Andrew A. Nierenberg

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

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

With 6.5 million Americans misusing a prescription drug in 2014 and 12% of American teenagers indicating lifetime use of over-the-counter cold medicine or cough syrup for getting high, misuse and abuse of prescription and over-thecounter drugs remains a major problem in the United States. Prescription and over-the-counter drug abuse often results from unused or unwanted medications remaining in the household cabinet. A potential solution to this problem lies in drug take-back programs which allow individuals to bring unused medications back to designated facilities for safe and proper disposal. In this commentary, we discuss the current state of drug take-back programs and their relevance to prescription and over-the-counter drug abuse. We conclude with suggestions on future directions in drug disposal that can help fight against prescription and overthe- counter drug abuse.

In this issue of JCP, Zhou and colleagues review and integrate placebo-controlled efficacy trials of medications for treatment-resistant depression (TRD) to compare efficacy in a meta-analysis. They conclude that, among 11 augmentation options for TRD, aripiprazole and quetiapine have the most robust evidence for efficacy, with the caveats that these treatments carry substantial risks of adverse events and no long-term data are available. In the absence of direct comparisons, this exercise highlights the formidable challenges that clinicians face when making decisions.

Objectives: Patients with bipolar disorder frequently continue to experience residual anxiety and insomnia between mood episodes. In real-world practice, patients increasingly self-prescribe alternative medicines. Methods: We reviewed case reports, open-label, and placebo-controlled trials investigating the use of herbal medicines to treat anxiety and insomnia, and discussed their potential applications for bipolar disorder. Results: Eleven herbal medicines that have been studied in human subjects are included in this review. Mechanisms of action, efficacy, side effects, and drug-drug interactions are discussed. Based on currently available evidence, valerian seems to be the most promising candidate for insomnia and anxiety in bipolar disorder. Conclusions: Adjunctive herbal medicines may have the potential to alleviate these symptoms and improve the outcomes of standard treatment, despite limited evidence. Physicians need to have a more in-depth understanding of the evidence of benefits, risks, and drug interactions of alternative treatments.

Background Unipolar mania (UM), in which only manic episodes occur during the course of illness, may be an important clinical manifestation of bipolar disorder that is under-recognized and understudied. The aim of this study is, for the first time, to examine the prevalence of UM and its clinical characteristics in the community. Methods Among a total of 1,411 subjects with bipolar I disorder, we evaluated the prevalence of UM using three different criteria proposed in previous studies. We compared the clinical characteristics of subjects with UM to those with a more classic bipolar presentation with mania and lifetime major depressive episode (MDE). We additionally explored the proportion of subjects with UM who later experience at least one MDE during a 3-year follow-up period and determined risk factors for converting from UM to classic bipolar disorder. Results The prevalence rate of UM among those with bipolar disorder ranged from 5.0 to 7.2% depending on the criteria. UM was more common in male and nonwhite subjects. About half of individuals with UM experienced subthreshold depression. Individuals with UM had lower rates of comorbid anxiety disorders or attention deficit hyperactivity disorder (ADHD). During the follow-up, about 18% of subjects with UM experienced MDEs. Male, nonwhite, comorbid generalized anxiety disorder and ADHD predicted an increased transition from UM to classic bipolar disorder. Subthreshold depression was not associated with the risk of the transition. Conclusions UM is an infrequent but clinically distinct subtype of bipolar I disorder. Further research delineating the characteristics of UM is warranted.

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