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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 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.

Over the past decade, the use of integrative health modalities, such as mind-body interventions, art therapy, nutrition, and exercise, to treat stress-related mental health conditions, including posttraumatic stress disorder (PTSD), in military and veteran populations has been increasing. The use of integrative therapies for PTSD provides options for veterans who are not interested in traditional modalities, have limited access to traditional treatments, or are seeking a more comprehensive approach to managing their PTSD or subthreshold symptoms. These therapies show promise for improving overall well-being and comorbid conditions with PTSD, such as pain or migraines, but yield mixed data for PTSD symptoms. The aim of this article is to review the evidence for the most promising integrative health modalities for treating PTSD, with a special focus on the treatment of veterans, as well as to offer recommendations and suggestions for clinicians.

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.

Behavioral activation (BA) is an empirically based psychotherapy for depression that improves symptoms by increasing a client’s contact with sources of positive reinforcement by making behavioral changes. Core aspects of BA approaches include performance and monitoring of scheduled activities that are selected based on a client’s values or specific depressive behaviors. To address individual and environmental barriers to activation, many BA treatment manuals also include additional components such as mindfulness techniques, social skills training, and contingency management strategies. Evidence supports the effectiveness of BA for treating depression, and researchers have found it to be as effective as many standard treatments for depression, including pharmacotherapy, cognitive therapy, and cognitive–behavioral therapy. Future directions are discussed, such as the application of BA to special populations and settings, including for groups, remote delivery, and specific subpopulations.

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 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.

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 < 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.

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.

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.

Objective: Health uncertainty among healthcare workers has yet to be examined as a contributor to the psychological toll of the COVID-19 pandemic. We aimed to (1) characterize health uncertainty levels among healthcare workers in a large, U.S. hospital system during the COVID-19 pandemic and (2) examine associations between health uncertainty and psychological outcomes.Methods: From March to June 2020, healthcare workers in a large, urban U.S. healthcare system were invited to complete an online questionnaire. Self-report measures assessed sociodemographic characteristics and job roles, health uncertainty, and emotional wellbeing variables (anxiety, depression, loneliness, self-compassion, and coping confidence). Health uncertainty (categorical and continuous scores) was compared across each variable using correlations and ANOVAs.Results: Healthcare workers (N = 440) were on average 44.5 years of age, 88.9% female, and 84.5% non-Hispanic white. Over half (52%) endorsed experiencing health uncertainty “sometimes” to “all the time”. While unrelated to sociodemographic characteristics (ps > .05), health uncertainty was highest among pharmacists and technicians, with levels significantly higher than other roles including physicians (p < .05) and mental health and spiritual counselors (p < .05). Higher health uncertainty was associated with higher anxiety (p < .001), depression (p < .001), and loneliness (p < .001), higher self-compassion (p = .02), and lower coping confidence (p < .001).Conclusions: Health uncertainty during the COVID-19 pandemic is common among healthcare workers, with higher levels related to poorer emotional wellbeing and less confidence in their coping abilities. Further research is needed to understand the relationships between healthcare workers’ health uncertainties and associated factors (i.e., job roles) and to identify whether health uncertainty may be a modifiable target for future interventions.

Objective: The COVID-19 pandemic has strained healthcare systems worldwide, placing a high psychological burden on frontline clinicians. There is an urgent need to better understand their stressors and determine if stressors differ by clinical role. The present study assessed the concerns among frontline clinicians across a large healthcare system during the COVID-19 pandemic to inform the development of tailored supportive services.Methods: From March – June 2020, frontline clinicians across the Mass General Brigham healthcare system were invited to register for an adapted mind-body resiliency group program. Clinicians completed pre- and post-program assessments asking them to report their COVID-19-related concerns. Qualitative data were analyzed in aggregate and by clinical role using content analysis to identify overarching domains.Results: Frontline clinicians’ concerns fall within seven domains: concerns for self, patients, family members, staff, existential concerns, systems-level concerns, and job-level concerns. Concerns for self and existential concerns were most commonly reported across clinical roles. Long-term care clinicians were highly concerned about patients’ wellbeing while rehabilitation therapists were highly concerned about their family members’ health. Across groups, nurse practitioners and physician assistants more often reported job-level concerns. Concerns for staff and systems level concerns were less frequently reported across clinical roles.Conclusions: Frontline clinicians share common pandemic-related concerns, but nuances exist among the concerns most frequently reported across clinical roles. Interventions that offer stress management and resiliency training may be helpful for addressing pandemic-related concerns overall. Future research should determine if tailored support services by clinical role may be warranted.

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.

The purpose of this review is to critically assess the evidence for exercise as an adjunct intervention for major depressive disorder and bipolar disorder, chronic conditions characterized by frequent comorbid conditions as well as interepisodic symptoms with poor quality of life and impaired functioning. Individuals with these mood disorders are at higher risk of cardiovascular disease and premature death in part because of increased rates of obesity, inactivity, and diabetes mellitus compared to the general population. Exercise may not only mitigate the increased risk of cardiovascular disease, but could also potentially improve the long term outcomes of mood disorders.We conducted a literature review on the impact of exercise on mood disorders and associated comorbid conditions as well as possible biological mechanisms. We found that exercise impacts both the physical health parameters of mood disorders as well as mental health outcomes. Exercise also positively impacts conditions frequently comorbid with mood disorders (i.e. anxiety, pain, and insomnia). There are multiple candidate biomarkers for exercise, with brain-derived neurotrophic factor and oxidative stress as two main promising components of exercise's anti-depressant effect.Exercise appears to be a promising adjunct treatment for mood disorders. We conclude with recommendations for future research of exercise as an adjunct intervention for mood disorders.

Cognitive impairments and biases, which are prevalent in patients with mood and anxiety disorders, can affect quality of life and functioning. Traditional treatments are only insufficiently addressing these impairments and biases. We review the cognitive impairments and biases present in these disorders as well as treatments targeting these domains. Interventions aimed at improving cognitive impairments and biases may help improve cognitive deficits and overall functioning in patients with mood and anxiety disorders. Direct comparisons of treatments for cognitive impairments or biases versus more traditional psychosocial interventions have produced diverse results. Overall, treatments for cognitive impairments and cognitive biases warrant additional study in clinical trials. Future research should explore cognitive remediation and cognitive bias modification adjunctive to psychosocial treatments to optimize patient outcomes in mood and anxiety disorders.

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.

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 × 109/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 × 109/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.

Bipolar disorder is a serious mental illness characterized by alternating periods of elevated and depressed mood. Sleep disturbances in bipolar disorder are present during all stages of the condition and exert a negative impact on overall course, quality of life, and treatment outcomes. We examine the partnership between circadian system (process C) functioning and sleep-wake homeostasis (process S) on optimal sleep functioning and explore the role of disruptions in both systems on sleep disturbances in bipolar disorder. A convergence of evidence suggests that sleep problems in bipolar disorder result from dysregulation across both process C and process S systems. Biomarkers of depressive episodes include heightened fragmentation of rapid eye movement (REM) sleep, reduced REM latency, increased REM density, and a greater percentage of awakenings, while biomarkers of manic episodes include reduced REM latency, greater percentage of stage I sleep, increased REM density, discontinuous sleep patterns, shortened total sleep time, and a greater time awake in bed. These findings highlight the importance of targeting novel treatments for sleep disturbance in bipolar disorder.

Background Few brief, self-report measures exist that can reliably predict adverse suicidality outcomes in patients with BD. This study utilized the Concise Health Risk Tracking Self-Report (CHRT) to assess suicidality in patients with BD and examined its psychometric performance, clinical correlates, and prospective value in predicting adverse events related to suicidality. Methods The CHRT was administered at baseline and follow-up to 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. The Columbia Suicide Severity Rating Scale (CSSRS) was used at baseline to assess lifetime history of suicide attempts and related behaviors. Clinician-rated measures of mood (Bipolar Inventory of Symptoms Scale) and bipolar symptoms (Clinical Global Impressions-Bipolar Version) were conducted at baseline and follow-up. Results The CHRT showed excellent internal consistency and construct validity and was highly correlated with clinician ratings of depression, anxiety, and overall functioning at baseline and throughout the study. Baseline CHRT scores significantly predicted risk of subsequent suicidality-related Serious Adverse Events (sSAEs), after controlling for mood and comorbidity. Specifically, the hazard of a sSAE increased by 76% for every 10-point increase in baseline CHRT score. Past history of suicide attempts and related behaviors, as assessed by the CSSRS, did not predict subsequent sSAEs. Limitations The CSSRS was used to assess static risk factors in terms of past suicidal behaviors and may have been a more powerful predictor over longer-term follow-up. Conclusions The CHRT offers a quick and robust self-report tool for assessing suicidal risk and has important implications for future research and clinical practice.

Background and Objectives Topiramate is effective for alcohol use disorders (AUDs) among non-psychiatric patients. We examined topiramate for treating comorbid AUDs in bipolar disorder (BD).

OBJECTIVE 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. METHOD 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. RESULTS 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). CONCLUSIONS 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. TRIAL REGISTRATION ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

BACKGROUND: Little is known about specific mood symptoms that may confer risk for suicidal ideation (SI) among patients with bipolar disorder (BD). We evaluated prospectively whether particular symptoms of depression and mania precede the onset or worsening of SI, among adults with or without a history of a suicide attempt. METHODS: We examined prospective data from a large (N = 2,741) cohort of patients participating in the Systematic Treatment Enhancement Program for BD (STEP-BD). We evaluated history of suicide attempts at baseline, and symptoms of depression and mania at baseline and follow-up visits. Hierarchical linear modeling tested whether specific mood symptoms predicted subsequent levels of SI, and whether the strength of the associations differed based on suicide attempt history, after accounting for the influence of other mood symptoms and current SI. RESULTS: Beyond overall current depression and mania symptom severity, baseline SI, and illness characteristics, several mood symptoms, including guilt, reduced self-esteem, psychomotor retardation and agitation, increases in appetite, and distractibility predicted more severe levels of subsequent SI. Problems with concentration, distraction, sleep loss and decreased need for sleep predicted subsequent SI more strongly among individuals with a suicide attempt history. CONCLUSIONS: Several specific mood symptoms may confer risk for the onset or worsening of SI among treatment-seeking patients with BD. Individuals with a previous suicide attempt may be at greater risk in part due to greater reactivity to certain mood symptoms in the form of SI. However, overall, effect sizes were small, suggesting the need to identify additional proximal predictors of SI.

Background Affective symptoms and medical comorbidities have a negative impact on the course of bipolar disorder. The aim of this analysis was to examine how the perceptions of physical health and functioning in individuals with bipolar disorder relate to their mood symptoms. Methods We analyzed longitudinal data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) on the physical subscales of the Short Form Health Survey (SF-36) (physical functioning, role limitations due to physical problems, bodily pain, and general health). Results Participants’ perception of their overall physical health predicted severity of mania/hypomania, depression, and life satisfaction at concurrent and future visits. Perceptions of role limitations due to physical health problems predicted depressive symptoms and poor life satisfaction. Worse bodily pain predicted symptoms of mania/hypomania. Reports of specific or concrete physical limitations in daily life showed no associations with psychiatric symptoms at concurrent assessments, but did predict worse course of illness one year later. SF-36 scores showed significant, but small associations with the presence of medical comorbidities. Limitations: Perceptions of physical health and quality of life were self-report, potentially lending themselves to transient negative biases, particularly among depressed participants. Additionally, the SF-36 was selected as a generic, widely used measure; as a result, it was not specific to the illness burden of bipolar disorder. Conclusion Overall, broad perceptions of poor physical health were associated with worse course of illness over the 24 months of the study. Though further research is warranted, changes in subjective physical health related quality of life, even independent of objective health changes, may offer important insight into global wellbeing and be targets of psychotherapy treatment.

Objective People with bipolar disorder are at high risk of suicide, but no clinically useful scale has been validated in this population. The aim of this study was to evaluate the psychometric properties in bipolar disorder of the 7- and 12-item versions of the Concise Health Risk Tracking Self-Report (CHRT-SR), a scale measuring suicidal ideation, suicidal behavior, and associated symptoms. Methods The CHRT was administered to 283 symptomatic outpatients with bipolar I or II disorder who were randomized to receive lithium plus optimized personalized treatment (OPT), or OPT without lithium in a six month longitudinal comparative effectiveness trial. Participants were assessed using structured diagnostic interviews, clinician-rated assessments, and self-report questionnaires. Results The internal consistency (Cronbach α) was 0.80 for the 7-item CHRT-SR and 0.90 for the 12-item CHRT-SR with a consistent factor structure, and three independent factors (current suicidal thoughts and plans, hopelessness, and perceived lack of social support) for the 7-item version. CHRT-SR scores are correlated with measures of depression, functioning, and quality of life, but not with mania scores. Conclusions The 7- and 12-item CHRT-SR both had excellent psychometric properties in a sample of symptomatic subjects with bipolar disorder. The scale is highly correlated with depression, functioning, and quality of life, but not with mania. Future research is needed to determine whether the CHRT-SR will be able to predict suicide attempts in clinical practice.

Student veterans are an at-risk population given the challenges of military experience, reintegration to civilian life, and attending college. Therefore, there is a need for innovative programs to support student veterans. The present study sought to determine the acceptability and effectiveness of a 10-week mind-body stress reduction intervention for student veterans, or Resilient Student Warrior.Eighty-six student veterans took part in the 10-week mind-body stress reduction course, Resilient Student Warrior.Results showed a significant improvement in reports of stress reactivity, mindfulness, sleep disturbance and coping skills for stress (p 0.05), but not self-efficacy, perceived stress, depressive or post-traumatic stress disorder symptoms. The intervention was reported as helpful by 96% of participants, with 95% of participants stating they would recommend the course to others.Future studies should further assess the effectiveness of mind-body interventions among the student veteran population.

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.

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.

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.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.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.Sample size limitations prevented an analysis of whether the BISS cutoff score of 10 performed differently across varied anxiety disorders.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.

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.

Background Despite ongoing advances in the treatment of mood disorders, a substantial proportion of people diagnosed with major depression or bipolar disorder remain symptomatic over time. Yoga, which has been shown to reduce stress and depressive symptoms, as well as to improve overall quality of life, shows promise as an adjunctive treatment. However, dissemination of yoga for clinical populations remains challenging. The purpose of this pilot study was to test the feasibility and acceptability of an online yoga intervention for individuals with mood disorders. Methods In total, 56 adults who reported being diagnosed with a mood disorder (bipolar disorder, major depressive disorder, cyclothymia, or schizoaffective disorder) were recruited from MoodNetwork, an online community of individuals with mood disorders. A feedback survey and a measure of positive and negative affect were administered before and after a 30-minute online Hatha yoga class. Results In total, 44 individuals (78.6%) completed all components of the yoga class. The mean score on a 10-point Likert scale rating how much participants liked the online yoga class was 7.24 (SD=2.40). Most participants (67.9%) reported that they would be "somewhat likely" or "very likely" to participate in an online yoga program again. There was a statistically significant decrease in negative affect after completing the class (t=-6.05; P 0.10). Discussion These preliminary data support the utility of online yoga tailored specifically for people with mood disorders as a possible adjunctive intervention that warrants further investigation.

ObjectiveImmunological 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.MethodsWe 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.ResultsThe 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.ConclusionImmune 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.

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.

Many veterans deployed after 9/11/2001 are impacted by subthreshold levels of posttraumatic stress, anxiety, or other psychological health problems that may interfere with successful reintegration. Conventional treatments, including medication and trauma-focused individual psychotherapies, may not be optimally adapted, accepted, or effective to treat these subsyndromal symptoms.We developed "Resilient Warrior," a 4-session, group-based, mind-body stress-management and resilience program targeted to build skills and assessed whether its format was accessible and acceptable, and potentially efficacious, to support resilience among service members.From April 2014 to October 2014, 15 participants (53.3% women; mean age=36.6 y; SD=6.2) were surveyed for program acceptability and feasibility and completed self-reported psychological health outcomes before and after program participation. The majority (71.4%) of participants reported that the program included the right number of sessions, and all of them reported that it was helpful and relevant and that they would recommend it to others. While changes in self-reported resilience were only marginal, participation was associated with improvements in depressive symptoms, perceived stress, anxiety, and general sense of self efficacy.These pilot data provide preliminary support that "Resilient Warrior," a group-based, stress reduction and resilience program, may improve psychological health in service members even when delivered in community settings. Randomized controlled trials with longer follow-up periods are needed to establish efficacy and effectiveness for this program.背景：“9/11” 后派遣的许多退 伍军人受到了次阈值水平的创伤 后应激、焦虑或可能以干扰其成 功再融入社会的其他心理健康问 题影响。常规治疗，包括药物治 疗和关注创伤的个体心理治疗， 可能并不最佳适应于、被接受或 有效治疗这些亚症候症状。方法：我们开发了Resilient Warrior 这一项 4 阶段、基于小 组的身心压力管理和康复计划，旨 在于建立技巧并评定其形式是否可 理解及可接受以及是否可能有效， 以支持服务机构人员康复。结果：从 2014 年 4 月至 2014 年 10 月，15 名参与者（53.3% 女 性；平均年龄 = 36.6 岁；SD=6.2 ）就计划可接受性和可行性接受 研究并且完成参与计划前后的心 理 健 康 自 我 报 告 结 果 。 大 部 分 (71.4%) 参与者报告该计划包括合 适次数的课程，并且他们均报告 本计划有益并且愿意向其他人推 荐。尽管变化自我报告的康复变 化仅为最低限度，但是参与过程 与抑郁症状、感知压力、焦虑和 总体自我效能感改善相关。结论：这些试验性数据提供以下 初步支持：Resilient Warrior 这一基于小组的减少压力和康复 计划，可以改善服务机构人员的 心理健康，甚至在社区环境下开 展时也是如此。需要随访时间更 长的随机分组对照试验以确定本 计划的疗效和有效性。.Muchos veteranos destacados tras el 11S están afectados por niveles subumbrales de estrés postraumático, ansiedad u otros trastornos psicológicos que podrían interferir en su correcta reintegración. Los tratamientos convencionales, como la medicación y la psicoterapia individual centrada en el trauma, podrían no estar bien adaptados y aceptados o no resultar eficaces a la hora de tratar estos síntomas subsindrómicos.Hemos desarrollado Resilient Warrior, un programa de resistencia y control del estrés de 4 sesiones en grupo que combina cuerpo y mente, con el objetivo de desarrollar habilidades y evaluado para comprobar si su formato resulta accesible y aceptable, así como potencialmente eficaz, para aumentar la resistencia de las fuerzas armadas.Desde abril hasta octubre de 2014, se encuestó a 15 participantes (53,3 % de mujeres; media de edad = 36,6; DE = 6,2) para evaluar la aceptabilidad y viabilidad del programa. Los participantes completaron unos cuestionarios de salud psicológica autonotificados antes y después de su participación en el programa. La mayoría de los participantes (71,4 %) respondió que el programa incluía un número adecuado de sesiones, y todos afirmaron que les había resultado útil y apropiado y que se lo recomendarían a otras personas. Aunque los cambios en la resistencia autonotificada fueron mínimos, la participación en el programa se vio asociada con mejorías de los síntomas de depresión, estrés percibido, ansiedad y sensación general de la propia eficiencia.Estos datos piloto ofrecen un respaldo preliminar del hecho de que el programa de resistencia y reducción del estrés en grupo Resilient Warrior podría mejorar la salud psicológica de los miembros de las fuerzas armadas incluso al llevarse a cabo en ámbitos comunitarios. Es necesario efectuar ensayos controlados y aleatorizados con mayores periodos de seguimiento para determinar la eficacia y efectividad de este programa.

McElroy SL, Kemp DE, Friedman ES, Reilly-Harrington NA, SylviaLG, Calabrese JR, Rabideau DJ, Ketter TA, Thase ME, Singh V,Tohen M, Bowden CL, Bernstein EE, Brody BD, Deckersbach T,Kocsis JH, Kinrys G, Bobo WV, Kamali M, McInnis MG, Leon AC,Faraone S, Nierenberg AA, Shelton RC. Obesity, but not metabolicsyndrome, negatively affects outcome in bipolar disorder.Objective: Examine the effects of obesity and metabolic syndrome onoutcome in bipolar disorder.Method: The Comparative Effectiveness of a Second GenerationAntipsychotic Mood Stabilizer and a Classic Mood Stabilizer forBipolar Disorder (Bipolar CHOICE) study randomized 482participants with bipolar disorder in a 6-month trial comparing lithium-and quetiapine-based treatment. Baseline variables were comparedbetween groups with and without obesity, with and without abdominalobesity, and with and without metabolic syndrome respectively. Theeffects of baseline obesity, abdominal obesity, and metabolic syndromeon outcomes were examined using mixed effects linear regressionmodels.Results: At baseline, 44.4% of participants had obesity, 48.0% hadabdominal obesity, and 27.3% had metabolic syndrome; neitherobesity, nor abdominal obesity, nor metabolic syndrome wereassociated with increased global severity, mood symptoms, orsuicidality, or with poorer functioning or life satisfaction. Treatmentgroups did not differ on prevalence of obesity, abdominal obesity, ormetabolic syndrome. By contrast, among the entire cohort, obesity wasassociated with less global improvement and less improvement in totalmood and depressive symptoms, suicidality, functioning, and lifesatisfaction after 6 months of treatment. Abdominal obesity wasassociated with similar findings. Metabolic syndrome had no effect onoutcome.Conclusion: Obesity and abdominal obesity, but not metabolicsyndrome, were associated with less improvement after 6 months oflithium- or quetiapine-based treatment.

Objectives Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS). Methods LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) vs. OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes. Results African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups. Conclusions African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group.

Objectives: Individuals with bipolar disorder are more frequently overweight or obese than the general population, but the reasons for this association are unknown. The aim of this study is to further understand the etiology of overweight and obesity in bipolar disorder. Methods: We invited patients in a specialty outpatient bipolar clinic to complete the Eating Inventory. Patients provided self-reported restraint, disinhibition, and perceived hunger as well as general perceptions of dietary intake. Results: Sixty-two individuals (37 female) between the ages of 18 and 67 (M = 41.5, SD = 13.38) and with an average body mass index (BMI) of 27.18 (SD = 5.71) completed the survey. Disinhibition and perceived hunger were positively correlated with BMI and self-reported difficulty eating healthy foods. Restraint was positively correlated with healthy eating ( ps < .05). Stepwise linear regressions revealed that hunger was the most significant predictor of BMI (F(1) = 8.134, p = .006). Those participants with bipolar I or II disorder reported greater hunger scores ( p < .01) and difficulty eating healthily ( p < .05) than those without a full diagnosis. Conclusions: These results suggest that disinhibition and perception of hunger may be linked to the disproportionately high rate of obesity in bipolar disorder.

Objective:Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT).Method:The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder–Severity (CGI-BP-S) and “necessary clinical adjustments” (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score ≤2 for 2 months) and treatment with second-generation antipsychotics. The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.Results:The authors observed no s...

The aims of this study were to evaluate correlates and predictors of life functioning and quality of life in bipolar disorder during a comparative effectiveness trial of moderate doses of lithium.In the Lithium treatment moderate-dose use study (LiTMUS), 283 symptomatic outpatients with bipolar disorder type I or II were randomized to receive lithium plus "optimal personalized treatment (OPT)", or OPT alone. Participants were assessed using structured diagnostic interviews, clinician-rated blinded assessments, and questionnaires. We employ linear mixed effects models to test the effect of treatment overall and adjunct lithium specifically on quality of life or functioning. Similar models are used to examine the association of baseline demographics and clinical features with quality of life and life functioning.Quality of life and impaired functioning at baseline were associated with lower income, higher depressive severity, and more psychiatric comorbid conditions. Over 6 months, patients in both treatment groups improved in quality of life and life functioning (p-Values0.0001); without a statistically significant difference between the two treatment groups (p-Values0.05). Within the lithium group, improvement in quality of life and functioning was not associated with concurrent lithium levels at week 12 or week 24 (p-Values0.05). Lower baseline depressive severity and younger age of onset predicted less improvement in functioning over 6 months.Optimized care for bipolar disorder improves overall quality of life and life functioning, with no additional benefit from adjunct moderate doses of lithium. Illness burden and psychosocial stressors were associated with worse quality of life and lower functioning in individuals with bipolar disorder.

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. The current 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.

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.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.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.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.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).

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.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.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's0.80). 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.This was a pilot feasibility and acceptability trial; results should be interpreted with caution.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.

Background Bipolar disorder is characterized by impairments in cognitive functioning, both during acute mood episodes and periods of euthymia, which interfere with functioning. Cognitive functioning is typically assessed using laboratory-based tests, which may not capture how cognitive dysfunction is experienced in real-life settings. Little is known about the specific illness characteristics of bipolar disorder that contribute to cognitive dysfunction in everyday life. Methods Participants met DSM-IV criteria for bipolar I disorder ( n = 68) in a depressed or euthymic state. Everyday executive functioning was evaluated using the Behavior Rating Inventory of Executive Functioning (BRIEF) and the Frontal Systems Behavior Rating Scale (FrSBe). Participants completed clinician rated measures of mood state (Hamilton Depression Rating Scale, Young Mania Rating Scale), prior illness course and co-morbidities (Mini International Neuropsychiatric Interview), as well as self-report measures of psychotropic medication use and medical co-morbidity. Results Individuals in this study reported significant impairment in every domain of executive functioning. These deficits were associated with a multitude of illness factors, some directly impacted by mood symptoms and others shaped by illness chronicity, psychiatric comorbidity, medical co-morbidity, and medication use. Discussion Executive functioning problems observed in everyday functioning in bipolar disorder are not entirely mood-state dependent. Cognitive rehabilitation for executive dysfunction should be considered an important adjunctive treatment for many individuals with bipolar disorder.

Background Little is known about the longer-term effects of adjunctive benzodiazepines on symptom response during treatment in patients with bipolar disorders. Methods The study sample consisted of 482 patients with bipolar I or II disorder enrolled in a 6-month, randomized, multi-site comparison of lithium- and quetiapine-based treatment. Changes in clinical measures (BISS total and subscales, CGI-BP, and CGI-Efficacy Index) were compared between participants who did and did not receive benzodiazepine treatment at baseline or during follow-up. Selected outcomes were also compared between patients who did and did not initiate benzodiazepines during follow-up using stabilized inverse probability weighted analyses. Results Significant improvement in all outcome measures occurred within each benzodiazepine exposure group. Benzodiazepine users (at baseline or during follow-up) experienced significantly less improvement in BISS total, BISS irritability, and CGI-BP scores than did benzodiazepine non-users. There were no significant differences in these measures between patients who did and did not initiate benzodiazepines during follow-up in the weighted analyses. There was no significant effect of benzodiazepine use on any outcome measure in patients with comorbid anxiety or substance use disorders. Limitations This is a secondary analysis of data from a randomized effectiveness trial that was not designed to address differential treatment response according to benzodiazepine use. Conclusions Adjunctive benzodiazepines may not significantly affect clinical outcome in lithium- or quetiapine-treated patients with bipolar I or II disorder over 6 months, after controlling for potential confounding factors.

Background Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient’s intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment – Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis. Purpose The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data. Methods We fit marginal models to assess whether a patient’s self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods. Results Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time. Limitations LiTMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well specified. Conclusions In LiTMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial.

Previous studies have shown that individuals with autism spectrum disorders and attention- deficit/hyperactivity disorder (ADHD) experience sensory over-responsivity (SOR) in which a heightened response is evoked by stimuli in the environment. These individuals also display symptoms of anxiety such as irritability, avoidance, and sweating. Deep touch pressure, a technique in which firm touch is applied to the body either by the self or by a machine, has been shown to improve functioning and reduce symptoms of anxiety in these populations. A patient presenting with bipolar I disorder and comorbid anxiety, ADHD, and dyslexia was taught deep touch pressure strategies to alleviate severe symptoms of sensory over-responsivity and anxiety. The patient reported that the techniques were helpful as they allowed her to cope with potentially overwhelming situations in her environment. Clinician-rated functioning also improved over the course of treatment. This case study suggests that deep touch pressure may be useful in patients with bipolar disorder who have SOR and anxiety as comorbid conditions.

Background Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity. Method To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies. Results As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity. Conclusions LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes. Limitations Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.

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.