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Aim: Bipolar disorder (BD) and borderline personality disorder (BPD) are both serious psychiatric conditions that elevate the risk for harmful outcomes. Although these conditions represent distinct diagnostic entities, existing research suggests that approximately 20% of individuals with BD meet the criteria for comorbid BPD. Individuals with comorbid BD/BPD appear to have a markedly more severe and phenomenologically distinct clinical course when compared with those with BD alone. However, treatments have generally not been tested in this specific population, and currently, no formal treatment guidelines exist for this subgroup of patients., Method: In the current paper, we review the epidemiological and descriptive research characterizing those with comorbid BD/BPD and discuss the impact of this comorbidity on psychosocial treatment. We also review current findings on evidence-based treatments for BD and BPD that show promise in treating those with comorbid BD/BPD., Results: In our review of the literature, we highlight the importance of recognizing this comorbidity and discuss avenues for developing and integrating evidence-based treatment approaches for this understudied clinical population., Conclusions: Although formal trials of interventions targeted to comorbid BD/BPD are limited, there is promising evidence regarding the possibility of using or integrating existing evidence-based approaches for this population. There are also several areas of clinical practice improvement and future research directions that stem from this literature., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Bipolar disorder and posttraumatic stress disorder (PTSD) commonly co-occur, but no treatment guidelines exist for this population. Prolonged exposure (PE) is a well-established and efficacious treatment for PTSD, untested in patients with comorbid bipolar disorder. The current study evaluates the feasibility and preliminary efficacy of PE for patients with bipolar disorder and PTSD., Methods: Participants were enrolled in PE and completed assessments of PTSD symptoms, suicidality, state and trait anxiety, depression, and mania at baseline, Sessions 5 and 10, and at 6-months post-treatment., Results: 32 patients enrolled in this study, with 75 % (24/32) completing all ten PE sessions and 50 % completing 6-month follow-up assessments. PTSD symptoms decreased from baseline to Session 10 and continued to decrease throughout the follow-up period. Suicidality, measured by implicit associations between self and death, showed a similar pattern of decrease over treatment and follow-up periods. Suicidal thinking and depressive symptoms decreased from baseline through Session 10 and rebounded slightly, remaining below baseline at 6-months follow-up. State and trait anxiety increased initially through Session 5 but then decreased and remained stable. Mania scores remained stable at all assessment periods., Limitations: The study is limited by a small sample size and absence of a control condition. Criterion A trauma was not required, limiting generalizability, and there was significant attrition at follow-up., Conclusions: These findings suggest that PE is a feasible and preliminarily efficacious treatment for patients with bipolar disorder and comorbid PTSD, and support the conduct of a fully powered efficacy of PE for this comorbidity., Competing Interests: Declaration of competing interest Andrew A. Nierenberg: Dr. Nierenberg is in the scientific advisory board of Altimate, Flow, Milken Center for Strategic Philanthropy, Myriad, and 4M Therapeutics. He is also a consultant at Alkermes, Clexio, Ginger/Headspace Health, Janssen, Merck, Neuronetic, NeuroRX, Otsuka, Protagenics, SAGE, Sunovion, and Unravel Bioscience. He receives honoraria from Belvior, Psychiatric Annals Slack Publication, and Wiley Depression and Anxiety. He also receives royalties from Guilford Publications, and unravel Bioscience. Finally, he is in the adjudication committee for Novartis. He has received grant funding from PCORI. Louisa G. Sylvia: Dr. Sylvia has received grant funding from PCORI, NIH, HRSA Tiny Blue Dot Foundation and AFSP. She has also received funding as a member of the Milken Institute's Scientific Advisory Board as well as royalties form New Harbinger for her two published books on bipolar disorder., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Bipolar disorder affects approximately 8 million adults in the US and approximately 40 million individuals worldwide., Observations: Bipolar disorder is characterized by recurrent episodes of depression and mania or hypomania. Bipolar depressive episodes are similar to major depressive episodes. Manic and hypomanic episodes are characterized by a distinct change in mood and behavior during discrete time periods. The age of onset is usually between 15 and 25 years, and depression is the most frequent initial presentation. Approximately 75% of symptomatic time consists of depressive episodes or symptoms. Early diagnosis and treatment are associated with a more favorable prognosis. Diagnosis and optimal treatment are often delayed by a mean of approximately 9 years following an initial depressive episode. Long-term treatment consists of mood stabilizers, such as lithium, valproate, and lamotrigine. Antipsychotic agents, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine, are recommended, but some are associated with weight gain. Antidepressants are not recommended as monotherapy. More than 50% of patients with bipolar disorder are not adherent to treatment. Life expectancy is reduced by approximately 12 to 14 years in people with bipolar disorder, with a 1.6-fold to 2-fold increase in cardiovascular mortality occurring a mean of 17 years earlier compared with the general population. Prevalence rates of metabolic syndrome (37%), obesity (21%), cigarette smoking (45%), and type 2 diabetes (14%) are higher among people with bipolar disorder, contributing to the risk of early mortality. The annual suicide rate is approximately 0.9% among individuals with bipolar disorder, compared with 0.014% in the general population. Approximately 15% to 20% of people with bipolar disorder die by suicide., Conclusions and Relevance: Bipolar disorder affects approximately 8 million adults in the US. First-line therapy includes mood stabilizers, such as lithium, anticonvulsants, such as valproate and lamotrigine, and atypical antipsychotic drugs, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine.

Objective: Bipolar disorder (BD) is complicated by a dynamic, chronic course along with multiple comorbid psychiatric and medical conditions, making it challenging for clinicians to treat and patients to thrive. To efficiently manage the complexity of BD and help patients recover, we developed a Focused Integrated Team-based Treatment Program for Bipolar Disorder (FITT-BD). The purpose of this paper is to describe how we developed this clinic and the lessons we learned., Methods: We developed FITT-BD by integrating strategies from stepped care, collaborative care, and learning health care systems. We describe the rationale, details, and lessons learned in developing FITT-BD., Results: By integrating stepped care, collaborative care, and a learning health care system approach, FITT-BD aims to reduce barriers to care, leverage the expertise of a multidisciplinary treatment team, ensure patient-centeredness, and use assessments to inform and continuously improve outcomes in real time. We learned that there are challenges in the creation of a web-based application that tracks the treatment of patients within a network of hospitals., Conclusions: The success of FITT-BD will be determined by the degree to which it can increase treatment access, improve treatment adherence, and help individuals with BD achieve their treatment goals. We expect that FITT-BD will improve outcomes in the context of ongoing clinical care., Public Health Significance: The treatment of BD is challenging and complex. We propose a new treatment model for BD: FITT-BD. We expect that this program will be a patient-centered approach that improves outcomes in the context of ongoing clinical care for patients with BD., Competing Interests: L.G.S. has received grant funding from PCORI, NIH, HRSA, and AFSP. She has also received funding as a member of the Milken Institute’s Scientific Advisory Board as well as royalties from New Harbinger for her 2 published books on bipolar disorder. A.T.P. and A.K.G. have received research support from the National Institutes of Health. A.A.N. has received support for consulting services from Alkermes, Clexio, Ginger/Headspace Health, Janssen, Merck, Neuronetics, NeuroRx, Otsuka, Protagenics, SAGE, Sunovion, and for service on Scientific Advisory Boards from Milken Center for Strategic Philanthropy, and Myriad Bipolar; he has received honoraria from Belvior, EISAI, and Psychiatric Annals Slack Publications and royalties from Guilford Publications, Up-to-Date Wolters Kluwer Health, and Wiley Depression and Anxiety. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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

Background: Bipolar disorder is among the top 10 causes of disability worldwide. The Short-Form Six-Dimension (SF-6D) is a frequently used measure of preference-based health-related quality of life (HRQOL). However, this measure's psychometric performance has not been tested in outpatient patients with bipolar disorder., Aims of the Study: This study assessed the psychometric properties of the SF-6D, including convergent validity, known-groups validity, and responsiveness., Methods: We examined convergent validity between the SF-6D and four condition-specific measures of functioning (LIFE-RIFT), life satisfaction (QLESQ), depressive symptoms (MADRS), and manic symptoms (YMRS). We used known-groups validity tests to compare the SF-6D health utility values estimated for patients in different clinical states, including depression, mania, hypomania, and recovered. We assessed the responsiveness of the SF-6D by comparing the sensitivity of the SF-6D utility values to longitudinal changes in the four condition-specific measures during the same period of time. We conducted all analyses using data from 2,627 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) clinical trial., Results: The SF-6D demonstrated moderate (0.3-0.7) convergence with the LIFE-RIFT, QLESQ, and MADRS measures. Convergence with the manic symptoms measure (YMRS) was weak (<0.3). For known-groups validity, the SF-6D distinguished the recovered state from the three symptomatic clinical states. For responsiveness, the measure did not show floor or ceiling effects. The SF-6D utility value increased when mental health improved, with a small ES of 0.3 over the 1-year period, which was comparable to the four condition-specific measures., Discussion: The SF-6D demonstrated moderate convergent validity, moderate responsiveness, and it can distinguish the differences between known-groups that had been identified in literature. The SF-6D may be a suitable measure of preference-based HRQOL for patients with bipolar disorder, but caution is needed due to its lower convergence with the YMRS mania scale., Limitations: The subsample of patients in manic episode was small, which may reduce the reliability of study findings regarding this specific clinical state. In terms of generalizability, the STEP-BD study sample is based on patients who received treatment in bipolar specialty clinics affiliated with academic medical centers, which may be different from other outpatient clinics., Implications for Health Care Provision and Use: The mean health utility value for patients with hypomania is significantly lower than the mean value for recovered patients. This finding emphasizes the importance of treating hypomania., Implication for Health Policies: This study validates an existing approach toward generating health utility values for bipolar disorder. These utility values can be used to create quality-adjusted life years (QALYs), which are the most commonly used measure of health benefit in cost-effectiveness studies., Implications for Further Research: Studies with larger samples of patients with mania are needed to study measures of health utility in this patient population.

Background: The goals of this study were to introduce psychological well-being as an important subject of inquiry in bipolar disorder, to compare well-being in a cohort of patients with bipolar disorder with that of a normative sample, and to assess whether common measures of well-being and mood measure empirically distinct phenomena., Methods: Participants were outpatients with bipolar I disorder in remission (N=37) from the Enhancing Emotion Regulation in Bipolar Disorder (EERBD) study and a matched community normative sample from the Midlife in the United States (MIDUS) survey (N=6297). The Psychological Well-Being Scale (PWBS) was used to measure psychological well-being. We calculated means and SD of scores on the PWBS and evaluated the differences between the scores of the bipolar I and community samples. We also tested the association between raw and change scores in depression [Hamilton Rating Scale for Depression (HAM-D)] and eudaimonic well-being (PWBS) using Spearman correlation coefficients., Results: The MIDUS survey sample (N=6297) was 48% male, with a mean age of 47 years (SD=13 y). The EERBD sample (N=37) was 27% male, with a mean age of 41 years (SD=11 y). In the bipolar sample, the baseline mean score on the HAM-D was 12.7 (SD=6.0) and the mean score on the Young Mania Rating Scale was 6.1 (SD=6.2). The baseline mean sum score on the PWBS in the normative community MIDUS sample was 100 (SD=14), while that of the bipolar I EERBD sample was 79 (SD=15) at baseline, 84 (SD=13) posttreatment, and 84 (SD=12) at the 3-month follow-up assessment. The effect sizes of the differences at all timepoints were large (Hedges g=1.42 at baseline, 1.11 at the end of treatment, and 1.06 at the 3-mo follow-up). No association was found between the PWBS and depression scores., Conclusions: Outpatients with bipolar disorder in remission demonstrated substantially impaired psychological well-being, despite low levels of depressive symptoms, compared with a normative community sample., Competing Interests: L.S. receives funding from NIH, PCORI, Samsung, and Takeda and royalties from New Harbinger. A.A.N. has financial interests at Alkermes, Jazz Pharma, Sage Pharma, Otsuka, Neuronetics, Acadia Pharm, Esai, Myriad, Sunovion, Neurostar, Merck, Ginger, and Protogenics. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied., Methods: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool)., Results: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment., Conclusion: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response., Methods: We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models., Results: Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response., Limitations: Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors., Conclusions: Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression., (Copyright © 2021. Published by Elsevier B.V.)

Using network analysis, we estimated the structure of relations among manic and depressive symptoms, respectively, in 486 patients (59% women; age: M = 37, SD = 12.1) with bipolar disorder prior to their entering a clinical trial. We computed three types of networks: (a) Gaussian graphical models (GGMs) depicting regularized partial correlations, (b) regression-based GGMs depicting nonregularized partial correlations, and (c) directed acyclic graphs (DAGs) via a Bayesian hill-climbing algorithm. Low energy and elevated energy were consistently identified as central nodes in the GGMs and as key parent nodes in the DAGs. Across analyses, pessimism about the future and depressed mood were the symptoms most strongly associated with suicidal thoughts and behavior. These exploratory analyses provide rich information about how bipolar disorder symptoms relate to one another, thereby furnishing a foundation for investigating how bipolar disorder symptoms may operate as a causal system. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: We aimed to study the probability of bipolar depression response at 24 weeks given initial non-response., Methods: We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS<10)., Results: We included 592 participants with bipolar depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks., Conclusions: Among patients with bipolar depression and non-response after 6 weeks treatment, representing an adequate bipolar depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for bipolar depression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: We investigated the feasibility and acceptability of a brief sleep intervention and sleep monitoring device in bipolar disorder (BD), as well as the intervention's effectiveness in reducing suicidal ideation through improved sleep quality and duration., Methods: Participants (N=13) with BD received 4 sessions of cognitive-behavioral therapy for sleep disturbance and completed assessments of the intervention and sleep device acceptability, mood, suicidal ideation, and sleep at pretreatment and posttreatment., Results: Feasibility and acceptability of the intervention were high at both pretreatment and posttreatment and did not significantly change by the intervention's conclusion, although participants reported being significantly more likely to recommend the intervention to others at posttreatment. The sleep device was easy to understand, wear, and did not interfere with participants' sleep. Suicidal ideation and depressive symptoms significantly decreased from pretreatment to posttreatment (P<0.05). There were small, but not significant, improvements in the percentage of time spent in stable sleep and total average nightly sleep., Conclusion: The potential of this intervention for reducing suicidal ideation and improving sleep is promising, but future research is warranted., Competing Interests: The authors have no conflicts of interest in direct application to this study or the device to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Psychotic symptoms during bipolar depressive episodes, especially in outpatients, are under recognized and studied by clinicians and researchers. We examined the relationship between psychotic symptoms during a depressive episode and suicidal ideation in bipolar patients., Methods: Participants (N = 351) were adult, depressed outpatients with bipolar disorder (BD) in a comparative effectiveness study of quetiapine versus lithium. Psychotic symptoms were assessed via Bipolar Inventory of Signs and Symptoms Scale (BISS) and depressive episodes via Mini-International Neuropsychiatric Interview (MINI). Because only 4.84% (N = 17) endorsed psychotic symptoms, we performed iterative multivariate matching with non-psychotic participants. On every matched population, a multiple regression analysis examined whether psychotic symptoms were associated with suicidal ideation, via the Concise Health Risk Taking scale (CHRT-12)., Results: Averaged across the 50 matched populations, current psychotic symptoms predicted active suicidal ideation on the CHRT, but not a passive propensity toward suicide or total CHRT scores, after adjusting for common correlates of suicidality (e.g., previous suicidal behavior) (β=0.59, p=.01, R2= 0.41)., Limitations: Our study was limited by three factors. First, the generalizability of our study was limited as the sample included only outpatients. Next, the analysis was cross-sectional and does not allow for causal interpretation. Lastly, our study lacked information regarding the content and mood congruency of participants' psychosis., Conclusion: While a small proportion of BD outpatients had current symptoms of psychosis during their depressive episode, those who did were more likely to endorse active suicidal thoughts, including suicide methods and plans., (Copyright © 2021. Published by Elsevier B.V.)

Background: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response., Methods: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate-Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts., Results: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales., Conclusions: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants., (© 2020 Wiley Periodicals LLC.)

Background: Bipolar disorder is a heritable disorder, and we aimed to assess the impact of family history of mental disorders in first-degree relatives on the severity and course of bipolar disorder., Methods: The Bipolar CHOICE (lithium versus quetiapine) and LiTMUS (optimized treatment with versus without lithium) comparative effectiveness studies were similar trials among bipolar disorder outpatients studying four different randomized treatment arms for 24 weeks. Patients self-reported on six severe mental disorders among first-degree relatives. We performed ANOVA and linear regression regarding disease severity measures, sociodemographic and cardiometabolic markers and mixed effects linear regression to evaluate treatment response., Results: Among 757 patients, 644 (85.1%) reported at least one first-degree relative with a severe mental disorder (mean=2.8; standard deviation=2.2; range=0-13). Depression (67.1%), alcohol abuse (51.0%) and bipolar disorder (47.0%) were the most frequently reported disorders. Familial psychiatric history correlated with several disease severity measures (hospitalizations, suicide attempts, and earlier onset) and sociodemographic markers (lower education and household income) but not with cardiometabolic markers (e.g. cholesterol or waist circumference) or cardiovascular risk scores, e.g. the Framingham risk score. Patients with familial psychiatric history tended to require more psychopharmacological treatment (p=0.054) but responded similarly (all p>0.1) to all four treatment arms., Conclusions: Our findings indicate that familial psychiatric history is common among outpatients with bipolar disorder and correlates with disease severity and sociodemographic measures. Patients with a greater familial psychiatric load required more intense treatment but achieved similar treatment responses compared to patients without familial psychiatric history., Competing Interests: Declaration of Competing Interest The other authors declare no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: The association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular-bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment., Methods: An international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps., Results: The association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular-bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets., Conclusions: Further research focused on the vascular-bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Lithium and quetiapine can cause weight gain, but their comparative longer term anthropometric effects are unknown, as are the potential moderating effects of baseline binge-eating (BE) behavior., Methods: We assessed 6 month changes in body weight, body mass index (BMI) and waist circumference in 482 adults with DSM-IV bipolar disorders who participated in a comparative effectiveness study of lithium and quetiapine with evidence-based adjunctive treatment (Bipolar CHOICE). Anthropometric measurements were obtained at baseline, and at 2, 4, 6, 8, 12, 16, 20, and 24 weeks. BE behavior was defined as affirmative responses to MINI items M1 and M3 at baseline. Data were analyzed using a mixed model repeated measures approach, adjusted for baseline values of dependent measures., Results: On average, body weight and BMI increased over 6 months with lithium and quetiapine. However, those treated with quetiapine experienced greater increases from baseline in body weight (peak change, + 3.6 lbs. vs. + 1.4 lbs.) and BMI (peak change, + 0.6 kg/m 2 vs. + 0.3 kg/m 2 ), starting at 2 weeks (group x time, F 8,3052   = 2.9, p = 0.003 for body weight, F 8,3052   = 3.0, p = 0.002 for BMI). Significant increases in waist circumference were observed only with quetiapine. The relationship between drug treatment and changes in body weight (group x time x binge eating status, F 1,2770   = 2.0, p = 0.002), BMI (F 1,2767   = 2.0, p = 0.002), and waist circumference (women only, F 25,1621   = 2.9, p < 0.0001) were moderated by BE behavior. The largest increases over 24 weeks in body weight and BMI, and waist circumference in women, occurred for quetiapine-treated patients with baseline binge-eating, relative to quetiapine-treated patients without binge eating and lithium-treated patients with or without baseline binge-eating., Limitations: Bipolar CHOICE was not designed to study anthropometric outcomes., Conclusions: Greater changes in body weight, BMI, and waist circumference occurred with quetiapine- versus lithium-based treatment over 6 months of treatment. The effects of study drugs on these anthropometric measures were moderated by BE behavior at baseline., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: While bipolar disorder (BD) and posttraumatic stress disorder (PTSD) frequently co-occur and individually have a higher risk of suicide compared to the general population, few studies have examined the impact of comorbid PTSD on suicidal ideation in patients with BD., Methods: We analyzed baseline data from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for bipolar disorder study (Bipolar CHOICE), a 6-month, pharmacological comparative effectiveness trial of individuals with BD. Bipolar CHOICE enrolled 482 individuals. A hierarchical multiple regression analysis assessed whether comorbid PTSD was associated with increased suicidal ideation as assessed by the Concise Health Risk Tracking Scale (CHRT) total and factor scores, while controlling for common correlates of suicidal ideation in this population such as a current major depressive episode, comorbid anxiety disorders, severity of illness and previous suicide attempts., Results: Consistent with our hypothesis, diagnosis of comorbid PTSD was a significant predictor of the CHRT total score (β=2.59, p=.03). Comorbid PTSD was also a significant predictor of the CHRT propensity factor (β=2.32, adjusted p=.04), but was not a significant predictor of the active suicidal thoughts factor. Additionally, all participants with comorbid PTSD (N = 58) endorsed current suicidal ideation (p=.005) and were more likely to have had a previous suicide attempt (p<.001) compared to those without PTSD., Limitations: Generalizability beyond outpatient settings is limited, mixed affective states were not assessed, and analyses were cross-sectional., Conclusions: Patients have an increased risk of suicidal ideation when PTSD is comorbid with BD., Competing Interests: Declaration of Competing of Interest All other authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Background: The ADHD Self Report Scale is a self-report measure that assesses attentional problems. We sought to validate the ASRS by establishing neural correlates using functional magnetic imaging in healthy controls and individuals with bipolar disorder (BD), who commonly exhibit attentional problems., Methods: ASRS questionnaires and functional MRI data in conjunction with the Multi-source Interference Task (MSIT) were collected from 36 healthy control and 36 BD participants. We investigated task specific changes in the dorsal anterior cingulate cortex (dACC, Brodmann area 32) and their correlations with ASRS subscale scores, inattention and hyperactivity, in both cohorts., Results: As hypothesized, the dACC showed significant increases in BOLD activation between the interference and noninterference conditions. For the ASRS scale as well as its Inattention and Hyperactivity subscales, there was a significant negative correlation with the dACC BOLD for the whole group., Conclusions: The ASRS is sensitive to attentional difficulties in BD, suggesting that it is a valid tool for assessing attentional difficulties in patients with BD., Competing Interests: Declaration of Competing Interest Abigail Testo has no conflicts of interest. Julia Felicione has no conflicts of interest. Dr. Amy Peters has no conflicts of interest. Dr. Amy Peters's sources of funding include NIH National Institute of Mental Health, Translational Neuroscience Training for Clinicians T32 MH 112485. Dr. Kristen Ellard does not have any conflicts of interest. Dr. Kristen Ellard's sources of funding include NIH National Institute of Neurological Disorders and Stroke (NINDS) Training Program in Recovery and Restoration of CNS Health and Function (T32 NS100663-01). Aishwarya Gosai has no conflicts of interest. Emily Hahn has no conflicts of interest. Conor Shea has no conflicts of interest. Dr. Louisa Sylvia reports grants from the Elizabeth Dole Foundation, National Institute of Health, American Foundation of Suicide Prevention, Takeda, and PCORI as well as personal fees from Clinical Trials Network and Institute and New Harbinger. Dr. Darin Dougherty has no conflicts of interest. Dr. Deckersbach's research has been funded by NIH, NIMH, PCORI, NARSAD, TSA, IOCDF, Tufts University, DBDAT, Otsuka Pharmaceuticals, Cogito, Inc, Sunovion. and Assurex. He has received honoraria, consultation fees and/or royalties from the MGH Psychiatry Academy, BrainCells Inc., Clintara, LLC., Systems Research and Applications Corporation, Boston University, the Catalan Agency for Health Technology Assessment and Research, the National Association of Social Workers Massachusetts, the Massachusetts Medical Society, Tufts University, NIDA, NIMH, Oxford University Press, and Guilford Press. He has also participated in research funded by Assurex, DARPA, NIH, NIMH, NIA, AHRQ, PCORI, Janssen Pharmaceuticals, The Forest Research Institute, Shire Development Inc., Medtronic, Cyberonics, Northstar, Takeda, and Sunovion., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Not all patients with bipolar depression have suicidal ideation (SI). This study examines some factors that link bipolar depression to SI., Methods: 482 individuals with bipolar I or II were randomized to either lithium or quetiapine plus adjunctive personalized therapy in a 24 week comparative effectiveness trial. Severity of depression and SI were assessed with the Bipolar Inventory of Symptoms Scale (BISS). We examined potential moderators (age, gender, age of illness onset, bipolar type, comorbid anxiety, substance use, past suicide attempts, childhood abuse and treatment arm) and mediators (severity of anxiety, mania, irritability, impairment in functioning (LIFE-RIFT) and satisfaction and enjoyment of life (Q-LES-Q)) of the effect of depression on SI. Statistical analyses were conducted using generalized estimating equations with repeated measures., Results: Bipolar type and past suicide attempts moderated the effect of depression on SI. Life satisfaction mediated the effect of depression and SI. The relationship between anxiety, depression and SI was complex due to the high level of correlation. Treatment with lithium or quetiapine did not moderate the effect of depression on SI., Limitations: Suicide assessment was only done using an item on BISS. Patient population was not specifically chosen for high suicide risk., Discussion: Individuals with Bipolar II experienced more SI with lower levels of depression severity. A history of suicide predisposed patients to higher levels of SI given the same severity of depression. Reduced life satisfaction mediates the effect of depression on SI and may be a target for therapeutic interventions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Individuals with bipolar disorder are at greater risk for cardiovascular disease and are less likely to adhere to lifestyle interventions than the general population. To decrease cardiovascular risk and improve adherence to lifestyle interventions, we developed the Nutrition Exercise and Wellness Treatment (NEW Tx). NEW Tx is an 18-session, 20-week cognitive behavioral therapy-based treatment comprising 3 modules: Nutrition, Exercise, and Wellness. To evaluate the feasibility and acceptability of this intervention as well as predictors of treatment satisfaction and expectations, 38 adult outpatients with bipolar disorder were randomized to either NEW Tx or a waitlist control condition. There was no statistically significant difference in dropout rates between the groups (26.3% in NEW Tx, 31.6% in the control condition). In the NEW Tx condition, participants attended a mean of 66.7% of sessions and reported moderate to high satisfaction. There were no study-related adverse events. We also found that expectations, but not perceived credibility (or believability), of NEW Tx (as measured by the Credibility/Expectancy Questionnaire) at baseline predicted treatment satisfaction (as measured by the Care Satisfaction Questionnaire) posttreatment. Manic symptoms at baseline predicted treatment satisfaction, and marital status predicted one's expectations of lifestyle interventions. Data suggest that NEW Tx is a feasible and acceptable intervention for individuals with bipolar disorder and that further research is warranted to explore potential moderators of treatment expectations and credibility in this clinical population.

Background: Complex polypharmacy (CP) is common in bipolar disorder (BD). We assessed the associations between CP, adherence, and side effect burden, and patient traits associated with clinical improvement in relationship to CP., Methods: We conducted a secondary analysis of 482 adult BD participants in the Bipolar CHOICE trial. We examined the associations between CP (use of ≥3 BD medications) and non-adherence (missing >30% of BD medication doses in the last 30 days) and side effect burden (Frequency, Intensity and Burden of Side Effects Rating scale) using multivariate models with patient random effects. We used logistic regression to assess the patient traits associated with remission among those with majority CP use (Clinical Global Impression-Severity for BD score ≤2 for 8+ weeks)., Results: 43% of patients had any CP and 25% had CP for the majority of the study. CP was associated with non-adherence (OR = 2.51, 95% CI [1.81, 3.50]), but not worse side effect burden. Among those with CP, 16% achieved remission; those with non-adherence, comorbid social or generalized anxiety disorder, or BD I vs. II were less likely to achieve remission among those with CP., Limitations: There could be unmeasured confounding between use of CP and side effect burden or adherence. Adherence was measured by self-report, which could be subject to reporting error., Conclusions: BD patients with CP were less likely to adhere to therapy, and those with worse adherence to CP were less likely to clinically respond. Clinicians should assess medication adherence prior to adding another agent to medication regimens., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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

Objectives: Lithium and quetiapine are known to be effective treatments for bipolar disorder. However, little information is available to inform prediction of response to these medications. Machine-learning methods can identify predictors of response by examining variables simultaneously. Further evaluation of models on a test sample can estimate how well these models would generalize to other samples., Methods: Data (N = 482) were drawn from a randomized clinical trial of outpatients with bipolar I or II disorder who received adjunctive personalized treatment plus either lithium or quetiapine. Elastic net regularization (ENR) was used to generate models for lithium and quetiapine; these models were evaluated on a test set., Results: Predictions from the lithium model explained 17.4% of the variance in actual observed scores of patients who received lithium in the test set, while predictions from the quetiapine model explained 32.1% of the variance of patients that received quetiapine. Of the baseline variables selected, those with the largest parameter estimates were: severity of mania; attention-deficit/hyperactivity disorder (ADHD) comorbidity; nonsuicidal self-injurious behavior; employment; and comorbidity with each of two anxiety disorders (social phobia/society anxiety and agoraphobia). Predictive accuracy of the ENR model outperformed the simple and basic theoretical models., Conclusion: ENR is an effective approach for building optimal and generalizable models. Variables identified through this methodology can inform future research on predictors of response to lithium and quetiapine, as well as future modeling efforts of treatment choice in bipolar disorder., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Depressive episodes are often prevalent among patients with bipolar disorder, but little is known regarding the differential patterns of development over time. We aimed to determine and characterize trajectories of depressive symptoms among adults with bipolar disorder during 6 months of systematic treatment., Methods: The pragmatic clinical trial, Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE), randomized 482 outpatients with bipolar disorder to lithium or quetiapine. Depressive symptoms were rated at up to 9 visits using the Montgomery-Asberg Depression Rating Scale (MADRS). Growth mixture modeling was utilized to identify trajectories and multinomial regression analysis estimated associations with potential predictors., Results: Four distinct trajectories of depressive symptoms were identified. The responding class (60.3%) with a rapid reduction and subsequent low level; the partial-responding class (18.4%) with an initial reduction followed by an increase during the remaining weeks; the fluctuating class (11.6%) with a fluctuation in depressive symptoms; and the non-responding class (9.7%) with sustained moderate-severe depressive symptoms. Bipolar type I predicted membership of the non-responding class and randomization to quetiapine predicted membership of either the responding or the non-responding class., Conclusion: Approximately 30% experienced a partial or fluctuating course, and almost 10% had a chronic course with moderate-severe depression during 6 months. Patients diagnosed with bipolar type 1 had higher risk of being categorized into a class with a worse outcome. While no differences in average overall outcomes occurred between the lithium and quetiapine groups, trajectory analysis revealed that the lithium group had more variable courses., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Individuals with bipolar disorder (BD) are more likely than the general population to develop risk factors associated with cardiovascular disease, one of the leading causes of morbidity and mortality in this clinical population. To address this disproportionate medical burden, we developed Nutrition Exercise and Wellness Treatment (NEW Tx), a lifestyle intervention for individuals with BD., Methods: In this study, participants were randomized to NEW Tx (n = 19) or a treatment as usual waitlist (n = 19). We examine the intervention's efficacy to improve the physical and psychological outcomes of individuals with BD. Assessors were blind to participant condition throughout study duration., Results: The NEW Tx group reported increased weekly exercise duration and overall functioning, and decreased depression and illness severity over the study duration. However, only improvements in functioning were significantly greater in the NEW Tx group than in the control group. There were no group differences in weight loss or mood symptoms over the study duration., Limitations: Limitations to this study include lack of objective measurement of exercise and a small and relatively homogeneous sample., Conclusions: These data suggest that a manualized lifestyle intervention for BD may not be ideal to improve lifestyle changes in this clinical population. Further research is needed to pilot personalized approaches to creating a healthy lifestyle in BD., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Bipolar disorders (BD) are characterized by emotion and cognitive dysregulation. Mapping deficits in the neurocircuitry of cognitive-affective regulation allows for potential identification of intervention targets. This study used functional MRI data in BD patients and healthy controls during performance on a task requiring cognitive and inhibitory control superimposed on affective images, assessing cognitive and affective interference., Methods: Functional MRI data were collected from 39 BD patients and 36 healthy controls during performance on the Multi-Source Interference Task overlaid on images from the International Affective Picture System (MSIT-IAPS). Analyses examined patterns of activation in a priori regions implicated in cognitive and emotional processing. Functional connectivity to the anterior insula during task performance was also examined, given this region's role in emotion-cognition integration., Results: BD patients showed significantly less activation during cognitive interference trials in inferior parietal lobule, dorsomedial prefrontal cortex, anterior insula, mid-cingulate, and ventrolateral prefrontal cortex regardless of affective valence. BD patients showed deviations in functional connectivity with anterior insula in regions of the default mode and frontoparietal control networks during negatively valenced cognitive interference trials., Conclusions: Our findings show disruptions in cognitive regulation and inhibitory control in BD patients in the presence of irrelevant affective distractors. Results of this study suggest one pathway to dysregulation in BD is through inefficient integration of affective and cognitive information, and highlight the importance of developing interventions that target emotion-cognition integration in BD., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Approximately 86-89% of patients with BD have a comorbid anxiety disorder associated with poor quality of life and reduced likelihood of recovery from an acute mood episode. The purpose of this study is to assess the prevalence and impact of comorbid anxiety using the Bipolar Inventory of Symptoms Scale (BISS) in patients with BD who participated in a 6-month pragmatic trial., Methods: Participants (N = 482) in the Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE) study were adults with BD I or II. Anxiety diagnoses were assessed with the MINI. Global illness severity was assessed using the Clinical Global Impression-Bipolar Version. Mood symptoms and anxiety severity were assessed using the BISS., Results: 61% of the study sample met criteria for a current anxiety disorder. Patients with a higher BISS anxiety score at baseline had a higher overall BD illness severity, depressive severity, and manic episode severity (p < 0.001). A single cutoff value of BISS anxiety had great sensitivity, yet poor specificity for determining a comorbid anxiety diagnosis. There were no significant differences in outcomes for individuals treated for anxiety disorders with anxiolytics compared with those who were not treated with anxiolytics., Limitations: Sample size limitations prevented an analysis of whether the BISS cutoff score of 10 performed differently across varied anxiety disorders., Conclusions: Given its ability to identify patients with co-occurring anxiety, the BISS anxiety subscale shows clinical utility as a screening measure though its application as a clinical assessment measure may not be advisable., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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

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

Background: Successful medication management for bipolar disorder requires clinicians to monitor and adjust regimens as needed, to achieve maximum effectiveness and patient adherence. This study aims to measure the prevalence of indications for medication adjustment at visits for bipolar disorder treatment; the frequency with which physicians recommend medication adjustments; and how strongly the indications predict the adjustments., Methods: Data included 3,094 visits for 457 patients in Bipolar CHOICE, a comparative effectiveness study that compared treatment with lithium versus quetiapine. A set of indications for adjustment was matched to reports of whether the physician recommended a medication adjustment at that visit, and what type. Associations between indication and adjustment were examined using bivariate tests and hierarchical logistic mixed effects models., Results: Medication adjustment was recommended at 63% of the visits where one of the indications was present, and at 53% of all visits. In multivariable analyses, adjustment was more likely to be recommended if there was an indication of non-response or side effects, for patients who started on quetiapine rather than lithium, or for patients who were female, married, employed or more educated., Limitations: The study's cross-sectional design implies that observed associations could result from confounding variables. Also, the CHOICE trial placed certain restrictions on physicians' medication choices, although this is not likely to have resulted in major alterations of prescribing patterns., Conclusions: Clinical inertia may help explain the lack of any adjustment recommendation at 37% of the visits where one of the indications was present. Other explanations could also apply, such as watchful waiting., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Up to 60% of patients with bipolar disorder develop a substance use disorder during their lifetime. The purpose of this paper was to assess the impact of substance use disorders on depression recovery among bipolar patients randomly assigned to different psychotropic medications and psychosocial interventions. We hypothesized that patients with a comorbid substance use disorder would benefit less from psychotherapy regardless of treatment intensity/length compared to patients without a comorbid substance use disorder., Method: We conducted post hoc analyses among bipolar disorder patients ( n = 270) with and without comorbid substance use disorders enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder randomized psychosocial intervention trial. All patients entered during or shortly after the onset of a bipolar depressive episode. Logistic regression and Cox proportional hazard models were used to assess whether current or past substance use disorders moderated the response of patients to intensive psychosocial intervention or brief psychoeducation with collaborative care, operationalized as full recovery from an episode of bipolar depression., Results: Current comorbid substance use disorders significantly predicted likelihood of recovery (odds ratio = 2.25, p = 0.025) and time to recovery (odds ratio = 1.71, p = 0.006) from bipolar depression. We found that 74.5% of patients with a current substance use disorder, compared to 56.5% without a current substance use disorder, recovered from bipolar depression. Past substance use disorders did not predict likelihood of recovery or time to recovery. Current substance use disorders did not significantly moderate response to intensive psychotherapy versus collaborative care., Conclusion: Contrary to our hypotheses, bipolar disorder participants with a current comorbid substance use disorder were more likely to recover from psychosocial treatment for bipolar depression than patients without a current comorbid substance use disorder. If this finding is replicated, it has implications for the ordering of treatment for patients with comorbid bipolar disorder and substance use disorders.

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a protein that regulates metabolism and inflammation by activating nuclear receptors, especially the family of peroxisome proliferator-activated receptors (PPARs). PGC-1 alpha and PPARs also regulate mitochondrial biogenesis, cellular energy production, thermogenesis, and lipid metabolism. Brain energy metabolism may also be regulated in part by the interaction between PGC-1 alpha and PPARs. Because neurodegenerative diseases (Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and bipolar disorder have been associated with dysregulated mitochondrial and brain energy metabolism, PGC-1 alpha may represent a potential drug target for these conditions. The purpose of this article is to review the physiology of PGC-1 alpha, PPARs, and the role of PPAR agonists to target PGC-1 alpha to treat neurodegenerative diseases and bipolar disorder. We also review clinical trials of repurposed antidiabetic thiazolidines and anti-triglyceride fibrates (PPAR agonists) for neurodegenerative diseases and bipolar disorder. PGC-1 alpha and PPARs are innovative potential targets for bipolar disorder and warrant future clinical trials., (Copyright © 2018. Published by Elsevier Inc.)

Background: The impact of psychosis on the treatment of bipolar depression is remarkably understudied. The primary aim of this study was to compare treatment outcomes of bipolar depressed individuals with and without psychosis. The secondary aim was to compare the effect of lithium and quetiapine, each with adjunctive personalized treatments (APTs), in the psychotic subgroup., Methods: We assessed participants with DSM-IV bipolar depression included in a comparative effectiveness study of lithium and quetiapine with APTs (the Bipolar CHOICE study). Severity was assessed by the Bipolar Inventory of Symptoms Scale (BISS) and by the Clinical Global Impression Scale-Severity-Bipolar Version (CGI-S-BP). Mixed models were used to assess the course of symptom change, and Cox regression survival analysis was used to assess the time to remission., Results: Psychotic features were present in 10.6% (n = 32) of the depressed participants (n = 303). Those with psychotic features had higher scores on the BISS before (75.2 ± 17.6 vs. 54.9 ± 16.3; P < .001) and after (37.2 ± 19.7 vs. 26.3 ± 18.0; P = .003) 6-month treatment. The CGI-S-BP yielded similar results. Participants with and without psychosis had similar course of symptom improvement and similar time to remission. There was no significant difference in the treatment outcomes of lithium (n = 11) and quetiapine (n = 21) among the psychotic subgroup., Conclusion: Bipolar depressive episodes with psychotic features are more severe, and compared to nonpsychotic depressions, present a similar course of improvement. Given the small number of participants presenting psychosis, the lack of statistically significant difference between lithium- and quetiapine-based treatment of psychotic bipolar depressive episodes needs replication in a larger sample., (© 2018 Wiley Periodicals, Inc.)

Background and Objectives: Substance use disorders (SUDs) are present in up to 70% of patients with bipolar disorder (BD) and contribute to high rates of disability, morbidity, and treatment non-adherence. Despite this prevalence, few trials have investigated targeted psychosocial interventions for comorbid BD and SUDs., Methods: Using PubMed and PsycINFO, we conducted a search of the literature up to January 2018 for psychosocial interventions targeted to patients with comorbid BD and SUDs. We identified eight total trials. Of these studies, four randomized and two open trials targeted the types of substance use (alcohol and illicit drugs) of primary concern to mood stability; the remaining two studies, both open trials, targeted smoking cessation., Results: None of the randomized trials provided consistent evidence for management of both mood symptoms and substance use though integrated group therapy (IGT) demonstrated consistent beneficial effects on substance use outcomes. Other treatments showed benefit for mood symptoms without benefits for alcohol or illicit substance use. Small pilot studies of combined treatments for smoking cessation provided some initial promise., Conclusions: At present, IGT is the most-well validated and efficacious approach if substance use is targeted in an initial treatment phase. For a subsequent phase, additional psychosocial BD treatments may be needed for mood and functioning benefits., Scientific Significance: This review synthesizes the psychosocial interventions that have been conducted in comorbid BD and SUDs while also providing a perspective on which intervention elements are helpful for addressing substance use versus mood symptoms in patients with these co-occurring conditions. (Am J Addict 2018;27:188-201)., (© 2018 American Academy of Addiction Psychiatry.)

Background: Bipolar patients experience sleep disturbances during and between mood episodes. Yet the impact of sleep on treatment with different medications has not been fully explored. The purpose of this paper is to explore the potential impact of poor sleep at baseline on outcomes in a randomized effectiveness trial of quetiapine and lithium., Methods: The Bipolar CHOICE study was a 6-month, parallel group, multisite randomized controlled trial. Participants with bipolar disorder (N = 482; 59% female and age 18-70 years) received quetiapine or lithium. Patients were allowed to also receive adjunctive personalized treatments, which were guideline-informed, empirically-based medications added to treatment as needed. Medication changes were recorded as necessary clinical adjustments (NCA). Fisher's exact tests, mixed-regression models, and Mann-Whitney U tests were used to assess demographic and clinical characteristics as well as whether sleep disturbance would predict outcomes., Results: 63% of patients had baseline sleep disturbance. Individuals with sleep disturbance had worse bipolar illness severity, greater severity of depression, mania, anxiety, irritability, and psychosis, were less likely to have sustained response (17% vs. 29%; adjusted RR: 0.55, 95% CI: 0.38-0.78, p = 0.0006) and had more NCAs (median 0.71 vs. 0.59, p = 0.03)., Limitations: Our findings were limited by how we defined sleep disturbance, and by how severity of sleep disturbance was assessed with one item with a non-sleep specific measure., Conclusions: Baseline sleep disturbance was associated with more severe bipolar symptoms and worse 6-month outcomes. Further research is warranted on improving sleep in bipolar disorder, especially the role of psychosocial interventions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Suicidal ideation occurs frequently among individuals with bipolar disorder; however, its course and persistence over time remains unclear. We aimed to investigate 6-months trajectories of suicidal ideation among adults with bipolar disorder., Methods: The Bipolar CHOICE study randomized 482 outpatients with bipolar disorder to 6 months of lithium- or quetiapine-based treatment including other psychotropic medications as clinically indicated. Participants were asked at 9 visits about suicidal ideation using the Concise Health Risk Tracking scale. We performed latent Growth Mixture Modelling analysis to empirically identify trajectories of suicidal ideation. Multinomial logistic regression analyses were applied to estimate associations between trajectories and potential predictors., Results: We identified four distinct trajectories. The Moderate-Stable group represented 11.1% and was characterized by constant suicidal ideation. The Moderate-Unstable group included 2.9% with persistent thoughts about suicide with a more fluctuating course. The third (Persistent-low, 20.8%) and fourth group (Persistent-very-low, 65.1%) were characterized by low levels of suicidal ideation. Higher depression scores and previous suicide attempts (non-significant trend) predicted membership of the Moderate-Stable group, whereas randomized treatment did not., Limitations: No specific treatments against suicidal ideation were included and suicidal thoughts may persist for several years., Conclusion: More than one in ten adult outpatients with bipolar disorder had moderately increased suicidal ideation throughout 6 months of pharmacotherapy. The identified predictors may help clinicians to identify those with additional need for treatment against suicidal thoughts and future studies need to investigate whether targeted treatment (pharmacological and non-pharmacological) may improve the course of persistent suicidal ideation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Comorbid anxiety in bipolar disorder (BD) is associated with greater illness severity, reduced treatment response, and greater impairment. Treating anxiety in the context of BD is crucial for improving illness course and outcomes. The current study examined the feasibility, acceptability and preliminary efficacy of the Unified Protocol (UP), a transdiagnostic cognitive behavioral therapy, as an adjunctive treatment to pharmacotherapy for BD and comorbid anxiety disorders., Methods: Twenty-nine patients with BD and at least one comorbid anxiety disorder were randomized to pharmacotherapy treatment-as-usual (TAU) or TAU with 18 sessions of the UP (UP+TAU). All patients completed assessments every four weeks to track symptoms, functioning, emotion regulation and temperament. Linear mixed-model regressions were conducted to track symptom changes over time and to examine the relationship between emotion-related variables and treatment response., Results: Satisfaction ratings were equivalent for both treatment groups. Patients in the UP+TAU group evidenced significantly greater reductions over time in anxiety and depression symptoms (Cohen's d's>0.80). Baseline levels of neuroticism, perceived affective control, and emotion regulation ability predicted magnitude of symptom change for the UP+TAU group only. Greater change in perceived control of emotions and emotion regulation skills predicted greater change in anxiety related symptoms., Limitations: This was a pilot feasibility and acceptability trial; results should be interpreted with caution., Conclusions: Treatment with the UP+TAU was rated high in patient satisfaction, and resulted in significantly greater improvement on indices of anxiety and depression relative to TAU. This suggests that the UP may be a feasible treatment approach for BD with comorbid anxiety., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Psychotic bipolar depressive episodes remain remarkably understudied despite being common and having a significant impact on bipolar disorder. The aim of this study is to identify the characteristics of depressed bipolar patients with current psychosis compared to those without psychosis., Methods: We used baseline data of a comparative effectiveness study of lithium and quetiapine for bipolar disorder (the Bipolar CHOICE study) to compare demographic, clinical, and functioning variables between those with and without psychotic symptoms. Of the 482 participants, 303 (62.9%) were eligible for the present study by meeting DSM-IV criteria for an acute bipolar depressive episode. Univariate analyses were conducted first, and then included in a model controlling for symptom severity., Results: The sample was composed mostly of women (60.7%) and the mean age was 39.5±12.1 years. Psychosis was present in 10.6% (n=32) of the depressed patients. Psychotic patients had less education, lower income, and were more frequently single and unemployed. Psychosis was also associated with a more severe depressive episode, higher suicidality, more comorbid conditions and worse functioning. Most group differences disappeared when controlling for depression severity., Limitations: Only outpatients were included and the presence of psychosis in previous episodes was not assessed., Conclusion: Psychosis during bipolar depressive episodes is present even in an outpatient sample. Psychotic, depressed patients have worse illness outcomes, but future research is necessary to confirm if these outcomes are only associated with the severity of the disorder or if some of them are independent of it., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: DSM-5 changed the criteria from DSM-IV for mixed features in mood disorder episodes to include non-overlapping symptoms of depression and hypomania/mania. It is unknown if, by changing these criteria, the same group would qualify for mixed features. We assessed how those meeting DSM-5 criteria for mixed features compare to those meeting DSM-IV criteria., Methods: We analyzed data from 482 adult bipolar patients in Bipolar CHOICE, a randomized comparative effectiveness trial. Bipolar diagnoses were confirmed through the MINI International Neuropsychiatric Interview (MINI). Presence and severity of mood symptoms were collected with the Bipolar Inventory of Symptoms Scale (BISS) and linked to DSM-5 and DSM-IV mixed features criteria. Baseline demographics and clinical variables were compared between mood episode groups using ANOVA for continuous variables and chi-square tests for categorical variables., Results: At baseline, the frequency of DSM-IV mixed episodes diagnoses obtained with the MINI was 17% and with the BISS was 20%. Using DSM-5 criteria, 9% of participants met criteria for hypomania/mania with mixed features and 12% met criteria for a depressive episode with mixed features. Symptom severity was also associated with increased mixed features with a high rate of mixed features in patients with mania/hypomania (63.8%) relative to those with depression (8.0%)., Limitations: Data on mixed features were collected at baseline only and thus do not reflect potential patterns in mixed features within this sample across the study duration., Conclusions: The DSM-5 narrower, non-overlapping definition of mixed episodes resulted in fewer patients who met mixed criteria compared to DSM-IV., (Copyright © 2017. Published by Elsevier B.V.)

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

Background: Many mood disorder patients need analgesics due to increased pain sensitivity. Recent studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit antidepressant treatment, which requires replication before clinical recommendations., Methods: The Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study randomized participants to 6 months lithium or quetiapine treatment. Use of NSAIDs and paracetamol was assessed throughout the study period and psychopathology measured with the Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) and Bipolar Inventory of Symptoms Scale (BISS). The effects of NSAIDs and paracetamol on treatment outcome were examined using mixed effects linear regression adjusted for age, gender, body mass index, smoking status, exercise, and somatic diseases., Results: Among 482 participants, 177 (36.7%) used NSAIDs and/or paracetamol during the study. NSAID and paracetamol users did not differ from nonusers with respect to treatment outcome with lithium or quetiapine at any time point during 6 months treatment on the overall CGI-BP (β = 0.001 (95% CI = -0.01 to -0.01), P = .87), the BISS (β = 0.01 (95% CI = -0.17 to 0.15), P = .91), nor the CGI-BP subscales for depression or mania. Users of NSAIDs only (n = 76), paracetamol only (n = 62), and users of both NSAIDs and paracetamol (n = 39) showed no statistical difference compared to nonusers (all P > .3)., Conclusions: This is the first trial to show that use of NSAIDs and paracetamol, alone or in combination, does not affect lithium- or quetiapine-based bipolar disorder mood-stabilizing treatment outcomes. Prior studies have suggested that NSAIDs may inhibit antidepressant treatment, whereas our results support findings indicating no detrimental effects of NSAIDs or paracetamol on affective disorder treatment., (© 2017 Wiley Periodicals, Inc.)

This study examined whether sleep disturbance predicted or moderated responses to psychotherapy in participants who participated in STEP-BD, a national, multisite study that examined the effectiveness of different treatment combinations for bipolar disorder. Participants received either a brief psychosocial intervention called collaborative care (CC; n = 130) or intensive psychotherapy (IP; n = 163), with study-based pharmacotherapy. Participants (N = 243) were defined as current (past week) short sleepers (<6 hours/night), normal sleepers (6.5-8.5 hours/night), and long sleepers (≥9 hours/night), according to reported average nightly sleep duration the week before randomization. Sleep disturbances did not predict the likelihood of recovery nor time until recovery from a depressive episode. There was no difference in recovery rates between IP versus CC for normal sleepers, and medium effect sizes were observed for differences in short and long sleepers. In this study, sleep did not play a major role in predicting or moderating response to psychotherapy in bipolar disorder.

Background: Comparative effectiveness research uses multiple tools, but lacks outcome measures to assess large electronic medical records and claims data. Aggregate changes in medications in response to clinical need may serve as a surrogate outcome measure. We developed the Medication Recommendation Tracking Form (MRTF) to record the frequency, types, and reasons for medication adjustments in order to calculate Necessary Clinical Adjustments (NCAs), medication adjustments to reduce symptoms, maximize treatment response, or address problematic side effects., Methods: The MRTF was completed at every visit for 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial., Results: Responders had significantly fewer NCAs compared to non-responders. NCAs predicted subsequent response status such that every additional NCA during the previous visit decreased a patient's odds of response by approximately 30%. Patients with more severe symptoms had a greater number of NCAs at the subsequent visit. Patients with a comorbid anxiety disorder demonstrated a significantly higher rate of NCAs per month than those without a comorbid anxiety disorder. Patients with greater frequency, intensity, and interference of side effects had higher rates of NCAs. Participants with fewer NCAs reported a higher quality of life and decreased functional impairment., Limitations: The MRTF has not been examined in community clinic settings and did not predict response more efficiently than the Clinical Global Impression-Bipolar Version (CGI-BP)., Conclusions: The MRTF is a feasible proxy of clinical outcome, with implications for clinical training and decision-making. Analyses of big data could use changes in medications as a surrogate outcome measure., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: We sought to address how predictors and moderators of psychotherapy for bipolar depression - identified individually in prior analyses - can inform the development of a metric for prospectively classifying treatment outcome in intensive psychotherapy (IP) versus collaborative care (CC) adjunctive to pharmacotherapy in the Systematic Treatment Enhancement Program (STEP-BD) study., Methods: We conducted post-hoc analyses on 135 STEP-BD participants using cluster analysis to identify subsets of participants with similar clinical profiles and investigated this combined metric as a moderator and predictor of response to IP. We used agglomerative hierarchical cluster analyses and k-means clustering to determine the content of the clinical profiles. Logistic regression and Cox proportional hazard models were used to evaluate whether the resulting clusters predicted or moderated likelihood of recovery or time until recovery., Results: The cluster analysis yielded a two-cluster solution: 1) "less-recurrent/severe" and 2) "chronic/recurrent." Rates of recovery in IP were similar for less-recurrent/severe and chronic/recurrent participants. Less-recurrent/severe patients were more likely than chronic/recurrent patients to achieve recovery in CC (p=.040, OR=4.56). IP yielded a faster recovery for chronic/recurrent participants, whereas CC led to recovery sooner in the less-recurrent/severe cluster (p=.034, OR=2.62)., Limitations: Cluster analyses require list-wise deletion of cases with missing data so we were unable to conduct analyses on all STEP-BD participants., Conclusions: A well-powered, parametric approach can distinguish patients based on illness history and provide clinicians with symptom profiles of patients that confer differential prognosis in CC vs. IP., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: Bipolar disorder requires psychiatric medications, but even guideline-concordant treatment fails to bring many patients to remission or keep them euthymic. To address this gap, researchers have developed adjunctive psychotherapies. The purpose of this paper is to critically review the evidence for the efficacy of manualized psychosocial interventions for bipolar disorder., Methods: We conducted a search of the literature to examine recent (2007-present), randomized controlled studies of the following psychotherapy interventions for bipolar disorder: psychoeducation (PE), cognitive behavioral therapy (CBT), interpersonal and social rhythm therapy (IPSRT), dialectical behavior therapy (DBT), mindfulness-based cognitive therapy (MBCT), and family therapies such as family focused therapy (FFT)., Results: All of the psychotherapy interventions appear to be effective in reducing depressive symptoms. Psychoeducation and CBT are associated with increased time to mood episode relapse or recurrence. MBCT has demonstrated a particular effectiveness in improving depressive and anxiety symptoms. Online psychotherapy interventions, programs combining one or more psychotherapy interventions, and targeted interventions centering on particular symptoms have been the focus of recent, randomized controlled studies in bipolar disorder., Conclusions: Psychotherapy interventions for the treatment of bipolar disorder have substantial evidence for efficacy. The next challenge will to disseminate these psychotherapies into the community., (Copyright © 2016 Elsevier B.V. All rights reserved.)