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1.  Nutrition, Exercise, and Wellness Treatment in bipolar disorder: proof of concept for a consolidated intervention 
Background
This pilot study examines the proof of concept of a consolidated Nutrition, Exercise, and Wellness Treatment (NEW Tx) for overweight individuals with bipolar disorder.
Findings
Five participants completed NEW Tx, a 20-week individual cognitive behavioral therapy-based treatment comprising three modules: Nutrition teaches appropriate serving sizes and balanced diet; Exercise emphasizes increasing weekly physical activity; Wellness focuses on skills for healthy decision-making. Participants attended most sessions and reported high satisfaction with the treatment. Participants’ weight, cholesterol and trigyclerides decreased over the study duration as well as number of daily calories and sugar intake. We found that weekly exercise duration more than tripled over the study duration and depressive symptoms and functioning have improved.
Conclusions
These results offer proof of concept that consolidated NEW Tx is feasible and acceptable and has the potential to improve nutrition, exercise, wellness, and mood symptoms in bipolar disorder. Future iterations of NEW Tx will reflect the strengths and lessons learned from this study.
doi:10.1186/2194-7511-1-24
PMCID: PMC3961757  PMID: 24660139
Bipolar disorder; Exercise; Behavior therapy; Cognitive behavior therapy; Cardiovascular disease
2.  Do Comorbid Anxiety Disorders Moderate the Effects of Psychotherapy for Bipolar Disorder? Results From STEP-BD 
The American journal of psychiatry  2014;171(2):178-186.
Objective
At least 50% of individuals with bipolar disorder have a lifetime anxiety disorder. Individuals with both bipolar disorder and a co-occurring anxiety disorder experience longer illness duration, greater illness severity, and poorer treatment response. The study explored whether comorbid lifetime anxiety in bipolar patients moderates psychotherapy treatment outcome.
Method
In the Systematic Treatment Enhancement Program randomized controlled trial of psychotherapy for bipolar depression, participants received up to 30 sessions of intensive psychotherapy (family-focused therapy, interpersonal and social rhythm therapy, or cognitive-behavioral therapy) or collaborative care, a three-session comparison treatment, plus pharmacotherapy. Using the number needed to treat, we computed effect sizes to analyze the relationship between lifetime anxiety disorders and rates of recovery across treatment groups after 1 year.
Results
A total of 269 patients (113 women) with a comorbid lifetime anxiety disorder (N=177) or without a comorbid lifetime anxiety disorder (N=92) were included in the analysis. Participants with a lifetime anxiety disorder were more likely to recover with psychotherapy than with collaborative care (66% compared with 49% recovered over 1 year; number needed to treat=5.88, small to medium effect). For patients without a lifetime anxiety disorder, there was no difference between rates of recovery in psychotherapy compared with collaborative care (64% compared with 62% recovered; number needed to treat=50, small effect). Participants with one lifetime anxiety disorder were likely to benefit from intensive psychotherapy compared with collaborative care (84% compared with 53% recovered; number needed to treat=3.22, medium to large effect), whereas patients with multiple anxiety disorders exhibited no difference in response to the two treatments (54% compared with 46% recovered; number needed to treat=12.5, small effect).
Conclusions
Depressed patients with bipolar disorder and comorbid anxiety may be in particular need of additional psychotherapy for treating acute depression. These results need to be replicated in studies that stratify bipolar patients to treatments based on their anxiety comorbidity status.
doi:10.1176/appi.ajp.2013.13020225
PMCID: PMC3946300  PMID: 24077657
3.  Transdiagnostic Treatment of Bipolar Disorder and Comorbid Anxiety with the Unified Protocol: A Clinical Replication Series 
Behavior modification  2012;36(4):482-508.
Bipolar disorder (BD) is a chronic, debilitating disorder with recurrent manic and depressive episodes. Over 75% of bipolar patients have a current or lifetime diagnosis of a comorbid anxiety disorder. Comorbid anxiety in BD is associated with greater illness severity, greater functional impairment, and poorer illness-related outcomes. Effectively treating comorbid anxiety in individuals with BD has been recognized as one of the biggest unmet needs in the field of bipolar disorder. Recently, the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) was developed to be applicable to the full range of anxiety and mood disorders, based upon converging evidence from genetics, cognitive and affective neuroscience, and behavioral research suggesting common, core emotion-related pathology. Here, we present a preliminary evaluation of the efficacy of the UP for the treatment of BD with comorbid anxiety, in a clinical replication series consisting of three cases.
doi:10.1177/0145445512451272
PMCID: PMC3913370  PMID: 22822175
4.  General Medical Burden in Bipolar Disorder: Findings from the LiTMUS Comparative Effectiveness Trial 
Acta psychiatrica Scandinavica  2013;129(1):10.1111/acps.12101.
Objective
This study examined general medical illnesses and their association with clinical features of bipolar disorder.
Methods
Data were cross-sectional and derived from the Lithium Treatment – Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n=264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥ 4 and < 4, respectively.
Results
The baseline prevalence of significant medical comorbidity was 53% (n=139). Patients with high medical burden were more likely to present in a major depressive episode (P=.04), meet criteria for obsessive-compulsive disorder (P=.02), and experience a greater number of lifetime mood episodes (P=0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P=.002). Sixty-nine percent of the sample was overweight or obese as defined by body mass index (BMI), with African-Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥ 35; 31%, n=14).
Conclusions
The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns. (Funded by NIMH Contract N01MH80001; ClinicalTrials.gov number NCT00667745).
doi:10.1111/acps.12101
PMCID: PMC3789858  PMID: 23465084
Bipolar disorder; medical comorbidity; obesity; lithium; effectiveness
5.  Association Between Therapeutic Alliance, Care Satisfaction, and Pharmacological Adherence in Bipolar Disorder 
Journal of clinical psychopharmacology  2013;33(3):10.1097/JCP.0b013e3182900c6f.
Objectives
We sought to understand the association of specific aspects of care satisfaction, such as patients’ perceived relationship with their psychiatrist and access to their psychiatrist and staff, and therapeutic alliance with participants’ likelihood to adhere to their medication regimens among patients with bipolar disorder.
Methods
We examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder, an effectiveness study investigating the course and treatment of bipolar disorder. We expected that participants (n = 3037) with positive perceptions of their relationship with their psychiatrist and quality of psychopharmacologic care, as assessed by the Helping Alliance Questionnaire and Care Satisfaction Questionnaire, would be associated with better medication adherence. We utilized logistic regression models controlling for already established factors associated with poor adherence.
Results
Patients’ perceptions of collaboration, empathy, and accessibility were significantly associated with adherence to treatment in individuals with bipolar disorder completing at least 1 assessment. Patients’ perceptions of their psychiatrists’ experience, as well as of their degree of discussing medication risks and benefits, were not associated with medication adherence.
Conclusions
Patients’ perceived therapeutic alliance and treatment environment impact their adherence to pharmacotherapy recommendations. This study may enable psychopharmacologists’ practices to be structured to maximize features associated with greater medication adherence.
doi:10.1097/JCP.0b013e3182900c6f
PMCID: PMC3873324  PMID: 23609394
therapeutic alliance; clinical practice; medication adherence; bipolar disorder; treatment
6.  Andrew C Leon 
Neuropsychopharmacology  2012;37(13):2890.
doi:10.1038/npp.2012.201
PMCID: PMC3499720
7.  Sleep Disturbance in Euthymic Bipolar Patients 
Objective
Sleep disturbance is a common feature during mood episodes in bipolar disorder. The aim of this study was to investigate the prevalence of such symptoms among euthymic bipolar patients, and their association with risk for mood episode recurrence.
Method
A cohort of bipolar I and II subjects participating in the Systematic Treatment Enhancement Program for Bipolar Disorder who were euthymic for at least eight weeks were included in this analysis. Survival analysis was used to examine the association between sleep disturbance on the Montgomery-Asberg Depression Rating Scale (MADRS) and recurrence risk.
Results
73/483 bipolar I and II subjects reported at least mild sleep disturbance (MADRS sleep item ≥ 2) for the week prior to study entry. The presence of sleep problems was associated with a history of psychosis, number of previous suicide attempts, and anticonvulsant use. Sleep disturbance at study entry was significantly associated with risk for mood episode recurrence.
Conclusions
Sleep disturbance is not uncommon between episodes for individuals with bipolar disorder and may be associated with a more severe course of illness. This suggests that sleep disturbance is an important prodromal symptom of bipolar disorder and should be considered a target for pharmacologic or psychosocial maintenance treatment.
doi:10.1177/0269881111421973
PMCID: PMC3787715  PMID: 21965189
Bipolar disorder; sleep disturbance; relapse prevention; treatment
8.  Extreme Attributions Predict the Course of Bipolar Depression: Results from the STEP-BD Randomized Controlled Trial of Psychosocial Treatment 
Objective
Little is known about predictors of recovery from bipolar depression or moderators of treatment response. In the present study we investigated attributional style (a cognitive pattern of explaining the causes of life events) as a predictor of recovery from episodes of bipolar depression and as a moderator of response to psychotherapy for bipolar depression.
Method
106 depressed outpatients with DSM-IV bipolar I or II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomized to intensive psychotherapy for depression (n=62), or collaborative care (n=44), a minimal psychoeducational intervention. The primary outcome was recovery status at each study visit as measured by the Clinical Monitoring Form. Attributional style was measured at baseline using the Attributional Style Questionnaire. Data were collected between 1998 and 2005.
Results
All analyses were by intention to treat. Extreme attributions predicted a lower likelihood of recovery (p=.01, OR=0.93, 95% CI=.88-.98) and longer time until recovery (p<.01, OR=0.96, 95% CI=.93-.99), independent of the effects of initial depression severity. Among individuals with more pessimistic attributional styles, initial depression severity predicted a lower likelihood of recovery (p=.01, OR=0.64, 95% CI=.45-.91) and longer time until recovery (p<.001, OR=0.76, 95% CI=.66-.88). There was no difference in recovery rates between intensive psychotherapy and collaborative care (OR=0.90, 95% CI=0.40-2.01) in the full sample.
Conclusions
These results suggest that extreme, rigid attributions may be associated with a more severe course of depression, and that evaluating attributional style may help clinicians to identify patients who are at risk for experiencing a more severe course of depression.
doi:10.4088/JCP.12m08019
PMCID: PMC3646511  PMID: 23561230
9.  Mindfulness-based Cognitive Therapy for Non-remitted Patients with Bipolar Disorder 
CNS neuroscience & therapeutics  2011;18(2):133-141.
Introduction
Bipolar disorder is characterized by recurrent episodes of depression and/or mania along with inter-episodic mood symptoms that interfere with psychosocial functioning. Despite periods of symptomatic recovery, many individuals with bipolar disorder continue to experience substantial residual mood symptoms that often lead to the recurrence of mood episodes.
Aims
The present study explored whether a new mindfulness-based cognitive therapy (MBCT) for bipolar disorder would increase mindfulness, reduce residual mood symptoms, and increase emotion regulation abilities, psychological well-being, positive affect and psychosocial functioning. Following a baseline clinical assessment, 12 individuals with DSM-IV bipolar disorder were treated with 12 group sessions of MBCT.
Results
At the end of treatment, as well as at the 3-months follow-up, participants showed increased mindfulness, lower residual depressive mood symptoms, less attentional difficulties, and increased emotion regulation abilities, psychological well-being, positive affect and psychosocial functioning.
Conclusions
These findings suggest that treating residual mood symptoms with MBCT may be another avenue to improving mood, emotion regulation, well-being and functioning in individuals with bipolar disorder.
doi:10.1111/j.1755-5949.2011.00236.x
PMCID: PMC3738005  PMID: 22070469
Bipolar Disorder; Residual Symptoms; Well-being; Mindfulness-based Cognitive Therapy; Cognitive-Behavior Therapy
10.  Methods to Limit Attrition in Longitudinal Comparative Effectiveness Trials: Lessons from the Lithium Use for Bipolar Disorder (LiTMUS) Study 
Background
High attrition rates which occur frequently in longitudinal clinical trials of interventions for bipolar disorder limit the interpretation of results.
Purpose
The aim of this article is to present design approaches that limited attrition in the Lithium Use for Bipolar Disorder (LiTMUS) Study.
Methods
LiTMUS was a 6-month randomized, longitudinal multi-site comparative effectiveness trial that examined bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium, in addition to other treatments needed for mood stabilization administered in a guideline-informed, empirically supported, and personalized fashion (N=283).
Results
Components of the study design that may have contributed to the low attrition rate of the study included use of: (1) an intent-to-treat design; (2) a randomized adjunctive single-blind design; (3) participant reimbursement; (4) intent-to-attend the next study visit (includes a discussion of attendance obstacles when intention is low); (5) quality care with limited participant burden; and (6) target windows for study visits.
Limitations
Site differences and the effectiveness and tolerability data have not been analyzed yet.
Conclusions
These components of the LiTMUS study design may have reduced the probability of attrition which would inform the design of future randomized clinical effectiveness trials.
doi:10.1177/1740774511427324
PMCID: PMC3700408  PMID: 22076437
Attrition; Randomized Clinical Trial Design; Bipolar disorder; Lithium
11.  Residual Symptoms in Depressed Outpatients Who Respond by 50% But Do Not Remit to Antidepressant Medication 
Little is known about the quantity or quality of residual depressive symptoms in patients with major depressive disorder (MDD) who have responded but not remitted with antidepressant treatment. This report describes the residual symptom domains and individual depressive symptoms in a large representative sample of outpatients with nonpsychotic MDD who responded without remitting after up to 12 weeks of citalopram treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Response was defined as 50% or greater reduction in baseline 16-item Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR16) by treatment exit, and remission as a final QIDS-SR16 of less than 6. Residual symptom domains and individual symptoms were based on the QIDS-SR16 and classified as either persisting from baseline or emerging during treatment. Most responders who did not remit endorsed approximately 5 residual symptom domains and 6 to 7 residual depressive symptoms. The most common domains were insomnia (94.6%), sad mood (70.8%), and decreased concentration (69.6%). The most common individual symptoms were midnocturnal insomnia (79.0%), sad mood (70.8%), and decreased concentration/decision making (69.6%). The most common treatment-emergent symptoms were midnocturnal insomnia (51.4%) and decreased general interest (40.0%). The most common persistent symptoms were midnocturnal insomnia (81.6%), sad mood (70.8%), and decreased concentration/decision making (70.6%). Suicidal ideation was the least common treatment-emergent symptom (0.7%) and the least common persistent residual symptom (17.1%). These findings suggest that depressed outpatients who respond by 50% without remitting to citalopram treatment have a broad range of residual symptoms. Individualized treatments are warranted to specifically address each patient's residual depressive symptoms.
doi:10.1097/JCP.0b013e31820ebd2c
PMCID: PMC3677201  PMID: 21346613
depression; STAR*D; residual; symptoms; treatment response
12.  Customization in Prescribing for Bipolar Disorder 
Health Economics  2011;21(6):653-668.
For many disorders, patient heterogeneity requires physicians to customize their treatment to each patient’s needs. We test for the existence of customization in physicians’ prescribing for bipolar disorder, using data from a naturalistic clinical effectiveness trial of bipolar disorder treatment (STEP-BD), which did not constrain physician prescribing. Multinomial logit is used to model the physician’s choice among five combinations of drug classes. We find that our observed measure of the patient’s clinical status played only a limited role in the choice among drug class combinations, even for conditions such as mania that are expected to affect class choice. However, treatment of a patient with given characteristics differed widely depending on which physician was seen. The explanatory power of the model was low. There was variation within each physician’s prescribing, but the results do not suggest a high degree of customization in physicians’ prescribing, based on our measure of clinical status.
doi:10.1002/hec.1737
PMCID: PMC3164906  PMID: 21506194
Bipolar disorder; pharmaceuticals; prescribing decisions; personalization
13.  Development of an Integrated Psychosocial Treatment to Address the Medical Burden Associated with Bipolar Disorder 
Journal of psychiatric practice  2011;17(3):224-232.
We developed an integrated psychosocial treatment for bipolar disorder to decrease the disproportionate medical burden associated with this illness. Three treatment modules, Nutrition/weight loss, Exercise, and Wellness Treatment (NEW Tx) were administered in twelve 60-minute group sessions over 14 weeks. After the first group (N = 4) had completed the treatment, it was revised, and then a second group (N = 6) completed the revised treatment. Participants completed all of the study assessments and attended 82% of the sessions. Both groups added over 100 minutes of weekly exercise to their baseline duration. Participants in the second group showed improvements in their quality of life, depressive symptoms, and weight. It appears that NEW Tx may be a feasible intervention with promising pilot data for reducing the medical burden in bipolar disorder, but future research is needed to further evaluate the efficacy of NEW Tx.
doi:10.1097/01.pra.0000398419.82362.32
PMCID: PMC3659403  PMID: 21587004
bipolar disorder; psychosocial treatment; diet; exercise; cognitive-behavioral therapy
14.  Psychosocial Treatments for Bipolar Depression: A 1-Year Randomized Trial From the Systematic Treatment Enhancement Program 
Archives of general psychiatry  2007;64(4):419-426.
Context
Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder.
Objective
To examine the benefits of 4 disorder-specific psychotherapies in conjunction with pharmacotherapy on time to recovery and the likelihood of remaining well after an episode of bipolar depression.
Design
Randomized controlled trial.
Setting
Fifteen clinics affiliated with the Systematic Treatment Enhancement Program for Bipolar Disorder.
Patients
A total of 293 referred outpatients with bipolar I or II disorder and depression treated with protocol pharmacotherapy were randomly assigned to intensive psychotherapy (n=163) or collaborative care (n=130), a brief psychoeducational intervention.
Interventions
Intensive psychotherapy was given weekly and biweekly for up to 30 sessions in 9 months according to protocols for family-focused therapy, interpersonal and social rhythm therapy, and cognitive behavior therapy. Collaborative care consisted of 3 sessions in 6 weeks.
Main Outcome Measures
Outcome assessments were performed by psychiatrists at each pharmacotherapy visit. Primary outcomes included time to recovery and the proportion of patients classified as well during each of 12 study months.
Results
All analyses were by intention to treat. Rates of attrition did not differ across the intensive psychotherapy (35.6%) and collaborative care (30.8%) conditions. Patients receiving intensive psychotherapy had significantly higher year-end recovery rates (64.4% vs 51.5%) and shorter times to recovery than patients in collaborative care (hazard ratio, 1.47; 95% confidence interval, 1.08–2.00; P=.01). Patients in intensive psychotherapy were 1.58 times (95% confidence interval, 1.17–2.13) more likely to be clinically well during any study month than those in collaborative care (P=.003). No statistically significant differences were observed in the outcomes of the 3 intensive psychotherapies.
Conclusions
Intensive psychosocial treatment as an adjunct to pharmacotherapy was more beneficial than brief treatment in enhancing stabilization from bipolar depression. Future studies should compare the cost-effectiveness of models of psychotherapy for bipolar disorder.
Trial Registration
clinicaltrials.gov Identifier: NCT00012558
doi:10.1001/archpsyc.64.4.419
PMCID: PMC3579612  PMID: 17404119
15.  Stability of symptoms across major depressive episodes in bipolar disorder 
Bipolar disorders  2009;11(8):867-875.
Objective
Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated.
Methods
We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression.
Results
A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes.
Conclusion
While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.
doi:10.1111/j.1399-5618.2009.00764.x
PMCID: PMC3566555  PMID: 19922555
bipolar disorder; factor analysis; major depression; mixed state; psychosis; subtype; suicide; symptom stability
16.  Mindfulness-Based Cognitive Therapy for Bipolar Disorder: Effects on Cognitive Functioning 
Journal of Psychiatric Practice  2011;17(6):410-419.
Bipolar disorder is associated with impairments in cognition, including difficulties in executive functioning, even when patients are euthymic (neither depressed nor manic). The purpose of this study was to assess changes in self-reported cognitive functioning in patients with bipolar disorder who participated in an open pilot trial of mindfulness-based cognitive therapy (MBCT). Following MBCT, patients reported significant improvements in executive functioning, memory, and ability to initiate and complete tasks, as measured by the Behavior Rating Inventory of Executive Function (BRIEF) and the Frontal Systems Behavior Scale (FrSBe). Changes in cognitive functioning were correlated with increases in mindful, nonjudgmental observance and awareness of thoughts, feelings, and sensations, and were not associated with decreases in depression. Improvements tended to diminish after termination of treatment, but some improvements, particularly those in executive functioning, persisted after 3 months. These results provide preliminary evidence that MBCT may be a treatment option that can be used as an adjunct to medication to improve cognitive functioning in bipolar disorder.
doi:10.1097/01.pra.0000407964.34604.03
PMCID: PMC3277324  PMID: 22108398
bipolar disorder; executive functioning; cognitive functioning; mindfulness; mindfulness-based cognitive therapy (MBCT); psychosocial treatment
17.  Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia 
Bipolar Disorders  2009;11(7):701-710.
Objective
Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.
Methods
We assayed 276 publicly available ‘tag’ single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).
Results
Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL.
Conclusions
Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.
doi:10.1111/j.1399-5618.2009.00756.x
PMCID: PMC3401899  PMID: 19839995
association; bipolar disorder; circadian; gene; schizoaffective disorder; schizophrenia
18.  The Treatment of Minor Depression with St. John’s Wort or Citalopram: Failure to Show Benefit over Placebo 
Journal of psychiatric research  2011;45(7):931-941.
This paper presents new data addressing two important controversies in psychiatry: the construct of Minor Depression (MinD) and the efficacy of St. John’s Wort for milder forms of depressive disorders. Data are from a three-arm, 12 week, randomized clinical trial of investigating the efficacy of St. John’s Wort (810 mg/day), citalopram (20 mg/day), or placebo for acute treatment of MinD. Due to a high placebo response on all outcome measures, neither St. John’s Wort nor citalopram separated from placebo on change in depressive symptom severity, quality of life, or well-being. However, systematic assessment of potential adverse effects (AEs) led to three important observations: (1) prior to the administration of study compound, 60% of subjects endorsed items that would be characterized as AEs once study compound was administered, (2) St. John’s Wort and citalopram were each associated with a significant number of new or worsening AEs during treatment, and (3) using a structured interview for identifying AEs at baseline and during treatment is informative. MinD was not responsive to either a conventional antidepressant or a nutraceutical, and both compounds were associated with a notable side effects burden. Other treatment approaches for MinD should be investigated.
doi:10.1016/j.jpsychires.2011.05.001
PMCID: PMC3137264  PMID: 21632064
19.  Cognitive Rehabilitation for Bipolar Disorder: An Open Trial for Employed Patients with Residual Depressive Symptoms 
CNS neuroscience & therapeutics  2010;16(5):298-307.
Introduction
Bipolar Disorder is characterized by recurrent episodes of depression and/or mania along with interepisodic mood symptoms that interfere with psychosocial functioning. Despite periods of symptomatic recovery, individuals with bipolar disorder often continue to experience impairments in psychosocial functioning, particularly occupational functioning. Two determinants of psychosocial functioning of euthymic (neither fully depressed nor manic) individuals with bipolar disorder are residual depressive symptoms and cognitive impairment (i.e. difficulties with executive functioning, attention and memory).
Aims
The present study explored whether a new cognitive remediation (CR) treatment designed to treat residual depressive symptoms and, for the first time to the best of our knowledge, address cognitive impairment would be associated with improvement in psychosocial functioning in individuals with bipolar disorder. Following a neuropsychological and clinical assessment 18 individuals with DSM-IV bipolar disorder were treated with 14 individual sessions of CR.
Results
Results indicated that at the end of treatment, as well as at the 3-months follow-up, patients showed lower residual depressive symptoms, and increased occupational, as well as overall psychosocial functioning. Pre-treatment neuropsychological impairment predicted treatment response. Improvements in executive functioning were associated with improvements in occupational functioning.
Conclusions
These findings suggest that treating residual depressive symptoms and cognitive impairment may be an avenue to improving occupational and overall functioning in individuals with bipolar disorder.
doi:10.1111/j.1755-5949.2009.00110.x
PMCID: PMC2888654  PMID: 19895584
Bipolar Disorder; Occupational Functioning; Psychosocial Functioning; Cognitive Impairment; Cognitive-Behavior Therapy
20.  The Influence of Menopausal Status and Postmenopausal Use of Hormone Therapy on Presentation of Major Depression in Women 
Menopause (New York, N.Y.)  2010;17(4):828-839.
Objective:
The purpose of this study was to determine whether there are differences in depression characteristics among premenopausal, perimenopausal, and postmenopausal women with major depressive disorder. This study also evaluated these differences between postmenopausal women with major depressive disorder who are taking and not taking hormone therapy.
Methods:
Analyses conducted with data from the Sequenced Treatment Alternatives to Relieve Depression study focused on female outpatients with non-psychotic major depressive disorder seeking treatment in 41 primary or psychiatric care settings across the United States. Baseline demographic and clinical characteristics were compared among women not taking hormone therapy who were premenopausal (N=950), perimenopausal (N=380), or postmenopausal (N=562). These comparisons were also made between postmenopausal women (n=768) taking (N=171) or not taking (N=562) hormone therapy.
Results:
After adjusting for sociodemographic and clinical baseline differences, premenopausal women were more likely to present with irritability than either peri- or postmenopausal women, and were more likely to have decreased appetite and less likely to have early morning insomnia than perimenopausal women. Postmenopausal women were more likely to have suicidal ideation and poorer physical functioning than either of the other groups, and were more likely to have sympathetic arousal and gastrointestinal symptoms than premenopausal women. After adjusting for baseline differences, postmenopausal women taking hormone therapy had better physical functioning, fewer melancholic features, less sympathetic arousal, and more lack of involvement in activities than women not taking hormone therapy.
Conclusions:
Menopausal status and postmenopausal use of hormone therapy may influence the clinical presentation of major depressive episodes in women.
doi:10.1097/gme.0b013e3181d770a8
PMCID: PMC2949279  PMID: 20616669
menopause; hormone therapy; depression; major depressive disorder
21.  Bipolar Disorder with frequent mood episodes in the National Comorbidity Survey Replication (NCS-R) 
Molecular psychiatry  2009;15(11):1075-1087.
Virtually nothing is known about the epidemiology of rapid cycling bipolar disorder (BPD) in community samples. Nationally representative data are reported here for the prevalence and correlates of a surrogate measure of DSM-IV rapid cycling BPD from the National Comorbidity survey Replication (NCS-R), a national survey of the US household population. DSM-IV disorders were assessed in the NCS-R with the WHO Composite International Diagnostic Interview (CIDI). Although the CIDI did not assess rapid cycling, it did assess the broader category of 12-month BPD with frequent mood episodes (FME), having at least four episodes of mania/hypomania or major depression in the 12 months before interview. Roughly one-third of NCS-R respondents with lifetime DSM-IV BPD and half with 12-month BPD met criteria for FME. FME was associated with younger age-of-onset (of BP-I, but not BP-II) and higher annual persistence (73% of the years since first onset of illness with an episode) than non-FME BPD. No substantial associations of FME vs. non-FME BPD were found with socio-demographics, childhood risk factors (parental mental disorders, other childhood adversities), or comorbid DSM-IV disorders. However, FME manic episodes had greater clinical severity than non-FME episodes (assessed with a fully-structured version of the Young Mania Rating Scale) and FME hypomanic episodes had greater role impairment than non-FME episodes (assessed with the Sheehan Disability Scales). Whether these indicators of severity merely reflect attenuated effects of rapid cycling or independent effects of sub-threshold rapid cycling warrants further study given the high proportion of lifetime cases that met criteria for FME.
doi:10.1038/mp.2009.61
PMCID: PMC2891194  PMID: 19564874
Bipolar Disorder; Rapid-cycling bipolar disorder; Mania; Hypomania; National Comorbidity Survey Replication (NCS-R); Comorbidity; Treatment
22.  An Evaluation of the Quick Inventory of Depressive Symptomatology and the Hamilton Rating Scale for Depression: A Sequenced Treatment Alternatives to Relieve Depression Trial Report 
Biological psychiatry  2005;59(6):493-501.
Background
Nine DSM-IV-TR criterion symptom domains are evaluated to diagnose major depressive disorder (MDD). The Quick Inventory of Depressive Symptomatology (QIDS) provides an efficient assessment of these domains and is available as a clinician rating (QIDS-C16), a self-report (QIDS-SR16), and in an automated, interactive voice response (IVR) (QIDS-IVR16) telephone system. This report compares the performance of these three versions of the QIDS and the 17-item Hamilton Rating Scale for Depression (HRSD17).
Methods
Data were acquired at baseline and exit from the first treatment step (citalopram) in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Outpatients with nonpsychotic MDD who completed all four ratings within ±2 days were identified from the first 1500 STAR*D subjects. Both item response theory and classical test theory analyses were conducted.
Results
The three methods for obtaining QIDS data produced consistent findings regarding relationships between the nine symptom domains and overall depression, demonstrating interchangeability among the three methods. The HRSD17, while generally satisfactory, rarely utilized the full range of item scores, and evidence suggested multidimensional measurement properties.
Conclusions
In nonpsychotic MDD outpatients without overt cognitive impairment, clinician assessment of depression severity using either the QIDS-C16 or HRSD17 may be successfully replaced by either the self-report or IVR version of the QIDS.
doi:10.1016/j.biopsych.2005.08.022
PMCID: PMC2929841  PMID: 16199008
Quick Inventory of Depressive Symptomatology; Inventory of Depressive Symptomatology; item response theory; Samejima graded response model; depressive symptoms
23.  Cigarette smoking is associated with suicidality in bipolar disorder 
Bipolar disorders  2009;11(7):766-771.
Objectives
Cigarette smoking in individuals with bipolar disorder has been associated with suicidal behavior, although the precise relationship between the two remains unclear.
Methods
In this prospective observational study of 116 individuals with bipolar disorder, we examined the association between smoking and suicidality as measured by Linehan’s Suicide Behaviors Questionnaire (SBQ) and prospective suicide attempts over a nine-month period. Impulsivity was measured by the Barratt Impulsiveness Scale.
Results
Smoking was associated with higher baseline SBQ scores in univariate and adjusted analyses, but was not significant after statistical adjustment for impulsivity in a regression model. A higher proportion of smokers at baseline made a suicide attempt during the follow-up period (5/31, 16.1%) compared to nonsmokers (3/85, 3.5%); p = 0.031, odds ratio = 5.25 (95% confidence interval: 1.2–23.5). Smoking at baseline also significantly predicted higher SBQ score at nine months.
Conclusions
In this study, current cigarette smoking was a predictor of current and nine-month suicidal ideation and behavior in bipolar disorder, and it is likely that impulsivity accounts for some of this
doi:10.1111/j.1399-5618.2009.00744.x
PMCID: PMC2918237  PMID: 19840000
bipolar disorder; impulsivity; nicotine; smoking; substance abuse; suicidality
24.  Impact of Substance Use Disorders on Recovery From Episodes of Depression in Bipolar Disorder Patients: Prospective Data From the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) 
The American journal of psychiatry  2009;167(3):289-297.
Objective
Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder.
Method
Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode.
Results
During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state.
Conclusions
Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.
doi:10.1176/appi.ajp.2009.09020299
PMCID: PMC2918249  PMID: 20008948
25.  A Double-Blind Randomized Controlled Trial of Ethyl-Eicosapentaenoate (EPA-E) for Major Depressive Disorder 
The Journal of clinical psychiatry  2009;70(12):1636-1644.
Objective
We examined the efficacy and tolerability of ethyl-eicosapentaenoate (EPA-E) monotherapy for major depressive disorder (MDD) in a double-blind, randomized controlled pilot study.
Methods
57 adults with DSM-IV MDD were randomized from 1/2003-6/2006 to receive 1 gram/day of EPA or placebo (PBO) for 8 weeks. Response criteria were based on the Hamilton-D-17 scale. Subjects' plasma lipid profiles were examined by gas chromatography.
Results
35 subjects (63% female; mean age 45+/-13 yrs) were eligible for the intent to treat (ITT) analysis. In the ITT sample, mean HAM-D-17 scores decreased from 21.6+/-2.7 to 13.9+/-8.9 for the EPA group (n=16) and from 20.5+/-3.6 to 17.5+/-7.5 for the PBO group (n=19) (p=0.123); the effect size for EPA was 0.55. ITT response rates were 38% (6/16) for EPA, and 21% (4/19) for PBO (p=0.45). Among the 24 study completers, mean HAM-D-17 scores decreased from 21.3+/-3.0 to 11.1+/-8.1 for the EPA group and from 20.5+/-3.8 to 16.3+/-6.9 for the PBO group (p=0.087); the effect size for EPA was 0.73. Completer response rates were 45% (5/11) for EPA, and 23% (3/13) for PBO (p=0.39). Among EPA subjects, baseline n-6/n-3 ratio was associated with decrease in HAM-D-17 score (r= -0.686, p=0.030) and with treatment response (p=0.032); change in n-6/n-3 ratio was associated with change in HAM-D-17 score (r=0.784, p=0.032). Side effects, reported in 2 EPA subjects and 5 PBO subjects, were exclusively gastrointestinal, mild, and not associated with discontinuation.
Conclusions
EPA demonstrated an advantage over placebo that did not reach statistical significance, possibly due to the small sample and low completer rates, which were the major study limitations.
doi:10.4088/JCP.08m04603
PMCID: PMC2918427  PMID: 19709502
eicosapentaenoic acid; docosahexaenoic acid; DHA; EPA; omega-3; n-3; depression

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