Michael Ostacher

All Publications

• Clinical decision support for bipolar depression using large language models. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Perlis, R. H., Goldberg, J. F., Ostacher, M. J., Schneck, C. D. 2024

  Abstract

  Management of depressive episodes in bipolar disorder remains challenging for clinicians despite the availability of treatment guidelines. In other contexts, large language models have yielded promising results for supporting clinical decisionmaking. We developed 50 sets of clinical vignettes reflecting bipolar depression and presented them to experts in bipolar disorder, who were asked to identify 5 optimal next-step pharmacotherapies and 5 poor or contraindicated choices. The same vignettes were then presented to a large language model (GPT4-turbo; gpt-4-1106-preview), with or without augmentation by prompting with recent bipolar treatment guidelines, and asked to identify the optimal next-step pharmacotherapy. Overlap between model output and gold standard was estimated. The augmented model prioritized the expert-designated optimal choice for 508/1000 vignettes (50.8%, 95% CI 47.7-53.9%; Cohen's kappa=0.31, 95% CI 0.28-0.35). For 120 vignettes (12.0%), at least one model choice was among the poor or contraindicated treatments. Results were not meaningfully different when gender or race of the vignette was permuted to examine risk for bias. By comparison, an un-augmented model identified the optimal treatment for 234 (23.0%, 95% CI 20.8-26.0%; McNemar's p<0.001 versus augmented model) of the vignettes. A sample of community clinicians scoring the same vignettes identified the optimal choice for 23.1% (95% CI 15.7-30.5%) of vignettes, on average; McNemar's p<0.001 versus augmented model. Large language models prompted with evidence-based guidelines represent a promising, scalable strategy for clinical decision support. In addition to prospective studies of efficacy, strategies to avoid clinician overreliance on such models, and address the possibility of bias, will be needed.

  View details for DOI 10.1038/s41386-024-01841-2

  View details for PubMedID 38480911

• COVID-19 and substance use disorders: a review of international guidelines for frontline healthcare workers of addiction services. BMC psychiatry Ostinelli, E. G., Smith, K., Zangani, C., Ostacher, M. J., Lingford-Hughes, A. R., Hong, J. S., Macdonald, O., Cipriani, A. 2022; 22 (1): 228

  Abstract

  BACKGROUND: People with substance use disorders may be at a greater risk of contracting COVID-19 infection and developing medical complications. Several institutional and governmental health agencies across the world developed ad hoc guidance for substance use disorder services and care of individuals misusing substances. We aimed to synthesise the best available recommendations on management and care of people with or at risk of substance use disorders during the COVID-19 pandemic from existing guidelines published in UK, USA, Australia, Canada, New Zealand, and Singapore.METHODS: We systematically searched existing guidelines and websites from 28 international institutions and governmental bodies in the context of the COVID-19 pandemic (May 4th 2021). We summarized the extracted data as answers to specific clinical questions.RESULTS: We organised the available recommendations from 19 sources in three sections. First, we focused on general advice and recommendations for people who misuse alcohol or drugs during the COVID-19 pandemic, the design of contingency plans, safeguarding issues for children and families of service users and advice to the public, patients, and carers. Then, we summarised specific guidelines for people who use illicit drugs and related services, such as opioid substitution treatment and needle and syringe programmes. Finally, we provided a synthesis on specific recommendations for services supporting people who misuse alcohol and key topics in the field, such as management of alcohol detoxification and safe transition between supervised and unsupervised consumption.CONCLUSIONS: Available guidance reflected different approaches, ranging from being extremely cautious in providing recommendations other than generic statements to proposing adaptation of previously available guidelines to confront the challenges of the COVID-19 pandemic. After the early phase, guidance focused on reduction of infection transmission and service delivery. Guidance did not provide advice on infection prevention via vaccination programmes and service access strategies tailored to individuals with substance use disorders.

  View details for DOI 10.1186/s12888-022-03804-7

  View details for PubMedID 35361184

• Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial. JAMA Oslin, D. W., Lynch, K. G., Shih, M., Ingram, E. P., Wray, L. O., Chapman, S. R., Kranzler, H. R., Gelernter, J., Pyne, J. M., Stone, A., DuVall, S. L., Lehmann, L. S., Thase, M. E., PRIME Care Research Group, Aslam, M., Batki, S. L., Bjork, J. M., Blow, F. C., Brenner, L. A., Chen, P., Desai, S., Dieperink, E. W., Fears, S. C., Fuller, M. A., Goodman, C. S., Graham, D. P., Haas, G. L., Hamner, M. B., Helstrom, A. W., Hurley, R. A., Icardi, M. S., Jurjus, G. J., Kilbourne, A. M., Kreyenbuhl, J., Lache, D. J., Lieske, S. P., Lynch, J. A., Meyer, L. J., Montalvo, C., Muralidhar, S., Ostacher, M. J., Paschall, G. Y., Pfeiffer, P. N., Prieto, S., Przygodzki, R. M., Ranganathan, M., Rodriguez-Suarez, M. M., Roggenkamp, H., Schichman, S. A., Schneeweis, J. S., Simonetti, J. A., Steinhauer, S. R., Suppes, T., Umbert, M. A., Vassy, J. L., Voora, D., Wiechers, I. R., Wood, A. E. 2022; 328 (2): 151-161

  Abstract

  Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment.Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes.Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications.Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n=966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n=978).Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9≤5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters.Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P<.001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P=.005) (P<.001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P=.02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P=.45).Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission.Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

  View details for DOI 10.1001/jama.2022.9805

  View details for PubMedID 35819423

• Slowly Working Toward More Treatments for Depression in Bipolar II Disorder. The American journal of psychiatry Ostacher, M. J. 2021; 178 (12): 1075-1076

  View details for DOI 10.1176/appi.ajp.2021.21101028

  View details for PubMedID 34855451

• Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial. JAMA psychiatry Katz, I. R., Rogers, M. P., Lew, R., Thwin, S. S., Doros, G., Ahearn, E., Ostacher, M. J., DeLisi, L. E., Smith, E. G., Ringer, R. J., Ferguson, R., Hoffman, B., Kaufman, J. S., Paik, J. M., Conrad, C. H., Holmberg, E. F., Boney, T. Y., Huang, G. D., Liang, M. H., Li+ plus Investigators, Agrawal, D., Akhtar, N., Androsenko, M., Berger, B., Bhat, V., Brenner, L., Chalasani, L., Chang, D., Chen, P. P., Cornejo, B., Cory, D., Davidson, D., Dickmann, P., Duncan, E., Fernando, R., Floyd, K. C., Forman, S., Gale, P., Geete, J., Ignatowski, M., Jones, K., Juergens, T., Jurjus, G., Khatkhate, G., Konicki, E. P., Krahn, D., Larson, G., Leckband, S., Mack, J., Matthews, S., Mayo, L., McGlade, E., Michalets, J., Miller, E., Muly, E., Niculescu, A., Ostacher, M., Padala, P., Padala, K., Pazzaglia, P., Raskind, M., Renshaw, P., Shivakumar, G., Smith, J. C., Sullivan, D., Suppes, P., Swann, A., Thomas, L., Thompson, S., Turner, E., Umbert, M., Westermeyer, J., Wood, A., Wortzel, H., Yurgelun-Todd, D. 2021

  Abstract

  Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression.Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event.Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019.Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo.Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group.Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities.Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

  View details for DOI 10.1001/jamapsychiatry.2021.3170

  View details for PubMedID 34787653

• Incorporating clinical research into recommendations for addressing global mental health needs: Updating the World Health Organization's Essential Medicines List. Comprehensive psychiatry Machado, I. K., Lippert, C., Ostacher, M. J. 2021; 109: 152245

  View details for DOI 10.1016/j.comppsych.2021.152245

  View details for PubMedID 34186286

• Investigation of a Capnometry Guided Respiratory Intervention in the Treatment of Posttraumatic Stress Disorder. Applied psychophysiology and biofeedback Ostacher, M. J., Fischer, E., Bowen, E. R., Lyu, J., Robbins, D. J., Suppes, T. 2021

  Abstract

  Evidence-based treatments for posttraumatic stress disorder (PTSD), including psychotherapies and medications, have high dropout and nonresponse rates, suggesting that more acceptable and effective treatments for PTSD are needed. Capnometry Guided Respiratory Intervention (CGRI) is a digital therapeutic effective in panic disorder that measures and displays end-tidal carbon dioxide (EtCO2) and respiratory rate (RR) in real-time within a structured breathing protocol and may have benefit in PTSD by moderating breathing and EtCO2 levels. We conducted a single-arm study of a CGRI system, Freespira®, to treat symptoms of PTSD. Participants with PTSD (n = 55) were treated for four weeks with twice-daily, 17-min at-home CGRI sessions using a sensor and tablet with pre-loaded software. PTSD and associated symptoms were assessed at baseline, end-of treatment, 2-months and 6-months post-treatment. Primary efficacy outcome was 50% of participants having ≥ 6-point decrease in Clinician Administered PTSD Scale (CAPS-5) score at 2-month follow up. Tolerability, usability, safety, adherence and patient satisfaction were assessed. CGRI was well tolerated, with 88% [95% CI 74-96%] having ≥ 6-point decrease in CAPS-5 scores at 2-months post-treatment follow up. Mean CAPS-5 scores decreased from 49.5 [s.d. = 9.2] at baseline to 27.1 [s.d. = 17.8] at 2-months post-treatment follow up. Respiratory rate decreased and EtCO2 levels increased. Associated mental and physical health symptoms also improved. This CGRI intervention was safe, acceptable, and well-tolerated in improving symptoms in this study in PTSD. Further study against an appropriate comparator is warranted.Trial registration Clinicaltrials.gov NCT#03039231.

  View details for DOI 10.1007/s10484-021-09521-3

  View details for PubMedID 34468913

• Using big data to advance mental health research. Evidence-based mental health Duffy, A., Faurholt-Jepsen, M., Ostacher, M. 2020

  View details for DOI 10.1136/ebmental-2020-300143

  View details for PubMedID 31959731

• A Simple Suggestion: Make Follow-Up Appointments for All Patients After Discharge, Especially Those With Co-Occurring Addictions. The Journal of clinical psychiatry Ostacher, M. J. 2020; 81 (5)

  View details for DOI 10.4088/JCP.20com13652

  View details for PubMedID 32936542

• How genome-wide association studies (GWAS) made traditional candidate gene studies obsolete NEUROPSYCHOPHARMACOLOGY Duncan, L. E., Ostacher, M., Ballon, J. 2019; 44 (9): 1518–23

  View details for DOI 10.1038/s41386-019-0389-5

  View details for Web of Science ID 000475474900003

• How genome-wide association studies (GWAS) made traditional candidate gene studies obsolete. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Duncan, L. E., Ostacher, M., Ballon, J. 2019

  View details for PubMedID 30982060

• Management of Posttraumatic Stress Disorder JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ostacher, M. J., Cifu, A. S. 2019; 321 (2): 200-201

  View details for DOI 10.1001/jama.2018.19290

  View details for Web of Science ID 000455606300018

• Bipolar and Related Disorders AMERICAN PSYCHIATRIC ASSOCIATION PUBLISHING TEXTBOOK OF PSYCHIATRY, 7TH EDITION Miller, S., Ostacher, M., Suppes, T., Roberts, L. W. 2019: 279–306

  View details for Web of Science ID 000550979400013

• Pilot Randomized Controlled Trial of Web-Delivered Acceptance and Commitment Therapy Versus Smokefree.gov for Smokers With Bipolar Disorder. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco Heffner, J. L., Kelly, M. M., Waxmonsky, J. n., Mattocks, K. n., Serfozo, E. n., Bricker, J. B., Mull, K. E., Watson, N. L., Ostacher, M. n. 2019

  Abstract

  Smokers with bipolar disorder (BD) are less successful at quitting than the general population. In this study, we evaluated in a pilot randomized controlled trial a novel, targeted, web-based intervention for smokers with BD based on acceptance and commitment therapy (ACT) and designed for reach and disseminability.Daily smokers (n=51) with bipolar I or II disorder were recruited from four US sites and randomly assigned to one of two web-based smoking cessation interventions-ACT-based WebQuit Plus (n=25) or Smokefree.gov (n=26) over a 10-week treatment period. All participants received nicotine patch for 8 weeks. Key outcomes were trial design feasibility, intervention acceptability, and cessation at end-of-treatment and 1-month follow-up.We screened 119 to enroll 51 participants (target sample size=60) over 24 months. The most common reason for ineligibility was inability to attend study appointments. Retention was 73% at end-of-treatment and 80% at follow-up, with no differences by arm. Mean number of logins was twice as high for WebQuit Plus (10.3 vs. 5.3). Usefulness of program skills was rated higher for WebQuit Plus (75% vs. 29%). Biochemically-confirmed, 7-day abstinence at end-of-treatment was 12% in WebQuit Plus vs. 8% in Smokefree.gov (OR=1.46, 95% CI=0.21-9.97). At follow-up, abstinence rates were 8% in both arms.Trial design produced favorable retention rates, although alternative recruitment methods will be needed for a larger trial. At end-of-treatment, acceptability and estimated effect size of WebQuit Plus relative to Smokefree.gov were promising and support continued program refinement and evaluation.In this first randomized, controlled trial of a targeted intervention for smokers with bipolar disorder, we found that the ACT-based WebQuit Plus intervention, delivered in combination with nicotine patch, had promising acceptability and cessation outcomes relative to Smokefree.gov. The observed signals for acceptability and cessation suggest that the WebQuit Plus program should be refined based on participant feedback and evaluated in a larger trial. Feasibility findings from this study also provide direction for refining trial procedures to enhance recruitment of smokers with bipolar disorder.

  View details for DOI 10.1093/ntr/ntz242

  View details for PubMedID 31883336

• Ethical Issues in the Diagnosis and Treatment of Bipolar Disorders. Focus (American Psychiatric Publishing) Ostacher, M. J. 2019; 17 (3): 265–68

  View details for DOI 10.1176/appi.focus.20190010

  View details for PubMedID 32047373

  View details for PubMedCentralID PMC6999205

• Management of Posttraumatic Stress Disorder. JAMA Ostacher, M. J., Cifu, A. S. 2018

  View details for PubMedID 30556838

• Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis PLOS MEDICINE De Crescenzo, F., Ciabattini, M., D'Alo, G., De Giorgi, R., Del Giovane, C., Cassar, C., Janiri, L., Clark, N., Ostacher, M., Cipriani, A. 2018; 15 (12)

  View details for DOI 10.1371/journal.pmed.1002715

  View details for Web of Science ID 000454833300007

• A Novel Study Design to Systematically Explore the Impact of Trial Methodology on Psychopharmacological Treatment Outcome in Patients with Depression. Pharmacopsychiatry Severus, E. n., Sauer, C. n., Bauer, M. n., Ostacher, M. n., Anghelescu, I. G. 2018

  Abstract

  Randomized, double-blind, placebo-controlled trials were developed to draw rather unbiased conclusions regarding the efficacy of antidepressants in the treatment of a major depressive episode (internal validity), mostly with the purpose of formal approval of new compounds in this indication. However, at the same time, data suggest that the very process of randomization and blinded administrations of placebo will have a significant impact on the efficacy of the antidepressant tested and therefore may limit the external validity of results obtained from this type of studies. Therefore, there is an urgent need to systematically study the impact of randomization/placebo control/blinding on patient population, efficacy, tolerability, and external validity in the psychopharmacological treatment of patients with a major depressive episode.To develop a study design that allows the systematic exploration of the impact of trial design on characteristics of included patient population and outcome.We propose a study design including sample size calculation and statistical analysis in which patients with a major depressive episode are randomized to 3 distinct study designs that differ with regard to control, randomization, and blindness.The results of the proposed study design may have substantial consequences when it comes to how to best interpret the results of traditional randomized, double-blind, placebo-controlled trials in the acute treatment of major depressive disorder. Furthermore, they may lead to the implementation of new study designs that may be more suitable for assessing the effectiveness of new antidepressant compounds in everyday clinical practice.

  View details for PubMedID 29975972

• Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Major Depressive Disorder JOURNAL OF CLINICAL PSYCHIATRY McIntyre, R. S., Suppes, T., Tandon, R., Ostacher, M. 2017; 78 (6): 703–13

  Abstract

  Herein we provide the 2015 update for the Florida Best Practice Psychotherapeutic Medication Guidelines (FPG) for major depressive disorder (MDD). The FPG represent evidence-based decision support for practitioners providing care to adults with MDD.The consensus meeting included representatives from the Florida Agency for Health Care Administration (FAHCA), advocacy members, academic experts in MDD, and multidisciplinary mental health clinicians, as well as health policy experts. The FAHCA provided funding support for the FPG.Evidence was limited to results from adequately powered, randomized, double-blind, placebo-controlled trials; in addition, pooled-, meta-, and network-analyses were included. Recommendations were based on consensus arrived at by the multistakeholder Florida Expert Panel. Articles selected were identified on the electronic search engine PubMed with the dates 2010 to present. The search terms were major depressive disorder, psychopharmacology, antidepressants, psychotherapy, neuromodulation, complementary alternative medicines, pooled-analysis, meta-analysis, and network-analysis. Bibliographies of the identified articles were manually searched for additional citations not identified in the original search.A consensus meeting comprising all representatives took place on September 25-26, 2015, in Tampa, Florida. Guiding principles (eg, emphasis on the most rigorous evidence for efficacy, safety, and tolerability) were discussed, defined, and operationalized prior to review of extant data. As MDD often pursues a recurrent and chronic course, principles of practice, measurement-based care, and comprehensive assessment and management of overall physical and mental health were emphasized. Evidence supporting pretreatment major depressive episode specifiers (eg, mixed features, anxious distress) and the role of pharmacogenomics (and other biological-behavioral markers) in informing treatment selection were comprehensively discussed. Algorithmic priority was assigned to agents with relatively greater therapeutic index (ie, efficacy) and minimal propensity for safety and tolerability disadvantages.The updated 2015 FPG provide concise, pragmatic, evidence-based decision support for treatment selection and sequencing for adults with MDD. Principles of practice include measurement-based care, priority to both psychiatric and medical comorbidity, identification of DSM-5-defined specifiers (eg, mixed features), suicide risk assessment, and evaluation of cognitive symptoms. The FPG have purposefully aimed to minimize emphasis on "expert opinion" and instead differentially emphasized extant evidence for pharmacologic treatments.

  View details for PubMedID 28682531

• Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Bipolar Disorder: A Novel, Practical, Patient-Centered Guide for Clinicians. journal of clinical psychiatry Ostacher, M. J., Tandon, R., Suppes, T. 2016; 77 (7): 920-926

  Abstract

  This report describes the 2014 update of the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Bipolar Disorder, intended to provide frontline clinicians with a simple, evidence-based approach to treatments for 3 phases of bipolar disorder: acute depression, acute mania, and maintenance.The consensus meeting included representatives from the Florida Agency for Health Care Administration, pharmacists, health care policy experts, mental health clinicians, and experts in bipolar disorder. The effort was funded by the Florida Agency for Health Care Administration.The available published and nonpublished data from trials in the treatment of bipolar I disorder were reviewed. Evidence for efficacy and harm from replicated randomized clinical trials, systematic reviews and meta-analyses, or non-replicated randomized clinical trials was included. No recommendations were made with evidence from other sources.Decisions regarding the structure of the guidelines were made during a stakeholder meeting in Tampa, Florida, on September 20 and 21, 2013. Better proven and safer/more efficacious treatments were to be utilized before using those with less evidence and/or greater risk. Safety and risk of harm were balanced against potential benefit. Lower-quality evidence was recommended only if higher-level treatments were found to be ineffective or not tolerated, because of patient preference, or because of past treatment success. While respecting patient and clinician choice, the guidelines are structured to encourage evidence-based, safe prescribing first.This iteration of the Florida guidelines for the treatment of bipolar disorder is a practical, simple, patient-focused guide to treatment for acute mania and acute bipolar depression and maintenance treatment that considers safety and harm in the hierarchy of treatment choices. While using strict evidence-based criteria for inclusion in recommendations, it eliminates expert opinion as a level of evidence while respecting clinician and patient choice in treatment decision-making.

  View details for DOI 10.4088/JCP.15cs09841

  View details for PubMedID 26580001

• A randomized, placebo-controlled proof-of-concept trial of adjunctive topiramate for alcohol use disorders in bipolar disorder. American journal on addictions Sylvia, L. G., Gold, A. K., Stange, J. P., Peckham, A. D., Deckersbach, T., Calabrese, J. R., Weiss, R. D., Perlis, R. H., Nierenberg, A. A., Ostacher, M. J. 2016; 25 (2): 94-98

  Abstract

  Topiramate is effective for alcohol use disorders (AUDs) among non-psychiatric patients. We examined topiramate for treating comorbid AUDs in bipolar disorder (BD).Twelve participants were randomized to topiramate or placebo for 12 weeks.The topiramate group, with two out of five participants (40%) completing treatment, experienced less improvement in drinking patterns than the placebo group, with five out of seven participants (71%) completing treatment.Topiramate did not improve drinking behavior and was not well-tolerated. This study failed to recruit adequately. Problems surrounding high attrition, a small study sample, and missing data preclude interpretation of study findings.This is the first randomized, placebo-controlled trial of topiramate for AUDs in BD. (Am J Addict 2016;25:94-98).

  View details for DOI 10.1111/ajad.12346

  View details for PubMedID 26894822

  View details for PubMedCentralID PMC4791182

• 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

• Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome-wide association. Bipolar disorders Ostacher, M. J., Iosifescu, D. V., Hay, A., Blumenthal, S. R., Sklar, P., Perlis, R. H. 2014; 16 (2): 199-203

  Abstract

  Motivated by genetic association data implicating L-type calcium channels in bipolar disorder liability, we sought to estimate the tolerability, safety, and efficacy of isradipine in the adjunctive treatment of bipolar depression.A total of 12 patients with bipolar I or II depression entered this pilot, proof-of-concept eight-week investigation and 10 returned for at least one post-baseline visit. They were initiated on isradipine at 2.5 mg and titrated up to 10 mg daily, with blinded assessments of depression using the Montgomery-Åsberg Depression Rating Scale (MADRS) as well as adverse effects.Among the 10 patients, three had bipolar II disorder; all but two reported current episode duration longer than six months. In all, four of 10 completed the study; no significant adverse events were observed, although one subject discontinued treatment per protocol because of possible hypomanic symptoms which had resolved prior to study visit. In a mixed-effects model, mean improvement in depression severity, assessed by MADRS, was 2.1 (standard error = 0.36) points/week (p < 0.001). Two of the 10 subjects remitted and four of the 10 subjects experienced 50% or greater symptomatic improvement with treatment.Isradipine merits further investigation for the treatment of bipolar depression. This preliminary trial illustrates the potential utility of genetic investigation in identifying psychiatric treatment targets.

  View details for DOI 10.1111/bdi.12143

  View details for PubMedID 24372835

• Telehepatology Use and Satisfaction Among Vulnerable Cirrhosis Patients Across Three Healthcare Systems in the Coronavirus Disease Pandemic Era. Gastro hep advances Athavale, P., Wong, R. J., Satre, D. D., Monto, A., Cheung, R., Chen, J. Y., Batki, S. L., Ostacher, M. J., Snyder, H. R., Widiarto, B. D., Oh, S. Y., Liao, M., Viviani, A. M., Khalili, M. 2024; 3 (2): 201-209

  Abstract

  Telehealth has emerged as an important mode of cirrhosis care delivery, but its use and satisfaction among vulnerable populations (eg, racial/ethnic minorities, socioeconomically disadvantaged, substance use disorders) are unknown. We evaluated digital capacity, telehealth use, satisfaction and associated factors among patients receiving hepatology care via telehealth (telehepatology) across 2 Veterans Affairs and 1 safety-net Healthcare systems.English- and Spanish-speaking adults with cirrhosis (N = 256) completed surveys on telehealth use and satisfaction, quality of life, pandemic stress, alcohol use and depression. Logistic regression analyses assessed telehealth use and general linear models evaluated telehealth satisfaction.The mean age was 64.5 years, 80.9% were male and 35.9% Latino; 44.5% had alcohol-associated cirrhosis; 20.8% had decompensated cirrhosis; 100% had digital (phone/computer) capacity; and 75.0% used telehepatology in the prior 6 months. On multivariable analysis, participants with alcohol-associated (vs not) cirrhosis were less likely and those with greater pandemic stress were more likely to use telehepatology (odds ratio = 0.46 and 1.41, respectively; P < .05). Better quality of life was associated with higher telehepatology satisfaction and older age was associated with lower satisfaction (β = 0.01 and -0.01, respectively; P < .05). Latinos had higher satisfaction, but alcohol use disorder was associated with less satisfaction with telehepatology visits (β = 0.22 and -0.02, respectively; P < .05).Participants had high telehepatology capacity, yet demographics and alcohol-related problems influenced telehepatology use and satisfaction. Findings underscore the need for interventions to enhance patient experience with telehepatology for certain vulnerable groups including those with alcohol-associated cirrhosis in order to optimize care delivery.

  View details for DOI 10.1016/j.gastha.2023.11.006

  View details for PubMedID 39129958

  View details for PubMedCentralID PMC11307565

• Single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression - A first-in-kind open-label pilot study. Journal of affective disorders Ellis, S., Bostian, C., Feng, W., Fischer, E., Schwartz, G., Eisen, K., Lean, M., Conlan, E., Ostacher, M., Aaronson, S., Suppes, T. 2024

  Abstract

  The enduring and severe depression often suffered by Veterans causes immense suffering and is associated with high rates of suicide and disability. This is the first study to evaluate the efficacy and safety of psilocybin in Veterans with severe treatment-resistant depression (TRD).15 Veterans with severe TRD (major depressive episode failing to respond to ≥5 treatments, or lasting >2 years) received 25 mg of psilocybin. Primary outcome was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Response was defined s ≥ 50 % reduction in MADRS, and remission as ≤10 MADRS score. Psychedelic experience was assessed using the Five-Dimensional Altered States of Consciousness scale (5D-ASC). Safety measures included assessment of suicidality and adverse events. Participants on antidepressants were tapered to avoid drug interactions.Of 15 participants, 60 % met response and 53 % met remission criteria at Week 3. At 12 weeks, 47 % maintained response, and 40 % remission. Co-morbid PTSD did not significantly influence study outcomes. The psychedelic experience reported in 5D-ASC did not correlate with response. Participants judged to need antidepressants were restarted and considered non-responders from that timepoint (n = 4). No unexpected adverse events occurred.Limitations include the small sample size, and the uncontrolled and unblinded nature of the study.In this first study on psilocybin for Veterans with severe TRD, a surprising response and remission was seen. Many Veterans had PTSD though no moderating impact of response was observed. The degree of psychedelic experience did not correlate with depression changes. Further study is warranted.ClinicalTrials.gov Identifier: NCT04433858.

  View details for DOI 10.1016/j.jad.2024.09.133

  View details for PubMedID 39343309

• Understanding the relationship between childhood abuse and affective symptoms in bipolar disorder: New insights from a network analysis. Psychiatry research Wrobel, A. L., Turner, M., Dean, O. M., Berk, M., Sylvia, L. G., Thase, M. E., Deckersbach, T., Tohen, M., McInnis, M. G., Kocsis, J. H., Shelton, R. C., Ostacher, M. J., Iosifescu, D. V., McElroy, S. L., Turner, A., Nierenberg, A. A. 2024; 342: 116197

  Abstract

  The impact of childhood abuse on the presentation of bipolar disorder could be further elucidated by comparing the networks of affective symptoms among individuals with and with no history of childhood abuse. Data from 476 participants in the Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study were used to fit several regularised Gaussian Graphical Models. Differences in the presentation of depressive and manic symptoms were uncovered: only among participants with a history of childhood abuse, inadequacy and pessimism were central symptoms in the network of depressive symptoms, while racing thoughts was an important symptom in the network of manic symptoms. Following network theory, focusing treatments at the symptom-level and on central symptoms - like inadequacy, pessimism, and racing thoughts - could be an effective approach for managing affective symptoms among the sizeable proportion of people with bipolar disorder who have experienced childhood abuse. This study contributes a thorough investigation of the networks of affective symptoms among participants with and with no history of childhood abuse, albeit limited by the use of a binary, self-report measure of childhood abuse, thereby emphasising the importance of assessing for childhood abuse and taking needed steps towards identifying novel targets for treating bipolar disorder.

  View details for DOI 10.1016/j.psychres.2024.116197

  View details for PubMedID 39317000

• Alcohol Use and Substance Use Treatment Engagement Among Patients With Alcohol-Associated Cirrhosis in Three Hospital-Based Hepatology Practices Snyder, H., Satre, D., Shumway, M., Batki, S., Ostacher, M., Tompkins, D., Monto, A., Wong, R., Cheung, R., Parekh, P., Hua, W., Widiarto, D., Oh, S., Liao, M., Khalili, M. ELSEVIER IRELAND LTD. 2024

  View details for DOI 10.1016/j.drugalcdep.2023.110450

  View details for Web of Science ID 001280690400468

• A Double-blind, Randomized, Placebo-controlled plus Open Trial of Adjunctive Suvorexant for Treatment-resistant Insomnia in Patients with Bipolar Disorder. CNS spectrums Cafaro, R., Macellaro, M., Suppes, T., Dell'Osso, B., Ketter, T., Ostacher, M., Miller, S., Chang, L., Lyu, J., Wang, P. W. 2024: 1-26

  View details for DOI 10.1017/S1092852924000336

  View details for PubMedID 38782461

• Advancing research: a commentary on the untapped potential of acceptance and commitment therapy in alcohol use disorder treatment. Alcohol and alcoholism (Oxford, Oxfordshire) Garel, N., Brodsky, K. L., Ostacher, M. J. 2024; 59 (4)

  Abstract

  Alcohol use disorder poses a significant global health threat, with profound consequences for individuals, families, and communities, necessitating continued exploration of novel treatment approaches. Acceptance and Commitment Therapy, an evidence-based approach for various mental health disorders, offers promise in addressing alcohol use disorder as well, but controlled trials are lacking, highlighting a crucial gap in research.

  View details for DOI 10.1093/alcalc/agae042

  View details for PubMedID 38938218

• What Does a Systematic Review of Cannabis and PTSD Tell Us? That We Need to Learn More. The Journal of clinical psychiatry Ostacher, M. J. 2024; 85 (1)

  View details for DOI 10.4088/JCP.23com15279

  View details for PubMedID 38353646

• Problematic alcohol use and its impact on liver disease quality of life in a multicenter study of patients with cirrhosis. Hepatology communications Luk, J. W., Satre, D. D., Cheung, R., Wong, R. J., Monto, A., Chen, J. Y., Batki, S. L., Ostacher, M. J., Snyder, H. R., Shui, A. M., Liao, M., Haight, C. G., Khalili, M. 2024; 8 (2)

  Abstract

  Management of cirrhosis is challenging and has been complicated by the COVID-19 pandemic due to decreased access to care, increased psychological distress, and alcohol misuse. Recently, The National Institute on Alcohol Abuse and Alcoholism has broadened the definition of recovery from alcohol use disorder to include quality of life (QoL) as an indicator of recovery. This study examined the associations of alcohol-associated cirrhosis etiology and problematic drinking with liver disease QoL (LDQoL).Patients with cirrhosis (N=329) were recruited from 3 sites (63% from 2 Veterans Affairs Health Care Systems and 37% from 1 safety net hospital) serving populations that are economically or socially marginalized. Cirrhosis etiology was ascertained by chart review of medical records. Problematic drinking was defined by ≥8 on the Alcohol Use Disorders Identification Test. Multivariable general linear modeling adjusting for age, sex, race/ethnicity, site, pandemic-related stress, and history of anxiety/depressive disorder were conducted. Sensitivity analyses further adjusted for indicators of liver disease severity.Participants were on average 64.6 years old, 17% female, 58% non-White, 44% with alcohol-associated cirrhosis, and 17% with problematic drinking. Problematic drinking was significantly associated with worse LDQoL scores in the overall scale and in the memory/concentration and health distress subscales. These associations remained significant after adjusting for indicators of liver disease severity, including Model for End-Stage Liver Disease-Sodium score and decompensated cirrhosis status.Among patients with cirrhosis, problematic drinking was associated with worse LDQoL, especially in the domains of memory/concentration and health distress. Assessment and awareness of cognitive deficits and negative emotionality within the context of cirrhosis and problematic drinking may help clinicians provide better integrated care for this population.

  View details for DOI 10.1097/HC9.0000000000000379

  View details for PubMedID 38315141

• Alcohol Use Patterns During and After the COVID-19 Pandemic Among Veterans in the United States. The American journal of medicine Wong, R. J., Yang, Z., Ostacher, M., Zhang, W., Satre, D., Monto, A., Khalili, M., Singal, A. K., Cheung, R. 2023

  Abstract

  BACKGROUND: Veterans may be especially susceptible to increased alcohol consumption following the COVID-19 pandemic. We aim to evaluate trends in alcohol use among U.S. Veterans before, during, and following the onset of the COVID-19 pandemic.METHODS: All U.S. Veterans utilizing Veterans Affairs healthcare facilities in the U.S. from March 1, 2018 to February 28, 2023 with ≥1 AUDIT-C score were categorized into 1) No alcohol use (AUDIT-C = 0), 2) Low-risk alcohol use (AUDIT-C 1-2 for women, 1-3 for men), and 3) High-risk alcohol use (AUDIT-C ≥ 3 for women, ≥ 4 for men). Trends in the proportion of Veterans reporting high-risk alcohol use, stratified by sex, age, race/ethnicity, and urbanicity were evaluated.RESULTS: Among a cohort of 2.15 to 2.60 million Veterans, 15.5% reported high-risk alcohol use during March 2018-February 2019, which declined to 14.6% during the first year of the pandemic, increased to 15.2% in the second year, and then decreased to 14.9% from March 2022-February 2023. Among non-Hispanic whites, African Americans, Asians, and Hispanics, the proportion of women reporting high-risk alcohol use surpassed that of men during the onset of the pandemic and beyond. The greatest proportion of high-risk alcohol use was observed among young Veterans aged 18-39 years (17-27%), which was consistent across all race/ethnic groups.CONCLUSIONS: High-risk alcohol use among U.S. Veterans has increased since the COVID-19 pandemic onset, and in the third year following pandemic onset, 15% of Veterans overall and over 20% of young Veterans aged 18-39 years reported high -risk alcohol use.

  View details for DOI 10.1016/j.amjmed.2023.11.013

  View details for PubMedID 38052382

• Mixed states and suicidality in bipolar disorder: Does mixity really matter? Macellaro, M., Cafaro, R., Suppes, T., Ostacher, M. J., Dell'Osso, B., Lyu, J., Frye, M. A., Kupka, R. W., McElroy, S. L., Nolen, W. A., Keck, P. E., Post, R. M., Grunze, H. WILEY. 2023: 116-117

  View details for Web of Science ID 001036881100169

• An open label study of the safety and efficacy of psilocybin in veterans with severe treatment-resistant depression Ellis, S., Suppes, T., Fischer, E., Feng, W., Eisen, K., Lean, M., Conlan, B., Lyu, J., Ostacher, M., Aaronson, S. WILEY. 2023: 90

  View details for Web of Science ID 001036881100095

• HIGH ENGAGEMENT AND SATISFACTION WITH TELEHEALTH SERVICES AMONG UNDERSERVED CIRRHOSIS PATIENTS ACROSS THREE HEALTHCARE SYSTEMS DURING THE COVID-19 PANDEMIC Wong, R. J., Satre, D. D., Shumway, M., Monto, A., Cheung, R., Chen, J. Y., Batki, S. L., Ostacher, M. J., Snyder, H., Parekh, P., Hua, W., Widiarto, B. D., Oh, S., Liao, M., Khalili, M. WILEY. 2022: S1072-S1073

  View details for Web of Science ID 000870796603229

• 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

• A pilot trial of quetiapine, lithium, or placebo added to divalproex sodium for hypomanic or manic episodes in ambulatory adults with bipolar I disorder. International journal of bipolar disorders Cosgrove, V. E., Allende, S., Gwizdowski, I., Grace Fischer, E., Ostacher, M., Suppes, T. 2022; 10 (1): 7

  Abstract

  BACKGROUND: Many patients with bipolar I disorder do not respond to monotherapy treatment with mood-stabilizing medications, and combination regimens are commonly used in both inpatient and outpatient settings for the acute and maintenance treatment of bipolar disorder. We studied whether combination therapy is more effective than monotherapy for the acute treatment of subjects with bipolar I disorder currently experiencing manic symptoms. The primary hypothesis was that combination treatments would be associated with greater reductions in symptoms of mania and hypomania than monotherapy alone. The secondary hypothesis was that combination therapies would be associated with lower depression levels than monotherapy alone. Last, a post-hoc exploratory aim was used to examine whether the effect of side effect severity on risk-of-dropout would be greater in combination therapies than in monotherapy alone.RESULTS: In this 12-week, double-blind, placebo-controlled ambulatory pilot trial, participants (n=75) with bipolar I disorder were randomly assigned to: (1) monotherapy divalproex plus placebo (DVP+PBO), (2) combination therapy of divalproex plus blinded lithium (DVP+Li) or (3) divalproex plus blinded quetiapine (DVP+QTP). Combination therapies (vs. monotherapy) were not associated with improved symptoms of mania, hypomania or depression. The effect of side effect severity on study retention did not differ between combination therapies and monotherapy. However, the risk-of-dropout was significantly greater in the DVP+Li arm versus the DVP+PBO arm.CONCLUSIONS: No longitudinal differences in mania, hypomania or depression were found between combination therapies and monotherapy. The effect of side effect severity on study retention did not differ between groups. Due to the small sample size and differential rates of attrition between treatment arms, results of this pilot trial must be interpreted with caution. Trial registration ClinicalTrials.gov identifier: NCT00183443.

  View details for DOI 10.1186/s40345-022-00252-w

  View details for PubMedID 35235061

• 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

• Treating substance use disorders in patients with bipolar disorder Ostacher, M. WILEY. 2021: 32

  View details for Web of Science ID 000663051300071

• Moderators of the association between depressive, manic, and mixed mood symptoms and suicidal ideation and behavior: An analysis of the National Network of Depression Centers Mood Outcomes Program. Journal of affective disorders Fiedorowicz, J. G., Persons, J. E., Assari, S., Ostacher, M. J., Goes, F. S., Nurnberger, J. I., Coryell, W. H. 2020

  Abstract

  BACKGROUND: It has not been established that suicide risk with mixed symptoms is any greater than the depressive component or if there is synergy between depressive and manic symptoms in conveying suicide risk.METHODS: The National Network of Depression Centers Mood Outcomes Program collected data from measurement-based care for 17,179 visits from 6,105 unique individuals with clinically diagnosed mood disorders (998 bipolar disorder, 5,117 major depression). The Patient Health Questionaire-8 (PHQ-8) captured depressive symptoms and the Altman Self-Rating Mania scale (ASRM) measured hypomanic/manic symptoms. Generalized linear mixed models assessed associations between depressive symptoms, manic symptoms, and their interaction (to test for synergistic effects of mixed symptoms) on the primary outcome of suicidal ideation or behavior (secondarily suicidal behavior only) from the Columbia-Suicide Severity Rating Scale (C-SSRS). Moderation was assessed.RESULTS: PHQ-8 scores were strongly associated with suicide-related outcomes across diagnoses. ASRM scores showed no association with suicidal ideation/behavior in bipolar disorder and an inverse association in major depression. There was no evidence of synergy between depressive and manic symptoms. There was no moderation by sex, race, or mood disorder polarity. Those over 55 years of age showed a protective effect of manic symptoms, which was lost when depressive symptoms were also present (mixed symptoms).DISCUSSION: Mixed depressive and manic symptoms convey no excess risk of suicidal ideation or behavior beyond the risk conveyed by the depressive symptoms alone. Depressive symptoms are strongly linked to suicidal ideation and suicidal behavior and represent an important and potentially modifiable risk factor for suicide.

  View details for DOI 10.1016/j.jad.2020.11.101

  View details for PubMedID 33234283

• Changed Primary Outcome Between Trial Registration and Publication. JAMA internal medicine Kleinman, R. A., Ostacher, M. J. 2020

  View details for DOI 10.1001/jamainternmed.2020.2183

  View details for PubMedID 32677662

• 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

• Clinical factors related to suicide risk in individuals who experience mixed states Persons, J., Fiedorowicz, J., Ostacher, M., Coryell, W. WILEY. 2020: 89–90

  View details for Web of Science ID 000540293800196

• 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

• Clinical Significance and Outcomes in Trial of Nabiximols for Treatment of Cannabis Dependence. JAMA internal medicine Kleinman, R. A., Ostacher, M. J. 2020; 180 (1): 163

  View details for DOI 10.1001/jamainternmed.2019.5667

  View details for PubMedID 31904785

• Preliminary findings on topiramate for addressing health behaviors in comorbid bipolar disorder and alcohol use disorder. Psychiatry research Gold, A. K., Sylvia, L. G., Nierenberg, A. A., Ostacher, M. J. 2020; 289: 113037

  View details for DOI 10.1016/j.psychres.2020.113037

  View details for PubMedID 32447093

• A Novel Study Design to Systematically Explore the Impact of Trial Methodology on Psychopharmacological Treatment Outcome in Patients with Depression PHARMACOPSYCHIATRY Severus, E., Sauer, C., Bauer, M., Ostacher, M., Anghelescu, I. 2019; 52 (4): 170–74

  View details for DOI 10.1055/a-0643-4796

  View details for Web of Science ID 000478833700002

• Depressive symptoms carry an increased risk for suicidal ideation and behavior in bipolar disorder without any additional contribution of mixed symptoms JOURNAL OF AFFECTIVE DISORDERS Fiedorowicz, J. G., Persons, J. E., Assari, S., Ostacher, M. J., Zandi, P., Wang, P. W., Thase, M. E., Frye, M. A., Coryell, W., Natl Network Depression Ctr 2019; 246: 775–82

  View details for DOI 10.1016/j.jad.2018.12.057

  View details for Web of Science ID 000457276200093

• Prazosin and Alcohol Use Disorder. The American journal of psychiatry Kleinman, R. A., Ostacher, M. J. 2019; 176 (2): 165

  View details for PubMedID 30704280

• Prazosin and Alcohol Use Disorder AMERICAN JOURNAL OF PSYCHIATRY Kleinman, R., Ostacher, M. J. 2019; 176 (2): 165

  View details for DOI 10.1176/appi.ajp.2018.18101143

  View details for Web of Science ID 000462846000013

• 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

• Psychiatric and Medical Comorbidities With Bipolar II Disorder BIPOLAR II DISORDER: RECOGNITION, UNDERSTANDING, AND TREATMENT Rosenblat, J. D., Ostacher, M. J., McIntyre, R. S., Swartz, H. A., Suppes, T. 2019: 71–98

  View details for Web of Science ID 000549764100005

• Depressive symptoms carry an increased risk for suicidal ideation and behavior in bipolar disorder without any additional contribution of mixed symptoms. Journal of affective disorders Fiedorowicz, J. G., Persons, J. E., Assari, S., Ostacher, M. J., Zandi, P., Wang, P. W., Thase, M. E., Frye, M. A., Coryell, W., of the National Network of Depression Centers Bipolar Disorders Interest Group 2018; 246: 775–82

  Abstract

  OBJECTIVES: To determine whether the risk of suicidal ideation or behavior during mixed states exceeds that attributable to the depressive components of these states alone in bipolar disorder.METHODS: We utilized real-world, longitudinal clinical data collected on 290 patients with bipolar disorders (bipolar I, bipolar II, and bipolar not otherwise specified (NOS)) from the National Network of Depression Centers (NNDC) Clinical Care Registry (CCR) seen for 891 visits over a mean of 27.5 weeks. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9), manic symptoms with the Altman Self-Rating Mania (ASRM), and suicidal ideation and behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), obtained as part of the routine, measurement-based care provided across the NNDC. The relations between depressive symptoms, manic symptoms, and the interaction thereof (mixed symptoms) on coinciding suicidal ideation and behavior were modeled in generalized linear mixed models.RESULTS: Depressive symptoms, as measured by the PHQ-9, were strongly associated with suicidal ideation and behavior (p < 0.0001), while there was no significant association with manic symptoms as measured by the ASRM or the interaction between depressive and manic symptoms. Similar results were observed when the outcome was restricted to suicidal behavior and when mood was modeled categorically. There was evidence of a gender by ASRM interaction (p = 0.011) and risk of suicidal ideation or behavior was significant for women, but not men with manic symptoms.LIMITATIONS: Diagnoses were based on clinician assessment and not structured interview. Mood assessments were self-reported rather than clinician-administered. Suicidal ideation was more frequently observed than suicidal behavior (23/272 visits where outcome positive).CONCLUSIONS: Depression represents the primary mood state accounting for suicide risk in bipolar disorder. Co-occurring symptoms of mania (mixed symptoms) do not appear to convey an elevated risk for suicidal ideation or behavior beyond that explained by the depressive symptoms alone.

  View details for PubMedID 30623823

• Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis. PLoS medicine De Crescenzo, F., Ciabattini, M., D'Alo, G. L., De Giorgi, R., Del Giovane, C., Cassar, C., Janiri, L., Clark, N., Ostacher, M. J., Cipriani, A. 2018; 15 (12): e1002715

  Abstract

  BACKGROUND: Clinical guidelines recommend psychosocial interventions for cocaine and/or amphetamine addiction as first-line treatment, but it is still unclear which intervention, if any, should be offered first. We aimed to estimate the comparative effectiveness of all available psychosocial interventions (alone or in combination) for the short- and long-term treatment of people with cocaine and/or amphetamine addiction.METHODS AND FINDINGS: We searched published and unpublished randomised controlled trials (RCTs) comparing any structured psychosocial intervention against an active control or treatment as usual (TAU) for the treatment of cocaine and/or amphetamine addiction in adults. Primary outcome measures were efficacy (proportion of patients in abstinence, assessed by urinalysis) and acceptability (proportion of patients who dropped out due to any cause) at the end of treatment, but we also measured the acute (12 weeks) and long-term (longest duration of study follow-up) effects of the interventions and the longest duration of abstinence. Odds ratios (ORs) and standardised mean differences were estimated using pairwise and network meta-analysis with random effects. The risk of bias of the included studies was assessed with the Cochrane tool, and the strength of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We followed the PRISMA for Network Meta-Analyses (PRISMA-NMA) guidelines, and the protocol was registered in PROSPERO (CRD 42017042900). We included 50 RCTs evaluating 12 psychosocial interventions or TAU in 6,942 participants. The strength of evidence ranged from high to very low. Compared to TAU, contingency management (CM) plus community reinforcement approach was the only intervention that increased the number of abstinent patients at the end of treatment (OR 2.84, 95% CI 1.24-6.51, P = 0.013), and also at 12 weeks (OR 7.60, 95% CI 2.03-28.37, P = 0.002) and at longest follow-up (OR 3.08, 95% CI 1.33-7.17, P = 0.008). At the end of treatment, CM plus community reinforcement approach had the highest number of statistically significant results in head-to-head comparisons, being more efficacious than cognitive behavioural therapy (CBT) (OR 2.44, 95% CI 1.02-5.88, P = 0.045), non-contingent rewards (OR 3.31, 95% CI 1.32-8.28, P = 0.010), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13-14.69, P = 0.031). CM plus community reinforcement approach was also associated with fewer dropouts than TAU, both at 12 weeks and the end of treatment (OR 3.92, P < 0.001, and 3.63, P < 0.001, respectively). At the longest follow-up, community reinforcement approach was more effective than non-contingent rewards, supportive-expressive psychodynamic therapy, TAU, and 12-step programme (OR ranging between 2.71, P = 0.026, and 4.58, P = 0.001), but the combination of community reinforcement approach with CM was superior also to CBT alone, CM alone, CM plus CBT, and 12-step programme plus non-contingent rewards (ORs between 2.50, P = 0.039, and 5.22, P < 0.001). The main limitations of our study were the quality of included studies and the lack of blinding, which may have increased the risk of performance bias. However, our analyses were based on objective outcomes, which are less likely to be biased.CONCLUSIONS: To our knowledge, this network meta-analysis is the most comprehensive synthesis of data for psychosocial interventions in individuals with cocaine and/or amphetamine addiction. Our findings provide the best evidence base currently available to guide decision-making about psychosocial interventions for individuals with cocaine and/or amphetamine addiction and should inform patients, clinicians, and policy-makers.

  View details for PubMedID 30586362

• 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

• Lurasidone compared to other atypical antipsychotic monotherapies for bipolar depression: A systematic review and network meta-analysis WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY Ostacher, M., Ng-Mak, D., Patel, P., Ntais, D., Schlueter, M., Loebel, A. 2018; 19 (8): 586–601

  Abstract

  To assess the efficacy and tolerability of lurasidone versus other atypical antipsychotic monotherapy agents in patients with bipolar depression, using a Bayesian network meta-analysis.Fourteen randomised clinical trials (6221 patients) of lurasidone, quetiapine (extended release and immediate release), aripiprazole, olanzapine, and ziprasidone for bipolar depression were included. Efficacy assessments included change in the Montgomery-Åsberg Depression Rating Scale (MADRS), rates of response (≥50% improvement in MADRS) and remission (MADRS ≤12 at study endpoint), and change in the Clinical Global Impressions-Bipolar Disorder-Severity (CGI-BP-S) scale. Tolerability outcomes included weight, somnolence, extrapyramidal symptoms (EPS), and all-cause discontinuation. Changes from baseline or odds ratios (OR) with 95% credible intervals (CrI) were evaluated.Improvement in the MADRS associated with lurasidone treatment was significantly greater than placebo (-4.70, 95%CrI: -7.20, -2.21), aripiprazole (-3.62, 95%CrI: -7.04, -0.20), and ziprasidone (-3.38, 95%CrI: -6.68, -0.11), but not olanzapine (-0.15, 95%CrI: -3.12, 2.74) or quetiapine (0.10, 95%CrI: -2.68, 2.84). Results for improvement in the CGI-BP-S, and for response and remission were similar. Lurasidone was associated with less weight gain than olanzapine (-2.54 kg, 95%CrI: -3.42, -1.67) and quetiapine (-0.83kg, 95%CrI: -1.59, -0.08); and with lower rates of somnolence than quetiapine (OR: 0.33, 95%CrI: 0.11, 0.82) and ziprasidone (OR: 0.34, 95%CrI: 0.09, 0.93). No significant differences among atypical antipsychotic agents were observed in rates of discontinuation or in rates of EPS.In this network meta-analysis, lurasidone was found to be more efficacious than aripiprazole and ziprasidone, and was associated with less weight gain than quetiapine and olanzapine and less somnolence than quetiapine and ziprasidone.

  View details for PubMedID 28264635

• 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

• Bipolar II should only exist if we can actually study treatments of it. Otherwise, what purpose does it serve? BIPOLAR DISORDERS Ostacher, M. J. 2018; 20 (4): 395–96

  View details for PubMedID 29446216

• Depression With Mixed Features in Major Depressive Disorder: A New Diagnosis or There All Along? The Journal of clinical psychiatry Ostacher, M. J., Suppes, T. 2018

  View details for PubMedID 29419949

• Depression With Mixed Features in Major Depressive Disorder: A New Diagnosis or There All Along? JOURNAL OF CLINICAL PSYCHIATRY Ostacher, M. J., Suppes, T. 2018; 79 (2): 94–95

  View details for DOI 10.4088/JCP.17ac11974

  View details for Web of Science ID 000436392200039

• Guidelines for the recognition and management of mixed depression CNS SPECTRUMS Stahl, S. M., Morrissette, D. A., Faedda, G., Fava, M., Goldberg, J. F., Keck, P. E., Lee, Y., Malhi, G., Marangoni, C., McElroy, S. L., Ostacher, M., Rosenblat, J. D., Sole, E., Suppes, T., Takeshima, M., Thase, M. E., Vieta, E., Young, A., Zimmerman, M., McIntyre, R. S. 2017; 22 (2): 203-219

  Abstract

  A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

  View details for DOI 10.1017/S1092852917000165

  View details for Web of Science ID 000400910800015

  View details for PubMedID 28421980

• 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

• Mixed features in major depressive disorder: diagnoses and treatments CNS SPECTRUMS Suppes, T., Ostacher, M. 2017; 22 (2): 155-160

  Abstract

  For the first time in 20 years, the American Psychiatric Association (APA) updated the psychiatric diagnostic system for mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Perhaps one of the most notable changes in the DSM-5 was the recognition of the possibility of mixed symptoms in major depression and related disorders (MDD). While MDD and bipolar and related disorders are now represented by 2 distinct chapters, the addition of a mixed features specifier to MDD represents a structural bridge between bipolar and major depression disorders, and formally recognizes the possibility of a mix of hypomania and depressive symptoms in someone who has never experienced discrete episodes of hypomania or mania. This article reviews historical perspectives on "mixed states" and the recent literature, which proposes a range of approaches to understanding "mixity." We discuss which symptoms were considered for inclusion in the mixed features specifier and which symptoms were excluded. The assumption that mixed symptoms in MDD necessarily predict a future bipolar course in patients with MDD is reviewed. Treatment for patients in a MDD episode with mixed features is critically considered, as are suggestions for future study. Finally, the premise that mood disorders are necessarily a spectrum or a gradient of severity progressing in a linear manner is argued.

  View details for DOI 10.1017/S1092852917000256

  View details for Web of Science ID 000400910800009

  View details for PubMedID 28462772

• Increased Suicidal Ideation in Patients with Co-Occurring Bipolar Disorder and Post-Traumatic Stress Disorder. Archives of suicide research Carter, J. M., Arentsen, T. J., Cordova, M. J., Ruzek, J., Reiser, R., Suppes, T., Ostacher, M. J. 2016: 1-12

  Abstract

  Suicide risk increases for those with Bipolar Disorder or PTSD, however little research has focused on risk for co-occurring Bipolar Disorder and PTSD. The aim of this article was to evaluate increased suicide risk in co-occurring disorders, and differences in suicide risk for patients with Bipolar I versus Bipolar II. This study evaluated suicide risk in patients with co-occurring PTSD and Bipolar Disorder (n = 3,158), using the MADRS and Suicide Questionnaire. Those with history of PTSD had significantly higher suicidal ideation than those without (U = 1063375.00, p < .0001). Those with Bipolar I had higher risk than those with Bipolar II. Patients with Bipolar I and PTSD were at higher risk for suicidal ideation, implying the importance of diagnosis and risk assessment.

  View details for PubMedID 27310106

• 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

• Stratifying Risk for Renal Insufficiency Among Lithium-Treated Patients: An Electronic Health Record Study NEUROPSYCHOPHARMACOLOGY Castro, V. M., Roberson, A. M., McCoy, T. H., Wiste, A., Cagan, A., Smoller, J. W., Rosenbaum, J. F., Ostacher, M., Perlis, R. H. 2016; 41 (4): 1138-1143

  Abstract

  Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (p<0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithium-treated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk.

  View details for DOI 10.1038/npp.2015.254

  View details for Web of Science ID 000369786900021

  View details for PubMedID 26294109

  View details for PubMedCentralID PMC4748438

• Antidepressants in Type II Versus Type I Bipolar Depression A Randomized Discontinuation Trial JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Voehringer, P. A., Ostacher, M. J., El-Mallakh, R. S., Holtzman, N. S., Thommi, S. B., Whitham, E. A., Sullivan, M. C., Baldassano, C. F., Goodwin, F. K., Baldessarini, R. J., Ghaemi, S. N. 2015; 35 (5): 605-608

  Abstract

  We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I).Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings.In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission.The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes.

  View details for DOI 10.1097/JCP.0000000000000384

  View details for PubMedID 26267418

• Antidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial JOURNAL OF AFFECTIVE DISORDERS El-Mallakh, R. S., Voehringer, P. A., Ostacher, M. M., Baldassano, C. F., Holtzman, N. S., Whitham, E. A., Thommi, S. B., Goodwin, F. K., Ghaemi, S. 2015; 184: 318-321

  Abstract

  The use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic.As part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a priori secondary outcome, rapid cycling as a predictor of response in 68 patients randomized to continue vs. discontinue antidepressant treatment, after initial response for an acute major depressive episode. Outcomes assessed were percent time well and total number of episodes. All patients received standard mood stabilizers.In those continued on antidepressants (AD), rapid cycling (RC) subjects experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44) more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean difference in depressive episodes per year RC vs. NRC was 0.85 ± 0.37 (SE), df = 28, p = 0.03). In the AD continuation group, RC patients also had 28.8% less time in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p = 0.004). No such differences between RC and NRC subjects were seen in the AD discontinuation group (Table 1). Analyses within the rapid-cycling subgroup alone were consistent with the above comparisons between RC and NRC subjects, stratified by maintenance antidepressant treatment, though limited by sample size.In an a priori analysis, despite preselection for good antidepressant response and concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling was associated with worsened maintenance outcomes, especially for depressive morbidity, vs. antidepressant discontinuation.

  View details for DOI 10.1016/j.jad.2015.04.054

  View details for Web of Science ID 000358554600046

  View details for PubMedID 26142612

  View details for PubMedCentralID PMC4519402

• 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

• Monotherapy Antidepressant Treatment is Not Associated With Mania in Bipolar I Disorder. American journal of psychiatry Ostacher, M. J., Perlis, R. H., GeddeS, J. 2015; 172 (6): 586-?

  View details for DOI 10.1176/appi.ajp.2015.14111443

  View details for PubMedID 26029807

• Patterns of response to aripiprazole, lithium, haloperidol, and placebo across factor scores of mania. International journal of bipolar disorders Ostacher, M. J., Suppes, T., Swann, A. C., Eudicone, J. M., Landsberg, W., Baker, R. A., Carlson, B. X. 2015; 3: 11-?

  Abstract

  A previous factor analysis of Young Mania Rating Scale and Montgomery-Åsberg Depression Rating Scale items identified composite factors of depression, mania, sleep disturbance, judgment/impulsivity, and irritability/hostility as major components of psychiatric symptoms in acute mania or mixed episodes in a series of trials of antipsychotics. However, it is unknown whether these factors predict treatment outcome.Data from six double-blind, randomized, controlled clinical trials with aripiprazole in acute manic or mixed episodes in adults with bipolar I disorder were pooled for this analysis and the previously identified factors were examined for their value in predicting treatment outcome. Treatment efficacy was assessed for aripiprazole (n = 1,001), haloperidol (n = 324), lithium (n = 155), and placebo (n = 694) at baseline, days 4, 7, and 10, and then weekly to study end. Mean change in factor scores from baseline to week 3 was assessed by receiver operating characteristics curves for percentage factor change at day 4 and week 1.Subjects receiving aripiprazole, haloperidol, and lithium significantly improved mania factor scores versus placebo. Factors most predictive of endpoint efficacy for aripiprazole were judgment/impulsivity at day 4 and mania at week 1. Optimal factor score improvement for outcome prediction was approximately 40% to 50%. Early efficacy predicted treatment outcome across all factors; however, response at week 1 was a better predictor than response at day 4.This analysis confirms clinical benefits in early treatment/assessment for subjects with bipolar mania and suggests that certain symptom factors in mixed or manic episodes may be most predictive of treatment response.

  View details for DOI 10.1186/s40345-015-0026-0

  View details for PubMedID 25945321

• 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

• The Impact of Antipsychotic Medications on Sleep-dependent Consolidation of Motor Procedural Memory in Subjects with Bipolar I Disorder Ostacher, M., Stickgold, R., Iosifescu, D., Feldman, A., Grimm, D., Suppes, T., Manoach, D. NATURE PUBLISHING GROUP. 2014: S494–S495

  View details for Web of Science ID 000345905002035

• 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

• Controversies in the psychopharmacology of bipolar disorder. journal of clinical psychiatry Post, R. M., Ostacher, M. J., Singh, V. 2014; 75 (11)

  Abstract

  Few studies have examined the decision-making process for selecting a mood stabilizer or antipsychotic for patients with bipolar disorder. Despite a lack of evidence regarding their efficacy, conventional unimodal antidepressants continue to be used in bipolar treatment regimens. This article examines pharmacologic principles that can facilitate the evidence-based use of mood stabilizers and antipsychotics in patients with bipolar disorder. Choosing therapies for the maintenance of bipolar disorder, clinical decision making upon observation of a partial response, the use of combination therapies, and benefit/harm considerations when choosing a treatment for bipolar depression will be reviewed.

  View details for DOI 10.4088/JCP.13095tx2cj

  View details for PubMedID 25470106

• When Positive Isn't Positive: The Hopes and Disappointments of Clinical Trials JOURNAL OF CLINICAL PSYCHIATRY Ostacher, M. J. 2014; 75 (10): E1186-E1187

  View details for DOI 10.4088/JCP.14com09427

  View details for Web of Science ID 000345557300010

  View details for PubMedID 25373128

• 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

• 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

• 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

• What can ICD-11 be that DSM-5 cannot? Australian and New Zealand journal of psychiatry Ostacher, M. J. 2014; 48 (3): 283-284

  View details for DOI 10.1177/0004867414521507

  View details for PubMedID 24566299

• 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

• Alcohol and the law. Handbook of clinical neurology Karasov, A. O., Ostacher, M. J. 2014; 125: 649-657

  Abstract

  Society has had an interest in controlling the production, distribution, and use of alcohol for millennia. The use of alcohol has always had consequences, be they positive or negative, and the role of government in the regulation of alcohol is now universal. This is accomplished at several levels, first through controls on production, importation, distribution, and use of alcoholic beverages, and second, through criminal laws, the aim of which is to address the behavior of users themselves. A number of interventions and policies reduce alcohol-related consequences to society by regulating alcohol pricing, targeting alcohol-impaired driving, and limiting alcohol availability. The legal system defines criminal responsibility in the context of alcohol use, as an enormous percentage of violent crime and motor death is associated with alcohol intoxication. In recent years, recovery-oriented policies have aimed to expand social supports for recovery and to improve access to treatment for substance use disorders within the criminal justice system. The Affordable Care Act, also know as "ObamaCare," made substantial changes to access to substance abuse treatment by mandating that health insurance include services for substance use disorders comparable to coverage for medical and surgical treatments. Rather than a simplified "war on drugs" approach, there appears to be an increasing emphasis on evidence-based policy development that approaches alcohol use disorders with hope for treatment and prevention. This chapter focuses on alcohol and the law in the United States.

  View details for DOI 10.1016/B978-0-444-62619-6.00038-0

  View details for PubMedID 25307602

• 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

• 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

• Presentation and prevalence of PTSD in a bipolar disorder population: A STEP-BD examination JOURNAL OF AFFECTIVE DISORDERS Hernandez, J. M., Cordova, M. J., Ruzek, J., Reiser, R., Gwizdowski, I. S., Suppes, T., Ostacher, M. J. 2013; 150 (2): 450-455

  Abstract

  BACKGROUND: Co-occurring psychiatric diagnoses have a negative impact on quality of life and change the presentation and prognosis of bipolar disorder (BD). To date, comorbidity research on patients with BD has primarily focused on co-occurring anxiety disorders and trauma history; only recently has there been a specific focus on co-occurring PTSD and BD. Although rates of trauma and PTSD are higher in those with bipolar disorder than in the general population, little is known about differences across bipolar subtypes. METHODS: Using the NIMH STEP-BD dataset (N=3158), this study evaluated whether there were baseline differences in the prevalence of PTSD between participants with bipolar disorder I (BDI) and bipolar disorder II (BDII), using the MINI and the Davidson Trauma Scale. Differences in PTSD symptom clusters between patients with BDI and BDII were also evaluated. RESULTS: A significantly greater proportion of participants with BDI had co-occurring PTSD at time of study entry (Χ(2)(1)=12.6; p<.001). BDI and BDII subgroups did not significantly differ in re-experiencing, avoidance, or arousal symptoms. LIMITATIONS: The analysis may suggest a correlational relationship between PTSD and BD, not a causal one. Further, it is possible this population seeks treatment more often than individuals with PTSD alone. Finally, due to the episodic nature of BD and symptom overlap between the two disorders, misdiagnosis is possible. CONCLUSIONS: PTSD may be more prevalent in patients with BDI. However, the symptom presentation of PTSD appears similar across BD subtypes. Individuals should be thoroughly assessed for co-occurring diagnoses in an effort to provide appropriate treatment.

  View details for DOI 10.1016/j.jad.2013.04.038

  View details for Web of Science ID 000323563300039

  View details for PubMedID 23706842

• Association Between Therapeutic Alliance, Care Satisfaction, and Pharmacological Adherence in Bipolar Disorder JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Sylvia, L. G., Hay, A., Ostacher, M. J., Miklowitz, D. J., Nierenberg, A. A., Thase, M. E., Sachs, G. S., Deckersbach, T., Perlis, R. H. 2013; 33 (3): 343-350

  Abstract

  OBJECTIVES: We sought to understand the association of specific aspects of care satisfaction, such as patients' perceived relationship with their psychiatrist and access to their psychiatrist and staff, and therapeutic alliance with participants' likelihood to adhere to their medication regimens among patients with bipolar disorder. METHODS: We examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder, an effectiveness study investigating the course and treatment of bipolar disorder. We expected that participants (n = 3037) with positive perceptions of their relationship with their psychiatrist and quality of psychopharmacologic care, as assessed by the Helping Alliance Questionnaire and Care Satisfaction Questionnaire, would be associated with better medication adherence. We utilized logistic regression models controlling for already established factors associated with poor adherence. RESULTS: Patients' perceptions of collaboration, empathy, and accessibility were significantly associated with adherence to treatment in individuals with bipolar disorder completing at least 1 assessment. Patients' perceptions of their psychiatrists' experience, as well as of their degree of discussing medication risks and benefits, were not associated with medication adherence. CONCLUSIONS: Patients' perceived therapeutic alliance and treatment environment impact their adherence to pharmacotherapy recommendations. This study may enable psychopharmacologists' practices to be structured to maximize features associated with greater medication adherence.

  View details for DOI 10.1097/JCP.0b013e3182900c6f

  View details for Web of Science ID 000318871400009

  View details for PubMedID 23609394

• Raising the bar for the evidence in evidence-based guidelines BIPOLAR DISORDERS Ostacher, M. J. 2013; 15 (1): 50-53

  View details for DOI 10.1111/bdi.12032

  View details for Web of Science ID 000313892900003

  View details for PubMedID 23339674

• Multivariate analysis of bipolar mania: Retrospectively assessed structure of bipolar I manic and mixed episodes in randomized clinical trial participants JOURNAL OF AFFECTIVE DISORDERS Swann, A. C., Suppes, T., Ostacher, M. J., Eudicone, J. M., McQuade, R., Forbes, A., Carlson, B. X. 2013; 144 (1-2): 59-64

  Abstract

  Manic episodes are heterogeneous. Mixed states may differ in important clinical characteristics from other manic episodes. However, it has not been established whether mixed states are a distinct type of episodes, or a common basic structure exists across manic episodes.Using 2179 well-characterized subjects in the pretreatment phase of six randomized, clinical trials, we conducted rotated factor analysis followed by cluster analysis, using all items from the Young Mania Rating Scale and the Montgomery-Åsberg Depression Scale. Analyses were conducted for all subjects (n=2179) and for those in Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) mixed (n=644) and non-mixed (n=1535) episodes separately.There were five factors characterized (in order of variance accounted for) as depression, mania, sleep disturbance, judgment/impulsivity and irritability/hostility. Cluster analysis identified five clusters. Three were predominately manic, with depression scores below average for the overall group. Two had high average depression scores; these clusters differed in irritability/hostility. Judgment/impulsivity scores were similar across factors. Essentially identical factors and clusters existed whether analyses were done in all subjects or only in subjects classified by DSM-IV as mixed or non-mixed.Exclusion criteria of studies may limit generalizability of findings.All manic episodes, whether mixed or non-mixed, shared a similar structure according to factor/cluster analysis. Patients with high depression factor scores were heterogeneous with respect to irritability. These data suggest that depressive symptoms should be considered a dimensional property across manic episodes, rather than as defining a specific type of episode.

  View details for DOI 10.1016/j.jad.2012.05.061

  View details for Web of Science ID 000311640300008

  View details for PubMedID 22858209

• 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

• Sleep disturbance in euthymic bipolar patients JOURNAL OF PSYCHOPHARMACOLOGY Sylvia, L. G., Dupuy, J. M., Ostacher, M. J., Cowperthwait, C. M., Hay, A. C., Sachs, G. S., Nierenberg, A. A., Perlis, R. H. 2012; 26 (8): 1108-1112

  Abstract

  Sleep disturbance is a common feature during mood episodes in bipolar disorder. The aim of this study was to investigate the prevalence of such symptoms among euthymic bipolar patients, and their association with risk for mood episode recurrence. A cohort of bipolar I and II subjects participating in the Systematic Treatment Enhancement Program for Bipolar Disorder who were euthymic for at least 8 weeks were included in this analysis. Survival analysis was used to examine the association between sleep disturbance on the Montgomery-Asberg Depression Rating Scale (MADRS) and recurrence risk. A total of 73/483 bipolar I and II subjects reported at least mild sleep disturbance (MADRS sleep item ≥2) for the week prior to study entry. The presence of sleep problems was associated with a history of psychosis, number of previous suicide attempts, and anticonvulsant use. Sleep disturbance at study entry was significantly associated with risk for mood episode recurrence. Sleep disturbance is not uncommon between episodes for individuals with bipolar disorder and may be associated with a more severe course of illness. This suggests that sleep disturbance is an important prodromal symptom of bipolar disorder and should be considered a target for pharmacologic or psychosocial maintenance treatment.

  View details for DOI 10.1177/0269881111421973

  View details for Web of Science ID 000306508700007

  View details for PubMedID 21965189

• The Impact of Caffeine, Nicotine, and Alcohol on Outcome in Bipolar Disorder: A STEP-BD Examination Ostacher, M. J., Hoblyn, J., Perlis, R. ELSEVIER SCIENCE INC. 2012: 61S

  View details for Web of Science ID 000302466000194

• 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

• Evidence-based pharmacotherapy of major depressive disorder ESSENTIAL EVIDENCE-BASED PSYCHOPHARMACOLOGY, 2ND EDITION Dupuy, J. M., Ostacher, M. J., Huffman, J., Perlis, R. H., Nierenberg, A. A., Stein, D. J., Lerer, B., Stahl, S. M. 2012: 53-72

  View details for Web of Science ID 000329193200005

• A critical review of pharmacotherapy for major depressive disorder INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Dupuy, J. M., Ostacher, M. J., Huffman, J., Perlis, R. H., Nierenberg, A. A. 2011; 14 (10): 1417-1431

  Abstract

  Newer generation antidepressant drugs, with improvements in safety and tolerability, have replaced tricyclic antidepressants as first-line treatment of depressive illness. However, no single antidepressant drug from any class has distinguished itself as the obvious first-line treatment of major depression. The choice of therapy is driven primarily by patient choice, with informed consent for the risks of adverse effects. Cost has become an additional factor in this decision as several of the newer antidepressant drugs are now available in generic form. Several augmentation and drug-switching strategies have demonstrated benefit in refractory illness. While no single strategy distinguished itself as superior to the others, some have been more rigorously tested. Ongoing efforts at improving effectiveness, time to response, and tolerability have led to novel drug therapies. Efforts at characterizing predictors of treatment outcomes now include pharmacogenetic studies.

  View details for DOI 10.1017/S1461145711000083

  View details for Web of Science ID 000297106000012

  View details for PubMedID 21349226

• Sleep disturbance in euthymic bipolar patients: a STEP-BD study 9th International Conference on Bipolar Disorder (ICBD) Sylvia, L. G., Dupuy, J., Ostacher, M., Cowperthwait, C., Hay, A., Sachs, G., Nierenberg, A. A., Perlis, R. WILEY-BLACKWELL. 2011: 97–97

  View details for Web of Science ID 000300102400242

• Association Between Bipolar Spectrum Features and Treatment Outcomes in Outpatients With Major Depressive Disorder ARCHIVES OF GENERAL PSYCHIATRY Perlis, R. H., Uher, R., Ostacher, M., Goldberg, J. F., Trivedi, M. H., Rush, A. J., Fava, M. 2011; 68 (4): 351-360

  Abstract

  It has been suggested that patients with major depressive disorder (MDD) who display pretreatment features suggestive of bipolar disorder or bipolar spectrum features might have poorer treatment outcomes.To assess the association between bipolar spectrum features and antidepressant treatment outcome in MDD.Open treatment followed by sequential randomized controlled trials.Primary and specialty psychiatric outpatient centers in the United States.Male and female outpatients aged 18 to 75 years with a DSM-IV diagnosis of nonpsychotic MDD who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.Open treatment with citalopram followed by up to 3 sequential next-step treatments.Number of treatment levels required to reach protocol-defined remission, as well as failure to return for the postbaseline visit, loss to follow-up, and psychiatric adverse events. For this secondary analysis, putative bipolar spectrum features, including items on the mania and psychosis subscales of the Psychiatric Diagnosis Screening Questionnaire, were examined for association with treatment outcomes.Of the 4041 subjects who entered the study, 1198 (30.0%) endorsed at least 1 item on the psychosis scale and 1524 (38.1%) described at least 1 recent maniclike/hypomaniclike symptom. Irritability and psychoticlike symptoms at entry were significantly associated with poorer outcomes across up to 4 treatment levels, as were shorter episodes and some neurovegetative symptoms of depression. However, other indicators of bipolar diathesis including recent maniclike symptoms and family history of bipolar disorder as well as summary measures of bipolar spectrum features were not associated with treatment resistance.Self-reported psychoticlike symptoms were common in a community sample of outpatients with MDD and strongly associated with poorer outcomes. Overall, the data do not support the hypothesis that unrecognized bipolar spectrum illness contributes substantially to antidepressant treatment resistance.

  View details for DOI 10.1001/archgenpsychiatry.2010.179

  View details for Web of Science ID 000289165900004

  View details for PubMedID 21135313

• Advances in bipolar disorder: selected sessions from the 2011 International Conference on Bipolar Disorder 9th International Conference on Bipolar Disorder (ICBD) Kupfer, D. J., Angst, J., Berk, M., Dickerson, F., Frangou, S., Frank, E., Goldstein, B. I., Harvey, A., Laghrissi-Thode, F., Leboyer, M., Ostacher, M. J., Sibille, E., Strakowski, S. M., Suppes, T., Tohen, M., Yolken, R. H., Young, L. T., Zarate, C. A. BLACKWELL SCIENCE PUBL. 2011: 1–25

  Abstract

  Recently, the 9(th) International Conference on Bipolar Disorder (ICBD) took place in Pittsburgh, PA, June 9-11, 2011. The conference focused on a number of important issues concerning the diagnosis of bipolar disorders across the life span, advances in neuroscience, treatment strategies for bipolar disorders, early intervention, and medical comorbidity. Several of these topics were discussed in four plenary sessions. This meeting report describes the major points of each of these sessions and included (1) strategies for moving biology forward; (2) bipolar disorder and the forthcoming new DSM-5 nomenclature; (3) management of bipolar disorders-both theory and intervention, with an emphasis on the medical comorbidities; and, (4) a review of several key task force reports commissioned by the International Society for Bipolar Disorder (ISBD).

  View details for DOI 10.1111/j.1749-6632.2011.06336.x

  View details for Web of Science ID 000301290100001

  View details for PubMedID 22191553

• Transition to Mania During Treatment of Bipolar Depression NEUROPSYCHOPHARMACOLOGY Perlis, R. H., Ostacher, M. J., Goldberg, J. F., Miklowitz, D. J., Friedman, E., Calabrese, J., Thase, M. E., Sachs, G. S. 2010; 35 (13): 2545-2552

  Abstract

  Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients.

  View details for DOI 10.1038/npp.2010.122

  View details for Web of Science ID 000284104400007

  View details for PubMedID 20827274

  View details for PubMedCentralID PMC3055576

• Antidepressant Discontinuation in Bipolar Depression: A Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Randomized Clinical Trial of Long-Term Effectiveness and Safety JOURNAL OF CLINICAL PSYCHIATRY Ghaemi, S. N., Ostacher, M. M., El-Mallakh, R. S., Borrelli, D., Baldassano, C. F., Kelley, M. E., Filkowski, M. M., Hennen, J., Sachs, G. S., Goodwin, F. K., Baldessarini, R. J. 2010; 71 (4): 372-380

  Abstract

  To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression.In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, conducted between 2000 and 2007, 70 patients with DSM-IV-diagnosed bipolar disorder (72.5% non-rapid cycling, 70% type I) with acute major depression, initially responding to treatment with antidepressants plus mood stabilizers, and euthymic for 2 months, were openly randomly assigned to antidepressant continuation versus discontinuation for 1-3 years. Mood stabilizers were continued in both groups.The primary outcome was mean change on the depressive subscale of the STEP-BD Clinical Monitoring Form. Antidepressant continuation trended toward less severe depressive symptoms (mean difference in DSM-IV depression criteria = -1.84 [95% CI, -0.08 to 3.77]) and mildly delayed depressive episode relapse (HR = 2.13 [1.00-4.56]), without increased manic symptoms (mean difference in DSM-IV mania criteria = +0.23 [-0.73 to 1.20]). No benefits in prevalence or severity of new depressive or manic episodes, or overall time in remission, occurred. Type II bipolar disorder did not predict enhanced antidepressant response, but rapid-cycling course predicted 3 times more depressive episodes with antidepressant continuation (rapid cycling = 1.29 vs non-rapid cycling = 0.42 episodes/year, P = .04).This first randomized discontinuation study with modern antidepressants showed no statistically significant symptomatic benefit with those agents in the long-term treatment of bipolar disorder, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with modern antidepressant continuation.clinicaltrials.gov Identifier: NCT00012558.

  View details for DOI 10.4088/JCP.08m04909gre

  View details for Web of Science ID 000277059300001

  View details for PubMedID 20409444

• Impact of Substance Use Disorders on Recovery From Episodes of Depression in Bipolar Disorder Patients: Prospective Data From the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) AMERICAN JOURNAL OF PSYCHIATRY Ostacher, M. J., Perlis, R. H., Nierenberg, A. A., Calabrese, J., Stange, J. P., Salloum, I., Weiss, R. D., Sachs, G. S. 2010; 167 (3): 289-297

  Abstract

  Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder.Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode.During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state.Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.

  View details for DOI 10.1176/appi.ajp.2009.09020299

  View details for Web of Science ID 000275056300010

  View details for PubMedID 20008948

  View details for PubMedCentralID PMC2918249

• Clinical Features Associated With Poor Pharmacologic Adherence in Bipolar Disorder: Results From the STEP-BD Study JOURNAL OF CLINICAL PSYCHIATRY Perlis, R. H., Ostacher, M. J., Miklowitz, D. J., Hay, A., Nierenberg, A. A., Thase, M. E., Sachs, G. S. 2010; 71 (3): 296-303

  Abstract

  Poor medication adherence is common among bipolar patients.We examined prospective data from 2 cohorts of individuals from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1999-2005) with bipolar disorder. Clinical and sociodemographic features associated with missing at least 25% of doses of at least 1 medication were assessed using logistic regression, and a risk stratification model was developed and validated.Of 3,640 subjects with 48,287 follow-up visits, 871 (24%) reported nonadherence on 20% or more study visits. Clinical features significantly associated (P < .05) with poor adherence included rapid cycling, suicide attempts, earlier onset of illness, and current anxiety or alcohol use disorder. Nonadherence during the first 3 months of follow-up was associated with less improvement in functioning at 12-month follow-up (P < .03). A risk stratification model using clinical predictors accurately classified 80.6% of visits in an independent validation cohort.Risk for poor medication adherence can be estimated and may be useful in targeting interventions.

  View details for DOI 10.4088/JCP.09m05514yel

  View details for Web of Science ID 000276273500011

  View details for PubMedID 20331931

• Assuring That Double-Blind Is Blind AMERICAN JOURNAL OF PSYCHIATRY Perlis, R. H., Ostacher, M., Fava, M., Nierenberg, A. A., Sachs, G. S., Rosenbaum, J. F. 2010; 167 (3): 250-252

  View details for DOI 10.1176/appi.ajp.2009.09060820

  View details for Web of Science ID 000275056300005

  View details for PubMedID 20194487

• Benzodiazepine Use and Risk of Recurrence in Bipolar Disorder: A STEP-BD Report JOURNAL OF CLINICAL PSYCHIATRY Perlis, R. H., Ostacher, M. J., Miklowitz, D. J., Smoller, J. W., Dennehy, E. B., Cowperthwait, C., Nierenberg, A. A., Thase, M. E., Sachs, G. S. 2010; 71 (2): 194-200

  Abstract

  Benzodiazepines are widely prescribed to patients with bipolar disorder, but their impact on relapse and recurrence has not been examined.We examined prospective data from a cohort of DSM-IV bipolar I and II patients who achieved remission during evidence-guided naturalistic treatment in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (conducted in the United States between 1999 and 2005). Risk for recurrence among individuals who did or did not receive benzodiazepine treatment was examined using survival analysis. Cox regression was used to adjust for clinical and sociodemographic covariates. Propensity score analysis was used in a confirmatory analysis to address the possible impact of confounding variables.Of 1,365 subjects, 349 (25.6%) were prescribed a benzodiazepine at time of remission from a mood episode. After adjusting for potential confounding variables, the hazard ratio for mood episode recurrence among benzodiazepine-treated patients was 1.21 (95% CI, 1.01-1.45). The effects of benzodiazepine treatment on relapse remained significant after excluding relapses occurring within 90 days of recovery, or stratifying the sample by propensity score, a summary measure of likelihood of receiving benzodiazepine treatment. In an independent cohort of 721 subjects already in remission at study entry, effects of similar magnitude were observed.Benzodiazepine use may be associated with greater risk for recurrence of a mood episode among patients with bipolar I and II disorder. The prescribing of benzodiazepines, at a minimum, appears to be a marker for a more severe course of illness.

  View details for DOI 10.4088/JCP.09m05019yel

  View details for Web of Science ID 000274762100010

  View details for PubMedID 20193647

• Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial LANCET Geddes, J. R., Goodwin, G. M., Rendell, J., Azorin, J., Cipriani, A., Ostacher, M. J., Morriss, R., Alder, N., Juszczak, E., Lewis, S., Attenburrow, M., Carter, B., Hainsworth, J., Healey, C., Stevens, W., Van der Cucht, E., Young, H., Davies, C., Peto, R., Barnes, T. R., Curtis, V., Johnson, T., de Silva, A., Marven, M., Berry, D., Arif, M., Bruce, J., Drybala, G., Hayden, E., Jhingan, H. P., Marudkar, M., Hillier, R., Barrett, S., Lidder, J. S., McCartney, M., Middleton, H., Ononve, F., Solanki, R. D., Agell, I., Anjum, R., Hunt, N., Jones, P., Ramana, R., Chase, J., Ayuba, L., Macmillan, I., Michael, A., Frangou, S., Gijsman, H., Parker, E., Phillips, M., Behr, G., Tyrer, P., Conway, A., Ferrier, N., Oakley, T., Tower, N., Young, A., Chitty, R., Littlejohns, C., Suri, A., Iqbal, M., Zikis, P., Anderson, I., O'Driscoll, D., Robbins, N., Ash, G., Chaudhry, I., Duddu, V., Reed, P., Van Wyk, S., Vohra, A., Zingela, Z., Mahmood, T., Diedricks, H., Faizal, M. A., McCarthy, J., Morriss, R., Briess, D., Ceccherini-Nelli, A., Clifford, E., Croos, R., Davis, J. D., De Silva, L., Eranti, S., Mahmoud, R., Maurya, A., Partovi-Tabar, P., Rahim, Y., Tuson, J., Greening, J., Campbell, C., Grewal, J. S., Kumar, A., Schultewolter, D., Baldwin, D., Best, N., Herod, N., Polson, R., Shawcross, C., Khan, U., Almoshmosh, N., El-Adl, M., Rao, C., Timmins, B., Attenburrow, M., Bale, R., Bansal, S., Bhagwagar, Z., Carre, A., Cartright, J., Chalmers, J., Chisuse, A., Davison, P., Elwell, D., Fazel, S., Geaney, D., Hampson, S., Harrison, P., Henderson, E., Johnson, S., Massey, C., Ogilvie, A., O'Leary, D., Oppenheimer, C., Orr, M., Quested, D., Sargent, P., Wilkinson, P., Hussain, T., Franklin, S., King, J., White, J., Anagnosti, O., Bruce-Jones, B., Evans, J., Woodin, G., Kirov, G., Laugharne, R., Blewett, A. E., Gupta, S., Saluja, B., Kelly, C., Leeman, T., Macauley, M., Shields, D., Anderson, J., McRae, A., Taylor, M., Carrick, L., Hare, E., Morrison, D., Azorin, J., Maurel, M., Derouet, J., le Garzic, N., Millet, B., Droulout, T., Henry, C., Leboyer, M., Meary, A., Barbui, C., Cipriani, A., Imperadore, G., Tansella, M., Ostacher, M., Sachs, G. 2010; 375 (9712): 385-395

  Abstract

  Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder.330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332.59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy.Stanley Medical Research Institute; Sanofi-Aventis.

  View details for DOI 10.1016/S0140-6736(09)61828-6

  View details for Web of Science ID 000274305500026

  View details for PubMedID 20092882

• Suicidal ideation and depressive symptoms among bipolar patients as predictors of the health and well-being of caregivers BIPOLAR DISORDERS Chessick, C. A., Perlick, D. A., Miklowitz, D. J., Dickinson, L. M., Allen, M. H., Morris, C. D., Gonzalez, J. M., Marangell, L. B., Cosgrove, V., Ostacher, M. 2009; 11 (8): 876-884

  Abstract

  Few studies have addressed the physical and mental health effects of caring for a family member with bipolar disorder. This study examined whether caregivers' health is associated with changes in suicidal ideation and depressive symptoms among bipolar patients observed over one year.Patients (N = 500) participating in the Systematic Treatment Enhancement Program for Bipolar Disorder and their primary caregivers (N = 500, including 188 parental and 182 spousal caregivers) were evaluated for up to one year as part of a naturalistic observational study. Caregivers' perceptions of their own physical health were evaluated using the general health scale from the Medical Outcomes Study 36-item Short-Form Health Survey. Caregivers' depression was evaluated using the Center for Epidemiological Studies of Depression Scale.Caregivers of patients who had increasing suicidal ideation over time reported worsening health over time compared to caregivers of patients whose suicidal ideation decreased or stayed the same. Caregivers of patients who had more suicidal ideation and depressive symptoms reported more depressed mood over a one-year reporting period than caregivers of patients with less suicidal ideation or depression. The pattern of findings was consistent across parent caregivers and spousal caregivers.Caregivers, rightly concerned about patients becoming suicidal or depressed, may try to care for the patient at the expense of their own health and well-being. Treatments that focus on the health of caregivers must be developed and tested.

  View details for Web of Science ID 000271899700008

  View details for PubMedID 19922556

  View details for PubMedCentralID PMC2796426

• 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

• Stability of symptoms across major depressive episodes in bipolar disorder BIPOLAR DISORDERS Perlis, R. H., Ostacher, M. J., Uher, R., Nierenberg, A. A., Casamassima, F., Kansky, C., Calabrese, J. R., Thase, M., Sachs, G. S. 2009; 11 (8): 867-875

  Abstract

  Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated.We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression.A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes.While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.

  View details for Web of Science ID 000271899700007

  View details for PubMedID 19922555

  View details for PubMedCentralID PMC3566555

• Cigarette smoking is associated with suicidality in bipolar disorder BIPOLAR DISORDERS Ostacher, M. J., LeBeau, R. T., Perlis, R. H., Nierenberg, A. A., Lund, H. G., Moshier, S. J., Sachs, G. S., Simon, N. M. 2009; 11 (7): 766-771

  Abstract

  Cigarette smoking in individuals with bipolar disorder has been associated with suicidal behavior, although the precise relationship between the two remains unclear.In this prospective observational study of 116 individuals with bipolar disorder, we examined the association between smoking and suicidality as measured by Linehan's Suicide Behaviors Questionnaire (SBQ) and prospective suicide attempts over a nine-month period. Impulsivity was measured by the Barratt Impulsiveness Scale.Smoking was associated with higher baseline SBQ scores in univariate and adjusted analyses, but was not significant after statistical adjustment for impulsivity in a regression model. A higher proportion of smokers at baseline made a suicide attempt during the follow-up period (5/31, 16.1%) compared to nonsmokers (3/85, 3.5%); p = 0.031, odds ratio = 5.25 (95% confidence interval: 1.2-23.5). Smoking at baseline also significantly predicted higher SBQ score at nine months.In this study, current cigarette smoking was a predictor of current and nine-month suicidal ideation and behavior in bipolar disorder, and it is likely that impulsivity accounts for some of this relationship.

  View details for Web of Science ID 000270826100010

  View details for PubMedID 19840000

  View details for PubMedCentralID PMC2918237

• Retrospective age at onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study BIPOLAR DISORDERS Perlis, R. H., Dennehy, E. B., Miklowitz, D. J., DelBello, M. P., Ostacher, M., Calabrese, J. R., Ametrano, R. M., Wisniewski, S. R., Bowden, C. L., Thase, M. E., Nierenberg, A. A., Sachs, G. 2009; 11 (4): 391-400

  Abstract

  Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms.We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Age at illness onset was identified retrospectively by clinician assessment at study entry.Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two-year follow-up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups.Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation.

  View details for DOI 10.1111/j.1399-5618.2009.00686.x

  View details for Web of Science ID 000265934000006

  View details for PubMedID 19500092

• Brain GABA levels in patients with bipolar disorder PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Kaufman, R. E., Ostacher, M. J., Marks, E. H., Simon, N. M., Sachs, G. S., Jensen, J. E., Renshaw, P. F., Pollack, M. H. 2009; 33 (3): 427-434

  Abstract

  A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients. GENERAL METHODS: We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls.There were no significant differences in GABA, glutamate or glutamine between patients and controls.Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder.

  View details for DOI 10.1016/j.pnpbp.2008.12.025

  View details for Web of Science ID 000265470500007

  View details for PubMedID 19171176

• Galantamine-ER For Cognitive Dysfunction In Bipolar Disorder and Correlation with Hippocampal Neuronal Viability: A Proof-of-Concept Study CNS NEUROSCIENCE & THERAPEUTICS Iosifescu, D. V., Moore, C. M., Deckersbach, T., Tilley, C. A., Ostacher, M. J., Sachs, G. S., Nierenberg, A. A. 2009; 15 (4): 309-319

  Abstract

  Many subjects with bipolar disorder experience significant cognitive dysfunction, even when euthymic, but few studies assess biological correlates of or treatment strategies for cognitive dysfunction.Nineteen subjects with bipolar disorder in remission, who reported subjective cognitive deficits, were treated with open-label galantamine-ER 8-24 mg/day for 4 months. Ten healthy volunteers matched for age and gender were also assessed. Mood and subjective cognitive questionnaires were administered monthly. At the beginning and the end of the trial all subjects were administered neuropsychological tests, including tests of attention (Conners CPT) and episodic memory (CVLT). Bipolar subjects underwent proton magnetic resonance spectroscopy (1H-MRS) measurements before and after treatment, healthy volunteers completed baseline 1H-MRS. We acquired 1H-MRS data at 4.0 T from voxels centered on the left and right hippocampus to measure hippocampal N-acetyl aspartate (NAA, a measure of neuronal viability) and choline containing compounds (Cho, a marker of lipid metabolism and membrane turn-over).Compared to healthy volunteers, bipolar subjects had higher baseline subjective cognitive deficits and lower scores on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). After treatment, bipolar subjects experienced significant improvement of subjective cognitive scores and on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). In the left hippocampus NAA increased and choline (Cho) decreased in bipolar subjects during treatment.Bipolar subjects had cognitive dysfunction; treatment with Galantamine-ER was associated with improved cognition and with increases in neuronal viability and normalization of lipid membrane metabolism in the left hippocampus. This study was registered on ClinicalTrials.gov (NCT00181636).

  View details for DOI 10.1111/j.1755-5949.2009.00090.x

  View details for Web of Science ID 000271517300003

  View details for PubMedID 19889129

• An fMRI investigation of working memory and sadness in females with bipolar disorder: a brief report BIPOLAR DISORDERS Deckersbach, T., Rauch, S. L., Buhlmann, U., Ostacher, M. J., Beucke, J., Nierenberg, A. A., Sachs, G., Dougherty, D. D. 2008; 10 (8): 928-942

  Abstract

  Functional magnetic resonance imaging (fMRI) studies have documented abnormalities in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex in bipolar disorder in the context of working memory tasks. It is increasingly recognized that DLPFC regions play a role in mood regulation and the integration of emotion and cognition. The purpose of the present study was to investigate with fMRI the interaction between acute sadness and working memory functioning in individuals with bipolar disorder.Nine depressed individuals with DSM-IV bipolar I disorder (BP-I) and 17 healthy control participants matched for age, gender, education, and IQ completed a 2-back working memory paradigm under no mood induction, neutral state, or acute sadness conditions while undergoing fMRI scanning. Functional MRI data were analyzed with SPM2 using a random-effects model.Behaviorally, BP-I subjects performed equally well as control participants on the 2-back working memory paradigm. Compared to control participants, individuals with BP-I were characterized by more sadness-specific activation increases in the left DLPFC (BA 9/46) and left dorsal anterior cingulate (dACC).Our study documents sadness-specific abnormalities in the left DLPFC and dACC in bipolar disorder that suggest difficulties in the integration of emotion (sadness) and cognition. These preliminary findings require further corroboration with larger sample sizes of medication-free subjects.

  View details for DOI 10.1111/j.1399-5618.2008.00633.x

  View details for Web of Science ID 000261054400009

  View details for PubMedID 19594508

• Euthymic patients with bipolar disorder show decreased reward learning in a probabilistic reward task BIOLOGICAL PSYCHIATRY Pizzagalli, D. A., Goetz, E., Ostacher, M., Iosifescu, D. V., Perlis, R. H. 2008; 64 (2): 162-168

  Abstract

  Bipolar disorder (BPD) features cycling mood states ranging from depression to mania with intermittent phases of euthymia. Bipolar disorder subjects often show excessive goal-directed and pleasure-seeking behavior during manic episodes and reduced hedonic capacity during depressive episodes, indicating that BPD might involve altered reward processing. Our goal was to test the hypothesis that BPD is characterized by impairments in adjusting behavior as a function of prior reinforcement history, particularly in the presence of residual anhedonic symptoms.Eighteen medicated BPD subjects and 25 demographically matched comparison subjects performed a probabilistic reward task. To identify putative dysfunctions in reward processing irrespective of mood state, primary analyses focused on euthymic BPD subjects (n = 13). With signal-detection methodologies, response bias toward a more frequently rewarded stimulus was used to objectively assess the participants' propensity to modulate behavior as a function of reinforcement history.Relative to comparison subjects, euthymic BPD subjects showed a reduced and delayed acquisition of response bias toward the more frequently rewarded stimulus, which was partially due to increased sensitivity to single rewards of the disadvantageous stimulus. Analyses considering the entire BPD sample revealed that reduced reward learning correlated with self-reported anhedonic symptoms, even after adjusting for residual manic and anxious symptoms and general distress.The present study provides preliminary evidence indicating that BPD, even during euthymic states, is characterized by dysfunctional reward learning in situations requiring integration of reinforcement information over time and thus offers initial insights about the potential source of dysfunctional reward processing in this disorder.

  View details for DOI 10.1016/j.biopsych.2007.12.001

  View details for Web of Science ID 000257187700011

  View details for PubMedID 18242583

  View details for PubMedCentralID PMC2464620

• Correlates of subjective and objective burden among caregivers of patients with bipolar disorder ACTA PSYCHIATRICA SCANDINAVICA Ostacher, M. J., Nierenberg, A. A., Iosifescu, D. V., Eidelman, P., Lund, H. G., Ametrano, R. M., Kaczynski, R., Calabrese, J., Miklowitz, D. J., Sachs, G. S., Perlick, D. A., Gro, S. F. 2008; 118 (1): 49-56

  Abstract

  We examined the relationship between mood symptoms and episodes in patients with bipolar disorder and burden reported by their primary caregivers.Data on subjective and objective burden reported by 500 primary caregivers for 500 patients with bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were collected using semistructured interviews. Patient data were collected prospectively over 1 year. The relationship between patient course and subsequent caregiver burden was examined.Episodes of patient depression, but not mood elevation, were associated with greater objective and subjective caregiver burden. Burden was associated with fewer patient days well over the previous year. Patient depression was associated with caregiver burden even after controlling for days well.Patient depression, after accounting for chronicity of symptoms, independently predicts caregiver burden. This study underscores the important impact of bipolar depression on those most closely involved with those whom it affects.

  View details for DOI 10.1111/j.1600-0447.2008.01201.x

  View details for Web of Science ID 000256684000007

  View details for PubMedID 18582347

• Anxiety is associated with impulsivity in bipolar disorder JOURNAL OF ANXIETY DISORDERS Taylor, C. T., Hirshfeld-Becker, D. R., Ostacher, M. J., Chow, C. W., LeBeau, R. T., Pollack, M. H., Nierenberg, A. A., Simon, N. M. 2008; 22 (5): 868-876

  Abstract

  Impulsivity and anxiety, common features of bipolar disorder (BD), are each associated with a number of negative outcomes in BD. The relationship between anxiety and impulsivity, however, has not been a focus of study in BD. In this paper, we present data regarding the association between anxiety and impulsivity as measured by the Barratt impulsiveness scale (BIS-11) in 114 outpatients with BD. Results revealed that patients with a comorbid anxiety disorder displayed significantly higher levels of impulsivity relative to patients without an anxiety disorder. Moreover, a broad range of anxiety-related symptom domains was associated with greater impulsivity. Exploratory analyses also revealed that baseline anxiety symptoms were associated with elevated impulsivity at 9-month follow-up, although these relationships were less robust after covariate adjustment. These data demonstrate that anxiety is positively associated with impulsivity in patients with BD. Further studies are needed to elucidate the implications of and reasons for this association.

  View details for DOI 10.1016/j.janxdis.2007.09.001

  View details for Web of Science ID 000256189100011

  View details for PubMedID 17936573

• A brief review of antidepressant efficacy, effectiveness, indications, and usage for major depressive disorder JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE Nierenberg, A. A., Ostacher, M. J., Huffman, J. C., Ametrano, R. M., Fava, M., Perlis, R. H. 2008; 50 (4): 428-436

  Abstract

  Antidepressants treat major depressive disorder (MDD) with the burden of associated side effects and difficulties with compliance. The purpose of this article is to review the efficacy and effectiveness of antidepressants for MDD.The authors conducted a focused review of selected key issues and references relevant to the clinically relevant pharmacologic treatment of MDD. Principles of treatment are reviewed. Antidepressants reviewed include SSRIs, mixed norepinephrine or serotonin uptake inhibitors, dopamine or norepinephrine uptake inhibitors, norepinephrine uptake inhibitors, antidepressants with mixed properties, and monoamine oxidase inhibitors. Augmentation and psychotherapy strategies are reviewed.Antidepressant efficacy has been established in randomized clinical trials and effectiveness studies for acute and long-term treatment, but many patients do not achieve remission. Augmentation strategies and focused psychotherapy can be helpful.Antidepressants help most patients with MDD but some are resistant to treatment and have a difficult long-term course.

  View details for DOI 10.1097/JOM.0b013e31816b5034

  View details for Web of Science ID 000255108100007

  View details for PubMedID 18404015

• Complicated grief and impaired sleep in patients with bipolar disorder BIPOLAR DISORDERS Maytal, G., Zalta, A. K., Thompson, E., Chow, C. W., Perlman, C., Ostacher, M. J., Pollack, M. H., Shear, K., Simon, N. M. 2007; 9 (8): 913-917

  Abstract

  To examine the relationship of sleep disturbance with complicated grief (CG) in patients with bipolar disorder (BD).Adults with DSM-IV BD were asked if they ever experienced significant loss and, if so, completed the Inventory of Complicated Grief. Subjective sleep disturbance was assessed with the Pittsburgh Sleep Quality Index (PSQI). The association of CG with sleep disturbance was assessed in univariate t-tests, and in multivariate analyses controlling for the presence of anxiety disorder comorbidity and current bipolar recovery status.Individuals with CG had significantly higher mean PSQI scores (10.9 versus 7.9, p = 0.003) than those without CG. Further, within the group of BD participants who had experienced a significant loss, those with CG had significantly poorer sleep (p = 0.01). CG remained significantly associated with greater sleep impairment after adjustment for comorbid anxiety disorder and bipolar mood state. This additive impairment in sleep with CG comorbidity was evident for four of the PSQI component scales: sleep quality, sleep duration, sleep efficiency and sleep disturbance.Our data indicate a significant association of CG with poor sleep in individuals with BD. Disturbed sleep may be a mechanism by which CG increases the burden of illness in BD.

  View details for Web of Science ID 000251414300016

  View details for PubMedID 18076543

• Intensive psychosocial intervention enhances functioning in patients with bipolar depression: Results from a 9-month Randomized controlled trial AMERICAN JOURNAL OF PSYCHIATRY Miklowitz, D. J., Otto, M. W., Frank, E., Reilly-Harrington, N. A., Kogan, J. N., Sachs, G. S., Thase, M. E., Calabrese, J. R., Marangell, L. B., Ostacher, M. J., Patel, J., Thomas, M. R., Araga, M., Gonzalez, J. M., Wisniewski, S. R. 2007; 164 (9): 1340-1347

  Abstract

  Psychosocial interventions are effective adjuncts to pharmacotherapy in delaying recurrences of bipolar disorder; however, to date their effects on life functioning have been given little attention. In a randomized trial, the authors examined the impact of intensive psychosocial treatment plus pharmacotherapy on the functional outcomes of patients with bipolar disorder over the 9 months following a depressive episode.Participants were 152 depressed outpatients with bipolar I or bipolar II disorder in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. All patients received pharmacotherapy. Eighty-four patients were randomly assigned to intensive psychosocial intervention (30 sessions over 9 months of interpersonal and social rhythm therapy, cognitive behavior therapy [CBT], or family-focused therapy), and 68 patients were randomly assigned to collaborative care (a 3-session psychoeducational treatment). Independent evaluators rated the four subscales of the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) (relationships, satisfaction with activities, work/role functioning, and recreational activities) through structured interviews given at baseline and every 3 months over a 9-month period.Patients in intensive psychotherapy had better total functioning, relationship functioning, and life satisfaction scores over 9 months than patients in collaborative care, even after pretreatment functioning and concurrent depression scores were covaried. No effects of psychosocial intervention were observed on work/role functioning or recreation scores during this 9-month period.Intensive psychosocial treatment enhances relationship functioning and life satisfaction among patients with bipolar disorder. Alternate interventions focused on the specific cognitive deficits of individuals with bipolar disorder may be necessary to enhance vocational functioning after a depressive episode.

  View details for DOI 10.1176/appi.apj.2007.07020311

  View details for Web of Science ID 000249266600012

  View details for PubMedID 17728418

  View details for PubMedCentralID PMC3579578

• Current suicide ideation and prior suicide attempts of bipolar patients as influences on caregiver burden SUICIDE AND LIFE-THREATENING BEHAVIOR Chessick, C. A., Perlick, D. A., Miklowitz, D. J., Kaczynski, R., Allen, M. H., Morris, C. D., Marangell, L. B., STED-BD Family Experience Collabor 2007; 37 (4): 482-491

  Abstract

  We examined whether caregivers of bipolar patients reporting current suicidal ideation and/or a history of a suicide attempt reported higher levels of burden and/or poorer health compared to caregivers of patients without these suicidality indices. In a cross-sectional design, caregivers (N = 480) associated with (a) patients with current suicidal ideation or (b) patients with a positive lifetime history of at least one suicide attempt, reported lower general health scores than caregivers associated with patients with neither of these indices. Parents of patients with at least one lifetime attempt reported more burden secondary to role dysfunction than spouses. Levels of depression in caregivers varied with whether the caregiver was a spouse or a parent, and whether patients had a history of suicide attempts, current suicidal ideation, or both.

  View details for DOI 10.1521/suli.2007.37.4.482

  View details for Web of Science ID 000249184400011

  View details for PubMedID 17896888

• Prevalence and correlates of burden among caregivers of patients with bipolar disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder BIPOLAR DISORDERS Perlick, D. A., Rosenheck, R. A., Miklowitz, D. J., Chessick, C., Wolff, N., Kaczynski, R., Ostacher, M., Patel, J., Desai, R. 2007; 9 (3): 262-273

  Abstract

  Caring for a relative with schizophrenia or dementia is associated with reports of high caregiver burden, symptoms of depression, poor physical health, negligence of the caregiver's own health needs, elevated health service use, low use of social supports, and financial strain. This study presents the design and preliminary data on the costs and consequences of caring for a relative or friend with bipolar disorder from the Family Experience Study, a longitudinal study of the primary caregivers to 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder.Subjects were primary caregivers of 500 patients with bipolar disorder diagnosed by the Mini International Neuropsychiatric Interview and the Affective Disorder Evaluation. Caregivers were evaluated within 1 month after patients entered Systematic Treatment Enhancement Program using measures of burden, coping, health/mental health, and use of resources and costs.Eighty-nine percent, 52%, and 61% of caregivers, respectively, experienced moderate or higher burden in relation to patient problem behaviors, role dysfunction, or disruption of household routine. High burden caregivers reported more physical health problems, depressive symptoms, health risk behavior and health service use, and less social support than less burden caregivers. They also provided more financial support to their bipolar relative.Burdens experienced by family caregivers of people with bipolar disorder are associated with problems in health, mental health, and cost. Psychosocial interventions targeting the strains of caregiving for a patient with bipolar disorder are needed.

  View details for Web of Science ID 000245392900009

  View details for PubMedID 17430301

• 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

• The association of comorbid anxiety disorders with suicide attempts and suicidal ideation in outpatients with bipolar disorder 39th Annual Meeting of the Association-for-Behavioral-and-Cognitive-Therapies Simon, N. M., Zalta, A. K., Otto, M. W., Ostacher, M. J., Fischmann, D., Chow, C. W., Thompson, E. H., Stevens, J. C., Demopulos, C. M., Nierenberg, A. A., Pollack, M. H. PERGAMON-ELSEVIER SCIENCE LTD. 2007: 255–64

  Abstract

  Individuals with bipolar disorder are at increased risk for suicide attempts and completion. Although anxiety may be a modifiable suicide risk factor among bipolar patients, anxiety disorder comorbidity has not been highlighted as critical in identification of high-risk individuals nor has its treatment been integrated into suicide prevention strategies. In this study, ancillary to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 120 outpatients with bipolar disorder completed detailed assessment of suicidal ideation and behaviors. We examined the association of current and lifetime comorbid anxiety disorders with suicidal ideation and behaviors univariately and with adjustment for potential confounders in regression models. Lifetime anxiety disorders were associated with a more than doubling of the odds of a past suicide attempt, and current anxiety comorbidity was associated with a more than doubling of the odds of current suicidal ideation. Individuals with current anxiety disorders had more severe suicidal ideation, a greater belief suicide would provide relief, and a higher expectancy of future suicidal behaviors. However, some of these associations appeared to be better accounted for by measures of bipolar severity including an earlier age at bipolar onset and a lack of current bipolar recovery. Comorbid anxiety disorders may play a role in characteristics of bipolar disorder that then elevate risk for suicidal ideation and attempts. While further research is needed to establish the precise nature of these associations, our data support that the presence of comorbid anxiety disorders in individuals with bipolar disorder should trigger careful clinical assessment of suicide risk.

  View details for DOI 10.1016/j.jpsychires.2006.08.004

  View details for Web of Science ID 000243214000008

  View details for PubMedID 17052730

• Comorbid alcohol and substance abuse dependence in depression: Impact on the outcome of antidepressant treatment PSYCHIATRIC CLINICS OF NORTH AMERICA Ostacher, M. J. 2007; 30 (1): 69-?

  Abstract

  Major depressive disorder often co-occurs with substance use disorders, especially alcohol use disorders, and the course of each of these problems seems be complicated by the other. Diagnosing and treating these patients is challenging. A significant difficulty for clinicians is deciding whether to treat a mood episode in a patient who has current substance use or a substance use disorder, and what is the optimal treatment for that patient. This article discusses the prevalence of depressive and substance use disorder, the course of illness of comorbid depression and substance use disorders, and treatment response.

  View details for DOI 10.1016/j.psc.2006.12.009

  View details for Web of Science ID 000245636000007

  View details for PubMedID 17362804

• Understanding the link between anxiety symptoms and suicidal ideation and behaviors in outpatients with bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Simon, N. M., Pollack, M. H., Ostacher, M. J., Zalta, A. K., Chow, C. W., Fischmann, D., Demopulos, C. M., Nierenberg, A. A., Otto, M. W. 2007; 97 (1-3): 91-99

  Abstract

  Prior studies suggest an association between anxiety comorbidity and suicidal ideation and behaviors in bipolar disorder. However, the nature of this association remains unclear.We examined a range of anxiety symptoms, including panic, phobic avoidance, anxiety sensitivity, worry and fear of negative evaluation, in 98 patients with bipolar disorder. We predicted that each anxiety dimension would be linked to greater suicidal ideation and behavior as measured by Linehan's Suicide Behaviors Questionnaire (SBQ), greater depressive rumination, and poorer emotional processing and expression.Each anxiety dimension except fear of negative evaluation was associated with greater SBQ score, greater rumination, and lower levels of emotional processing in univariate analyses. Depressive rumination was a significant predictor of higher SBQ scores in a stepwise multivariate model controlling for age, gender, bipolar subtype, and bipolar recovery status; the association between the anxiety symptom dimensions and SBQ score was found to be redundant with depressive rumination. Emotional processing emerged as protective against suicidal ideation and behaviors in men only, while emotional expression was a significant predictor of lower SBQ scores for women and for the full sample; however, emotional expression was not significantly correlated with anxiety symptoms. Confirmatory analyses examining only those in recovery or recovered (n=68) indicated that the link between rumination and suicidality was not explained by depression.Interpretation is limited by the cross-sectional study design.These findings indicate that increased ruminations may mediate the association between anxiety and suicidal ideation/behavior. In men, lower emotional processing may also play a role in this relationship.

  View details for DOI 10.1016/j.jad.2006.05.027

  View details for Web of Science ID 000243734600011

  View details for PubMedID 16820212

• Factors associated with stigma among caregivers of patients with bipolar disorder in the STEP-BD study PSYCHIATRIC SERVICES Gonzalez, J. M., Perlick, D. K., Mildowitz, D. J., Kaczynski, R., Hernandez, M., Rosenheck, R. A., Culver, J. L., Ostacher, M. J., Bowden, C. L. 2007; 58 (1): 41-48

  Abstract

  Little is known about the factors contributing to mental illness stigma among caregivers of people with bipolar disorder.A total of 500 caregivers of patients participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study were interviewed in a cross-sectional design on measures of stigma, mood, burden, and coping. Relatives and friends with bipolar disorder were assessed on measures of diagnosis and clinical status, determined by a days-well measure derived from psychiatrist ratings of DSM-IV episode status. Because patients' clinical status varied widely, separate models were run for patients who were euthymic for at least three-fourths of the past year (well group) and for those who met criteria for an affective episode for at least one-fourth of the previous year (unwell group). Stepwise multiple regression was used to identify patient, illness, and caregiver characteristics associated with caregiver stigma.In the unwell group, greater mental illness stigma was associated with bipolar I (versus II) disorder, less social support for the caregiver, fewer caregiver social interactions, and being a caregiver of Hispanic descent. In the well group, greater stigma was associated with being a caregiver who is the adult child of a parent with bipolar disorder, who has a college education, who has fewer social interactions, and who cares for a female bipolar patient.Mental illness stigma was found to be prevalent among caregivers of persons with bipolar disorder who have active symptoms as well as for caregivers of those who have remitted symptoms. Stigma is typically associated with factors identifying patients as "different" during symptomatic periods. Research is needed to understand how the stigma experienced by caregivers during stable phases of illness differs from the stigma experienced during patients' illness states.

  View details for Web of Science ID 000243384200007

  View details for PubMedID 17215411

• The relationship between smoking and suicidal behavior, comorbidity, and course of illness in bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Ostacher, M. J., Nierenberg, A. A., Perlis, R. H., Eidelman, P., Borrelli, D. J., Tran, T. B., Ericson, G. M., Weiss, R. D., Sachs, G. S. 2006; 67 (12): 1907-1911

  Abstract

  The rate of smoking in people with bipolar disorder is much greater than in the general population, but the implications of smoking for the course of bipolar disorder have not been well studied. The purpose of this retrospective study was to examine the relationship between smoking, severity of bipolar disorder, suicidal behavior, and psychiatric and substance use disorder comorbidity.We evaluated 399 outpatients with bipolar disorder who were treated in a bipolar specialty clinic from December 1999 to October 2004. Diagnosis, mood state, course of illness, functioning, and psychiatric comorbidities were assessed using the Affective Disorders Evaluation and the Mini-International Neuropsychiatric Interview.Of the 399 patients evaluated, 155 (38.8%) had a history of daily smoking. Having ever smoked was associated with earlier age at onset of first depressive or manic episode, lower Global Assessment of Functioning scores, higher Clinical Global Impressions-Bipolar Disorder scale scores, lifetime history of a suicide attempt (47% for smokers vs. 25% for those who had never smoked), and lifetime comorbid disorders: anxiety disorders, alcohol abuse and dependence, and substance abuse and dependence. In a logistic regression model including these factors, suicide attempts and substance dependence were significantly associated with smoking in patients with bipolar disorder.Bipolar patients with lifetime smoking were more likely to have earlier age at onset of mood disorder, greater severity of symptoms, poorer functioning, history of a suicide attempt, and a lifetime history of comorbid anxiety and substance use disorders. Smoking may be independently associated with suicidal behavior in bipolar disorder.

  View details for Web of Science ID 000243085800009

  View details for PubMedID 17194268

• Update on bipolar disorder and substance abuse: recent findings and treatment strategies. journal of clinical psychiatry Ostacher, M. J., Sachs, G. S. 2006; 67 (9)

  Abstract

  Between 40% and 70% of people with bipolar disorder have a history of substance use disorder. A current or past comorbid substance use disorder may lead to worse outcomes for bipolar disorder, including more symptoms, more suicide attempts, longer episodes, and lower quality of life. Unfortunately, few treatments have been studied in patients with both illnesses, and large controlled trials are needed. Evidence from small studies suggests that some treatments proven for bipolar disorder (e.g., divalproex, lithium, quetiapine, lamotrigine, and psychotherapy) may decrease substance abuse or dependence. Both the bipolar disorder and the substance use disorder should be considered when determining the best management strategy. Once treatment has begun, clinicians should ensure that medication and psychotherapy are administered appropriately and that treatment is modified when there is inadequate response.

  View details for PubMedID 17081077

• Aripiprazole-related tardive dyskinesia CNS SPECTRUMS Maytal, G., Ostacher, M., Stern, T. A. 2006; 11 (6): 435-?

  Abstract

  The low prevalence of extrapyramidal symptoms associated with atypical antipsychotics has led to their widespread use during the past decade. Aripiprazole, the newest medication in this class, has been associated with extrapyramidal symptoms (eg, akathisia) and with improvement of tardive dyskinesia (TD), but to date it has not been associated with the development of TD. We report a case of TD associated with the use of aripiprazole 15 mg/day for 18 months for refractory depression. Symptoms of TD resolved within several weeks of discontinuation of aripiprazole.

  View details for Web of Science ID 000238607600010

  View details for PubMedID 16816781

• Seasonal changes in clinical status in bipolar disorder: a prospective study in 1000 STEP-BD patients ACTA PSYCHIATRICA SCANDINAVICA Friedman, E., Gyulai, L., Bhargava, M., Landen, M., Wisniewski, S., Foris, J., Ostacher, M., Medina, R., Thase, M. 2006; 113 (6): 510-517

  Abstract

  To investigate seasonal and regional effects on bipolar I and II patients.The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) patients were prospectively examined for monthly change in prevalence rates of depressed and recovered clinical status over the year. General Estimating Equation modeling was used to assess the effect of season on prevalence rates. Additionally, patients were stratified by bipolar subtype and by region.A significantly higher prevalence rate of depression is observed in the northern sites, a significant prevalence by month effect is found only in the bipolar II patients.The prevalence of depression is greater in patients from the northern vs. southern STEP-BD sites. Seasonal peak prevalence rates of depression differ by region. Bipolar II patients were more ill year-round and demonstrated greater monthly fluctuation in prevalence rates of being ill than did bipolar I patients. We conclude that seasonal effects upon bipolar patients vary by region and bipolar subtype.

  View details for DOI 10.1111/j.1600-0447.2005.00701.x

  View details for Web of Science ID 000237347800009

  View details for PubMedID 16677228

• Validity of the distinction between primary and secondary substance use disorder in patients with bipolar disorder: Data from the first 1000 STEP-BD participants AMERICAN JOURNAL ON ADDICTIONS Fossey, M. D., Otto, M. W., Yates, W. R., Wisniewski, S. R., Gyulai, L., Allen, M. H., Miklowitz, D. J., Coon, K. A., Ostacher, M. J., Neel, J. L., Thase, M. E., Sachs, G. S., Weiss, R. D. 2006; 15 (2): 138-143

  Abstract

  The validity of a primary/secondary substance use disorder (SUD) distinction was evaluated in the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder. Patients with primary SUD (n = 116) were compared with those with secondary SUD (n = 275) on clinical course variables. Patients with secondary SUD had fewer days of euthymia, more episodes of mania and depression, and a greater history of suicide attempts. These findings were fully explained by variations in age of onset of bipolar disorder. The order of onset of SUDs was not linked to bipolar outcomes when age of onset of bipolar disorder was statistically controlled. The primary/secondary distinction for SUD is not valid when variations in the age of onset of the non-SUD are linked to course characteristics.

  View details for DOI 10.1080/10550490500528423

  View details for Web of Science ID 000236579000004

  View details for PubMedID 16595351

• 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

• 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

• The evidence for antidepressant use in bipolar depression JOURNAL OF CLINICAL PSYCHIATRY Ostacher, M. J. 2006; 67: 18-21

  Abstract

  Mood elevation, which includes mania, hypomania, and mixed states, was previously considered the defining symptom of bipolar disorder, but bipolar depression by comparison is actually a much more substantial challenge to diagnose and treat. Recent studies, including research by the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), found that patients with bipolar disorder spend longer periods of time in depressive episodes and are more likely to relapse to depression compared with mania or hypomania. However, the treatment of bipolar depression is hampered by the limited number and varying quality of available studies of pharmacologic treatments to guide clinical decision making. Clinicians should rely on studies with the highest level of evidence (category A) when prescribing appropriate antidepressant treatments. The standard care pathways outlined by STEP-BD to aid clinicians in treating varying phases of bipolar disorder provide data on the use of various treatments for bipolar depression and their outcomes. While some treatments have the potential to induce mania, others appear to have some efficacy without inducing mania.

  View details for Web of Science ID 000240838500004

  View details for PubMedID 17029492

• The integration of measurement and management for the treatment of bipolar disorder: A STEP-BD model of collaborative care in psychiatry JOURNAL OF CLINICAL PSYCHIATRY Nierenberg, A. A., Ostacher, M. J., Borrelli, D. J., Iosifescu, D. V., Perlis, R. H., Desrosiers, A., Armistead, M. S., Calkins, A. W., Sachs, G. S. 2006; 67: 3-7

  Abstract

  Patients with bipolar disorder are among the most challenging to treat. These patients frequently present with complex mood and other symptoms that change over time, complex psychiatric and medical comorbid conditions, and multiple medications. Clinicians rarely systematically assess or measure all of these factors and instead rely on memory and general impressions. It is imperative that clinicians systematically track and monitor these relevant variables to ensure treatment decisions are based on precise clinical data. By integrating measurement and management, clinicians and patients can collaborate to assess the effectiveness of treatments and to make joint decisions about critical points at which to adjust treatment. This method was shown to be successful in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

  View details for Web of Science ID 000240838500001

  View details for PubMedID 17029489

• Prevalence and correlates of tobacco use in bipolar disorder: data from the first 2000 participants in the Systematic Treatment Enhancement Program GENERAL HOSPITAL PSYCHIATRY Waxmonsky, J. A., Thomas, M. R., Miklowitz, D. J., Allen, M. H., Wisniewski, S. R., Zhang, H. W., Ostacher, M. J., Fossey, M. D. 2005; 27 (5): 321-328

  Abstract

  Only a few small descriptive studies have examined the prevalence and correlates of tobacco use among bipolar patients. We predicted that poorly controlled manic, depressed and mixed states, and the presence of psychotic symptoms, would be associated with a greater prevalence of smoking among patients with bipolar disorder.We examined the prevalence of smoking in a cross-sectional sample of 1904 patients with bipolar disorder enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) database. We also examined the relationship between smoking and other factors including: bipolar subtype, current clinical status, illness severity (e.g., number of prior mood episodes), age of bipolar onset, gender, education, socioeconomic status, and concurrent substance use.At STEP-BD program entry, 31.2% of patients reported that they were smokers. Patients who were male, less educated, and/or had lower income were more likely to be smokers (P<.01). Additionally, patients with rapid cycling, comorbid psychiatric disorders, and/or substance abuse, and those experiencing a current episode of illness were more likely to be smokers (P<.0001). More lifetime depressive and manic episodes as well as greater severity of depressive and manic symptoms were associated with smoking (P<.001). Use of atypical antipsychotic medications was more prevalent among smokers (P=.04).Clinical and demographic variables are associated with smoking in this sample of bipolar patients. Longitudinal analyses are needed to determine how mood and bipolar symptoms interact with smoking over the episodic course of bipolar disorder. Additional studies should focus on whether controlling bipolar symptoms is associated with cessation of smoking.

  View details for DOI 10.1016/j.genhosppsych.2005.05.003

  View details for Web of Science ID 000232450100004

  View details for PubMedID 16168792

• Clinical and diagnostic implications of lifetime attention-deficit/hyperactivity disorder comorbidity in adults with bipolar disorder: Data from the first 1000 STEP-BD participants Conference on Pediatric Bipolar Disorder Nierenberg, A. A., Miyahara, S., Spencer, T., Wisniewski, S. R., Otto, M. W., Simon, N., Pollack, M. H., Ostacher, M. J., Yan, L., Siegel, R., Sachs, G. S. ELSEVIER SCIENCE INC. 2005: 1467–73

  Abstract

  Systematic studies of children and adolescents with a diagnosis of bipolar disorder show that rates of attention-deficit/hyperactivity disorder (ADHD) range from 60% to 90%, but the prevalence and implications of ADHD in adults with bipolar disorder are less clear.The first consecutive 1000 adults with bipolar disorder enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were assessed for lifetime ADHD. The retrospective course of bipolar disorder, current mood state, and prevalence of other comorbid psychiatric diagnoses were compared for the groups with and without lifetime comorbid ADHD.The overall lifetime prevalence of comorbid ADHD in this large cohort of bipolar patients was 9.5% (95% confidence interval 7.6%-11.4%); 14.7% of male patients and 5.8% of female patients with bipolar disorder had lifetime ADHD. Patients with bipolar disorder and ADHD had the onset of their mood disorder approximately 5 years earlier. After adjusting for age of onset, those with ADHD comorbidity had shorter periods of wellness and were more frequently depressed. We found that patients with bipolar disorder comorbid with ADHD had a greater number of other comorbid psychiatric diagnoses compared with those without comorbid ADHD, with substantially higher rates of several anxiety disorders and alcohol and substance abuse and dependence.Lifetime ADHD is a frequent comorbid condition in adults with bipolar disorder, associated with a worse course of bipolar disorder and greater burden of other psychiatric comorbid conditions. Studies are needed that focus on the efficacy and safety of treating ADHD comorbid with bipolar disorder.

  View details for DOI 10.1016/j.biopsych.2005.01.036

  View details for Web of Science ID 000229570500033

  View details for PubMedID 15950022

• Does recovery from substance use disorder matter in patients with bipolar disorder? JOURNAL OF CLINICAL PSYCHIATRY Weiss, R. D., Ostacher, M. J., Otto, M. W., Calabrese, J. R., Fossey, M., Wisniewski, S. R., Bowden, C. L., Nierenberg, A. A., Pollack, M. H., Salloum, I. M., Simon, N. M., Thase, M. E., Sachs, G. S. 2005; 66 (6): 730-735

  Abstract

  To examine the potential impact of recovery from substance use disorder (SUD) on the course of bipolar disorder among patients diagnosed with both bipolar and substance use disorders according to DSM-IV criteria.As part of the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), we examined bipolar disorder status (i.e., whether the patient is recovering or recovered), role functioning, and quality of life in the first 1000 patients to enter the STEP-BD study. We compared patients with no history of SUD, current SUD, and past SUD (i.e., lifetime SUD, but no current SUD) on these parameters. Data were collected between November 1999 and April 2001.A current clinical status of recovering or recovered from bipolar disorder was less likely among patients with current or past SUD compared to patients with no SUD (p < .002). Recovering/recovered status did not differ significantly between patients with current SUD versus past SUD. All 3 groups differed significantly on measures of role functioning as assessed by the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT), with poorest role functioning among patients with current SUD, followed by patients with past SUD (p = .0002). Patients with current or past SUD reported significantly lower quality of life as measured by the LIFE-RIFT and the Quality of Life Enjoyment and Satisfaction Questionnaire and more lifetime suicide attempts (p < .001) than patients without an SUD; patients with past versus current SUD did not differ significantly on these measures.The results suggest that patients with bipolar disorder who experience sustained remission from an SUD fare better than patients with current SUD, but not as well as subjects with no history of SUD; differences among the 3 groups appear greatest in the area of role functioning.

  View details for Web of Science ID 000229989000009

  View details for PubMedID 15960566

• Functional recovery is limited in people with bipolar disorder. Evidence-based mental health Ostacher, M. J. 2004; 7 (3): 69-?

  View details for PubMedID 15273213

• Long-term implications of early onset in bipolar disorder: Data from the first 1000 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) BIOLOGICAL PSYCHIATRY Perlis, R. H., Miyahara, S., Marangell, L. B., Wisniewski, S. R., Ostacher, M., Delbello, M. P., Bowden, C. L., Sachs, G. S., Nierenberg, A. A. 2004; 55 (9): 875-881

  Abstract

  Early onset of mood symptoms in bipolar disorder has been associated with poor outcome in many studies; however, the factors that might contribute to poor outcome have not been adequately investigated.The first consecutive 1000 adult bipolar patients enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder were assessed at study entry to determine details of their age of onset of mood symptoms. Clinical course, comorbidity, and functional status and quality of life were compared for groups with very early (age < 13 years), early (age 13-18 years), and adult (age > 18 years) onset of mood symptoms.Of 983 subjects in whom age of onset could be determined, 272 (27.7%) experienced very early onset, and 370 (37.6%) experienced early onset. Earlier onset was associated with greater rates of comorbid anxiety disorders and substance abuse, more recurrences, shorter periods of euthymia, greater likelihood of suicide attempts and violence, and greater likelihood of being in a mood episode at study entry.Very early or early onset of bipolar disorder might herald a more severe disease course in terms of chronicity and comorbidity. Whether early intervention might modify this risk merits further investigation.

  View details for DOI 10.1016/j.biopsych.2004.01.022

  View details for Web of Science ID 000220922100001

  View details for PubMedID 15110730

• Older patients are eligible for trial of lithium and valproate BRITISH MEDICAL JOURNAL Rendell, J. M., Geddes, J. R., Ostacher, M. J. 2003; 327 (7411): 395-396

  View details for Web of Science ID 000184864200041

  View details for PubMedID 12920009

  View details for PubMedCentralID PMC1126812

• Mirtazapine in the treatment of mood and anxiety disorders. Expert review of neurotherapeutics Ostacher, M. J., Eisner, L., Nierenberg, A. A. 2003; 3 (4): 425-433

  Abstract

  Mirtazapine is a new antidepressant whose effects on presynaptic adrenergic receptors leads to increased serotonergic transmission, and thus its antidepressant and antianxiety effects. It is equal in practical effectiveness to any currently marked antidepressant but may exert its effects earlier than some others. It is safe, well-tolerated and a useful addition to the drugs currently available for the treatment of mood and anxiety disorders.

  View details for DOI 10.1586/14737175.3.4.425

  View details for PubMedID 19810927

• Clinical and community-service activities of psychiatric teaching hospitals ACADEMIC PSYCHIATRY Stroup, T. S., Dorwart, R. A., Hoover, C. W., Yeung, E., Ostacher, M. 1999; 23 (3): 123-127

  View details for DOI 10.1007/BF03340039

  View details for Web of Science ID 000082256500002

• ASSOCIATION BETWEEN BORDERLINE PERSONALITY STRUCTURE AND HISTORY OF CHILDHOOD ABUSE IN ADULT VOLUNTEERS COMPREHENSIVE PSYCHIATRY Salzman, J. P., Salzman, C., WOLFSON, A. N., Albanese, M., LOOPER, J., Ostacher, M., SCHWARTZ, J., CHINMAN, G., Land, W., Miyawaki, E. 1993; 34 (4): 254-257

  Abstract

  Childhood abuse has been implicated as a leading factor in the development of borderline personality disorder (BPD). Data in this report, drawn from an ongoing study of the therapeutic effect of fluoxetine in BPD patients, were gathered in an attempt to replicate previous findings indicating a history of physical abuse in 71% and sexual abuse in 67% of adult BPD subjects. Thirty-one subjects for a study of the pharmacological treatment of BPD or BPD traits met criteria for the study. Those who had been previously hospitalized for a psychiatric disorder, who had recently been suicidal, or who had recent histories of self-mutilation were excluded. Specific information about childhood abuse was gathered using questions from a previous study of abuse histories in BPD patients. All subjects were then interviewed in greater depth regarding past experiences of abuse as part of the ongoing study of the relationship of childhood attachment experience and adult psychopathology. Six of 31 subjects (19.4%) reported a definite history of childhood physical and/or sexual abuse. Four of these subjects met criteria for full BPD, and two met criteria for BPD traits. Three of 31 subjects reported a history of physical abuse (9.7%); five reported a history of sexual abuse (16.1%). Two of the six who reported abuse reported both physical and sexual abuse. A history of childhood abuse is not necessarily linked to the development of BPD or BPD traits in all individuals. The following hypothesis is suggested: BPD may represent a spectrum of symptomatic severity.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993LP30200007

  View details for PubMedID 8348804