- Clinical Psychopharmacology
- Resistant Depression
Professor - Med Center Line, Psychiatry and Behavioral Sciences
Honors & Awards
Teacher of the Year, Dept. Of Psychiatry (1998, 2000, 2001)
America's Best Doctors; Psychiatry, Best Doctors (2009-2015)
Medical Education:University of California at San Francisco School of Medicine (1989) CA
Residency:Stanford University Medical Center (1993) CA
Internship:Stanford University Medical Center (1990) CA
Board Certification: Psychiatry, American Board of Psychiatry and Neurology (1995)
Fellowship:Stanford University Medical Center (1993) CA
DMH, UCSF/UC Berkeley, Mental Health (1986)
MD, UCSF, Medicine (1989)
Current Research and Scholarly Interests
Treatment resistant depression.
Novel biological interventions in the treatment of mental illness.
Anti-glucocorticoid drugs in the treatment of mood disorders.
Augmentation strategies in the treatment of depression.
International Study to Predict Optimised Treatment - in Depression
The aim of this study is to identify genetic, physical (brain) and psychological (cognitive) markers (or combinations of them) that predict specific response to a range of antidepressants treatment (Escitalopram, Venlafaxine, Sertraline) in patients diagnosed with major depressive disorder. This study is focused on outcomes which may impact on how "personalised medicine" is implemented in depression.
Treatment Trial for Psychogenic Nonepileptic Seizures
The investigators propose that patients who receive targeted pharmacotherapy (sertraline) or focused psychotherapy (cognitive behavioral therapy-informed psychotherapy (CBT-ip) for NES) or combined treatment (CBT-ip + sertraline) will report fewer nonepileptic seizures (NES) compared to patients who receive community care / treatment as usual (TAU). The purpose of this study is to provide pilot testing and data to inform the future multicenter randomized controlled trial based on the hypothesis.
Functional MRI Before and After Treatment for Depression
The purpose of this study is to help us understand how depression changes brain activity and how this relates to mood, anxiety, and cognitive functions like memory. We also hope to develop a brain imaging test that will predict either before or within two weeks of starting a medicine whether the treatment will work.
Stanford is currently not accepting patients for this trial. For more information, please contact Maureen H Chang, B.S., 650-725-4620.
Investigate Efficacy & Safety of RO4995819 vs. Placebo as Adjunct Tx in Patients w/Major Depressive Disorder
The purpose of the study is to explore the efficacy of 6 weeks treatment of an investigational medication, RO4995819, versus placebo as adjunctive therapy in patients with major depression.
Stanford is currently not accepting patients for this trial. For more information, please contact Maureen Chang, B.S., 650-725-4620.
Radiosurgical Neuromodulation for Refractory Depression
This study is designed to evaluate the safety and effectiveness of an investigational procedure for treating people with treatment resistant bipolar depression (TRD). Precise dose delivery of radiation to the predetermined targets in the brain will be accomplished with known Cyberknife stereotactic radiosurgery methods. This technology is considered to be noninvasive (does not physically invade your body). We will be studying if the Cyberknife influences the sensitivity of certain nerves of your brain. Although many clinical treatments for psychiatric conditions have been done using stereotactic radiosurgery, the present study is experimental, because we are seeking to use more moderate doses of radiation that are intended not to destroy any brain cells, but to normalize or modulate their function.
Stanford is currently not accepting patients for this trial. For more information, please contact Jessica Hawkins, (650) 723 - 8323.
Ropinirole Controlled Release (CR) as an Adjunctive Agent in the Treatment of Major Depression
This is an 8 week study for patients who are currently taking antidepressant medication but not fully responding. Ropinirole CR would be taken in conjunction with current antidepressant medication. Patients come into the clinic once a week when starting on the medication and then once every other week for the remainder of the 8 weeks.
Stanford is currently not accepting patients for this trial. For more information, please contact Jessica Hawkins, (650) 723 - 8323.
Graduate and Fellowship Programs
Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).
Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5mg/kg over 40min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1mg/kg (n=18), a single dose of ketamine 0.2mg/kg (n=20), a single dose of ketamine 0.5mg/kg (n=22), a single dose of ketamine 1.0mg/kg (n=20), and a single dose of midazolam 0.045mg/kg (active placebo) (n=19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group*time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5mg/kg) and high dose (1mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1mg/kg) was significant only prior to adjustment (p=0.02, p-adj=0.14, d=-0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5mg/kg and 1.0mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine.TRIAL REGISTRATION: NCT01920555.
View details for DOI 10.1038/s41380-018-0256-5
View details for PubMedID 30283029
Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein.
The American journal of psychiatry
2018; 175 (3): 251–61
Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials.The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression.The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.
View details for DOI 10.1176/appi.ajp.2017.17020172
View details for PubMedID 29241359
View details for PubMedCentralID PMC5832545
Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial.
The lancet. Psychiatry
2017; 4 (11): 839–49
Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted.Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162.Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery.This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy.Abbott (previously St Jude Medical).
View details for DOI 10.1016/S2215-0366(17)30371-1
View details for PubMedID 28988904
Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression
Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.
View details for DOI 10.1038/tp.2016.61
View details for Web of Science ID 000377305600005
View details for PubMedID 27138798
Utility of event-related potentials in predicting antidepressant treatment response: An iSPOT-D report
2015; 25 (11): 1981-1990
It is essential to improve antidepressant treatment of major depressive disorder (MDD) and one way this could be achieved is by reducing the number of treatment steps by employing biomarkers that can predict treatment outcome. This study investigated differences between MDD patients and healthy controls in the P3 and N1 component from the event-related potential (ERP) generated in a standard two-tone oddball paradigm. Furthermore, the P3 and N1 are investigated as predictors for treatment outcome to three different antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D)--a multi-center, international, randomized, prospective practical trial--1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression. P3 and N1 latencies and amplitudes were analyzed using a peak-picking approach and further replicated by using exact low resolution tomography (eLORETA). A reduced P3 was found in MDD patients compared to controls by a peak-picking analysis. This was validated in a temporal global field power analysis. Source density analysis revealed that the difference in cortical activity originated from the posterior cingulate and parahippocampal gyrus. Male non-responders to venlafaxine-XR had significantly smaller N1 amplitudes than responders. This was demonstrated by both analytical methods. Male non-responders to venlafaxine-XR had less activity originating from the left insular cortex. The observed results are discussed from a neural network viewpoint.
View details for DOI 10.1016/j.euroneuro.2015.07.022
View details for Web of Science ID 000369152500014
View details for PubMedID 26282359
ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression
2015; 15 (4): 332-339
The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.The Pharmacogenomics Journal advance online publication, 9 December 2014; doi:10.1038/tpj.2014.72.
View details for DOI 10.1038/tpj.2014.72
View details for Web of Science ID 000358448500007
Frontal and rostral anterior cingulate (rACC) theta EEG in depression: Implications for treatment outcome?
2015; 25 (8): 1190-1200
In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram (EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression (HRSD17). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome.
View details for DOI 10.1016/j.euroneuro.2015.03.007
View details for Web of Science ID 000359875500014
View details for PubMedID 25936227
ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial
AMERICAN JOURNAL OF PSYCHIATRY
2015; 172 (8): 751-759
The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.
View details for DOI 10.1176/appi.ajp.2015.14050680
View details for Web of Science ID 000359274700015
View details for PubMedID 25815420
Cognitive and emotional biomarkers of melancholic depression: An iSPOT-D report
JOURNAL OF AFFECTIVE DISORDERS
2015; 176: 141-150
Depressed patients with melancholic features have distinct impairments in cognition and anhedonia, but it remains unknown whether these impairments can be quantified on neurocognitive biomarker tests of behavioral performance. We compared melancholic major depressive disorder (MDD) patients to non-melancholic MDD patients and controls on a neurocognitive test battery that assesses eight general and emotional cognitive domains including the hypothesized decision-making and reward-threat perception.MDD outpatients (n=1008) were assessed using a computerized battery of tests. MDD participants met DSM-IV criteria for MDD and had a score ≥16 on the 17-item Hamilton Rating Scale for Depression. Melancholic MDD was defined using the Mini-International Neuropsychiatric Interview and a psychomotor disturbance observer-rated CORE measure score >7. Controls were age- and gender-matched with no previous DSM-IV or significant medical history.Melancholic participants (33.7% of the MDD sample) exhibited significantly poorer performance than controls across each domain of cognitive function and for speed of emotion identification and implicit emotion priming. Compared to the non-melancholic group, specific disturbances were seen on tests of information speed, decision speed, and reward-relevant emotional processing of happy expressions, even after co-varying for symptom severity.Assessments were taken at only one medication-free time point. Reward was investigated using an emotional faces task.Melancholic MDD is distinguished by a specific neurocognitive marker profile consistent with reduced decision-making capacity under time demands and loss of reward sensitivity. This profile suggests an underlying deficit in mesolimbic-cortical circuitry for motivationally-directed behavior.
View details for DOI 10.1016/j.jad.2015.01.061
View details for Web of Science ID 000350975500019
View details for PubMedID 25710095
The International Study to Predict Optimized Treatment in Depression (iSPOT-D): Outcomes from the acute phase of antidepressant treatment.
Journal of psychiatric research
2015; 61: 1-12
We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder (MDD). The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients (18-65 years old) at 17 sites (five countries). At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the "none" to minimal/mild range for intensity and burden. Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.
View details for DOI 10.1016/j.jpsychires.2014.12.018
View details for PubMedID 25586212
Impairment and distress patterns distinguishing the melancholic depression subtype: An iSPOT-D report.
Journal of affective disorders
2015; 174: 493-502
This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress.Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress.Patients with melancholic features (n=339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants.Due to the cross-sectional nature of this study, causal pathways cannot be concluded.Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one׳s emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment.
View details for DOI 10.1016/j.jad.2014.10.046
View details for PubMedID 25554994
ABCB1 Genetic Variants and Neurocognitive Function Predict Antidepressant Outcomes
NATURE PUBLISHING GROUP. 2014: S521–S522
View details for Web of Science ID 000345905002075
Measuring severe adverse events and medication selection using a "PEER Report" for nonpsychotic patients: a retrospective chart review
NEUROPSYCHIATRIC DISEASE AND TREATMENT
2012; 8: 277-284
We previously reported on an objective new tool that uses quantitative electroencephalography (QEEG) normative- and referenced-electroencephalography sampling databases (currently called Psychiatric EEG Evaluation Registry [PEER]), which may assist physicians in determining medication selection for optimal efficacy to overcome trial-and-error prescribing. The PEER test compares drug-free QEEG features for individual patients to a database of patients with similar EEG patterns and known outcomes after pharmacological interventions. Based on specific EEG data elements and historical outcomes, the PEER Report may also serve as a marker of future severe adverse events (eg, agitation, hostility, aggressiveness, suicidality, homicidality, mania, hypomania) with specific medications. We used a retrospective chart review to investigate the clinical utility of such a registry in a naturalistic environment.This chart review demonstrated significant improvement on the global assessment scales Clinical Global Impression - Improvement and Quality of Life Enjoyment and Satisfaction - Short Form as well as time to maximum medical improvement and decreased suicidality occurrences. The review also showed that 54.5% of previous medications causing a severe adverse event would have been raised as a caution had the PEER Report been available at the time the drug was prescribed. Finally, due to the significant amount of off-label prescribing of psychotropic medications, additional, objective, evidence-based data aided the prescriber toward better choices.The PEER Report may be useful, particularly in treatment-resistant patients, in helping to guide medication selection. Based on the preliminary data obtained from this chart review, additional studies are warranted to establish the safety and efficacy of adding PEER data when making medication decisions.
View details for DOI 10.2147/NDT.S31665
View details for Web of Science ID 000305552300001
View details for PubMedID 22802691
View details for PubMedCentralID PMC3395405
- Response to Dr. Tsai's letter to the Editor - The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression JOURNAL OF PSYCHIATRIC RESEARCH 2011; 45 (1): 134–35
The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression
JOURNAL OF PSYCHIATRIC RESEARCH
2011; 45 (1): 64-75
To evaluate the efficacy of rEEG(®)-guided pharmacotherapy for the treatment of depression in those circumstances where rEEG and STAR*D provided different recommendations.This was a randomized, single-blind, parallel group, 12 center, US study of rEEG-guided pharmacotherapy vs. the most effective treatment regimens reported in the NIH sponsored STAR*D study. Relatively treatment-resistant subjects ≥18 years who failed one or more antidepressants were required to have a QIDS-16-SR score ≥13 and a MADRS score ≥26 at baseline. All subjects underwent a washout of all current medications (with some protocol-specified exceptions) for at least five half-lives before receiving a QEEG and rEEG report. Subjects randomized to rEEG were assigned a regimen based on the rEEG report. Control subjects who had failed only SSRI's in their current episode were randomized to receive venlafaxine XR. Control subjects who had failed antidepressants from ≥2 classes of antidepressants were randomized to receive a regimen from Steps 2-4 of the STAR*D study. Treatment lasted 12 weeks. The primary outcome measures were change from baseline for self-rated QIDS-SR16 and Q-LES-Q-SF.A total of 114 subjects were randomized and 89 subjects were evaluable. rEEG-guided pharmacotherapy exhibited significantly greater improvement for both primary endpoints, QIDS-SR16 (-6.8 vs. -4.5, p<0.0002) and Q-LES-Q-SF (18.0 vs. 8.9, p<0.0002) compared to control, respectively, as well as statistical superiority in 9 out of 12 secondary endpoints.These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression. If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice.
View details for DOI 10.1016/j.jpsychires.2010.05.009
View details for Web of Science ID 000287075200011
View details for PubMedID 20598710
Safety considerations of the use of second generation antipsychotics in the treatment of major depression: extrapyramidal and metabolic side effects.
Current drug safety
2010; 5 (3): 263-266
Second generation antipsychotics (SGAs) are increasingly employed in the treatment of depression. Adjunctive aripiprizole and olanzapine/ fluoxetine combination (OFC) have been approved in the US in the treatment of depression. Quetiapine also appears to be poised for an FDA approval as an adjunctive treatment for resistant depression. Historically, first generation antipsychotics were thought to carry an enhanced risk of certain side effects in the treatment of mood disorders, including an enhanced risk of extrapyramidal symptoms (EPS). The second generation antipsychotics are also known to be associated with a variety of metabolic side effects. The use of SGA in a depressed population may pose risks that differ from use in other conditions such as bipolar disorder and schizophrenia. In this paper, the risk of extrapyramidal and metabolic side effects is reviewed in depressed patients treated with second generation antipsychotics.
View details for PubMedID 20394571
- A Multisite Trial of Mifepristone for the Treatment of Psychotic Depression: A Site-by-Treatment Interaction (vol 30, pg 284, 2009) CONTEMPORARY CLINICAL TRIALS 2010; 31 (1): 134-134
- A Multisite Trial of Mifepristone for the Treatment of Psychotic Depression: A Site-by-Treatment Interaction (vol 30, pg 284, 2009) CONTEMPORARY CLINICAL TRIALS 2009; 30 (5): 497-497
Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function
2009; 34 (7): 1012-1018
Although many studies have examined separately the effects of depression and cortisol on cognition, no study has examined their relative or potentially additive effects. Our study simultaneously investigated the contributions of clinical status [major depression (MD) versus psychiatrically healthy controls (HC)] and cortisol on a hippocampal/mediotemporal mediated verbal memory task (Paragraph Recall) and a prefrontal cortex/cingulate mediated executive functioning task (Stroop). Thirty-seven unmedicated nondelusional MDs and 18 HCs underwent psychiatric ratings, hourly assessments of cortisol activity over 24 h, and neuropsychological assessments. Hierarchical multiple regressions indicated a significant effect of cortisol but not of diagnosis on verbal memory. Greater cortisol levels were related to poorer memory performance independent of group. In contrast, a significant interaction between cortisol and diagnosis was found for a color-word index of response inhibition. This interaction suggests that the detrimental effect of elevated cortisol level on this type of executive functioning exists only in the healthy control group but not in MDs. On an Interference score, another measure of response inhibition, cortisol had a significant independent effect, but neither the effects of diagnosis and the interaction attained full significance. Our study suggests that cortisol has an independent effect on verbal memory. Also, our study produced evidence of an interaction between diagnosis and cortisol on response inhibition.
View details for DOI 10.1016/j.psyneuen.2009.01.017
View details for Web of Science ID 000267471900008
View details for PubMedID 19261389
A multisite trial of mifepristone for the treatment of psychotic depression: A site-by-treatment interaction
CONTEMPORARY CLINICAL TRIALS
2009; 30 (4): 284-288
Major Depression with Psychotic Features (psychotic depression) is a common, debilitating psychiatric disease. We hypothesized that mifepristone, a cortisol receptor (GRII) antagonist, would significantly reduce psychotic symptoms in psychotic depression. Two hundred fifty-eight patients with psychotic depression enrolled at 29 sites were randomized to mifepristone or placebo for 7 days. The primary outcome was rapid and sustained response, defined as a 50% or greater decrease in Brief Psychiatric Rating Scale - Positive Symptom Subscale scores at the end of treatment (day7) and 49 days later (day 56). Cochran-Mantel-Haenszel compared proportions of responders to mifepristone versus placebo adjusting for site. Exploratory analyses compared response of patients with mifepristone plasma concentrations of > or =1800 ng/ml to placebo. The primary endpoint was not statistically significant. However, the Breslow-Day test indicated a statistically significant site-by-treatment interaction. Mifepristone produced significantly higher response among the twenty sites who participated from the trial onset (p<.05), whereas no difference was observed at the nine sites added late in the trial. Patients with mifepristone plasma levels > or =1800 ng/ml were significantly more likely to respond than placebo patients (Intent-to-Treat: OR=2.4, p=.03; Initial 20 sites: OR=4.1, p=.002). The results of this trial are instructive in two respects. First, while statistical adjustments for [corrected] site are common in multisite clinical trials, this study reminds trialists to formally evaluate the interaction of site by treatment.Second, the association between increased mifepristone plasma concentration levels and greater clinical response, detected despite the site-by-treatment interaction, suggests that higher plasma levels may be needed for maximizing the probability of a positive response.
View details for DOI 10.1016/j.cct.2009.03.001
View details for Web of Science ID 000266853900002
View details for PubMedID 19318138
Utility of Atypical Antipsychotics in the Treatment of Resistant Unipolar Depression
2009; 23 (5): 369-377
Many patients fail to achieve an adequate response to antidepressant medication. Growing evidence suggests that atypical antipsychotics may augment antidepressant effects, resulting in a greater potential for response. Atypical antipsychotics possess pharmacological actions that are associated with antidepressant properties, including serotonin 5-HT(2) receptor antagonist and 5-HT(1A) and dopamine receptor partial agonist activity. In fact, the term 'atypical antipsychotic' is an unfortunate remnant of the early indication of these drugs in the treatment of schizophrenia. Soon after their introduction, the usefulness of atypical antipsychotics in bipolar disorder was firmly established and their use in the treatment of mood disorders has far outpaced their use in schizophrenia and other psychotic disorders. Aripiprazole has become the first agent to receive US FDA approval for the adjunctive treatment of unipolar depression. Most recently, Symbyax, a fluoxetine/olanzapine combination, received FDA approval for the acute treatment of treatment-resistant depression. This is the first medication to be FDA approved for this indication. In the present article, the usefulness of antipsychotics in the treatment of resistant unipolar depression is reviewed.
View details for Web of Science ID 000266961000002
View details for PubMedID 19453199
Sildenafil treatment of women with antidepressant-associated sexual dysfunction - A randomized controlled trial
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2008; 300 (4): 395-404
Antidepressant-associated sexual dysfunction is a common adverse effect that frequently results in premature medication treatment discontinuation and for which no treatment has demonstrated efficacy in women.To evaluate the efficacy of sildenafil for sexual dysfunction associated with selective and nonselective serotonin reuptake inhibitors (SRIs) in women.An 8-week prospective, parallel-group, randomized, double-blind, placebo-controlled clinical trial conducted between September 1, 2003, and January 1, 2007, at 7 US research centers that included 98 previously sexually functioning, premenopausal women (mean [SD] age 37.1  years) whose major depression was remitted by SRIs but who were also experiencing sexual dysfunction.Forty-nine patients were randomly assigned to take sildenafil or placebo at a flexible dose starting at 50 mg adjustable to 100 mg before sexual activity.The primary outcome measure was the mean difference in change from baseline to study end (ie, lower ordinal score) on the Clinical Global Impression sexual function scale. Secondary measures included the Female Sexual Function Questionnaire, the Arizona Sexual Experience scale-female version, the University of New Mexico Sexual Function Inventory-female version, a sexual activity event log, and the Hamilton Depression Rating scale. Hormone levels were also assessed.In an intention-to-treat analysis, women treated with sildenafil had a mean Clinical Global Impression-sexual function score of 1.9 (95% confidence interval [CI], 1.6-2.3) compared with those taking placebo (1.1; 95% CI, 0.8-1.5), with a mean end point difference of 0.8 (95% CI, 0.6-1.0; P = .001). Assigning baseline values carried forward to the 22% of patients who prematurely discontinued resulted in a mean end point in the sexual function score of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil compared with 0.9 (95% CI, 0.6-1.3) among women taking placebo with a mean end point difference of 0.6 (95% CI, 0.3-0.8; P = .03). Baseline endocrine levels were within normal limits and did not differ between groups. The mean (SD) Hamilton scores for depression remained consistent with remission in both groups (4.0 [3.6]; P = .90). Headache, flushing, and dyspepsia were reported frequently during treatment, but no patients withdrew because of serious adverse effects.In this study population, sildenafil treatment of sexual dysfunction in women taking SRIs was associated with a reduction in adverse sexual effects.clinicaltrials.gov Identifier: NCT00375297.
View details for Web of Science ID 000257831200017
View details for PubMedID 18647982
Depression and smoking cessation: does the evidence support psychiatric practice?
Neuropsychiatric disease and treatment
2007; 3 (4): 487-493
Depression and smoking are highly comorbid. The vast majority of psychiatrists treating depressed patients do not target or treat nicotine dependence, and many inpatient psychiatric facilities implicitly condone smoking by providing 'smoke breaks'. The reasons for failure to treat are unclear, but are probably linked to the notion that depressed smokers are neither willing nor able to quit, and will become more depressed if they try. We review the clinical evidence on depression and smoking cessation, and find little support for current psychiatric practice. Although quitting smoking does appear to pose a risk for the development of depression, this risk is not clearly higher in those with a past history of depression than those without. Depressed smokers are as capable as nondepressed smokers of quitting smoking, and at least one-quarter of depressed smokers is willing to try. Sustained abstinence may even lead to improvement in depressive disorders. More research is needed to understand the relationship between depression and quitting smoking, but current clinical evidence suggests more resiliency among depressed smokers than common clinical wisdom would dictate.
View details for PubMedID 19300577
Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness.
Annals of clinical psychiatry
2007; 19 (3): 153-159
Partial response, no response, or residual symptoms following antidepressant therapy is common in clinical psychiatry. This study evaluated modafinil in patients with major depressive disorder (MDD) who were partial responders to adequate selective serotonin reuptake inhibitor (SSRI) therapy and excessive sleepiness and fatigue.This retrospective analysis pooled the data of patients (18-65 yrs) who participated in two randomized, double-blind, placebo-controlled studies of modafinil (6-week, flexible-dose study of 100-400 mg/day or 8-week, fixed-dose study of 200 mg/day) plus SSRI therapy. Patients (n=348) met criteria for several residual symptoms (Epworth Sleepiness Scale [ESS] score>or=10; 17-item Hamilton Depression Scale [HAM-D] score between 4 and 25; and Fatigue Severity Scale [FSS] score>or=4).Compared to placebo, modafinil augmentation rapidly (within 1 week) and significantly improved overall clinical condition (Clinical Global Impression-Improvement), wakefulness (ESS), depressive symptoms (17-item HAM-D), and fatigue (FSS) (p<.01 for all). At final visit, patients receiving modafinil augmentation experienced statistically significant improvements in overall clinical condition, wakefulness, and depressive symptoms. Modafinil was well tolerated in combination with SSRI.Results of this pooled analysis provide further evidence suggesting that modafinil is an effective and well-tolerated augmentation therapy for partial responders to SSRI therapy, particularly when patients continue to experience fatigue and excessive sleepiness.
View details for PubMedID 17729016
Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression
43rd Annual Meeting of the American-College-of-Neuropsychopharmacology
ELSEVIER SCIENCE INC. 2006: 1343–49
Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD). Recent studies have suggested that the antiglucocorticoid, mifepristone might have a role in the treatment of PMD. The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD.221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study. Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment.Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30% reduction in the Brief Psychiatric Rating Scale (BPRS). In addition, mifepristone treated patients were significantly more likely to achieve a 50% reduction in the BPRS Positive Symptom Scale (PSS). No significant differences were observed on measures of depression.A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD. This study suggests that the antiglucocorticoid, mifepristone, might represent an alternative to traditional treatments of psychosis in psychotic depression.
View details for DOI 10.1016/j.biopsych.2006.05.034
View details for Web of Science ID 000242735700011
View details for PubMedID 16889757
The neuropsychological profile of psychotic major depression and its relation to cortisol
2006; 60 (5): 472-478
Our study described the neuropsychological profile of psychotic major depression (PMD) compared to nonpsychotic major depression (NPMD) patients and psychiatrically healthy controls (HC). We predicted that higher cortisol levels would be associated with greater cognitive deficits.Twenty-nine PMDs, 24 NPMDs, and 26 HCs were recruited at Stanford University Medical Center. Psychiatric ratings, cortisol levels from 1800-0900 hours, and neuropsychological test data were obtained.PMDs had more severe cognitive impairments compared with NPMDs and HCs with the exception of simple verbal attention. PMDs had elevated mean cortisol levels from 1800 to 0100 hours which were significantly correlated with poorer verbal memory and psychomotor speed performance. Cortisol slopes from 1800 to 0100 hours were also significantly correlated with verbal memory and working memory.While PMDs' ability to attend passively to information appears intact, they have more difficulty processing, manipulating, and encoding new information. Elevated cortisol levels, as seen in PMD patients, are associated with poorer cognitive performance especially related to verbal memory for lists of words and working memory.
View details for DOI 10.1016/j.biopsych.2005.11.010
View details for Web of Science ID 000240506000007
View details for PubMedID 16483550
The efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats
BEHAVIOURAL BRAIN RESEARCH
2006; 171 (2): 225-229
Atypical antipsychotics, such as olanzapine, have been associated with clinically significant weight gain. Changes to the hypothalamic pituitary adrenal axis may partially mediate this weight increase. Two experiments were conducted to test the effects of mifepristone on both mitigating and preventing olanzapine-induced weight gain. In the first experiment, adult female Sprague-Dawley rats gained significantly more weight on average when administered olanzapine for 35 days compared to vehicle controls. Subsequently, the olanzapine-treated rats were randomized to three dose levels of mifepristone (20, 60, and 200 mg/kg) in conjunction with olanzapine. Weight measurements were taken for 21 additional days. Rats receiving olanzapine plus mifepristone rapidly lost a significant portion of the weight gained during the olanzapine only phase (p = 0.0001). Rats in the 200 mg/kg dose group had significantly less abdominal fat compared to controls (p < 0.001) at study end. In the second experiment, daily mifepristone (20, 60, 200 mg/kg) initiated concomitantly with olanzapine was compared with olanzapine alone to determine if mifepristone prevented olanzapine-induced weight gain. After 21 days of treatment, mifepristone treated rats gained significantly less weight and had significantly less abdominal fat than rats administered olanzapine alone (p = 0.0002). Results suggest that mifepristone, a potent glucocorticoid antagonist, may both reduce and prevent olanzapine-induced weight gain in rats.
View details for DOI 10.1016/j.bbr.2006.03.039
View details for Web of Science ID 000239197500006
View details for PubMedID 16782211
Augmentation and combination strategies for depression
158th Annual Scientific Meeting of the American-Psychiatric-Association
SAGE PUBLICATIONS LTD. 2006: 11–18
Treatment-resistant depression represents a common problem, with the vast majority of depressed patients showing incomplete response to antidepressant trials. Augmentation and combination strategies are commonly employed to address this problem, but there are few randomized, controlled studies to guide treatment choice. Indeed, some of the most common augmentation strategies in depression are those with the least controlled evidence. The popularity of bupropion, psychostimulants and atypical antipsychotics as augmentors may not be warranted by existing controlled studies, whereas two less commonly used augmentors-lithium and thyroid hormone- have substantial controlled evidence to support their use. This paper summarizes the state of the evidence for commonly used augmenting strategies and explores preliminary findings for more investigational approaches.
View details for DOI 10.1177/13597868064310
View details for Web of Science ID 000237852000003
View details for PubMedID 16644767
Serious adverse events and the Modafinil Augmentation Study - Reply
2006; 11 (5): 340-342
View details for Web of Science ID 000237649700003
An open maintenance trial using low frequency transcranial magnetic stimulation for treatment resistant unipolar and bipolar depression
61st Annual Convention of the Society-of-Biological-Psychiatry
ELSEVIER SCIENCE INC. 2006: 170S–170S
View details for Web of Science ID 000236767301130
The use of mifepristone in the treatment of neuropsychiatric disorders
TRENDS IN ENDOCRINOLOGY AND METABOLISM
2006; 17 (3): 117-121
Mifepristone is a potent glucocorticoid and progesterone receptor antagonist. The pathophysiology of a number of neuropsychiatric disorders implicates abnormalities in glucocorticoid function. These include mood disorders such as psychotic major depression and bipolar depression. In addition, cognitive disorders such as Alzheimer's disease might also be partially mediated by abnormalities in the hypothalamic-pituitary-adrenal axis. Preliminary studies suggest that mifepristone might have a role in the treatment of a number of neuropsychiatric disorders.
View details for DOI 10.1016/j.tem.2006.02.006
View details for Web of Science ID 000237145300007
View details for PubMedID 16530421
Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: A 12-week, open-label, extension study
2006; 11 (2): 93-102
Many patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitors have residual symptoms (eg, persistent fatigue, excessive sleepiness) despite an overall antidepressant response. Placebo-controlled studies indicate that modafinil, a wake-promoting agent, may relieve residual symptoms.This 12-week, open-label, dose titration, extension study followed an 8-week placebo-controlled study of modafinil augmentation in patients with MDD. The dose was 100-400 mg/day. The median stable dose was 300 mg/day. Assessments were the Epworth Sleepiness Scale, Brief Fatigue Inventory, Clinical Global Impression of Improvement scale, 17-item Hamilton Rating Scale for Depression, and Montgomery-Asberg Depression Rating Scale.Of the 245 patients treated, 194 completed the study; 70% reported Clinical Global Impression of Improvement scale responses of "much improved" or "very much improved" between open-label baseline and final visit (previous randomized modafinil group: 74%; placebo group: 66%). When data were analyzed for four subsets of patients (former modafinil responders, placebo responders, modafinil nonresponders, and placebo nonresponders), improvements in scores on all outcome measures were at least twice as great among former modafinil and placebo nonresponders compared with responders. Most common adverse events were headache (18%), nausea (9%), and dizziness (7%); all were generally mild to moderate in severity.Twelve weeks of modafinil augmentation relieved excessive sleepiness, reduced fatigue, and improved patients' overall clinical condition, including mood.
View details for Web of Science ID 000235789200009
View details for PubMedID 16520686
Detecting psychotic major depression using psychiatric rating scales
JOURNAL OF PSYCHIATRIC RESEARCH
2006; 40 (1): 22-29
The aim of this study was to assess whether individual or clusters of psychiatric symptoms can differentiate patients with psychotic major depression (PMD) from those with nonpsychotic depression (NPMD).Data were pooled from two studies investigating patients with moderate depression. A total of 129 subjects were studied. Patients in Sample 1 were unmedicated, while the majority of the patients in Sample 2 were taking psychotropic medications. Baseline rating scales were obtained for all subjects, including the Hamilton depression rating scale and the brief psychiatric rating scale (BPRS). We used discriminant function analyses, logistic regression, and ROC analyses to determine the patterns in symptoms that differentiated the groups.Psychotic patients were adequately differentiated by the unusual thought content (UTC) item of the BPRS. Even mild UTC endorsement was an indicator of PMD. Furthermore, results suggest that the positive symptom subscale of the BPRS was even better at differentiating PMD from NMPD patients. Sensitivity and specificity for this scale were 84% and 99%, respectively.Psychotic major depression is often undiagnosed and poorly treated. One reason for this trend is the failure of physicians to inquire in a more detailed manner about positive symptoms in patients with primary mood symptoms. Although physicians are not likely to have the time to conduct an entire BPRS during an evaluation, our results suggest that a few key symptoms, if assessed directly, may aid the psychiatrist to more effectively diagnose and subsequently treat their depressed patients.
View details for DOI 10.1016/j.jpsychires.2005.07.003
View details for Web of Science ID 000235466200002
View details for PubMedID 16165160
Update on augmentation of antidepressant response in resistant depression.
Current psychiatry reports
2005; 7 (6): 435-440
Most patients in acute depression trials fail to achieve remission with antidepressant monotherapy. Many patients seem to require more than one medication to achieve remission or adequate response. Augmentation strategies are commonly used in clinical practice, but most have been poorly studied. In addition, better-studied strategies, such as the use of lithium and thyroid augmentation, have not been well investigated in combination with newer antidepressants. Various novel strategies are being investigated as augmenting agents, including selective dopamine agonists, sex steroids, norepinephrine reuptake inhibitors, glucocorticoid-specific agents, and newer anticonvulsants. We review the status of augmentation strategies in the treatment of depression.
View details for PubMedID 16318821
The efficacy of divalproex sodium in the treatment of agitation associated with major depression
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
2005; 25 (5): 476-479
Agitation is both a feature of major depression and a common side effect of antidepressant treatment. Depressive agitation correlates with overall severity of illness and suicide risk, whereas treatment-emergent agitation may contribute to early discontinuation of pharmacotherapy. Thus, agitation merits investigation as a treatment target in clinical depression.In this study, adults with major depression were evaluated for change in agitation and other mood symptoms during adjunctive treatment with divalproex sodium. Twelve patients on antidepressants, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, were given low doses of divalproex sodium and evaluated repeatedly for symptoms of depression, anxiety, and agitation. Agitation severity was evaluated using the Overt Agitation Severity Scale and the Stanford Scale for Agitation Symptoms. Mood symptoms were assessed with the Hamilton Anxiety and the Hamilton Depression Rating Scales.Nine of 12 patients completed 4 weeks of treatment. All agitation scores decreased sharply, whereas depression (Hamilton Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale) symptoms decreased only modestly. Decreased agitation was not merely a function of decreases on the Hamilton Depression or Hamilton Anxiety Rating Scales. Relatively low doses of divalproex sodium appear to be useful in the treatment of agitation associated with major depression.The observation that decreases in agitation were not simply an artifact of overall change in depressive or anxiety symptoms is in keeping with the previous clinical impression that divalproex sodium has a specific effect on depressive agitation. Controlled clinical trials are needed to fully evaluate the utility and symptom specificity of divalproex sodium in depression.
View details for DOI 10.1097/01.jcp.0000177552.21338.b0
View details for Web of Science ID 000232287500015
View details for PubMedID 16160625
A placebo-controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction
JOURNAL OF CLINICAL PSYCHIATRY
2005; 66 (7): 844-848
Sexual side effects are among the common reasons patients discontinue selective serotonin reuptake inhibitors (SSRIs). While many antidotes have been proposed, few have been subjected to double-blind trials. Some evidence has suggested that bupropion may be an effective antidote for SSRI-induced sexual dysfunction. In this double-blind trial, the efficacy of a standard dose of bupropion sustained release (SR) is evaluated in the treatment of SSRI-induced sexual dysfunction.Patients with a history of SSRI-induced sexual side effects were randomly assigned to adjunctive treatment with either bupropion SR 150 mg daily or placebo for 6 weeks. Assessments of sexual function and interest included the Arizona Sexual Experiences Scale (ASEX), Brief Index of Sexual Functioning, and a 10-point visual analogue scale. Efficacy was defined as a 50% improvement on the ASEX at the end of 6 weeks. Data were collected from January 1999 to March 2001.Forty-one patients entered the study and completed the 6-week trial. No significant differences were seen between placebo and bupropion SR on the ASEX or on any measure of sexual functioning at the end of the trial.A fixed dose of 150 mg/day of bupropion SR taken in the morning does not appear to be effective in the treatment of SSRI-induced sexual dysfunction. Additional trials will be required to define what role, if any, bupropion might have in the treatment of SSRI-induced sexual side effects.
View details for Web of Science ID 000230663800006
View details for PubMedID 16013899
C-1073 (mifepristone) in the adjunctive treatment of Alzheimer's disease.
Current Alzheimer research
2005; 2 (2): 125-129
Alzheimer's disease is frequently associated with abnormalities in the hypothalamic pituitary adrenal axis. Elevated cortisol levels in Alzheimer's disease may in turn be associated with a more rapid progression of the illness. In addition, elevated cortisol levels may directly contribute to cognitive deficits in Alzheimer's disease. Mifepristone is a potent antagonist of the glucocorticoid receptor and blocks the central actions of cortisol. The purpose of this study is to determine the effects of glucocorticoid receptor blockade with mifepristone on cognition in Alzheimer's disease.
View details for PubMedID 15974908
Executive dysfunction in major depressive disorder.
Expert review of neurotherapeutics
2005; 5 (1): 79-83
Executive dysfunction is commonly seen in major depression. The types of executive deficits seen in depression include problems with planning, initiating and completing goal-directed activities. Executive dysfunction may vary as a function of the severity of depression. In addition, a subset of geriatric depression is also characterized by prominent deficits in executive functioning. The presence of executive dysfunction in depression is associated with vocational disability and possibly poorer treatment response. While few studies have examined the treatment of executive dysfunction in depression, preliminary work suggests that both pharmacologic interventions and psychosocial interventions such as problem solving therapy may be efficacious.
View details for PubMedID 15853477
A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness
JOURNAL OF CLINICAL PSYCHIATRY
2005; 66 (1): 85-93
Up to one half of depressed patients have partial or no response to antidepressant monotherapy. This multicenter, placebo-controlled study evaluated the efficacy of modafinil augmentation in major depressive disorder (MDD) patients with fatigue and excessive sleepiness despite selective serotonin reuptake inhibitor (SSRI) monotherapy.Patients (18-65 years) with a DSM-IV diagnosis of MDD and partial response to SSRI monotherapy (> or = 8 weeks) at a stable dose for > or = 4 weeks were eligible. Patients had screening/baseline 31-item Hamilton Rating Scale for Depression (HAM-D) scores of 14 to 26, Epworth Sleepiness Scale (ESS) scores > or = 10, and Fatigue Severity Scale (FSS) scores > or = 4. Patients were randomly assigned to augmentation therapy with modafinil 200 mg/day or placebo for 8 weeks. Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS).Of 311 enrolled patients who received > or = 1 dose of study drug, 158 were randomly assigned to modafinil (70% women) and 153 to placebo (72% women); 85% of each treatment group completed the study. At final visit, modafinil significantly improved patients' overall clinical condition compared with placebo on the basis of CGI-I scores (p = .02), and there were trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores versus placebo. Modafinil significantly reduced BFI scores for worst fatigue at final visit (p < .05 vs. placebo). There were no significant differences between modafinil and placebo at final visit in FSS or BFI total scores. Adverse events significantly more common during modafinil compared with placebo treatment were nausea (9% vs. 2%; p = .01) and feeling jittery (4% vs. 1%; p = .03).These findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness.
View details for Web of Science ID 000226493200012
View details for PubMedID 15669893
A double-blind, placebo controlled trial of C-1073 (mifepristone) in the treatment of psychotic major depression
43rd Annual Meeting of the American-College-of-Neuropsychopharmacology
NATURE PUBLISHING GROUP. 2004: S98–S98
View details for Web of Science ID 000225588000287
HPA axis activation in major depression and response to fluoxetine: a pilot study
2004; 29 (9): 1198-1204
Hypothalamic-pituitary-adrenal (HPA) axis activation is a frequently observed phenomenon in major depression. However, whether this activation has any implications for treatment is unknown. To address this question, we examined baseline response to metyrapone and 6-week response to fluoxetine. Premenopausal women (n = 20) who met criteria for major depression with no other confounding Axis I disorders, medications, or medical illnesses and were not taking hormonal contraceptives were evaluated with an evening metyrapone challenge before the onset of treatment. Twenty-one normal women were also studied with the evening metyrapone challenge. The depressed patients then entered an open label treatment with fluoxetine for 6 weeks. Subjects were classified as responders if they demonstrated a 50% or greater decrease in Hamilton Depression Rating Scale rating. As a group, the depressed women demonstrated significantly increased ACTH secretion compared to control women before the onset of treatment, during the metyrapone challenge. Before treatment, women who were non-responders to fluoxetine showed increased HPA axis activation compared to controls, while the fluoxetine responders did not differ significantly from normal subjects in their ACTH levels during metyrapone challenge. These results suggest that overactivity of the HPA axis may be one factor associated with slower response to fluoxetine. This may reflect the greater severity of subjects with HPA axis dysregulation or the need to normalize the HPA axis with medications for optimal response.
View details for DOI 10.1016/j.psyneuen.2004.02.002
View details for Web of Science ID 000223107600012
View details for PubMedID 15219644
Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder
2004; 29 (9): 1129-1137
Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.
View details for DOI 10.1016/j.psyneuen.2004.01.004
View details for Web of Science ID 000223107600004
View details for PubMedID 15219636
A prospective trial of modafinil as an adjunctive treatment of major depression
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
2004; 24 (1): 87-90
Modafinil is a wake-promoting agent approved by the Federal Drug Administration for the treatment of narcolepsy. Preliminary evidence indicates that modafinil may improve fatigue and excessive sleepiness associated with a variety of conditions. The purpose of this study was to investigate the utility of modafinil as an adjunctive treatment of depressed patients. Subjects with a history of major depression with partial response on a stable therapeutic dose of an antidepressant were eligible to participate. All subjects endorsed complaints of significant fatigue and/or excessive sleepiness on clinical assessment. Modafinil was added to their existing regimen at a dose of 100 to 400 mg/d for 4 weeks. Subjects were assessed at 2-week intervals for improvement using the standard depression scales (HDRS, BDI, CGI), fatigue scales (VASF, FSI), and a neuropsychologic battery. Thirty-five subjects were entered and 31 subjects completed the 4-week trial. Significant improvements were seen across all 3 measures of depression (HDRS, BDI, CGIS) and both measures of fatigue (VASF, FSI). On the neurocognitive battery, significant gains in the Stroop Interference Test were seen at 4 weeks, whereas the other cognitive tests showed no change. Modafinil may be a useful and a well-tolerated adjunctive agent to standard antidepressants in the treatment of major depression.
View details for DOI 10.1097/01.jcp.0000104910.75206.b9
View details for Web of Science ID 000188093400015
View details for PubMedID 14709953
Seizure duration with remifentanil/methohexital vs. methohexital alone in middle-aged patients undergoing electroconvulsive therapy
ACTA ANAESTHESIOLOGICA SCANDINAVICA
2003; 47 (9): 1064-1066
The object of this study was to test whether substituting part of the methohexital dose with the short-acting opioid remifentanil would prolong seizure duration in middle-aged patients while providing a similar depth of anesthesia as with methohexital alone. This has been reported for the combined use of methohexital and remifentanil in elderly patients, but has not been investigated in middle-aged patients likely to require a higher total dose of methohexital for inducing anesthesia.Seven patients (42+/-10 years; mean +/-SD) receiving electroconvulsive therapy (ECT) were anesthetized with methohexital (1.25 mg kg-1) or with methohexital (0.625 mg kg-1) plus remifentanil (1 micro g kg-1) in this randomized, double blind, crossover study. Additional methohexital was given as needed until loss of eyelash reflex was observed. Suxamethonium (1 mg kg-1) was used for muscular paralysis.Motor and EEG seizure durations were significantly longer after induction with methohexital plus remifentanil (45+/-14 and 58+/-15 s) than with methohexital alone (31+/-11 and 42+/-18 s). A methohexital dose of 1.2+/-0.3 and 1.9+/-0.3 mg was necessary to achieve loss of eyelash reflex if methohexital was used with and without remifentanil. Peak heart rate after ECT was significantly higher if remifentanil was coadministered with methohexital (148+/-12 vs. 126+/-24 b.p.m).Substituting part of the methohexital dose with remifentanil is a useful anesthetic technique to prolong seizure duration in middle-aged patients requiring a 1.5-fold higher induction dose of methohexital than elderly patients, the only population studied to date for the combined use of methohexital and remifentanil in ECT.
View details for Web of Science ID 000185251000003
View details for PubMedID 12969096
Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: A preliminary double-blind, placebo-controlled study
JOURNAL OF CLINICAL PSYCHIATRY
2003; 64 (9): 1057-1064
Fatigue and sleepiness are primary symptoms of depression that may not resolve with antidepressant therapy. Modafinil is a novel agent that has been shown to improve wakefulness and lessen fatigue in a variety of conditions. In this study, we examined the utility of modafinil as an adjunct therapy to treat fatigue and sleepiness in patients with major depression who are partial responders to antidepressants.Patients with partial response to anti-depressant therapy given for at least a 6-week period for a current major depressive episode (DSM-IV criteria) were enrolled in this 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients received once-daily doses (100-400 mg) of modafinil or matching placebo as adjunct treatment to ongoing antidepressant therapy. The effects of modafinil were evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Change (CGI-C), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Adverse events were monitored throughout the study.One hundred thirty-six patients were randomized to treatment, with 118 patients (87%) completing the study. Most patients (82%) were fatigued, and one half of patients (51%) were sleepy. Modafinil rapidly improved fatigue and daytime wakefulness, with significantly greater mean improvements from baseline than placebo in fatigue (FSS) scores at week 2 (p < .05) and sleepiness (ESS) scores at week 1 (p < .01); the differences between modafinil and placebo at week 6 were not statistically significant. Assessment of the augmentation effects of modafinil (HAM-D, CGI-C, and SF-36) did not significantly distinguish modafinil from placebo. Modafinil was well tolerated in combination with a variety of antidepressants.Modafinil may be a useful adjunct therapy for the short-term management of residual fatigue and sleepiness in patients who are partial responders to antidepressant therapy.
View details for Web of Science ID 000185457600011
View details for PubMedID 14628981
Safety of antidepressants in the elderly.
Expert opinion on drug safety
2003; 2 (4): 367-383
Until the 1980s, the two major classes of antidepressants, the tricyclics and the monoamine oxidase inhibitors (MAOIs), were effective but had severe side effects, requiring monitoring by psychiatrists. The past several years have brought new classes of antidepressants that are safer for the patient to take and far easier for the non-psychiatrist to prescribe. Whilst this is of enormous value, it leaves the physician with the dilemma of which one to prescribe. These new antidepressants cannot safely be used interchangeably. This paper will discuss each of the antidepressants presently available, with particular emphasis on safety in the elderly. Drug interactions, side effects and particular challenges to the older patient will be described. The authors will then advise a general strategy for prescribing antidepressants.
View details for PubMedID 12904093
A prospective trial of bupropion SR augmentation of partial and non-responders to Serotonergic antidepressants
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
2003; 23 (1): 27-30
Many patients fail to achieve an adequate response to a given antidepressant trial. The best-studied augmentation agents, lithium and thyroid supplementation are less commonly used. Augmenting antidepressants with bupropion has become an increasingly common strategy in the treatment of resistant depression. Several case reports and 2 open label studies suggest efficacy of this strategy. The purpose of this study is to further examine the utility of bupropion sustained release (SR) augmentation in patients with inadequate response to selective serotonin reuptake inhibitors. Patients who met DSM-IV criteria for major depression and had failed to achieve adequate response to an SSRI were considered for this study. Eligible patients were required to have a score of 16 on the 24-item Hamilton Depression Rating Scale (HDRS). Patients were treated openly for 6 weeks with bupropion SR added to their existing antidepressant. The dose range of bupropion was 150 to 300 mg per day. At each visit, patients were assessed using the Beck Depression Inventory (BDI), the Hamilton Depression Ratings Scale (HDRS), and the Clinical Global Impression (CGI). Twenty-eight patients (12 men, 16 women) entered the study. Twenty-five patients completed the six-week trial. With respect to the clinical benefit of bupropion SR augmentation, 15 out of 28, or 54% of patients, were classified as responders, showing a decrease in their HDRS or BDI scores of 50% or more between baseline and Week 6. This prospective, open-label trial supports the use of bupropion SR in the augmentation of SSRIs and venlafaxine. Placebo controlled trials should be completed to further evaluate the efficacy of this strategy.
View details for Web of Science ID 000180765000005
View details for PubMedID 12544372
The timing of electroconvulsive therapy and bispectral index after anesthesia induction using different drugs does not affect seizure duration
JOURNAL OF CLINICAL ANESTHESIA
2003; 15 (1): 29-32
To determine the association between bispectral index (BIS) and seizure duration obtained by electroconvulsive therapy (ECT) administered sooner or later after anesthetic induction.Prospective, randomized, crossover study.University-affiliated medical center.Nine ASA physical status I, II, and III patients undergoing a total of 31 ECTs.ECT was administered soon (<210 sec) or later (between 210 sec and 360 sec) after anesthetic induction. In each individual patient, drug regimens and ECT machine settings were identical.BIS immediately before the start of the ECT and the duration of the EEG seizure were recorded, as well as the time period between loss of consciousness and ECT administration.There was no relationship between BIS level and seizure duration. Moreover, seizure duration was not dependent on the time of ECT administration in the time window between one and 6 minutes after loss of consciousness.The hypnotic drug effect measured by the BIS is not correlated to the seizure duration obtained by ECT.
View details for DOI 10.1016/S0952-8180(02)00477-4
View details for Web of Science ID 000182004300006
View details for PubMedID 12657408
Fetal heart rate decelerations during ECT-induced seizures: is it important?
ACTA ANAESTHESIOLOGICA SCANDINAVICA
2003; 47 (1): 101-103
Electroconvulsive therapy (ECT) is sometimes indicated during pregnancy and may offer advantages over pharmacotherapy for the patient and the fetus (1,2). However, very little data is available on the impact of epileptic or ECT-induced seizures on the fetus. We report a case of brief fetal heart rate decelerations in a fetus associated with maternal ECT-induced convulsions.
View details for Web of Science ID 000179948400019
View details for PubMedID 12492807
The status of evidence-based guidelines and algorithms in the treatment of depression
2002; 32 (11): 658-663
View details for Web of Science ID 000179153800003
A dynamic algorithm for the treatment of psychotic major depression
2002; 32 (11): 681-691
View details for Web of Science ID 000179153800005
Novel strategies in the treatment of psychotic major depression
2002; 32 (11): 695-698
View details for Web of Science ID 000179153800006
An open label trial of C-1073 (mifepristone) for psychotic major depression
2002; 52 (5): 386-392
The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained.Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days.All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group.These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted.
View details for Web of Science ID 000177985100002
View details for PubMedID 12242054
Slowing the progression of cognitive decline in Alzheimer's disease using mifepristone
JOURNAL OF MOLECULAR NEUROSCIENCE
2002; 19 (1-2): 201-206
High circulating levels of glucocorticoid hormones adversely affect cognition. Previous studies exploring the hypothalamic-pituitary-adrenal (HPA) axis and basal cortisol levels in the elderly reported that subjects with mid-range cortisol levels outperformed subjects with high cortisol levels on assessments of memory and attention. This study examines the efficacy of mifepristone, a glucocorticoid-antagonist, in decelerating the rate of cortisol-related cognitive decline in subjects with mile-to-moderate Alzheimer's disease (AD). Rate of cognitve decline is compared in AD subjects randomized to receive 200 mg of mifepristone daily for 6 mo or placebo. The Alzheimer's Disease Assessment Scale (ADAS) and the Folstein Mini Mental Status Exam (MMSE) will be the primary measures used to assess change in cognitve function over the 6 mo period, supplemented by a neuropsychological battery testing memory and language and reasoning skills. During each visit, subjects will have samples collected for determination of plasma adrenocorticotropin (ACTH), serum cortisol and salivary cortisol levels to assess HPA axis activity. The placebo arm of this study also investigate whether subjects with high baseline cortisol levels experience greater declines in cognitive impairment over time relative to subjects with Ad who have low baseline cortisol levels. Additionally, this study test the hypothesis that AD subjects with elevated cortisol at baseline will perform more poorly on neuropsychological exams that do subjects with low cortisol.
View details for Web of Science ID 000177794700032
View details for PubMedID 12212781
Delusional major depression: new treatment approaches
Collegium Internationale Neuro-Psychopharmacologicum (CINP)
LIPPINCOTT WILLIAMS & WILKINS. 2002: S99–S100
View details for Web of Science ID 000179199800215
Effect of Hypericum perforatum (St John's wort) in major depressive disorder - A randomized controlled trial
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2002; 287 (14): 1807-1814
Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated.To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder.Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States.Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20.Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks.Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores.On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo.This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.
View details for Web of Science ID 000174881700033
View details for PubMedID 11939866
Cortisol feedback during the HPA quiescent period in patients with major depression
AMERICAN JOURNAL OF PSYCHIATRY
2001; 158 (12): 2083-2085
The authors tested the hypothesis that patients with major depression have a defect in the mechanism by which cortisol exerts negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis during the HPA axis quiescent period.Twenty-nine patients with major depression and 25 healthy comparison subjects were randomly assigned to administration of 15 mg cortisol or placebo infused over 2 hours beginning at 7:00 p.m. Cortisol and ACTH levels were measured at baseline and every 30 minutes from 7:30 p.m. to 11:00 p.m.Differences between the patients and the comparison subjects in the ACTH response to the cortisol infusion, relative to the ACTH response to placebo, were not found.The results provide some evidence that patients with major depression do not have an abnormality of cortisol feedback during the HPA axis quiescent period.
View details for Web of Science ID 000172452100028
View details for PubMedID 11729034
Is electroconvulsive therapy effective for the depressed patient with comorbid borderline personality disorder?
JOURNAL OF ECT
2001; 17 (2): 91-98
Among the more common current indications for electroconvulsive therapy (ECT) is treatment-resistant depression. Treatment resistance is correlated with a number of factors, including the presence of comorbid personality disorders, such as borderline personality disorder (BPD). A detailed review of the literature was undertaken and very few reports or studies have dealt specifically with ECT in borderline patients. Thirteen original reports on ECT outcome in personality disordered patients were identified. Depressed patients with a personality disorder, particularly BPD, may have a poorer outcome on some measures. However, the available data suggests that depression in these patients can be effectively treated with ECT. The depressed, borderline patient appears to have two distinct disorders, one which is responsive to ECT and the other which is not. Unfortunately, the literature is limited by lack of rigorous randomized treatment studies, lack of long-term follow-up, and other methodological weaknesses. Clinical guidelines are suggested.
View details for Web of Science ID 000169270500002
View details for PubMedID 11417933
Sertraline versus imipramine to prevent relapse in chronic depression
JOURNAL OF AFFECTIVE DISORDERS
2001; 65 (1): 27-36
Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study.After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment.Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment.The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates.Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.
View details for Web of Science ID 000168910100005
View details for PubMedID 11426506
Psychopharmacologic treatment strategies for depression, bipolar disorder, and schizophrenia
ANNALS OF INTERNAL MEDICINE
2001; 134 (1): 47-60
Patients with serious psychiatric disorders are frequently treated by primary care physicians, who may have difficulty keeping up with recent advances in psychiatry. This paper presents an updated synopsis for three major psychiatric illnesses: major depression, bipolar disorder, and schizophrenia. Current definitions, updated diagnostic criteria, short- and long-term treatment strategies with algorithms, and special challenges for the clinician are discussed for each of these illnesses. On the basis of each illness's distinct characteristics, five treatment principles are emphasized: 1) Treatment strategies should be long-term and should emphasize adherence, 2) treatment choice should be empirical, 3) combinations of medications may be helpful, 4) a combination of psychosocial and pharmacologic treatments may be more useful than either alone, and 5) the family or "significant others" as well as a consumer organization need to be involved. Some of the new directions in dinical research to refine these strategies and meet these challenges are also described.
View details for Web of Science ID 000166043300007
View details for PubMedID 11187420
Acute antidepressant effects of intravenous hydrocortisone and CRH in depressed patients: A double-blind, placebo-controlled study
AMERICAN JOURNAL OF PSYCHIATRY
2000; 157 (8): 1334-1337
The primary objective of this investigation was to examine the acute antidepressant effects of intravenous hydrocortisone and ovine corticotropin releasing hormone (CRH) infusions in patients with major depression.Twenty-two patients who met DSM-III-R criteria for nonpsychotic major depression were randomly assigned to receive intravenously 1 mg/kg of ovine CRH, 15 mg of hydrocortisone, or saline under double-blind conditions on day 1. Standard depression rating scales were completed on day 1 before the study medications were administered and again the following day (day 2).Patients treated with hydrocortisone demonstrated a significantly greater reduction in total 21-item Hamilton Depression Rating Scale scores (mean reduction=8.4 points or 37%) than patients given ovine CRH (mean=1.2 points) or placebo (mean=1.3 points).Acute hydrocortisone infusion is associated with a rapid and robust reduction in depressive symptoms. The authors discuss the therapeutic implications of these findings.
View details for Web of Science ID 000088520100027
View details for PubMedID 10910802
24-hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression
28th Annual Meeting of the International-Society-of-Psychoneuroendocrinology
AMER MEDICAL ASSOC. 2000: 755–60
Considerable research has been devoted to the hypothalamic-pituitary-adrenal (HPA) axis in depression, but relatively little attention has been given to intensive monitoring of hormone secretion over time. Such research is potentially important because the HPA axis has prominent circadian and ultradian periodicity. Comparison of depressed patients with and without psychotic features is also important because HPA axis abnormalities may be especially pronounced in psychotic depressed patients.Eleven patients with psychotic major depression (PMD patients), 38 patients with nonpsychotic major depression (NPMD patients), and 33 healthy control subjects, all drug free, were studied. Patients with PMD and NPMD were outpatients recruited primarily by advertisement. Subjects were admitted to a General Clinical Research Center and had blood drawn through an intravenous line for determination of cortisol and corticotropin (ACTH) levels every hour for 24 hours.Among NPMD patients, the 24-hour cortisol amplitude was significantly (P =.02) reduced in comparison with control subjects, while ACTH indices did not differ between NPMD patients and the control group. Among PMD patients, the ACTH 24-hour mean was significantly (P =.03) increased compared with controls, while PMD patients and the control group did not differ significantly in cortisol indices.In the population studied, PMD and NPMD patients have distinct profiles of HPA axis dysregulation.
View details for Web of Science ID 000088582000005
View details for PubMedID 10920463
Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness
AMERICAN JOURNAL OF PSYCHIATRY
2000; 157 (7): 1095-1100
At least three studies have indicated that patients with psychotic major depression studied under non-drug-free conditions differ from patients with nonpsychotic major depression and healthy comparison subjects on several measures of neuropsychological performance. The current study explored specific impairments in cognitive function in subjects with psychotic major depression, subjects with nonpsychotic major depression, and healthy comparison subjects studied under drug-free conditions.A battery of neuropsychological tests was administered to 11 patients with psychotic major depression, 32 patients with nonpsychotic major depression, and 23 normal comparison subjects under drug-free conditions. The three groups did not differ statistically in age, sex, or level of education. To ensure that participants had minimal levels of severity and endogenicity, all patients were required to have a score of at least 20 on the 21-item Hamilton Depression Rating Scale and a score of at least 7 on the Core Endogenomorphic Scale, which uses eight items from the Hamilton depression scale.Patients with psychotic major depression demonstrated significantly greater impairment than patients with nonpsychotic major depression and/or comparison subjects in attention and response inhibition (as measured by the Stroop color-word subscale score) as well as in verbal declarative memory (as measured by the Paragraph Recall Test).These data indicate that patients with psychotic major depression demonstrate impairment in functions thought to be mediated by the frontal cortex and mediotemporal lobes.
View details for Web of Science ID 000087931200011
View details for PubMedID 10873917
A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression.
New England journal of medicine
2000; 342 (20): 1462-1470
Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain.We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments.Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group. (P<0.001 for both comparisons). Among the 519 subjects who completed the study, the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group, as compared with 85 percent in the combined-treatment group (P<0.001 for both comparisons). The rates of withdrawal were similar in the three groups. Adverse events in the nefazodone group were consistent with the known side effects of the drug (e.g., headache, somnolence, dry mouth, nausea, and dizziness).Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.
View details for PubMedID 10816183
A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression
NEW ENGLAND JOURNAL OF MEDICINE
2000; 342 (20): 1462-1470
View details for Web of Science ID 000087068200001
- Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 2000; 20 (2): 274-275
- Negative-pressure pulmonary edema: A potential mazard in patients undergoing ECT JOURNAL OF ECT 1999; 15 (2): 168-170
The Texas Medication Algorithm Project: Report of the Texas Consensus Conference Panel on medication treatment of major depressive disorder
JOURNAL OF CLINICAL PSYCHIATRY
1999; 60 (3): 142-156
This article describes the development of consensus medication algorithms for the treatment of patients with major depressive disorder in the Texas public mental health system. To the best of our knowledge, the Texas Medication Algorithm Project (TMAP) is the first attempt to develop and prospectively evaluate consensus-based medication algorithms for the treatment of individuals with severe and persistent mental illnesses. The goals of the algorithm project are to increase the consistency of appropriate treatment of major depressive disorder and to improve clinical outcomes of patients with the disorder.A consensus conference composed of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of major depressive disorder in the Texas mental health system. After a series of presentations and panel discussions, the consensus panel met and drafted the algorithms.The panel consensually agreed on algorithms developed for both nonpsychotic and psychotic depression. The algorithms consist of systematic strategies to define appropriate treatment interventions and tactics to assure optimal implementation of the strategies. Subsequent to the consensus process, the algorithms were further modified and expanded iteratively to facilitate implementation on a local basis.These algorithms serve as the initial foundation for the development and implementation of medication treatment algorithms for patients treated in public mental health systems. Specific issues related to adaptation, implementation, feasibility testing, and evaluation of outcomes with the pharmacotherapeutic algorithms will be described in future articles.
View details for Web of Science ID 000079368100002
View details for PubMedID 10192589
Phenomenology and treatment of agitation
Closed Symposium on the Phenomenology and Treatment of Agression Across Psychiatric Illnesses
PHYSICIANS POSTGRADUATE PRESS. 1999: 17–20
Agitation is a troublesome, common symptom in major depression that can be difficult to manage. It is sometimes a side effect of antidepressant treatment and may occasionally represent a mixed bipolar episode. If agitation fails to respond to an antidepressant alone, treatment may be augmented with a benzodiazepine, a neuroleptic, or lithium. Preliminary evidence indicates that divalproex, which has been found useful for bipolar disorder and for agitation associated with Alzheimer's disease, may also be effective for agitated depression. A controlled trial is now underway.
View details for Web of Science ID 000081543500004
View details for PubMedID 10418809
ECT in dissociative identity disorder and comorbid depression
JOURNAL OF ECT
1998; 14 (4): 275-279
Dissociative identity disorder (DID), previously named multiple personality disorder, is a diagnosis often complicated by comorbid major depression. We report on four cases of DID associated with severe self-destructive behavior and comorbid major depression treated with electroconvulsive therapy (ECT). In three of the patients, ECT appeared to be helpful in treating the comorbid depression without adversely affecting the DID. The potential risks of using ECT in patients with DID are reviewed.
View details for Web of Science ID 000084422900011
View details for PubMedID 9871851
Serotonergic synergism: The risks and benefits of combining the selective serotonin reuptake inhibitors with other serotonergic drugs
Neuroscience Discussion Forum on a Decade of Serotonin Research
ELSEVIER SCIENCE INC. 1998: 341–47
It has become common clinical practice to combine the selective serotonin reuptake inhibitors with other serotonergic agents for augmentation or adjunctive purposes. The empirical basis for using these combinations remains limited, but is growing. Also growing is a literature that suggests that even the most apparently benign combinations of serotonergic drugs carry at least some risk of serious pharmacokinetic or pharmacodynamic drug interactions, such as a serotonin syndrome.
View details for Web of Science ID 000075793700005
View details for PubMedID 9755356
- Developing treatment algorithms for unipolar depression in cyberspace: International Psychopharmacology Algorithm Project (IPAP) PSYCHOPHARMACOLOGY BULLETIN 1998; 34 (3): 355-359
- Treatment of psychotic depression AMERICAN JOURNAL OF PSYCHIATRY 1997; 154 (11): 1625-1626
Does ketorolac prophylaxis prevent succinylcholine induced myalgias following electroconvulsive therapy?
LIPPINCOTT WILLIAMS & WILKINS. 1997: S20–S20
View details for Web of Science ID A1997WF78000020
Valproate in the treatment of agitation associated with depression
1996; 26 (7): S470-S473
View details for Web of Science ID A1996UY62800010
- Development of obsessive symptoms during nefazodone treatment AMERICAN JOURNAL OF PSYCHIATRY 1996; 153 (4): 577-578
SUMATRIPTAN PROPHYLAXIS FOR POSTELECTROCONVULSIVE THERAPY HEADACHES
1995; 35 (8): 502-503
Very little has been written about headaches following electroconvulsive therapy (ECT) but the incidence has been estimated at 26%. Patients with a history of migraine occasionally have similar headaches precipitated by ECT. In addition, some patients may have headaches that persist for months after a series of ECT treatments, while some patients who have a preexisting headache problem report improvement with ECT. Serotonergic mechanisms have been proposed both for the efficacy of ECT and its tendency to produce headaches in susceptible patients. There have been no studies on the prophylaxis or treatment of post-ECT headache. While various strategies have been suggested for these headaches, even case reports documenting the efficacy of these strategies are lacking. We, therefore, report a case of severe, refractory, post-ECT headaches which responded to prophylactic treatment with sumatriptan.
View details for Web of Science ID A1995RW29600014
View details for PubMedID 7591748
- PHYSICAL SYMPTOMS ASSOCIATED WITH PAROXETINE WITHDRAWAL AMERICAN JOURNAL OF PSYCHIATRY 1995; 152 (8): 1235-1236
PHARMACOTHERAPY OF PERSONALITY-DISORDERS
CURRENT OPINION IN PSYCHIATRY
1995; 8 (2): 102-105
View details for Web of Science ID A1995QM15000009
AN ALGORITHM FOR THE TREATMENT OF MAJOR DEPRESSION AND ITS SUBTYPES
1994; 24 (7): 341-347
View details for Web of Science ID A1994NX26200004