connectivity-based threshold segmentation algorithm as previously reported. Recognizing that cerebrum in laterally adjacent slices tends to have similar size and shape, we use the cerebrum segmentation result from the midsagittal brain MR image as a mask to guide cerebrum segmentation in adjacent lateral slices in an iterative fashion. This masking operation yields a masked image (preliminary cerebrum segmentation) for the next lateral slice, which may truncate brain region(s). Truncated regions are restored by first finding end points of their boundaries, by comparing the mask image and masked image boundaries, and then applying a connectivity-based algorithm. The resulting final extracted cerebrum image for this slice is then used as a mask for the next lateral slice. The algorithm yielded satisfactory fully automated cerebrum segmentations in three-dimensional sagittal brain MR images, and had performance superior to conventional edge detection algorithms for segmentation of cerebrum from 3D sagittal brain MR images.

  View details for Web of Science ID 000177605500001

  View details for PubMedID 12102751

• Olanzapine versus divalproex in the treatment of acute mania AMERICAN JOURNAL OF PSYCHIATRY Tohen, M., Baker, R. W., Altshuler, L. L., Zarate, C. A., Suppes, T., Ketter, T. A., Milton, D. R., Risser, R., Gilmore, J. A., Breier, A., Tollefson, G. A. 2002; 159 (6): 1011-1017

  Abstract

  The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial.A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures.The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment.The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.

  View details for Web of Science ID 000175951300019

  View details for PubMedID 12042191

• Synaptic, intracellular, and neuroprotective mechanisms of anticonvulsants: are they relevant for the treatment and course of bipolar disorders? JOURNAL OF AFFECTIVE DISORDERS Li, X. H., Ketter, T. A., Frye, M. A. 2002; 69 (1-3): 1-14

  Abstract

  Treatment of bipolar disorders has progressed significantly in the last decade due to advances in basic and clinical research. Much of this progress has centered on the development of a new generation of mood stabilizers-anticonvulsants. Valproic acid (VPA) and carbamazepine (CBZ) have clear mood stabilizing properties, while lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP) have been investigated to varying degrees. We provide an overview of mechanisms of these potentially mood-stabilizing anticonvulsants, review their commonalities and dissociations to the gold standard non-anticonvulsant mood stabilizer lithium. Regulations of the glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission are mostly studied mechanisms of anticonvulsants. The divergent effects of these agents indicate that this mode of action represents initial effect of anticonvulsants in regulating mood. Similar to lithium, intracellular mechanisms of anticonvulsants, primarily VPA and CBZ, include regulation of several protein kinase signaling pathways, leading to regulation of gene expression. Common genes that can be regulated by mood stabilizers are more likely to be the final normalizing components in bipolar disorders. Several anticonvulsants, such as VPA, LTG, and TPM, show neuronal protective function, a commonality with recently identified neuroprotective function of lithium, although the meaning of neuroprotection in bipolar disorders remains to be identified. Understanding the mechanisms of anticonvulsant mood stabilizers, integrated with clinical observations, may ultimately provide important new insights into the pathophysiology and treatment of bipolar disorders.

  View details for Web of Science ID 000176933500001

  View details for PubMedID 12103447

• 3 Tesla 1h-magnetic resonance spectroscopic measurements of prefrontal cortical gamma-aminobutyric acid (GABA) levels in bipolar disorder patients and healthy volunteers Wang, P. W., Dieckmann, N., Sailasuta, N., Adalsteinsson, E., Spielman, D., Ketter, T. A. ELSEVIER SCIENCE INC. 2002: 197S–197S

  View details for Web of Science ID 000174980400553

• Principal components of the beck depression inventory and regional cerebral metabolism in unipolar and bipolar depression 151st Annual Meeting of the American-Psychiatric-Association Dunn, R. T., Kimbrell, T. A., Ketter, T. A., Frye, M. A., Willis, M. W., Luckenbaugh, D. A., Post, R. M. ELSEVIER SCIENCE INC. 2002: 387–99

  Abstract

  We determined clustering of depressive symptoms in a combined group of unipolar and patients with bipolar disorder using Principle Components Analysis of the Beck Depression Inventory. Then, comparing unipolars and bipolars, these symptom clusters were examined for interrelationships, and for relationships to regional cerebral metabolism for glucose measured by positron emission tomography.[18F]-fluoro-deoxyglucose positron emission tomography scans and Beck Depression Inventory administered to 31 unipolars and 27 bipolars, all medication-free, mildly-to-severely depressed. BDI component and total scores were correlated with global cerebral metabolism for glucose, and voxel-by-voxel with cerebral metabolism for glucose corrected for multiple comparisons.In both unipolars and bipolars, the psychomotor-anhedonia symptom cluster correlated with lower absolute metabolism in right insula, claustrum, anteroventral caudate/putamen, and temporal cortex, and with higher normalized metabolism in anterior cingulate. In unipolars, the negative cognitions cluster correlated with lower absolute metabolism bilaterally in frontal poles, and in right dorsolateral frontal cortex and supracallosal cingulate.Psychomotor-anhedonia symptoms in unipolar and bipolar depression appear to have common, largely right-sided neural substrates, and these may be fundamental to the depressive syndrome in bipolars. In unipolars, but not bipolars, negative cognitions are associated with decreased frontal metabolism. Thus, different depressive symptom clusters may have different neural substrates in unipolars, but clusters and their substrates are convergent in bipolars.

  View details for Web of Science ID 000174512000007

  View details for PubMedID 11904133

• Age, sex and laterality effects on cerebral glucose metabolism in healthy adults PSYCHIATRY RESEARCH-NEUROIMAGING Willis, M. W., Ketter, T. A., Kimbrell, T. A., George, M. S., Herscovitch, P., Danielson, A. L., Benson, B. E., Post, R. M. 2002; 114 (1): 23-37

  Abstract

  Normal cerebral glucose metabolism (CMRglc) was assessed with positron emission tomography in 66 healthy adults (28 women, 38 men; mean age 39, range 20--69 years) to determine effects of age, sex and laterality on CMRglc using statistical parametric mapping. Significant age-related decreases in global metabolism (gCMRglc) were noted in the entire sample and in both sexes, as well as widespread and bilateral decreases in cortical absolute regional metabolism (rCMRglc) and more focal anterior paralimbic normalized rCMRglc. However, significant positive correlations of age with normalized rCMRglc were observed in cerebellum, thalamus and occipital areas. Although the declines in gCMRglc and rCMRglc with age did not significantly differ between sexes, men compared with women had significantly lower gCMRglc and widespread decreased cortical and subcortical absolute rCMRglc. In the entire sample, and similarly in both sexes, left greater than right asymmetry was observed in medial frontal gyrus, posterior thalamus, lingual gyrus, cuneus and superior cingulate. The opposite laterality appeared in mesio-anterior cerebellum, and lateral frontal and temporal regions. Few regions showed significant interactions of metabolic laterality with either age or sex. These findings contribute toward a convergence in the literature, and the regression models of CMRglc vs. age serve as a normative database to which patients may be compared.

  View details for Web of Science ID 000174349300003

  View details for PubMedID 11864807

• Impaired recognition of facial emotion in mania AMERICAN JOURNAL OF PSYCHIATRY Lembke, A., Ketter, T. A. 2002; 159 (2): 302-304

  Abstract

  Recognition of facial emotion was examined in manic subjects to explore whether aberrant interpersonal interactions are related to impaired perception of social cues.Manic subjects with bipolar I disorder (N=8), euthymic subjects with bipolar I (N=8) or bipolar II (N=8) disorder, and healthy comparison subjects (N=10) matched pictures of faces to the words "fear," "disgust," "anger," "sadness," "surprise," and "happiness."The manic subjects showed worse overall recognition of facial emotion than all other groups. They showed worse recognition of fear and disgust than the healthy subjects. The euthymic bipolar II disorder subjects showed greater fear recognition than the manic and euthymic bipolar I disorder subjects.Impaired perception of facial emotion may contribute to behaviors in mania. Impaired recognition of fear and disgust, with relatively preserved recognition of other basic emotions, contrasts with findings for depression and is consistent with a mood-congruent positive bias.

  View details for Web of Science ID 000173727500020

  View details for PubMedID 11823275

• Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders BIOLOGICAL PSYCHIATRY Obrocea, G. V., Dunn, R. M., Frye, M. A., Ketter, T. A., Luckenbaugh, D. A., Leverich, G. S., Speer, A. M., Osuch, E. A., Jajodia, K., Post, R. M. 2002; 51 (3): 253-260

  Abstract

  The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients.Forty-five patients with treatment refractory bipolar (n = 35) or unipolar (n = 10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression.Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression).In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants.

  View details for Web of Science ID 000173811000007

  View details for PubMedID 11839368

• Regional cerebral glucose utilization in patients with a range of severities of unipolar depression BIOLOGICAL PSYCHIATRY Kimbrell, T. A., Ketter, T. A., George, M. S., Little, J. T., Benson, B. E., Willis, M. W., Herscovitch, P., Post, R. M. 2002; 51 (3): 237-252

  Abstract

  Patients with unipolar depression are most often reported to have decreased regional cerebral glucose metabolism (rCMRglu) in dorsal prefrontal and anterior cingulate cortices compared with healthy control subjects, often correlating inversely with severity of depression.We measured rCMRglu with fluorine-18 deoxyglucose positron emission tomography (PET) in 38 medication-free patients with unipolar depression and 37 healthy control subjects performing an auditory continuous performance task to further investigate potential prefrontal and anterior paralimbic rCMRglu abnormalities in patients attending to this task.Compared with control subjects, the subgroup of patients with Hamilton depression scores of 22 or greater demonstrated decreased absolute rCMRglu in right prefrontal cortex and paralimbic/amygdala regions as well as bilaterally in the insula and temporoparietal cortex (right > left); they also exhibited increased normalized metabolic activity bilaterally in the cerebellum, lingula/cuneus, and brain stem. Severity of depression negatively correlated with absolute rCMRglu in almost the entire extent of the right cingulate cortex as well as bilaterally in prefrontal cortex, insula, basal ganglia, and temporoparietal cortex (right > left).Areas of frontal, cingulate, insula, and temporal cortex appear hypometabolic in association with different components of the severity and course of illness in treatment-resistant unipolar depression.

  View details for Web of Science ID 000173811000006

  View details for PubMedID 11839367

• Stabilization of mood from below versus above baseline in bipolar disorder: A new nomenclature JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Calabrese, J. R. 2002; 63 (2): 146-151

  Abstract

  Management of bipolar disorder has traditionally emphasized the acute treatment of mania. Although acute treatment of mania is a critical aspect of care, this emphasis has tended to overshadow other important phases of bipolar disorder, such as depression, hypomania, and subsyndromal symptoms. We offer a reconceptualization of bipolar disorder that highlights unmet needs and the importance of differential spectra of efficacy. In this reconceptualization, bipolar disorder can be viewed as an aberration of mood, behavior, and cognition from baseline (euthymia). "Below baseline" is characterized by depression and subsyndromal depression. "Above baseline" is characterized by mania, mixed states, hypomania, and subsyndromal mood elevation. In contrast to the treatment options for mania, the options for depression are limited. This new nomenclature emphasizes the need to develop mood stabilizers that possess the ability to stabilize mood "from below baseline," either alone or in combination with other agents. In this article, the treatment options for bipolar disorder, with a focus on depression and rapid cycling, are discussed according to this new conceptualization of management from below and above baseline.

  View details for Web of Science ID 000174048500010

  View details for PubMedID 11874216

• Predictors of treatment response in bipolar disorders: Evidence from clinical and brain imaging studies 50th Annual Meeting of the Canadian-Psychiatric-Association Ketter, T. A., Wang, P. W. PHYSICIANS POSTGRADUATE PRESS. 2002: 21–25

  Abstract

  The clinical features of bipolar disorders can be correlated with responses to medications. Patients who respond to lithium, for example, often present differently from those who respond to divalproex or carbamazepine, but the correlations are relatively modest. Brain-imaging tools, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), can relate brain function to clinical features and medication responses. For example, in depression, it appears that prefrontal cortical function is decreased while subcortical anterior paralimbic activity is increased. Preliminary evidence suggests that baseline metabolism increases and decreases in the left insula may be associated with carbamazepine and nimodipine responses, respectively, and that cerebral lithium concentrations may correlate with antimanic effects. Although it is not yet a clinical tool for bipolar disorders, brain imaging provides useful research data to understand the fundamental neurobiology of mood disorders and to more effectively target therapeutics.

  View details for Web of Science ID 000174419600005

  View details for PubMedID 11908918

• Pharmacokinetics of mood stabilizers and new anticonvulsants. Psychopharmacology bulletin Wang, P. W., Ketter, T. A. 2002; 36 (1): 44-66

  Abstract

  Mechanisms of action, efficacy spectra, pharmacokinetics, and adverse effects differentiate the mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA). Lithium, which has a low therapeutic index, is excreted through the kidneys, resulting in renally mediated, but not hepatically mediated, drug-drug interactions. CBZ also has a low therapeutic index and is metabolized primarily by a single isoform (CYP3A3/4). It has an active epoxide metabolite, is susceptible to CYP3A3/4 or epoxide hydrolase inhibitors, and is able to induce drug metabolism (both via cytochrome P450 oxidation and conjugation). CBZ thus has multiple problematic drug-drug interactions. In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, and it is less susceptible to pharmacokinetic drug interactions. Still, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of certain medications by displacing them from plasma proteins. The newer anticonvulsants lamotrigine, topiramate, and tiagabine have different, generally less problematic, hepatically mediated drug-drug interactions. Gabapentin, which is renally excreted, lacks hepatic drug-drug interactions, though bioavailability may be reduced at higher doses. Recently approved anticonvulsants, including oxcarbazepine, zonisamide, and levetiracetam, may have improved pharmacokinetic profiles compared to older agents. Novel psychotropic effects of these drugs may also be demonstrated, based on their mechanisms of action and preliminary clinical data.

  View details for PubMedID 12397847

• Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression JOURNAL OF AFFECTIVE DISORDERS Winsberg, M. E., DeGolia, S. G., Strong, C. M., Ketter, T. A. 2001; 67 (1-3): 207-212

  Abstract

  There have been few systematic studies of the treatment of bipolar II depression. While divalproex sodium (DVPX) is effective in acute mania, there are few data on the antidepressant effects of DVPX. Similarly, little is known regarding the use of DVPX administered in a single daily dose.We performed a 12-week open trial of DVPX monotherapy (mean dose 882 mg qhs, mean level 80.7 mug/ml) in nineteen (thirteen women, six men, mean age 29) bipolar II depressed outpatients. Eleven patients (six women, five men) were medication-naive (MN) and eight (seven women, one man) were mood stabilizer-naive (MSN), having had prior trials of antidepressants or stimulants. Mean illness and current depressive episode duration were 15.4 years and 11.8 weeks, respectively. DVPX was given as a single dose each evening starting with 250 mg at bedtime and increased by 250 mg at bedtime every 4 days until symptom relief or adverse effects were noted. Weekly prospective Hamilton Depression, Young Mania and Clinical Global Impression ratings were obtained.DVPX therapy was generally well tolerated. Twelve of nineteen patients (63%) responded (>50% decrease in Hamilton Depression ratings). MN patients compared to MSN patients tended to have a higher response rate (9/11 versus 3/8, P<0.08). Mean Hamilton scores decreased from 22.2 to 9.6 (P<0.0001) in the entire group, from 20.6 to 6.6 (P<0.0003) in MN patients, and from 24.2 to 14.7 (P=0.008) in MSN patients.Single daily dose DVPX monotherapy appeared to be well tolerated and substantially benefited 63% of patients with bipolar II depression. The trend towards a higher rate of antidepressant response to DVPX in MN patients (82%) compared to MSN patients (38%) could be due to a milder form or earlier phase of illness and the lack of prior medication exposure or failures. This uncontrolled open pilot study must be viewed with caution, and randomized double-blind placebo controlled studies of DVPX in bipolar II depression are warranted to confirm the possibility that single daily dose DVPX is an effective, well-tolerated, first-line monotherapy in this population.

  View details for Web of Science ID 000174633800023

  View details for PubMedID 11869770

• Post-dexamethasone cortisol correlates with severity of depression before and during carbamazepine treatment in women but not men ACTA PSYCHIATRICA SCANDINAVICA Osuch, E. A., Cora-Locatelli, G., Frye, M. A., Huggins, T., Kimbrell, T. A., Ketter, T. A., Callahan, A. M., Post, R. M. 2001; 104 (5): 397-401

  Abstract

  Previous studies show a state-dependent relationship between depression and post-dexamethasone suppression test (DST) cortisol level, as well as differences in DST response with age and gender.In this study, 74 research in-patients with affective disorders were given the DST on placebo and in a subgroup following treatment with carbamazepine. Depression was evaluated twice daily with the Bunney-Hamburg (BH) rating scale. Data were examined for the total subject population, by gender and by menopausal status in women.A robust positive correlation was observed between depression severity and post-DST cortisol in pre- and postmenopausal females, but not in males. This relationship persisted in women when restudied on a stable dose of carbamazepine (n=42).The pathophysiological implications of this selective positive relationship between severity of depression and post-DST cortisol in women, but not men, should be explored further.

  View details for Web of Science ID 000171785200013

  View details for PubMedID 11722323

• 3 Tesla 1H-magnetic resonance spectroscopic (MRS) detection of cerebral gamma-aminobutyric acid (GABA) in bipolar disorder patients and healthy volunteers Wang, P. W., Sachs, N., Sailasuta, N., Adalsteinsson, E., Spielman, D., Ketter, T. A. ELSEVIER SCIENCE INC. 2001: 27S–27S

  View details for Web of Science ID 000168163000093

• Family environment of children and adolescents with bipolar parents BIPOLAR DISORDERS Chang, K. D., Blasey, C., Ketter, T. A., Steiner, H. 2001; 3 (2): 73-78

  Abstract

  The effect of family environment on the development of bipolar disorder (BD) in children is not known. We sought to characterize families with children at high risk for developing BD in order to better understand the contributions of family environment to the development of childhood BD.We collected demographic data and parental ratings on the Family Environment Scale (FES) for 56 children (aged 6-18 years) from 36 families with at least one biological parent with BD. The cohort had previously been psychiatrically diagnosed according to semistructured interviews.Statistical comparisons with normative data indicated that parents' ratings were significantly lower on the FES Cohesion and Organization scales and were significantly higher on the FES Conflict scale. Multivariate analyses of variance indicated that families with both parents having a mood disorder had no significantly different FES scores than families with only one parent with a mood disorder (BD). Diagnostic data indicated that while 54% of the children in the sample had an Axis I disorder and 14% had BD, FES scores did not differ significantly for subjects with or without an Axis I disorder, or with or without BD.Families with a bipolar parent differ from the average family in having less cohesion and organization, and more conflict. Despite this difference, it does not appear that the environment alone of families with a bipolar parent determines the outcome of psychopathology in the children, or that the psychopathology of the children determines the family environment.

  View details for PubMedID 11333066

• Special issues in the treatment of paediatric bipolar disorder. Expert opinion on pharmacotherapy Chang, K. D., Ketter, T. A. 2001; 2 (4): 613-622

  Abstract

  Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.

  View details for PubMedID 11336611

• Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder BIOLOGICAL PSYCHIATRY Ketter, T. A., Kimbrell, T. A., George, M. S., Dunn, R. T., Speer, A. M., Benson, B. E., Willis, M. W., Danielson, A., Frye, M. A., Herscovitch, P., Post, R. M. 2001; 49 (2): 97-109

  Abstract

  Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable.Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose.Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency.In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established.

  View details for PubMedID 11164756

• A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders 151st Annual Meeting of the American-Psychiatric-Association Frye, M. A., Ketter, T. A., Kimbrell, T. A., Dunn, R. T., Speer, A. M., Osuch, E. A., Luckenbaugh, D. A., Cora-Locatelli, G., Leverich, G. S., Post, R. M. LIPPINCOTT WILLIAMS & WILKINS. 2000: 607–14

  Abstract

  There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

  View details for Web of Science ID 000165490400003

  View details for PubMedID 11106131

• Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients BIOLOGICAL PSYCHIATRY Osuch, E. A., Ketter, T. A., Kimbrell, T. A., George, M. S., Benson, B. E., Willis, M. W., Herscovitch, P., Post, R. M. 2000; 48 (10): 1020-1023

  Abstract

  We studied the relationship between regional cerebral metabolism and the severity of anxiety in mood disorder patients, controlling for depression severity.Fifty-two medication-free patients with unipolar or bipolar illness underwent positron emission tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and Spielberger Anxiety-State Scale scores were obtained for the week of the scan. Analyses were performed on globally normalized images and were corrected for multiple comparisons.After covarying for depression scores, age, and gender, Spielberger Anxiety-State Scale scores correlated directly with regional cerebral metabolism in the right parahippocampal and left anterior cingulate regions, and inversely with metabolism in the cerebellum, left fusiform, left superior temporal, left angular gyrus, and left insula. In contrast, covarying for anxiety scores, age, and gender, Hamilton Depression Rating Scale scores correlated directly with regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate, and right dorsolateral prefrontal cortices.Comorbid anxiety symptoms are associated with specific cerebral metabolic correlates that partially overlap with those in the primary anxiety disorders and differ from those associated with depression severity.

  View details for Web of Science ID 000165353800010

  View details for PubMedID 11082477

• Biology and recent brain imaging studies in affective psychoses. Current psychiatry reports Wang, P. W., Ketter, T. A. 2000; 2 (4): 298-304

  Abstract

  Psychosis is a cardinal symptom of schizophrenia, but also occurs in other psychiatric conditions, including mood disorders. In many instances, brain abnormalities in psychotic and mood disorders appear to be on a spectrum, with the most marked changes in schizophrenia, followed by psychotic mood disorders, followed by nonpsychotic mood disorders. Such observations are consistent with the notion that mood disorders and schizophrenia represent a continuum of disease. However, in some instances, cerebral changes with psychosis may be qualitatively different, rather than merely more severe than those seen in mood disorders, more consistent with the theory that they are discrete entities. We review brain imaging studies that have advanced our knowledge of psychosis in mood disorders, with respect to the continuum versus discrete entity hypotheses.

  View details for PubMedID 11122972

• Psychiatric phenomenology of child and adolescent bipolar offspring JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Chang, K. K., Steiner, H., Ketter, T. A. 2000; 39 (4): 453-460

  Abstract

  To establish prodromal signs of and risk factors for childhood bipolar disorder (BD) by characterizing youths at high risk for BD.Structured diagnostic interviews were performed on 60 biological offspring of at least one parent with BD. Demographics, family histories, and parental history of childhood disruptive behavioral disorders were also assessed.Fifty-one percent of bipolar offspring had a psychiatric disorder, most commonly attention-deficit/hyperactivity disorder (ADHD), major depression or dysthymia, and BD. BD in offspring tended to be associated with earlier parental symptom onset when compared with offspring without a psychiatric diagnosis. Bipolar parents with a history of childhood ADHD were more likely to have children with BD, but not ADHD. Offspring with bilineal risk had increased severity of depressed and irritable mood, lack of mood reactivity, and rejection sensitivity, while severity of grandiosity, euphoric mood, and decreased need for sleep were not preferentially associated with such offspring.Bipolar offspring have high levels of psychopathology. Parental history of early-onset BD and/or childhood ADHD may increase the risk that their offspring will develop BD. Prodromal symptoms of childhood BD may include more subtle presentations of mood regulation difficulties and less presence of classic manic symptoms.

  View details for PubMedID 10761347

• Automated segmentation of the corpus callosum in midsagittal brain magnetic resonance images OPTICAL ENGINEERING Lee, C., Huh, S., Ketter, T. A., Unser, M. 2000; 39 (4): 924-935

  View details for Web of Science ID 000086375900009

• Mood stabilizer augmentation with olanzapine in acutely manic children JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K. D., Ketter, T. A. 2000; 10 (1): 45-49

  Abstract

  We report on three cases of acutely manic prepubertal children diagnosed with bipolar disorder who were treated with olanzapine in addition to their existing mood stabilizer regimens. All three had marked improvement of their manic symptoms within 3-5 days of beginning olanzapine therapy as measured by clinician-rated instruments. Adverse effects included sedation and weight gain. These results suggest that olanzapine may have an antimanic or mood stabilizing effect in acutely manic children with bipolar disorder.

  View details for PubMedID 10755582

• Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder BIOLOGICAL PSYCHIATRY Winsberg, M. E., Sachs, N., Tate, D. L., Adalsteinsson, E., Spielman, D., Ketter, T. A. 2000; 47 (6): 475-481

  Abstract

  N-acetyl aspartate (NAA) is an amino acid present in high concentrations in neurons and is thus a putative neuronal marker. In vivo proton magnetic resonance spectroscopy ((1)H MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative disorders, suggesting decreased neuronal number, size, or function. Dorsolateral prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients, but it could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders. We measured DLPF NAA in patients with bipolar disorder and healthy control subjects using in vivo (1)H MRS.We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine (Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10 Bipolar II) and 20 age- and gender-matched healthy control subjects using (1)H MRS.DLPF NAA/Cr-PCr ratios were lower on the right hemisphere (p<.03) and the left hemisphere (p<.003) in bipolar disorder patients compared with healthy control subjects.These preliminary data suggest that bipolar disorder patients have decreased DLPF NAA/Cr-PCr. This finding could represent decreased neuronal density or neuronal dysfunction in the DLPF region.

  View details for Web of Science ID 000085836200001

  View details for PubMedID 10715353

• The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study 149th Annual Meeting of the American-Psychiatric-Association Frye, M. A., Ketter, T. A., Leverich, G. S., Huggins, T., Lantz, C., Denicoff, K. D., Post, R. M. PHYSICIANS POSTGRADUATE PRESS. 2000: 9–15

  Abstract

  Few studies have approached the subject of polypharmacotherapy systematically. This retrospective review of 178 patients with refractory bipolar disorder or unipolar depression (Research Diagnostic Criteria or DSM-III-R criteria) discharged from the National Institute of Mental Health (NIMH) Biological Psychiatry Branch between 1974 and 1996 was conducted to assess the degree and efficacy of "add-on" pharmacotherapy.Following completion of formal structured blinded research protocols, patients entered a treatment phase (often again on a blind basis) in which all agents available in the community could be utilized. Each patient's retrospective life chart and all prospective double-blind nurse- and self-rated NIMH data were reviewed. The overall degree of improvement at discharge was assessed by rating on the Clinical Global Impressions scale (CGI) as modified for bipolar illness (CGI-BP).A 78% improvement rate (moderate or marked on the CGI) was achieved at the time of discharge. There was a significant relationship between number of medications utilized at discharge as a function of discharge date (r = 0.45, p < .0001). The percentages of patients discharged on treatment with 3 or more medications were 3.3% (1974-1979), 9.3% (1980-1984), 34.9% (1985-1989), and 43.8% (1990-1995). No correlation was found between polypharmacy and age (r = -0.03, p = .66). Patients more recently discharged from the NIMH had an earlier age at illness onset, more lifetime weeks depressed, and a higher rate of rapid cycling than patients in the earlier cohorts.Increasing numbers of medications in more recent NIMH cohorts were required to achieve the same degree of improvement at hospital discharge. More systematic approaches to the complex regimens required for treatment of patients with refractory mood disorder are clearly needed.

  View details for Web of Science ID 000085402900003

  View details for PubMedID 10695639

• Baseline cerebral hypermetabolism associated with carbamazepine response, and hypometabolism with nimodipine response in mood disorders 148th Annual Meeting of the American-Psychiatric-Association Ketter, T. A., Kimbrell, T. A., George, M. S., Willis, M. W., Benson, B. E., Danielson, A., Frye, M. A., Herscovitch, P., Post, R. M. ELSEVIER SCIENCE INC. 1999: 1364–74

  Abstract

  Positron emission tomography (PET) studies have reported baseline (medication free) differences between mood disorder patients and healthy control subjects, but relatively little is known about relationships between baseline PET scans and treatment responses. Carbamazepine (CBZ) and to a more limited extent nimodipine (NIMO) seem useful in mood disorders. We explored whether baseline regional cerebral glucose metabolism (rCMRglu) could discriminate CBZ and NIMO responders from nonresponders and healthy control subjects.In refractory mood disorder patients, we examined relationships between responses to these drugs, assessed by Clinical Global Impression-Improvement scores, and baseline rCMRglu, determined with fluorine-18 deoxy-glucose and PET.CBZ responders had baseline left insular hyper-metabolism compared to healthy control subjects and nonresponders, whereas nonresponders had widespread (including left insular) hypometabolism. Degree of CBZ response correlated with baseline paralimbic (including insula) and prefrontal hypermetabolism. In responders but not nonresponders, CBZ decreased widespread metabolism, with the degree of decrease in left insula correlating with response. In contrast, NIMO responders but not nonresponders had baseline widespread (including left insular) hypometabolism. Left prefrontal and left insular baseline hypometabolism, but not metabolic changes with treatment correlated with degree of NIMO response.These data suggest that baseline anterior paralimbic and prefrontal hypermetabolism may be associated with CBZ response, and hypometabolism with NIMO response. Based on these preliminary data, further exploration of relationships between baseline PET scans and treatment responses is indicated.

  View details for PubMedID 10578451

• Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders Symposium on Behavioral Issues in Epilepsy, A Practical Approach to Diagnosis and Management Ketter, T. A., Post, R. M., Theodore, W. H. LIPPINCOTT WILLIAMS & WILKINS. 1999: S53–S67

  Abstract

  Antiepileptic drugs (AEDs) have various mechanisms of actions and therefore have diverse anticonvulsant, psychiatric, and adverse effect profiles. Two global categories of AEDs are identified on the basis of their predominant psychotropic profiles. One group has "sedating" effects in association with fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects. These actions may be related to a predominance of potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission induced by drugs such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The other group is associated with predominant attenuation of glutamate excitatory neurotransmission and has "activating" effects, with activation, weight loss, and possibly anxiogenic and antidepressant effects. This group includes agents such as felbamate and lamotrigine. Agents such as topiramate, with both GABAergic and antiglutamatergic actions, may have "mixed" profiles. Mechanisms of actions, activity in animal models of anxiety and depression, and clinical psychotropic effects of AEDs in psychiatric and epilepsy patients are reviewed in relationship to this proposed categorization. These considerations suggest the testable hypothesis that better psychiatric outcomes in seizure disorder patients could be achieved by treating patients with baseline "activated" profiles (insomnia, agitation, anxiety, racing thoughts, weight loss) with "sedating" predominantly GABAergic drugs, and conversely those with baseline "sedated" or anergic profiles (hypersomnia, fatigue, apathy, depression, sluggish cognition, weight gain) with "activating" predominantly antiglutamatergic agents. Systematic clinical investigation of more precise relationships of discrete mechanisms of actions to psychotropic profiles of AEDs is needed to assess the utility of this general proposition and define exceptions to this broad principle.

  View details for Web of Science ID 000082649700009

  View details for PubMedID 10496235

• Regional brain activity during transient self-induced anxiety and anger in healthy adults 50th Annual Meeting of the Society-of-Biological-Psychiatry Kimbrell, T. A., George, M. S., Parekh, P. I., Ketter, T. A., Podell, D. M., Danielson, A. L., Repella, J. D., Benson, B. E., Willis, M. W., Herscovitch, P., Post, R. M. ELSEVIER SCIENCE INC. 1999: 454–65

  Abstract

  Several studies have demonstrated that transient self-induced sadness activates anterior paralimbic structures. To further examine the specificity of these findings and the neural substrates involved in anger and anxiety, we studied the neural correlates of the induction of anxiety and anger in healthy adults.We used H2(15)O and positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in 16 healthy adults during the induction of transient anxiety, anger, and neutral emotions. Subjects achieved differential emotions by recalling prior life events while viewing affect-appropriate faces.Both the anxiety and anger conditions were associated with increased normalized rCBF in left inferior frontal and left temporal pole regions and decreased rCBF in right posterior temporal/parietal and right superior frontal cortex, compared to the neutral induction. Additionally, compared to neutral induction, anxiety was associated with increased rCBF in the left anterior cingulate and cuneus and decreased rCBF in right medial frontal cortex, while the anger induction was uniquely associated with increased rCBF in right temporal pole and thalamus.Self-generated transient states of anxiety and anger are associated with both overlapping and distinct regional brain activity patterns and provide a template for further dissection of specific components of normal and pathologic emotions.

  View details for Web of Science ID 000082036700002

  View details for PubMedID 10459394

• Metabolism and excretion of mood stabilizers and new anticonvulsants CELLULAR AND MOLECULAR NEUROBIOLOGY Ketter, T. A., Frye, M. A., Cora-Locatelli, G., Kimbrell, T. A., Post, R. M. 1999; 19 (4): 511-532

  Abstract

  1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug-drug interactions, while the renally excreted gabapentin lacks hepatic drug-drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects.

  View details for Web of Science ID 000080777400005

  View details for PubMedID 10379423

• Differences in dorsolateral prefrontal cortex N-acetyl aspartate in bipolar disorder subtypes using 1H MRS Winsberg, M. E., Sachs, N., Tate, D. L., Spielman, D. M., Ketter, T. A. ELSEVIER SCIENCE INC. 1999: 125S–125S

  View details for Web of Science ID 000079911600404

• Venlafaxine but not bupropion decreases cerebrospinal fluid 5-hydroxyindoleacetic acid in unipolar depression BIOLOGICAL PSYCHIATRY Little, J. T., Ketter, T. A., Mathe, A. A., Frye, M. A., Luckenbaugh, D., Post, R. M. 1999; 45 (3): 285-289

  Abstract

  While the antidepressants venlafaxine and bupropion are known to have different neurochemical profiles in vitro, their effects on human cerebral metabolism in vivo have not been directly compared.Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined in 14 never-hospitalized outpatients with unipolar depression and 10 age-similar healthy controls. Patients received a baseline lumbar puncture (LP), which was repeated after at least 6 weeks of randomized monotherapy with either venlafaxine or bupropion, while controls received only a baseline LP.Patients (n = 9) receiving venlafaxine showed a significant decrease (42%) in their CSF 5-HIAA concentrations after treatment, but no change in other CSF measures. In contrast, patients receiving bupropion (n = 8) showed no change in CSF measures compared to pretreatment values.While the mechanism for this differential effect of venlafaxine remains to be determined, the current study provides confirmation of the different aminergic effects of venlafaxine and bupropion.

  View details for Web of Science ID 000078518800007

  View details for PubMedID 10023503

• Possible gabapentin-induced thyroiditis JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Frye, M. A., Luckenbaugh, D., Kimbrell, T. A., Constantino, C., Grothe, D., Cora-Locatelli, G., Ketter, T. A. 1999; 19 (1): 94–95

  View details for DOI 10.1097/00004714-199902000-00015

  View details for Web of Science ID 000078082200014

  View details for PubMedID 9934948

• Gabapentin does not alter single-dose lithium pharmacokinetics JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Frye, M. A., Kimbrell, T. A., Dunn, R. T., Piscitelli, S., Grothe, D., Vanderham, E., Cora-Locatelli, G., Post, R. M., Ketter, T. A. 1998; 18 (6): 461-464

  Abstract

  Lithium (Li) and gabapentin are both exclusively eliminated by renal excretion. When used in combination, a competitive drug-drug interaction could possibly alter Li renal excretion with important clinical implications considering the rather narrow therapeutic index of Li. This study examined the single-dose pharmacokinetic profiles of Li in 13 patients receiving placebo and then steady-state gabapentin (mean daily dose: 3,646.15 mg). During both phases, a single 600-mg dose of Li was orally administered with serial Li levels obtained at time zero and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours. The pharmacokinetic parameters assessed were the following: area under the concentration time curve (AUC) for Li, maximal concentration of Li (Li Cmax), and time to reach peak Li concentration (Li Tmax). For patients receiving gabapentin, the mean Li AUC at 72 hours was 9.91+/-3.54 mmol x hr/mL and did not differ significantly from the mean Li AUC of 10.19+/-2.89 mmol x hr/mL for patients receiving placebo. The mean Li Cmax was 0.69+/-0.13 mmol/L for gabapentin patients and did not differ from the mean Li Cmax of 0.72+/-0.15 mmol/L for placebo patients. The mean serum Li Tmax was 1.38+/-0.62 hours for gabapentin patients and did not differ significantly from the mean serum Li Tmax of 1.5+/-0.91 hours for placebo patients. These data indicate that gabapentin treatment at this high therapeutic dose does not cause clinically significant alterations in short-term Li pharmacokinetics in patients with normal renal function. These preliminary data warrant further controlled study in a larger, more heterogenous patient sample and a longer duration of assessment, but they do suggest that these two medications may be administered in combination for the management of bipolar disorder.

  View details for Web of Science ID 000077425300007

  View details for PubMedID 9864078

• Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Pazzaglia, P. J., Post, R. M., Ketter, T. A., Callahan, A. M., Marangell, L. B., Frye, M. A., George, M. S., Kimbrell, T. A., Leverich, G. S., Cora-Locatelli, G., Luckenbaugh, D. 1998; 18 (5): 404-413

  Abstract

  Of 30 patients with treatment-refractory affective illness, 10 showed a moderate to marked response to blind nimodipine monotherapy compared with placebo on the Clinical Global Impressions Scale. Fourteen inadequately responsive patients (3 unipolar [UP], 11 bipolar [BP]) were treated with the blind addition of carbamazepine. Carbamazepine augmentation of nimodipine converted four (29%) of the partial responders to more robust responders. Patients who showed an excellent response to the nimodipine-carbamazepine combination included individual patients with patterns of rapid cycling, ultradian cycling, UP recurrent brief depression, and one with BP type II depression. When verapamil was blindly substituted for nimodipine, two BP patients failed to maintain improvement but responded again to nimodipine and remained well with a blind transition to another dihydropyridine L-type calcium channel blocker (CCB), isradipine. Mechanistic implications of the response to the dihydropyridine L-type CCB nimodipine alone and in combination with carbamazepine are discussed.

  View details for Web of Science ID 000076301000009

  View details for PubMedID 9790159

• Unsupervised connectivity-based thresholding segmentation of midsagittal brain MR images COMPUTERS IN BIOLOGY AND MEDICINE Lee, C., Huh, S., Ketter, T. A., Unser, M. 1998; 28 (3): 309-338

  Abstract

  In this paper, we propose an algorithm for automated segmentation of midsagittal brain MR images. First, we apply thresholding to obtain binary images. From the binary images, we locate some landmarks. Based on the landmarks and anatomical information, we preprocess the binary images, which substantially simplifies the subsequent operations. To separate regions what are incorrectly merged after this initial segmentation, a new connectivity-based threshold algorithm is proposed. Assuming that some prior information about the general shape and location of objects is available, the algorithm finds a boundary between two regions using the path connection algorithm and changing the threshold adaptively. In order to test the robustness of the proposed algorithm we applied the algorithm to 120 midsagittal brain images and obtained satisfactory results.

  View details for Web of Science ID 000076016900008

  View details for PubMedID 9784966

• Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder Winsberg, M. E., Sachs, N., Tate, D. L., Dunai, M., Strong, C. M., Spielman, D. M., Ketter, T. A. ELSEVIER SCIENCE INC. 1998: 23S–23S

  View details for Web of Science ID 000073240700076

• Brain imaging studies of treatments in mood disorders Ketter, T. A., Kennedy, S. H., Kimbrell, T. A., Wu, J. C., Sackeim, H. A., George, M. S. ELSEVIER SCIENCE INC. 1998: 61S–61S

  View details for Web of Science ID 000073240700208

• A potential cholinergic mechanism of procaine's limbic activation Benson, B. E., Carson, R. E., Sandoval, W., Linthicum, W. L., Kimbrell, T. A., Kieswetter, D. O., Herscovitch, P., Eckelman, W. C., McCann, U. D., Weiss, S. R., Post, R. M., Ketter, T. A. ELSEVIER SCIENCE INC. 1998: 27S–28S

  View details for Web of Science ID 000073240700091

• Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics JOURNAL OF AFFECTIVE DISORDERS Frye, M. A., Ketter, T. A., Altshuler, L. L., Denicoff, K., Dunn, R. T., Kimbrell, T. A., Cora-Locatelli, G., Post, R. M. 1998; 48 (2-3): 91-104

  Abstract

  Traditional neuroleptics are often utilized clinically for the management of bipolar disorder. Although effective as antimanic agents, their mood stabilizing properties are less clear. Additionally, their acute clinical side effect profile and long term risk of tardive dyskinesia, particularly in mood disorder patients, portend significant liability. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder focusing on clozapine as the prototypical agent. Although, preclinical research and clinical experience suggest that the atypical antipsychotics are distinctly different from typical antipsychotics, they themselves are heterogeneous in profiles of neuropharmacology, clinical efficacy, and tolerability. The early clinical experience of clozapine as a potential mood stabilizer suggests greater antimanic than antidepressant properties. Conversely, very preliminary clinical experience with risperidone suggests greater antidepressant than antimanic properties and some liability for triggering or exacerbating mania. Olanzapine and sertindole are under investigation in psychotic mood disorders. The foregoing agents and future drugs with atypical neuroleptic properties should come to play an increasingly important role, compared to the older classical neuroleptics, in the acute and long term management of bipolar disorder.

  View details for Web of Science ID 000072589200001

  View details for PubMedID 9543198

• Relationships between thyroid hormone and antidepressant responses to total sleep deprivation in mood disorder patients BIOLOGICAL PSYCHIATRY Parekh, P. I., Ketter, T. A., Altshuler, L., Frye, M. A., Callahan, A., Marangell, L., Post, R. M. 1998; 43 (5): 392-394

  Abstract

  Acute transient antidepressant effects of sleep deprivation are consistently observed in 50% of depressed patients, but the mechanisms of these, at times, dramatic improvements in mood have not been adequately elucidated. Some, but not all, studies suggest a relationship to increased thyroid-stimulating hormone (TSH) secretion.TSH and other thyroid indices were measured at 8:00 AM after a baseline night's sleep and at 8:00 AM following a night of total sleep deprivation (S.D.) in 34 medication-free, affective disorder patients assessed with Hamilton, Beck, and Bunney-Hamburg depression ratings as well as two hourly self-ratings on a visual analog scale.Compared with baseline, S.D. induced highly significant increases in TSH, levothyroxine, free levothyroxine, and triiodothyronine. The 12 S.D. responders tended to have greater TSH increases than the 15 nonresponders (p < .10). The change in Beck depression ratings significantly correlated with the change in TSH (r = -.40, p = .0496, n = 24).These data are consistent with several other reports of a significant relationship between degree of antidepressant response to S.D. and increases in TSH measured at 8:00 AM near their usual nadir. Acute removal of the sleep-related break on the hypothalamic-pituitary-thyroid axis remains a promising candidate for the mechanism of sleep deprivation-induced improvement in mood in depressed patients.

  View details for Web of Science ID 000072260000013

  View details for PubMedID 9513756

• Rapid efficacy of olanzapine augmentation in nonpsychotic bipolar mixed states JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Winsberg, M. E., DeGolia, S. G., Dunai, M., Tate, D. L., Strong, C. M. 1998; 59 (2): 83-85

  View details for Web of Science ID 000072288800011

  View details for PubMedID 9501894

• Psychosensory symptoms in bipolar disorder NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY Ali, S. O., Denicoff, K. D., Ketter, T. A., SmithJackson, E. E., Post, R. M. 1997; 10 (4): 223-231

  Abstract

  This study investigated psychosensory symptoms and their relationship to retrospective and prospective courses of illness, as well as therapeutic outcomes, in patients with bipolar disorder. Using the Silberman-Post Psychosensory Rating Scale (SP-PSRS), psychosensory symptoms were assessed in 51 patients who met Diagnostic and Statistical Manual, 3rd Edition-Revised (DSM-III-R) criteria for bipolar disorder and in 39 healthy, normal controls. Patients with bipolar disorder were enrolled in a 3-year, double-blind, randomized study comparing the prophylactic efficacy of lithium or carbamazepine in the first year, a crossover to the other drug in the second year, and the combination of both medications in the third year. Psychosensory scores from patients with bipolar disorder were compared with scores from healthy controls and with a variety of retrospective and prospective course of illness and treatment variables. Psychosensory symptoms occurred frequently in patients with bipolar I and II disorders, but were rare in healthy controls. When depressed, patients with bipolar II disorder (n = 23) reported more psychosensory symptoms when compared to patients with bipolar I disorder (n = 28), and those with a history of rapid cycling (n = 29) reported more psychosensory symptoms when compared to patients without a history of rapid cycling (n = 21). Psychosensory symptoms were not related to response to carbamazepine, lithium, or the combination of both drugs. Although the presence of psychosensory symptoms is associated with some bipolar subtypes (patients with bipolar II disorder and patients with a history of rapid cycling), they do not appear to predict treatment response. Further studies are needed to assess the pathophysiologic implications of the presence of psychosensory symptoms and their potential implications, if any, for directing therapeutics.

  View details for Web of Science ID A1997YD47200001

  View details for PubMedID 9359118

• Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients 19th Collegium-Internationale-Neuro-Psychopharmacologicum Congress Marangell, L. B., George, M. S., Callahan, A. M., Ketter, T. A., Pazzaglia, P. J., LHerrou, T. A., Leverich, G. S., Post, R. M. AMER MEDICAL ASSOC. 1997: 214–22

  Abstract

  Therapeutic effects of the tripeptide protirelin (thyrotropin-releasing hormone) have been postulated in the affective disorders, but direct assessment in humans has been hindered by poor blood-brain barrier permeability.Eight medication-free inpatients with refractory depression received 500 micrograms of protirelin via a lumbar intrathecal injection and an identical sham lumbar puncture procedure, separated by 1 week, in a double-blind crossover design.Five of eight patients responded to intrathecal protirelin, defined as a 50% or greater reduction in an abbreviated Hamilton Rating Scale for Depression score. Suicidality also was reduced significantly (P < .05). Responses were rapid and clinically robust, but short-lived.Administration of protirelin by an intrathecal route induced a rapid improvement in mood and suicidality in these refractory depressed patients, supporting the hypothesis that thyrotropin-releasing hormone could be a positive modulator of mood.

  View details for Web of Science ID A1997WP35500004

  View details for PubMedID 9075462

• Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders 147th Annual Meeting of the American-Psychiatric-Association Marangell, L. B., Ketter, T. A., George, M. S., Pazzaglia, P. J., Callahan, A. M., Parekh, P., Andreason, P. J., Horwitz, B., Herscovitch, P., Post, R. M. AMER PSYCHIATRIC PUBLISHING, INC. 1997: 224–30

  Abstract

  The author's goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients.Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism.Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism.These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.

  View details for Web of Science ID A1997WF15000014

  View details for PubMedID 9016272

• Comparative antidepressant effects of intravenous and intrathecal thyrotropin-releasing hormone: Confounding effects of tolerance and implications for therapeutics BIOLOGICAL PSYCHIATRY Callahan, A. M., Frye, M. A., Marangell, L. B., George, M. S., Ketter, T. A., LHERROU, T., Post, R. M. 1997; 41 (3): 264-272

  Abstract

  A significant amount of preclinical and human data indicate that thyrotropin-releasing hormone (TRH) has antidepressant effects. Although early studies showing these effects using intravenous TRH were not consistently replicated, it has been suggested that this could be explained by its poor blood-brain barrier penetration. For this reason we compared the antidepressant effect of intrathecal and intravenous TRH administered in a double-blind design to 2 treatment-refractory patients with bipolar II disorder. Each experienced a robust antidepressant response by both routes; subsequent open trials of intravenous TRH also were effective until apparent tolerance developed. Intrathecal TRH was readministered and both subjects again experienced robust antidepressant responses. These preliminary data suggest a differential mechanism of tolerance to the two routes of administration and raise the possibility that a subgroup of patients may be responsive to the antidepressant effects of TRH independent of its route of administration.

  View details for Web of Science ID A1997WF21800003

  View details for PubMedID 9024949

• Blunted left cingulate activation in mood disorder subjects during a response interference task (the stroop) JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES George, M. S., Ketter, T. A., Parekh, P. I., ROSINSKY, N., Ring, H. A., Pazzaglia, P. J., Marangell, L. B., Callahan, A. M., Post, R. M. 1997; 9 (1): 55-63

  Abstract

  Functional neuroimaging studies have found abnormal anterior cingulate activity in depressed subjects, and other studies have shown that the cingulate gyrus becomes active in healthy subjects during interference tasks. The authors hypothesized that subjects with mood disorder might show blunted cingulate activation during the standard Stroop interference task or during a modified version involving sadness-laden words. In contrast to 11 age- and sex-matched healthy control subjects who activated the left cingulate during the standard Stroop, 11 mood-disordered subjects activated the right anterior cingulate gyrus only slightly and instead showed increased activity in the left dorsolateral prefrontal and visual cortex. This study supports theories of blunted limbic and paralimbic activation and abnormal cingulate activity in depression and adds to the growing knowledge of the functional neuroanatomy of depression.

  View details for Web of Science ID A1997WD68800007

  View details for PubMedID 9017529

• The place of anticonvulsant therapy in bipolar illness PSYCHOPHARMACOLOGY Post, R. M., Ketter, T. A., Denicoff, K., Pazzaglia, P. J., Leverich, G. S., Marangell, L. B., Callahan, A. M., George, M. S., Frye, M. A. 1996; 128 (2): 115-129

  Abstract

  With the increasing recognition of lithium's inadequacy as an acute and prophylactic treatment for many patients and subtypes of bipolar illness, the search for alternative agents has centered around the mood stabilizing anticonvulsants carbamazepine and valproate. In many instances, these drugs are effective alone or in combination with lithium in those patients less responsive to lithium monotherapy, including those with greater numbers of prior episodes, rapid-cycling, dysphoric mania, co-morbid substance abuse or other associated medical problems, and patients without a family history of bipolar illness in first-degree relatives. Nineteen double-blind studies utilizing a variety of designs suggest that carbamazepine, or its keto-congener oxcarbazepine, is effective in acute mania; six controlled studies report evidence of the efficacy of valproate in the treatment of acute mania as well. Fourteen controlled or partially controlled studies of prophylaxis suggest carbamazepine is also effective in preventing both manic and depressive episodes. valproate prophylaxis data, although based entirely on uncontrolled studies, appear equally promising. Thus, both drugs are widely used and are now recognized as major therapeutic tools for lithium-nonresponsive bipolar illness. The high-potency anticonvulsant benzodiazepines, clonazepam and lorazepam, are used adjunctively with lithium or the anticonvulsant mood stabilizers as substitutes or alternatives for neuroleptics in the treatment of manic breakthroughs. Preliminary controlled clinical trials suggest that the calcium channel blockers may have antimanic or mood-stabilizing effects in a subgroup of patients. A new series of anticonvulsants has just been FDA-approved and warrant clinical trials to determine their efficacy in acute and long-term treatment of mania and depression. Systematic exploration of the optimal use of lithium and the mood-stabilizing anticonvulsants alone and in combination, as well as with adjunctive antidepressants, is now required so that more definitive treatment recommendations for different types and stages of bipolar illness can be more strongly evidence based.

  View details for Web of Science ID A1996VU30400001

  View details for PubMedID 8956373

• Gender differences in regional cerebral blood flow during transient self-induced sadness or happiness BIOLOGICAL PSYCHIATRY George, M. S., Ketter, T. A., Parekh, P. I., Herscovitch, P., Post, R. M. 1996; 40 (9): 859-871

  Abstract

  Men, compared to women, are less likely to experience mood disorders. We wondered if gender differences exist in the ability to self-induce transient sadness and happiness, and in regional cerebral blood flow (rCBF) either at rest or during transient emotions. Ten adult men and 10 age-matched women, all healthy and never mentally ill, were scanned using H2(15)O positron emission tomography at rest and during happy, sad, and neutral states self-induced by recalling affect-appropriate life events and looking at happy, sad, or neutral human faces. At rest, women had decreased temporal and prefrontal cortex rCBF, and increased brainstem rCBF. There were no significant between-group differences in difficulty, effort required, or the degree of happiness or sadness induced. Women activated a significantly wider portion of their limbic system than did men during transient sadness, despite similar self-reported changes in mood. These findings may aid in understanding gender differences with respect to emotion and mood.

  View details for Web of Science ID A1996VM69400006

  View details for PubMedID 8896772

• Evaluating the clinical significance of drug interactions: A systematic approach HARVARD REVIEW OF PSYCHIATRY Callahan, A. M., Marangell, L. B., Ketter, T. A. 1996; 4 (3): 153-158

  Abstract

  Remembering the myriad of psychotropic drug interactions is extremely difficult. Nevertheless, by applying a systematic approach, the clinician can often predict the occurrence and time course of such interactions. Several factors must be considered when assessing the potential consequences. Drug-related factors that increase the risk for clinically significant interactions include a low therapeutic index or narrow therapeutic window, a multiplicity of pharmacological actions, and inhibition or inducement of cytochrome P450 enzymes. Next, patient-related factors that can increase the risk for significant drug interactions should be considered. These include genetically based variations in drug-metabolizing capacity, as well as advanced age, underlying medical illness, and comorbid substance abuse. Finally, the literature should be carefully reviewed to as-certain the potential clinical relevance of available data. If a clinically significant drug interaction appears likely to occur, the patient's clinical status should be followed closely; therapeutic drug monitoring should be used if applicable and dosage adjustments made accordingly. Rational polypharmacy requires an understanding of the pharmacological principles governing drug interactions and a knowledge of the factors that increase the likelihood of clinically significant variations in drug action. This will allow the clinician to maximize beneficial effects while minimizing the risk of adverse events.

  View details for Web of Science ID A1996VH18100005

  View details for PubMedID 9384988

• Understanding emotional prosody activates right hemisphere regions ARCHIVES OF NEUROLOGY George, M. S., Parekh, P. I., ROSINSKY, N., Ketter, T. A., Kimbrell, T. A., Heilman, K. M., Herscovitch, P., Post, R. M. 1996; 53 (7): 665-670

  Abstract

  Defects in expressing or understanding the affective or emotional tone of speech (aprosodias) have been associated with right hemisphere dysfunction, while defects of propositional language have been linked to left hemisphere disease. The brain regions involved in recognition of emotional prosody in healthy subjects is less clear.To investigate the brain regions involved in understanding emotional prosody and to determine whether these differ from those involved in understanding emotion based on propositional content.We studied 13 healthy subjects using water labeled with radioactive oxygen 15 and positron emission tomography while they listened to 3 similar sets of spoken English sentences. In different tasks, their responses were based on the emotional propositional content, on the emotional intonation of the sentence (prosody), or on their ability to repeat the second word in the sentence (control).Understanding propositional content activated the prefrontal cortex bilaterally, on the left more than on the right. In contrast, responding to the emotional prosody activated the right prefrontal cortex.Neurologically healthy subjects activate right hemisphere regions during emotional prosody recognition.

  View details for Web of Science ID A1996UW17700013

  View details for PubMedID 8929174

• Felbamate monotherapy has stimulant-like effects in patients with epilepsy EPILEPSY RESEARCH Ketter, T. A., Malow, B. A., Flamini, R., Ko, D., White, S. R., Post, R. M., Theodore, W. H. 1996; 23 (2): 129-137

  Abstract

  The objective of this study was to assess the psychiatric effects of the antiepileptic drug (AED) felbamate (FBM) in patients with epilepsy. FBM is a new AED with a novel putative (antiglutaminergic) mechanism. Older AEDs such as carbamazepine and valproate have psychotropic properties, but the psychiatric effects of FBM and other new antiglutamatergic AEDs remain to be determined. Thirty inpatients with refractory epilepsy were openly tapered off all AEDs in conjunction with intensive presurgical monitoring prior to a two week randomized double-blind parallel trial of FBM monotherapy versus placebo, followed by open FBM therapy. Psychopathology was rated with weekly psychiatric rating scales. Anxiety, depression and seizures increased significantly with AED discontinuation. Acute blind FBM monotherapy yielded antiepileptic and stimulant-like effects (insomnia, anorexia, and anxiety), but failed to influence AED withdrawal-emergent psychopathology. Restarting original AEDs resolved such pathology in FBM drop outs. Chronic open FBM also had stimulant-like effects, with half of the patients displaying psychiatric deterioration and the other half modest improvement compared to baseline therapies. Baseline insomnia and anxiety may be markers for poorer psychiatric responses to chronic open FBM. FBM had stimulant-like effects, lacked anxiolytic effects, and failed to attenuate AED withdrawal-emergent psychopathology. Baseline insomnia or anxiety may predict poorer psychiatric responses to FBM. Further studies are required to assess whether the novel psychiatric effects observed with FBM also occur with other new antiglutamatergic AEDs.

  View details for Web of Science ID A1996UE00500005

  View details for PubMedID 8964274

• Reply to letter from Swartz on "Mania and lower serum cholesterol levels. Journal of clinical psychopharmacology Callahan, A. M., Ketter, T. A., CRUMLISH, J., Parekh, P., Brown, D. W., Post, R. M. 1996; 16 (1): 95-97

  View details for PubMedID 8834437

• Anterior paralimbic mediation of procaine-induced emotional and psychosensory experiences 48th Annual Meeting of the Society-of-Biological-Psychiatry Ketter, T. A., Andreason, P. J., George, M. S., Lee, C., Gill, D. S., Parekh, P. I., Willis, M. W., Herscovitch, P., Post, R. M. AMER MEDICAL ASSOC. 1996: 59–69

  Abstract

  Procaine activates limbic structures in animals. In humans, acute intravenous administration of procaine yields emotional and psychosensory experiences and temporal lobe fast activity. We studied procaine's acute effects on cerebral blood flow (CBF) in relationship to clinical responses.Cerebral blood flow was assessed by positron emission tomography with oxygen-15-labeled water in 32 healthy volunteers. Data were analyzed with statistical parametric mapping and magnetic resonance imaging-directed regions of interest.Procaine increased global CBF and, to a greater extent, anterior paralimbic CBF. Subjects with intense procaine-induced fear compared with those with euphoria had greater increases in left amygdalar CBF. Absolute and normalized left amygdalar CBF changes tended to correlate positively with fear and negatively with euphoria intensity. Procaine-induced visual hallucinations appeared associated with greater global and occipital CBF increases. Absolute occipital CBF increases appeared to correlate positively with visual hallucination intensity.Procaine increased anterior paralimbic CBF, and different clinical responses appeared to be associated with different patterns of CBF changes.

  View details for Web of Science ID A1996TP70000007

  View details for PubMedID 8540778

• Automated connectivity-based thresholding segmentation of midsagittal brain MR images Conference on Visual Communications and Image Processing 96 Lee, C., Unser, M., Ketter, T. A. SPIE-INT SOC OPTICAL ENGINEERING. 1996: 713–724

  View details for Web of Science ID A1996BF32D00067

• Venlafaxine or bupropion responders but not nonresponders show baseline prefrontal and paralimbic hypometabolism compared with controls 36th Annual Meeting of the New-Clinical-Drug-Evaluation-Unit Little, J. T., Ketter, T. A., Kimbrell, T. A., Danielson, A., Benson, B., Willis, M. W., Post, R. M. US GOVERNMENT PRINTING OFFICE. 1996: 629–35

  Abstract

  In this study, 11 unipolar depressed outpatients received baseline (medication-free) fluorine-18 deoxyglucose positron emission tomography scans prior to randomization to double-blind venlafaxine or bupropion monotherapy, with the option of a subsequent medication crossover. Based on Clinical Global impressions ratings, 6 of 11 responded to at least one medication. Regional cerebral glucose metabolic rate (rCMRglu) for these 6 responders was compared with 18 age- and gender-matched healthy controls; the 5 nonresponders were compared with 15 matched healthy controls. Compared with healthy controls, responders showed decreased (normalized > absolute) left middle frontal gyral, bilateral medial prefrontal, and bilateral temporal rCMRglu. In contrast, nonresponders showed decreased (normalized > absolute) cerebellar rCMRglu. These preliminary data suggest that among never-hospitalized unipolar depressed out-patients, those showing baseline prefrontal and paralimbic hypometabolism may be more likely to show a positive response to standard antidepressant treatments such as venlafaxine or bupropion.

  View details for Web of Science ID A1996WA89000013

  View details for PubMedID 8993084

• Rational polypharmacy in the bipolar affective disorders. Epilepsy research. Supplement Post, R. M., Ketter, T. A., Pazzaglia, P. J., Denicoff, K., George, M. S., Callahan, A., Leverich, G., Frye, M. 1996; 11: 153-180

  Abstract

  Bipolar affective illness represents a syndrome not readily treated by single agents. Approximately 50% of patients are inadequately responsive to lithium and the majority of patients require supplemental antidepressants, antimanic, antipsychotic or hypnotic medications. These traditional adjunctive medications are associated with potential problems. Antidepressants may precipitate mania (at a rate about double that of placebo) or cause cycle acceleration. Neuroleptics may be associated with either more profound or longer depressive phases, and clearly increase the risk of tardive dyskinesia, to which bipolar patients appear particularly predisposed. Moreover, there are subgroups of patients who are known to be poorly responsive to lithium. These include patients with rapid cycling, dysphoric mania, co-morbid drug or alcohol abuse, a pattern of depression-mania-well interval (D-M-I as opposed to the M-D-I pattern), and patients without a family history of bipolar illness in first-degree relatives. There is increasing recognition that the anticonvulsants carbamazepine and valproate are effective alternatives or adjuncts to lithium in the acute and long-term treatment of bipolar illness. Ideally, one would want to assess whether patients who were unresponsive to lithium were responsive to an anticonvulsant alone prior to utilizing lithium in addition to anticonvulsant combination therapy. However, from the clinical perspective, it is often more expedient to use an anticonvulsant adjunctively to lithium to assess the efficacy of this combination and establish mood stabilization. When lithium is not discontinued, the increased morbidity during lithium withdrawal also would not occur and would not confound the evaluation of the new agent. We suggest the initial use of acute adjuncts to lithium with the anticonvulsants carbamazepine or valproate (instead of neuroleptics) so that their efficacy can be assessed in the individual's acute episode, with the likelihood of a positive response in longer-term prophylaxis. Hypnotic benzodiazepines with anticonvulsant properties, such as clonazepam or lorazepam, are often used to help to induce sleep in escalating bipolar patients, and may be useful adjuncts as well. Patients who were inadequately responsive to either carbamazepine or valproate alone may be responsive to the anticonvulsant combination. In a similar fashion, one can also utilize several mood-stabilizing drugs (lithium and an anticonvulsant such as carbamazepine or valproate) in the treatment of depressive breakthroughs, and then augment this combination (if necessary) with a catecholamine-active antidepressant such as bupropion or a serotonin-selective reuptake inhibitor (SSRI) such as fluoxetine, paroxetine, sertraline or if necessary a monoamine oxidase inhibitor (MAOI). Once the patient has responded to a combination of drugs, it becomes problematic to decide whether the last agent added was the crucial ingredient in helping the patient achieve remission or that remission might have occurred with this agent alone. A conservative approach would have merit in patients who are finally stabilized on complex polypharmacy regimens only after many years of sequential trials; in this instance, the potential risk of re-exacerbating the illness with a taper of one of the drugs in the regimen. Rational polypharmacy should thus be implemented with careful delineation of the prior course of illness (typically using life chart methodology) and targeted treatment outcomes titrated against side effects, using sequential clinical trials in individual patients who have not adequately responded to monotherapy. In this fashion, it is hoped that pharmacodynamic differences among agents can be maximized and pharmacokinetic and side effects minimized.

  View details for PubMedID 9294735

• Developmental psychobiology of cyclic affective illness: Implications for early therapeutic intervention DEVELOPMENT AND PSYCHOPATHOLOGY Post, R. M., Weiss, S. R., Leverich, G. S., George, M. S., Frye, M., Ketter, T. A. 1996; 8 (1): 273-305

  View details for Web of Science ID A1996TW64100017

• Functional brain imaging, limbic function, and affective disorders NEUROSCIENTIST Ketter, T. A., George, M. S., Kimbrell, T. A., Benson, B. E., Post, R. M. 1996; 2 (1): 55-65

  View details for Web of Science ID A1996UV10000014

• Functional brain imaging, limbic function, and affective disorders. The Neuroscientist Ketter TA, George MS, Kimbrell TA, Benson BE, Post RM 1996; 1 (2): 55-65
• THE EMERGING ROLE OF CYTOCHROME-P450 3A IN PSYCHOPHARMACOLOGY JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Ketter, T. A., Flockhart, D. A., Post, R. M., Denicoff, K., Pazzaglia, P. J., Marangell, L. B., George, M. S., Callahan, A. M. 1995; 15 (6): 387-398

  Abstract

  Recent advances in molecular pharmacology have allowed the characterization of the specific isoforms that mediate the metabolism of various medications. This information can be integrated with older clinical observations to begin to develop specific mechanistic and predictive models of psychotropic drug interactions. The polymorphic cytochrome P450 2D6 has gained much attention, because competition for this isoform is responsible for serotonin reuptake inhibitor-induced increases in tricyclic antidepressant concentrations in plasma. However, the cytochrome P450 3A subfamily and the 3A3 and 3A4 isoforms (CYP3A3/4) in particular are becoming increasingly important in psychopharmacology as a result of their central involvement in the metabolism of a wide range of steroids and medications, including antidepressants, benzodiazepines, calcium channel blockers, and carbamazepine. The inhibition of CYP3A3/4 by medications such as certain newer antidepressants, calcium channel blockers, and antibiotics can increase the concentrations of CYP3A3/4 substrates, yielding toxicity. The induction of CYP3A3/4 by medications such as carbamazepine can decrease the concentrations of CYP3A3/4 substrates, yielding inefficiency. Thus, knowledge of the substrates, inhibitors, and inducers of CYP3A3/ and other cytochrome P450 isoforms may help clinicians to anticipate and avoid pharmacokinetic drug interactions and improve rational prescribing practices.

  View details for Web of Science ID A1995TK56700002

  View details for PubMedID 8748427

• FELBAMATE MONOTHERAPY - IMPLICATIONS FOR ANTIEPILEPTIC DRUG DEVELOPMENT EPILEPSIA Theodore, W. H., Albert, P., Stertz, B., Malow, B., Ko, D., White, S., Flamini, R., Ketter, T. 1995; 36 (11): 1105-1110

  Abstract

  We studied the effect of felbamate (FBM) monotherapy on seizure rate in patients with partial and secondarily generalized seizures undergoing presurgical monitoring at a single site. The study design was a double-blind placebo-controlled parallel monotherapy trial. Forty patients whose seizures had not been controlled by standard antiepileptic drugs (AEDs) were randomized. Seizure type was confirmed by video-EEG monitoring. All baseline AEDs were discontinued, and patients were drug-free for 5.3 +/- 2.4 days before randomization to FBM or placebo. After a 4-day titration, seizures were counted for 14 days. Patients receiving FBM had significantly lower seizure rates, whether all randomized patients, patients who survived titration, or study completers were compared. Eight of 19 placebo patients randomized to placebo, as compared with 13 of 21 receiving FBM, completed the 18-day study. Two FBM patients dropped out due to seizures, and 6 dropped out due to side effects, including anxiety, difficulty sleeping, abdominal discomfort, acute psychosis, and orobuccal dyskinesias. Ten placebo patients met the criteria for premature discontinuation owing to seizures, and 1 hd an episode of panic. There was no evidence of hepatic or hematologic toxicity. FBM reduces seizure frequency in patients with localization-related epilepsy.

  View details for Web of Science ID A1995TC20300006

  View details for PubMedID 7588454

• DAILY REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (RTMS) IMPROVES MOOD IN DEPRESSION NEUROREPORT George, M. S., Wassermann, E. M., Williams, W. A., Callahan, A., Ketter, T. A., Basser, P., Hallett, M., Post, R. M. 1995; 6 (14): 1853-1856

  Abstract

  Converging evidence points to hypofunction of the left prefrontal cortex in depression. Repetitive transcranial magnetic stimulation (rTMS) activates neurons near the surface of the brain. We questioned whether daily left prefrontal rTMS might improve mood in depressed subjects and report a pilot study of such treatment in six highly medication-resistant depressed inpatients. Depression scores significantly improved for the group as a whole (Hamilton Depression Scores decreased from 23.8 +/- 4.2 (s.d.) at baseline to 17.5 +/- 8.4 after treatment; t = 3.03, 5DF, p = 0.02, two-tailed paired t-test). Two subjects showed robust mood improvement which occurred progressively over the course of several weeks. In one subject, depression symptoms completely remitted for the first time in 3 years. Daily left prefrontal rTMS appears to be safe, well tolerated and may alleviate depression.

  View details for Web of Science ID A1995RX80800008

  View details for PubMedID 8547583

• CARBAMAZEPINE BUT NOT VALPROATE INDUCES BUPROPION METABOLISM JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Ketter, T. A., Jenkins, J. B., SCHROEDER, D. H., Pazzaglia, P. J., Marangell, L. B., George, M. S., Callahan, A. M., HINTON, M. L., Chao, J., Post, R. M. 1995; 15 (5): 327-333

  Abstract

  Bupropion (BUP) may be less likely than other antidepressants to cause switches into mania and rapid cycling, suggesting utility in bipolar disorder. The combination of BUP with the mood-stabilizing anticonvulsants carbamazepine (CBZ) or valproate (VPA) is a strategy that might further lessen the risk of mania. CBZ induces, and to a lesser extent VPA inhibits the hepatic metabolism of various medications, but their effects on BUP have not been previously studied. Inpatients with mood disorders had pharmacokinetic profiles of BUP and metabolites assessed after single, oral, 150-mg doses of BUP while receiving placebo (N = 17) or during chronic blind CBZ (N = 12) or VPA (N = 5) monotherapy. CBZ but not VPA therapy decreased BUP peak concentrations (Cmax) by 87% (p < 0.0001) and 24-h area under the curve (AUC) by 90% (p < 0.0001), threohydrobupropion Cmax by 81% (p <0.0009) and AUC by 86% (p < 0.002), and erythropydrobupropion Cmax by 86% (p < 0.05) and AUC by 96% (p < 0.05). CBZ increased hydroxybupropion (H-BUP) Cmax by 71% (p < 0.007) and AUC by 50% (p < 0.09) and H-BUP AUC by 94% (p < 0.02). Thus, CBZ markedly decreased BUP and increased H-BUP concentrations, whereas VPA did not affect BUP but increased H-BUP concentrations. Further studies are required to determine how these differential effects of CBZ and VPA on BUP pharmacokinetics influence the tolerability and efficacy of combination therapies with these agents.

  View details for Web of Science ID A1995RY19600004

  View details for PubMedID 8830063

• ADDITION OF MONOAMINE-OXIDASE INHIBITORS TO CARBAMAZEPINE - PRELIMINARY EVIDENCE OF SAFETY AND ANTIDEPRESSANT EFFICACY IN TREATMENT-RESISTANT DEPRESSION JOURNAL OF CLINICAL PSYCHIATRY Ketter, T. A., Post, R. M., Parekh, P. I., Worthington, K. 1995; 56 (10): 471-475

  Abstract

  Depression is often resistant to treatment with mood stabilizers. The antidepressant effects of carbamazepine can be potentiated by lithium supplementation, but some patients fail to respond to the combination. Although monoamine oxidase inhibitors (MAOIs) appear useful in atypical and bipolar depressions, concerns have been raised regarding safety and pharmacokinetic interactions when they are combined with carbamazepine.Ten inpatients (7 bipolar, 3 unipolar) with refractory DSM-III-R major depression, also resistant to double-blind treatment with carbamazepine, plus lithium augmentation in 8, received double-blind MAOI augmentation (phenelzine in 4, tranylcypromine in 6).All 10 patients tolerated the addition of an MAOI well, and mean self-rated side effect scores did not change significantly. Four of 10 patients improved substantially and became euthymic, allowing discharge from hospital on the carbamazepine +/- lithium plus MAOI combination. These 4 patients improved in spite of prior inadequate responses to the same MAOI without carbamazepine and carbamazepine without an MAOI.This preliminary evidence suggests that the addition of MAOIs to carbamazepine +/- lithium may be well tolerated, may not affect carbamazepine and lithium pharmacokinetics, and may provide relief of refractory depressive symptoms in some patients. Further studies are needed to establish the safety and efficacy of combining carbamazepine with MAOIs.

  View details for Web of Science ID A1995TA46300006

  View details for PubMedID 7559374

• Procaine-induced increases in limbic rCBF correlate positively with increases in occipital and temporal EEG fast activity. Brain topography Parekh, P. I., Spencer, J. W., George, M. S., Gill, D. S., Ketter, T. A., Andreason, P., Herscovitch, P., Post, R. M. 1995; 7 (3): 209-216

  Abstract

  Previous independent EEG and PET studies suggest that administration of intravenous procaine hydrochloride selectively activates limbic brain structures. To further elucidate procaine's effects and explore the relationship between quantitative EEG (qEEG) and regional cerebral blood flow (rCBF), we simultaneously recorded qEEG and sampled rCBF using O-15 water PET in 20 healthy volunteers during single-blind injections of saline (baseline condition) followed by intravenous procaine (1.84 mg/kg). After thorough screening of EEG records, a subgroup of 7 subjects with EEG data relatively free of both muscle and movement artifacts was selected for analysis. Quantitative spectral EEG data from right occipital and temporal leads were then correlated with each subject's PET rCBF values on a pixel by pixel basis, both at baseline and after procaine. The most striking finding was that the increases in occipital and temporal omega activity from baseline to procaine positively correlated with rCBF increases in the amygdala and its efferents (p < .05), in a pattern very similar to the rCBF increases seen after procaine administration. This suggests that omega activity may reflect activation of deeper brain limbic structures. Also, the convergence of EEG and PET data further supports procaine's selective limbic activation.

  View details for PubMedID 7599020

• BRAIN ACTIVITY DURING TRANSIENT SADNESS AND HAPPINESS IN HEALTHY WOMEN Annual Meeting of the Society-for-Biological-Psychiatry George, M. S., Ketter, T. A., Parekh, P. I., Horwitz, B., Herscovitch, P., Post, R. M. AMER PSYCHIATRIC PUBLISHING, INC. 1995: 341–51

  Abstract

  The specific brain regions involved in the normal emotional states of transient sadness or happiness are poorly understood. The authors therefore sought to determine if H2(15)O positron emission tomography (PET) might demonstrate changes in regional cerebral blood flow (rCBF) associated with transient sadness or happiness in healthy adult women.Eleven healthy and never mentally ill adult women were scanned, by using PET and H2(15)O, during happy, sad, and neutral states induced by recalling affect-appropriate life events and looking at happy, sad, or neutral human faces.Compared to the neutral condition, transient sadness significantly activated bilateral limbic and paralimbic structures (cingulate, medial prefrontal, and mesial temporal cortex), as well as brainstem, thalamus, and caudate/putamen. In contrast, transient happiness had no areas of significantly increased activity but was associated with significant and widespread reductions in cortical rCBF, especially in the right prefrontal and bilateral temporal-parietal regions.Transient sadness and happiness in healthy volunteer women are accompanied by significant changes in regional brain activity in the limbic system, as well as other brain regions. Transient sadness and happiness affect different brain regions in divergent directions and are not merely opposite activity in identical brain regions. These findings have implications for understanding the neural substrates of both normal and pathological emotion.

  View details for Web of Science ID A1995QJ60400004

  View details for PubMedID 7864258

• Automatic recognition of corpus callosum from sagittal brain MR images 1995 Symposium on Applications of Digital Image Processing XVIII Lee, C., Unser, M., Ketter, T. A. SPIE - INT SOC OPTICAL ENGINEERING. 1995: 528–534

  View details for Web of Science ID A1995BD96W00055

• ACTIVATION STUDIES IN MOOD DISORDERS Emerging Neuroanatomy of Depression Symposium, at the 1994 Annual Meeting of the American-Psychiatric-Association George, M. S., Ketter, T. A., Post, R. M. SLACK INC. 1994: 648–52

  View details for Web of Science ID A1994PX43600006

• PRIMARY MOOD DISORDERS - STRUCTURAL AND RESTING FUNCTIONAL-STUDIES Emerging Neuroanatomy of Depression Symposium, at the 1994 Annual Meeting of the American-Psychiatric-Association Ketter, T. A., George, M. S., Ring, H. A., Pazzaglia, P., Marangell, L., Kimbrell, T. A., Post, R. M. SLACK INC. 1994: 637–42

  View details for Web of Science ID A1994PX43600004

• SPATIAL ABILITY IN AFFECTIVE-ILLNESS - DIFFERENCES IN REGIONAL BRAIN ACTIVATION DURING A SPATIAL MATCHING TASK (H2O)-O-15 PET) NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY George, M. S., Ketter, T. A., Parekh, P., Gill, D. S., Huggins, T., Marangell, L., Pazzaglia, P. J., Post, R. M. 1994; 7 (3): 143-153

  View details for Web of Science ID A1994PC76500001

• ANTICONVULSANT WITHDRAWAL-EMERGENT PSYCHOPATHOLOGY NEUROLOGY Ketter, T. A., Malow, B. A., Flamini, R., White, S. R., Post, R. M., Theodore, W. H. 1994; 44 (1): 55-61

  Abstract

  We prospectively investigated psychopathology in 32 epilepsy inpatients openly withdrawn from all antiepileptic drugs (AEDs) prior to entering a controlled trial of an investigational AED. Psychiatric ratings and seizures increased significantly with AED discontinuation. Anxiety and depression were the most prominent symptoms. Thirty-eight percent of patients developed moderate-to-severe psychopathology, and 28% dropped out of the study at various stages due to psychiatric symptoms. In 22 patients openly restarted on AEDs, psychiatric ratings returned to baseline within 2 weeks. Increases in partial seizures were weakly related to emergent anxiety and depression. Increases in generalized seizures were related to increases in global impairment but not to increases in specific psychopathology. AED withdrawal-emergent psychopathology was not fully explained by increases in seizures, demographic factors, or psychiatric history and may be partially due to pharmacodynamic effects following drug discontinuation.

  View details for Web of Science ID A1994MR37100013

  View details for PubMedID 8290092

• A GLOBAL APPROACH TO MULTIVARIATE CORRELATION-ANALYSIS OF PET BRAIN IMAGES Conference on Mathematical Methods in Medical Imaging III, at the International Symposium on Optics, Imaging, and Instrumentation of the SPIE Lee, C. H., Unser, M., Ketter, T. A. SPIE - INT SOC OPTICAL ENGINEERING. 1994: 305–315

  View details for Web of Science ID A1994BA84G00026

• Regional brain activity when selecting a response despite interference: An H2 (15) O PET study of the stroop and an emotional stroop. Human brain mapping George, M. S., Ketter, T. A., Parekh, P. I., ROSINSKY, N., Ring, H., Casey, B. J., Trimble, M. R., Horwitz, B., Herscovitch, P., Post, R. M. 1994; 1 (3): 194-209

  Abstract

  The Stroop interference test requires a person to respond to specific elements of a stimulus while suppressing a competing response. Previous positron emission tomography (PET) work has shown increased activity in the right anterior cingulate gyrus during the Stroop test. It is unclear, however, whether the anterior cingulate participates more in the attentional rather than the response selection aspects of the task or whether different interference stimuli might activate different brain regions. We sought to determine (1) whether the Stroop interference task causes increased activation in the right anterior cingulate as previously reported, (2) whether this activation varied as a function of response time, (3) what brain regions were functionally linked to the cingulate during performance of the Stroop, and (4) whether a modified Stroop task involving emotionally distracting words would activate the cingulate and other limbic and paralimbic regions. Twenty-one healthy volunteers were scanned with H2 (15) O PET while they performed the Stroop interference test (standard Stroop), a modified Stroop task using distracting words with sad emotional content (sad Stroop), and a control task of naming colors. These were presented in a manner designed to maximize the response selection aspects of the task. Images were stereotactically normalized and analyzed using statistical parametric mapping (SPM). Predictably, subjects were significantly slower during the standard Stroop than the sad Stroop or the control task. The left mideingulate region robustly activated during the standard Stroop compared to the control task. The sad Stroop activated this same region, but to a less significant degree. Correlational regional network analysis revealed an inverse relationship between activation in the left mideingulate and the left insula and temporal lobe. Additionally, activity in different regions of the cingulate gyrus correlated with performance speed during the standard Stroop. These results suggest that the left midcingulate is likely to be part of a neural network activated when one attempts to override a competing verbal response. Finally, the left midcingulate region appears to be functionally coupled to the left insula, temporal, and frontal cortex during cognitive interference tasks involving language. These results underscore the important role of the cingulate gyrus in selecting appropriate and suppressing inappropriate verbal responses. © 1994 Wiley-Liss, Inc.

  View details for DOI 10.1002/hbm.460010305

  View details for PubMedID 24578040

• PRELIMINARY CONTROLLED TRIAL OF NIMODIPINE IN ULTRA-RAPID CYCLING AFFECTIVE DYSREGULATION PSYCHIATRY RESEARCH Pazzaglia, P. J., Post, R. M., Ketter, T. A., George, M. S., Marangell, L. B. 1993; 49 (3): 257-272

  Abstract

  We report the initial results of the first controlled double-blind trial of nimodipine, a calcium channel antagonist, in the acute and prophylactic treatment of patients with treatment-refractory affective dysregulation. Active drug nimodipine (A) was substituted for placebo (B) in 12 patients. Patients were studied in a B-A-B design, with 3 of the 12 patients rechallenged with active drug in a B-A-B-A design (patients 9, 10, and 11). Five of the nine patients who completed the drug trial responded. One of three patients suffering from ultra-ultra-rapid (ultradian) cycling bipolar II disorder (patient 6) showed an essentially complete response; the other two ultradian patients (patients 4 and 9) showed evidence of a partial response on manic and depressive oscillations, one of which was confirmed in a B-A-B-A design. Only one of five less rapidly, but continuously cycling patients showed an excellent response (patient 10), and this was confirmed in a B-A-B-A design. The one patient who had recurrent brief depression (patient 11) showed a complete resolution of severe depressive recurrences, with response re-confirmed in an extended prophylactic trial with a B-A-B-A design. In the eight patients who completed self-ratings, nimodipine was associated with a significant reduction in the magnitude of mood fluctuations compared with the baseline placebo condition. Further clinical study of nimodipine, a calcium channel blocker with a unique profile of behavioral and anticonvulsant properties, appears warranted in patients with treatment-refractory affective illness characterized by recurrent brief depression and ultradian cycling.

  View details for Web of Science ID A1993MT85800006

  View details for PubMedID 8177920

• SPECT AND PET IMAGING IN MOOD DISORDERS Symposium on SPECT Imaging in Psychiatry: a New Look at Depression, at the 146th Annual Meeting of the American-Psychiatric-Association George, M. S., Ketter, T. A., Post, R. M. PHYSICIANS POSTGRADUATE PRESS. 1993: 6–13

  Abstract

  Single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies are yielding a picture of clinical depression as a disorder associated with dysfunction in specific brain regions. These data support the view of depression as a disease of the brain in general and of the frontal and temporal lobes in particular. Frontal lobe hypometabolism is emerging as a common final pathway for most types of primary and secondary depression, regardless of the original cause. The severity of depression is often related to the degree of frontal hypometabolism, and preliminary studies indicate that the hypometabolism normalizes after treatment in concert with the patient's improved mood. Primary depression also is associated with abnormal activation of key brain areas, including discrete aspects of the frontal and temporal lobes, the amygdala, and the cingulate gyrus. Several areas of research are currently under way using SPECT or PET to explore further the neuroanatomy of depression.

  View details for Web of Science ID A1993MR84900002

  View details for PubMedID 8270597

• BRAIN-REGIONS INVOLVED IN RECOGNIZING FACIAL EMOTION OR IDENTITY - AN O-15 PET STUDY JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES George, M. S., Ketter, T. A., Gill, D. S., Haxby, J. V., Ungerleider, L. G., Herscovitch, P., Post, R. M. 1993; 5 (4): 384-394

  Abstract

  The functional neuroanatomy of emotion recognition is inadequately understood despite well-documented clinical situations where emotion recognition is impaired (aprosodia). Oxygen-15 water positron-emission tomography (PET) was used to study 9 healthy women volunteers during three match-to-sample conditions, each repeated twice: a study task matching facial emotions and control tasks matching spatial positions or facial identity. Results suggest that the higher order functional neural network for recognizing emotion in visual input likely involves the right anterior cingulate and the bilateral inferior frontal gyri.

  View details for Web of Science ID A1993MD59300005

  View details for PubMedID 8286936

• ANTIDEPRESSANT RESPONSE TO SLEEP-DEPRIVATION AS A FUNCTION OF TIME INTO DEPRESSIVE EPISODE IN RAPIDLY CYCLING BIPOLAR PATIENTS ACTA PSYCHIATRICA SCANDINAVICA Gill, D. S., Ketter, T. A., Post, R. M. 1993; 87 (2): 102-109

  Abstract

  Three patients with treatment-resistant rapidly cycling bipolar disorder were studied with multiple sleep deprivations (SD) during several depressive episodes to assess the effect of phase or duration of a depressive episode on SD response. There was little response to SD early in a depressive episode, but responses were often robust late in an episode, sometimes triggering its termination. In 2 subjects, the duration of antidepressant response to SD increased linearly as time into episode increased. Neither the number of SD given in an episode nor the medication status of the patients appeared to account for the observed increases in antidepressant response. These results suggest that the neurobiological substrates underlying depression may change over the course of an episode, resulting in an increased responsivity to sleep deprivation later compared with earlier in the course of an episode in rapidly cycling patients. The generalizability of these findings to unipolar patients remains to be explored.

  View details for Web of Science ID A1993KN63500005

  View details for PubMedID 8447235

• NEW DEVELOPMENTS IN THE USE OF ANTICONVULSANTS AS MOOD STABILIZERS INTERNATIONAL SYMP ON ANTIEPILEPTIC DRUGS IN PSYCHIATRY Post, R. M., Ketter, T. A., Pazzaglia, P. J., George, M. S., Marangell, L., Denicoff, K. KARGER. 1993: 132–37

  Abstract

  There is increasing recognition that lithium is inadequate in the treatment of up to 50% of bipolar patients. In addition to subgroups that are nonresponsive from the outset, loss of efficacy (tolerance) and discontinuation-induced refractoriness have recently been observed. The anticonvulsants carbamazepine and valproate are effective alternative or adjunctive treatments, but tolerance can also occur during their long-term prophylactic use. New treatment algorithms for this loss of efficacy, including combination therapies, require further systematic study. Preliminary data suggesting that some patients with extremely rapid and chaotic mood fluctuations may respond to the L-type calcium channel blocker nimodipine are presented, and the theoretical implications discussed.

  View details for Web of Science ID A1993LU18500004

  View details for PubMedID 8232827

• CARBAMAZEPINE-INDUCED INCREASES IN TOTAL SERUM-CHOLESTEROL - CLINICAL AND THEORETICAL IMPLICATIONS JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Brown, D. W., Ketter, T. A., CRUMLISH, J., Post, R. M. 1992; 12 (6): 431-437

  Abstract

  To assess the effect of carbamazepine (CBZ) upon total serum cholesterol, we examined 38 inpatients with affective illness and one with multiple personality disorder who received a course of CBZ monotherapy. CBZ therapy yielded significant increases in total serum cholesterol that became evident during the second week of therapy, persisted throughout therapy, and reversed in the first few weeks after discontinuation of therapy. CBZ-induced increases in total cholesterol appeared independent of initial mood state, diagnostic subtype, baseline cholesterol or thyroid indices; CBZ levels, doses, and level-to-dose ratios; and the degree of change in mood and thyroid indices. CBZ induction of enzymes mediating cholesterol synthesis is a possible mechanism of the increase in total cholesterol observed with CBZ therapy. Although preclinical studies suggest possible influence of cholesterol on neurotransmitter regulation and behavior, clinical studies have yielded conflicting data. There are insufficient data to support a role for cholesterol in the anticonvulsant and psychotropic mechanisms of CBZ. The increase in total serum cholesterol seen with CBZ therapy is likely due to an increase in the high density lipoprotein fraction and is thus not likely to be clinically problematic in relationship to atherosclerosis.

  View details for Web of Science ID A1992KA05400009

  View details for PubMedID 1474180

• CEREBRAL METABOLISM AND DEPRESSION IN PATIENTS WITH COMPLEX PARTIAL SEIZURES ARCHIVES OF NEUROLOGY Bromfield, E. B., Altshuler, L., Leiderman, D. B., Balish, M., Ketter, T. A., Devinsky, O., Post, R. M., Theodore, W. H. 1992; 49 (6): 617-623

  Abstract

  Twenty-three patients with complex partial seizures were evaluated with 18F-2-deoxyglucose positron emission tomography and with the Beck Depression Inventory. Five of 10 patients with left and zero of eight with right temporal electroencephalographic foci had depressive symptoms; one of five patients with poorly localized electroencephalographic foci also scored in the depressed range. Temporal, frontal, caudate, and thalamic normalized glucose metabolic rates among five patients with depressive symptoms and well-localized left temporal epileptogenic regions were compared with five patients without depressive symptoms but with similar electroencephalographic characteristics. Multifactorial analysis of variance yielded a significant nonlateralized mood by region interaction. Of nine individual regions compared, only inferior frontal cortex showed a significant difference in normalized regional metabolic rate between depressed and nondepressed patients. Metabolism in this region also distinguished patients with depressive symptoms from normal control subjects. Depressive symptoms in patients with complex partial seizures are associated with a bilateral reduction in inferior frontal glucose metabolism, compared with patients without depressive symptoms and normal control subjects. The frontal lobe hypometabolism observed in patients with depressions associated with epilepsy, Parkinson's disease, and primary affective disorder suggests that similar frontal lobe metabolic disturbances could underlie these conditions.

  View details for Web of Science ID A1992HX95800008

  View details for PubMedID 1596197

• PRINCIPLES OF CLINICALLY IMPORTANT DRUG-INTERACTIONS WITH CARBAMAZEPINE .2. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Ketter, T. A., Post, R. M., Worthington, K. 1991; 11 (5): 306-312

  View details for Web of Science ID A1991GG42300006

  View details for PubMedID 1765573

• PRINCIPLES OF CLINICALLY IMPORTANT DRUG-INTERACTIONS WITH CARBAMAZEPINE .1. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Ketter, T. A., Post, R. M., Worthington, K. 1991; 11 (3): 198-203

  View details for Web of Science ID A1991FN81700009

  View details for PubMedID 2066459

• Antiepileptic drugs in affective illness. Clinical and theoretical implications. Advances in neurology Post, R. M., Altshuler, L. L., Ketter, T. A., Denicoff, K., Weiss, S. R. 1991; 55: 239-277

  View details for PubMedID 2003410

• LACK OF BENEFICIAL-EFFECTS OF L-BACLOFEN IN AFFECTIVE-DISORDER INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Post, R. M., Ketter, T. A., Joffe, R. T., KRAMLINGER, K. L. 1991; 6 (4): 197-207

  Abstract

  GABAB mechanisms have been implicated in the antinociceptive, but not anticonvulsant effects of carbamazepine. A variety of antidepressants have been reported to upregulate GABAB receptors after chronic administration. The GABAB agonist l-baclofen was studied in depressed patients based on two separate rationales. l-Baclofen, in doses ranging from 10-55 mg/day, was administered to five patients with primary affective disorder. No patient showed a positive clinical response, while three patients showed a pattern of increasing depression or cycling during treatment and improvement during withdrawal. These preliminary data suggest that GABAB agonism is unlikely to produce antidepressant effects and may be unrelated to the mechanism of carbamazepine's antidepressant action. These data, taken with a reinterpretation of other findings that antidepressant modalities upregulate GABAB receptors in brain following chronic administration, suggest that GABAB antagonism rather than agonism may be a fruitful clinical strategy to explore in depression.

  View details for Web of Science ID A1991HH68800001

  View details for PubMedID 1816278

• TREATMENT OF RAPID CYCLING BIPOLAR ILLNESS 29TH ANNUAL MEETING OF THE NEW CLINICAL DRUG EVALUATION UNIT Post, R. M., Kramlinger, K. G., Altshuler, L. L., Ketter, T., Denicoff, K. US GOVERNMENT PRINTING OFFICE. 1990: 37–47

  Abstract

  Rapid cycling patients (greater than or equal to 4 episodes/year) often show inadequate response to lithium carbonate and are vulnerable to antidepressant-induced switches or cycle acceleration. Treatment with the anticonvulsant carbamazepine is now an accepted adjunct or alternative, and a series of uncontrolled studies also suggest the utility of valproate in this patient population. Clonazepam, suppressive doses of thyroid, calcium channel blockers, and other innovative treatments appear promising and deserve careful clinical investigation.

  View details for Web of Science ID A1990DL70200007

  View details for PubMedID 2196625

• PERSPECTIVES ON THE MECHANISM OF ACTION OF ELECTROCONVULSIVE-THERAPY - ANTICONVULSANT, PEPTIDERGIC, AND C-FOS PROTO-ONCOGENE EFFECTS CONVULSIVE THERAPY Nakajima, T., Post, R. M., Pert, A., Ketter, T. A., Weiss, S. R. 1989; 5 (3): 274-295

  View details for Web of Science ID A1989AL17400007