OBJECTIVE:To provide expert recommendations for the development of a specialty bipolar clinic that promotes best clinical practices for the delivery of safe and effective care. METHODS:Members of the National Network of Depression Centers (NNDC) Bipolar Clinics Work Group met in a series of 1-h monthly video calls over 18 months to discuss all aspects of their respective institution's bipolar clinics, including services provided, administrative processes, staffing models, characteristics of patients treated, patient volumes, finances, and research. The group also invited psychiatrists from outside of the NNDC who ran large bipolar clinics to contribute their thoughts and experiences on the subject. In addition, the NNDC sent a 20-question survey to all 27 sites asking clinic directors specific questions about their bipolar clinics, if applicable. Further meetings and discussions incorporating results from the survey took place to produce a comprehensive set of recommendations. RESULTS:Twenty-one of 27 NNDC sites (81%) responded to the survey. Twelve of 21 (57%) sites had a specific bipolar clinic, and another 4 (19%) were looking to start one. Clinics were based in university settings. The meetings, clinic survey, and discussions resulted in 10 recommendations describing services and operations for bipolar specialty clinics. CONCLUSIONS:Given the complexity of bipolar disorder, specialty clinics are important to enhance care. Clinics with a wide array of services that include consultation, medication management, bipolar-specific psychotherapies, and patient/family psychoeducation provide the most comprehensive care. Challenges to these clinics include maintaining ongoing patient access as well as ensuring long-term financial stability.

BACKGROUND:Cognitive impairment is common in bipolar disorder (BD), but the underlying pathophysiology remains unclear. This systematic review aimed to (1) summarize all literature describing relationships of biofluid biomarkers and cognition in BD and (2) identify which biofluid biomarkers correlate most consistently with cognition in BD. METHODS:This systematic review followed procedures of the PRISMA statement. PubMed, EMBASE, and PsycINFO were searched from inception until July 2023. Original studies assessing the relationships between biofluid biomarkers and cognitive functioning in adults with BD were included. Studies on neuroimaging markers and genetic biomarkers were excluded. RESULTS:We identified 60 studies, together describing 184 biofluid biomarkers that were measured in relation to cognitive functioning in BD. Biomarkers were organized into ten categories: oxidative stress markers (n = 14); growth factors (n = 13); neurotransmitters (n = 14); neuropeptides and hormones (n = 14); neurodegenerative markers (n = 11); inflammatory/immune markers (n = 59); serostatus to infectious agents (n = 11); amino acids, vitamins, and minerals (n = 7); metabolic factors (n = 23); hemogram, coagulation, and fibrinolysis markers (n = 18). Preliminary evidence for a significant relationship with cognition appeared for HSV-1 IgG, CRP, and homocysteine (Hcy); higher biomarker levels were associated with worse cognition. DISCUSSION:Included studies were heterogeneous and many were deemed to be of low quality following risk of bias assessment. The identified three biofluid biomarkers represent history of previous infections, current inflammation, and/or physical or psychological stress. Poor physical health, possibly represented by a broad range of biomarker aberrations, may play a role in the pathophysiology of cognitive impairment in BD. TRIAL REGISTRATION:PROSPERO registration number: CRD42021224226.

OBJECTIVES:This study aimed to investigate: (1) whether Body Mass Index (BMI) and peripheral inflammation are associated with cognitive performance in bipolar disorder (BD) and healthy controls (HCs), and (2) the potential mediating role of inflammation in the BMI-cognition link. METHODS:As part of an ongoing study, 127 participants (79 BD, 48 HCs) completed the MATRICS Consensus Cognitive Battery. C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α levels were quantified in blood, and a composite inflammation index was created and utilized in primary analyses. Regression and mediation analyses were conducted using SAS. RESULTS:The BD group had higher inflammation compared to HCs (p < 0.05). In the entire sample of BD individuals and HCs, higher BMI was associated with worse global cognitive performance, controlling for age, sex, diagnosis, education and medical comorbidity (beta = -0.22, p = 0.006). This association remained evident in the BD group, controlling for additional clinical factors (p < 0.05). Higher inflammation was associated with worse global cognition, controlling for relevant covariates in the entire sample (beta = -0.19, p = 0.024); however, this association was no longer significant in the BD group after controlling for additional clinical factors (p = 0.09). The indirect effect of BMI on global cognition through IL-6 was statistically different from zero (ab: beta = -0.09, CI = -0.18, -0.01) in the entire sample, holding age and sex constant, suggesting that IL-6 partially accounts for the association between BMI and cognitive performance. However, this finding should be interpreted cautiously, given the modest sample size and exploratory analyses suggesting that the indirect effect may differ by diagnostic group. CONCLUSIONS:BMI may serve as a potential biomarker and treatment target for obesity-related cognitive impairment in both BD and the general population, with IL-6 potentially contributing to this association.

OBJECTIVES:To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross-regional practices across North America, Europe, and the Pacific. METHODS:Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta-analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. RESULTS:The sample (N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention-deficit/hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first-generation antipsychotic prescriptions varied, with higher rates observed in Europe. CONCLUSIONS:Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context-specific guidelines. Gaps in data on medication-assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

The hallmark of bipolar disorder is hypomania or mania, and the predominant phase of illness is depression. Affecting approximately 40 million individuals worldwide, bipolar disorder is associated with a substantial psychosocial, medical, and financial burden and increased mortality from suicide and other causes. Diagnosis can be challenging due to symptom overlap with attention-deficit hyperactivity disorder, major depressive disorder, psychotic spectrum disorders, and personality disorders, which often leads to a delay in diagnosis. Recent advancements in understanding disease risk and pathophysiology have identified multigene risk and possible infectious and mitochondrial causes. Treatment approaches include pharmacotherapy, psychotherapy, and lifestyle modifications, which should always be patientcentred and aligned with individual goals and priorities. Future directions for bipolar disorder care include increasing the availability of psychosocial interventions aimed at self-management, addressing treatment-resistant bipolar depression, deepening the understanding of pathophysiology, and exploring novel interventions, such as ketamine, esketamine, other rapid-acting antidepressants, and various neuromodulation approaches.

The hallmark of bipolar disorder is hypomania or mania, and the predominant phase of illness is depression. Affecting approximately 40 million individuals worldwide, bipolar disorder is associated with a substantial psychosocial, medical, and financial burden and increased mortality from suicide and other causes. Diagnosis can be challenging due to symptom overlap with attention-deficit hyperactivity disorder, major depressive disorder, psychotic spectrum disorders, and personality disorders, which often leads to a delay in diagnosis. Recent advancements in understanding disease risk and pathophysiology have identified multigene risk and possible infectious and mitochondrial causes. Treatment approaches include pharmacotherapy, psychotherapy, and lifestyle modifications, which should always be patient-centred and aligned with individual goals and priorities. Future directions for bipolar disorder care include increasing the availability of psychosocial interventions aimed at self-management, addressing treatment-resistant bipolar depression, deepening the understanding of pathophysiology, and exploring novel interventions, such as ketamine, esketamine, other rapid-acting antidepressants, and various neuromodulation approaches.

OBJECTIVE:Sensory phenomena (SP) are aversive sensations driving repetitive behaviors in obsessive-compulsive disorder (OCD) and Tourette's disorder that are not well addressed by standard treatments. SP are related to the functioning of an interoceptive-sensorimotor circuit that may be modulated by the 5-HT3 receptor antagonist ondansetron. The present study employed an experimental medicine approach to test the effects of 4 weeks of high-dose ondansetron compared to placebo on SP severity and brain connectivity in a cohort of individuals with OCD and/or Tourette's disorder. METHODS:Of 51 participants who completed the study, 27 were assigned to receive 24 mg/day of ondansetron and 24 to receive placebo. Analyses examined changes in SP severity and, for participants with OCD, overall OCD severity from baseline to final visit. Functional MRI data were collected at both visits for analysis of intrinsic functional connectivity metrics characterizing global correlation (reflecting area "hubness") and local correlation (reflecting near-neighbor coherence). RESULTS:There were no significant differences between ondansetron and placebo in the reduction of SP or overall OCD severity in the full sample. In a subsample of participants with OCD taking concomitant serotonin reuptake inhibitors (SRIs), ondansetron was associated with a significant decrease in overall OCD severity and global connectivity of the medial sensorimotor cortex compared with placebo. Longitudinal reductions in SP severity were related to decreases in right sensorimotor hubness in both groups, and to brainstem local coherence only in participants taking ondansetron. CONCLUSIONS:There was no effect of high-dose ondansetron on SP. However, when used as an augmentation to SRIs, ondansetron reduced overall OCD severity, which may be related to changes in the "hubness" of the sensorimotor cortex. Ondansetron's ability to modulate brainstem connectivity may underlie its variable effectiveness in reducing SP.

The hallmark of bipolar disorder is hypomania or mania, and the predominant phase of illness is depression. Affecting approximately 40 million individuals worldwide, bipolar disorder is associated with a substantial psychosocial, medical, and financial burden and increased mortality from suicide and other causes. Diagnosis can be challenging due to symptom overlap with attention-deficit hyperactivity disorder, major depressive disorder, psychotic spectrum disorders, and personality disorders, which often leads to a delay in diagnosis. Recent advancements in understanding disease risk and pathophysiology have identified multigene risk and possible infectious and mitochondrial causes. Treatment approaches include pharmacotherapy, psychotherapy, and lifestyle modifications, which should always be patient-centred and aligned with individual goals and priorities. Future directions for bipolar disorder care include increasing the availability of psychosocial interventions aimed at self-management, addressing treatment-resistant bipolar depression, deepening the understanding of pathophysiology, and exploring novel interventions, such as ketamine, esketamine, other rapid-acting antidepressants, and various neuromodulation approaches.

INTRODUCTION:Major depressive disorder (MDD) and bipolar disorder (BD) are often associated with persistent cognitive deficits that impair psychosocial functioning. While pro-cognitive interventions show promise, trial findings are inconsistent, potentially due to baseline factors influencing treatment response. This systematic review summarizes evidence on pre-treatment characteristics associated with cognitive improvement and offers methodological recommendations. METHODS:A systematic search was conducted in PubMed/MEDLINE, EMBASE, PsycINFO, and Cochrane Library from inception to February 28, 2025. Eligible studies included primary or secondary analyses of randomized controlled trials (RCTs) investigating predictors of cognitive response to pro-cognitive interventions in MDD and/or BD. Two researchers independently conducted study selection and risk of bias assessments. Findings were synthesized qualitatively. RESULTS:Forty studies (N = 3864) were identified, covering pharmacological treatments (k = 20; N = 2299), psychological therapies (k = 16; N = 1165), brain stimulation (k = 2; N = 168), and physical activity (k = 2; N = 232). Poorer baseline cognitive performance was the most consistent predictor of greater cognitive improvement, though the direction of the effect was not entirely uniform across all studies. Baseline depression severity showed no significant association with cognitive outcomes. Age, education, sex, IQ, diagnosis, and medication status were similarly non-predictive. Risk of bias was high in 77% of studies, mainly due to deviations from specified outcomes, poor randomization processes, and inconsistent handling of missing data. Considerable heterogeneity in interventions, outcome measures, and sample characteristics limited replicability and precluded meta-analysis. CONCLUSION:Poorer baseline cognition emerged as the most reliable predictor of greater cognitive improvement across interventions. More rigorous, well-powered studies are needed to replicate these findings and identify robust predictors to guide personalized pro-cognitive treatment approaches in mood disorders.

BACKGROUND:Learning Health Networks (LHNs), such as the one described in Savitz et al. (in press), involve employing a network of treatment centers to produce standardized data from routine clinical practice, produce knowledge from that data, and systematically use that knowledge to inform care. To date, there are limited examples of LHNs in psychiatry. It is essential to establish robust dialogue around best practices for building LHNs to advance precision medicine in psychiatry. METHODS:A task group consensus on key elements of LHNs as applied to mood disorders was convened. Task group members reviewed current literature and ongoing LHN network efforts and evaluated opportunities and gaps within psychiatry broadly, and mood disorders specifically. RESULTS:Task group members noted four key considerations for building LHNs for mood disorders. First, obtain qualitative and quantitative stakeholder input at every stage of development, specifically input from patients and patients' families, clinicians and health system leadership. Second, collect data on objective measures of functioning, such as neuropsychological testing, quality of life indicators, and blood-based markers of health, alongside more standard measures such as symptom severity. Third, carefully consider the details of how new evidence-based practices will be identified and implemented. Fourth, identify a plan for sustainability. LIMITATIONS:Literature was reviewed and discussed among expert task group members, but this was not a systematic review. CONCLUSIONS:With stakeholder input, data on functioning as well as symptom severity, thoughtful implementation strategies, and an eye to sustainability, LHNs represent an important opportunity for advancement in the treatment of mood disorders.

This study introduces a novel multiagent reinforcement learning (MARL) algorithm designed for identifying and optimizing personalized recommendations in bipolar disorder. The algorithm leverages longitudinal offline data from wearables to recommend self-care strategies tailored to individual patients. We focus on self-care strategies involving physical activity (measured by steps), sleep duration, and bedtime consistency, aiming to reduce the periods of mood exacerbations. A key innovation of our MARL approach is the integration of copulas to model interagent dependencies, enhancing coordination among agents and improving policy learning. Findings suggest that following our algorithm's self-care recommendations could significantly reduce periods of elevated mood symptoms, resulting in improved overall well-being. Finally, the algorithm offers important clinical insights for treating bipolar patients, and shows promising theoretical properties independent of the specific application. Thus, this work not only advances MARL applications in personalized healthcare but also provides a new algorithmic approach for adaptive interventions in a wide range of chronic diseases.

IntroductionCognitive impairment estimations traditionally rely on the deviation of current cognitive performance from population norms (normative approach). Since bipolar disorder (BD) has been associated with above-average premorbid cognitive functioning in some studies, this approach might underestimate the extent of cognitive impairment in a proportion of patients. We examined whether intraindividual deviation of cognitive performance from premorbid estimates (idiographic approach) would more accurately estimate impairment in BD and assessed the functional relevance of this approach.MethodsThis study pooled euthymic patients with BD (N = 257) taking part in two cognitive remediation trials with comparable eligibility criteria and measures. All participants underwent a baseline assessment including measures of current cognition, premorbid IQ, psychosocial functioning and mood symptom severity. We estimated and compared the prevalence of normative versus idiographic impairment and examined the association of the idiographic approach with functioning.ResultsAccording to normative standards, 13%-31% of our euthymic sample was classified as cognitively impaired depending on the adopted cut-off. After accounting for premorbid IQ, idiographic impairment rates increased to 37%-64%. The difference between the two approaches was significant for each cut-off considered (0.5 and 1 SD). Idiographic cognitive impairment was significantly associated with psychosocial functioning, even after controlling for residual mood symptoms and demographic/clinical variables and functional impairment classification.ConclusionCommon practices for characterising cognitive impairment using a normative approach may underestimate the extent of impairment for a substantial proportion of euthymic patients with BD. Considering idiographic impairment provides an alternative, functionally relevant approach for cognition trials and clinical practice.

Bipolar Disorder (BD) is a highly complex and heterogeneous disorder. As such, accurate diagnosis is often delayed, and effective treatment options are limited. The Integrated Network, a program of Breakthrough Discoveries for thriving with Bipolar Disorder (BD2), was designed as a platform for longitudinal deep phenotyping of a diverse group of people with bipolar disorder to define disease trajectories and to gain insight into the biological drivers of the illness. Biosamples, including whole blood, serum, plasma, and peripheral blood mononuclear cells (PBMCs), will be collected longitudinally and will also be made available. The Integrated Network is designed to be the largest and most comprehensive prospective longitudinal study conducted in bipolar disorder, allowing for the development of precision-based treatment strategies that optimize quality of life for people living with bipolar disorder.