Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Cognition in older age bipolar disorder: An analysis of archival data across the globe.

BACKGROUND: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies. METHODS: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning. RESULTS: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning. LIMITATIONS: Cross-sectional design and loss of granularity due to harmonization. CONCLUSION: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD.

Change in neurocognitive functioning in patients with treatment-resistant depression with serial intravenous ketamine infusions: The Bio-K multicenter trial.

This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (ß =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504.

Perceived loneliness and social support in bipolar disorder: relation to suicidal ideation and attempts.

BACKGROUND: The suicide rate in bipolar disorder (BD) is among the highest across all psychiatric disorders. Identifying modifiable variables that relate to suicidal thoughts and behaviors (STBs) in BD may inform prevention strategies. Social connectedness is a modifiable variable found to relate to STBs in the general population, but differences exist across subgroups of the general population and findings specifically in BD have been equivocal. We aimed to clarify how perceived social connectedness relates to STBs in BD. METHOD: 146 adults (86 BD, 60 healthy controls) completed clinical interviews (Hamilton Depression Rating Scale; Structured Clinical Interview for DSM-5) and self-report measures of loneliness (UCLA Loneliness Scale) and social support (Interpersonal Support Evaluation List). Analyses explored differences in indicators of social connectedness (loneliness and social support) between BD participants and healthy controls, and explored relationships between STBs (lifetime suicide attempts and current suicidal ideation) and indicators of social connectedness in BD participants. RESULTS: BD participants reported significantly higher loneliness and lower social support than healthy controls. In BD participants, perceived social support was significantly related to both ever having attempted suicide and number of lifetime attempts. Interestingly, perceived loneliness, but not social support, was significantly associated with current suicidal ideation. CONCLUSIONS: Findings expand the evidence base supporting a relationship between perceived social connectedness and STBs in BD. They suggest that this modifiable variable could be a fruitful treatment target for preventing STBs in BD.

Cognitive Impairment and Depression in Mastocytosis: A Synthesis of the Literature.

PURPOSE OF REVIEW: Symptoms of depression and cognitive dysfunction are commonly reported in mastocytosis. The aims of this review paper are to summarize the current literature on cognitive dysfunction and depressive symptoms, elucidate some of the mechanistic pathways underlying depressive symptoms in mastocytosis, identify gaps in the literature, and offer guidance for future research in this area. RECENT FINDINGS: The study of cognition and depression in mastocytosis is in its infancy and the methodological flaws of the current literature limit interpretability. There is preliminary evidence that some individuals with mastocytosis might experience mild deficits in memory. On average, depression symptom scores fell within the mild to moderate or sub-syndromal range. Regrettably, only one study utilized a standardized diagnostic instrument to assess major depressive disorder. The authors' tendency to inaccurately equate depressive symptoms with a diagnosis of major depressive disorder presents a notable issue. The prevalence of cognitive deficits and depression appears to be similar to other chronic illnesses. Future work needs to better characterize cognition and characterize "depression" in this population.

Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Modafinil's effects on cognition and sleep quality in affectively-stable patients with bipolar disorder: a pilot study.

Introduction: Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil®), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients. Methods: Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8. Results: No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group. Discussion: Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot. Clinical trial registration: ClinicalTrials.gov, identifier NCT01965925.

The effect of aging on facial emotion recognition in bipolar disorder.

OBJECTIVE: Convergent data point to an exaggerated negativity bias in bipolar disorder (BD), and little is known about whether people with BD experience the 'positivity effect' with increasing age. METHOD: This is a cross sectional study of 202 participants with BD aged 18-65, and a sample (n = 53) of healthy controls (HCs). Participants completed the CANTAB Emotion Recognition Task (ERT). Using analysis of variance, we tested for a main effect of age, diagnosis, and an interaction of age x diagnosis on both negative and positive conditions. RESULTS: We observed increased accuracy in identifying positive stimuli in the HC sample as a function of increasing age, a pattern that was not seen in participants with BD. Specifically, there was a significant diagnosis by age cohort interaction on ERT performance that was specific to the identification of happiness, where the Later Adulthood cohort of HCs was more accurate when identifying happy faces relative to the same cohort of BD patients. CONCLUSION: Later life looks different for people with BD. With an aging population globally, gaining a clearer picture of the effects of recurrent mood dysregulation on the brain will be critical in guiding efforts to effectively optimize outcomes in older adults with BD.

Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Brain Morphological Characteristics of Cognitive Subgroups of Schizophrenia-Spectrum Disorders and Bipolar Disorder: A Systematic Review with Narrative Synthesis.

Despite a growing body of research, there is yet to be a cohesive synthesis of studies examining differences in brain morphology according to patterns of cognitive function among both schizophrenia-spectrum disorder (SSD) and bipolar disorder (BD) individuals. We aimed to provide a systematic overview of the morphological differences-inclusive of grey and white matter volume, cortical thickness, and cortical surface area-between cognitive subgroups of these disorders and healthy controls, and between cognitive subgroups themselves. An initial search of PubMed and Scopus databases resulted in 1486 articles of which 20 met inclusion criteria and were reviewed in detail. The findings of this review do not provide strong evidence that cognitive subgroups of SSD or BD map to unique patterns of brain morphology. There is preliminary evidence to suggest that reductions in cortical thickness may be more strongly associated with cognitive impairment, whilst volumetric deficits may be largely tied to the presence of disease.

The engagement problem: A review of engagement with digital mental health interventions and recommendations for a path forward.

Purpose of the review: Digital mental health interventions (DMHIs) are an effective and accessible means of addressing the unprecedented levels of mental illness worldwide. Currently, however, patient engagement with DMHIs in real-world settings is often insufficient to see clinical benefit. In order to realize the potential of DMHIs, there is a need to better understand what drives patient engagement. Recent findings: We discuss takeaways from the existing literature related to patient engagement with DMHIs and highlight gaps to be addressed through further research. Findings suggest that engagement is influenced by patient-, intervention- and systems-level factors. At the patient-level, variables such as sex, education, personality traits, race, ethnicity, age and symptom severity appear to be associated with engagement. At the intervention-level, integrating human support, gamification, financial incentives and persuasive technology features may improve engagement. Finally, although systems-level factors have not been widely explored, the existing evidence suggests that achieving engagement will require addressing organizational and social barriers and drawing on the field of implementation science. Summary: Future research clarifying the patient-, intervention- and systems-level factors that drive engagement will be essential. Additionally, to facilitate improved understanding of DMHI engagement, we propose the following: (a) widespread adoption of a minimum necessary 5-element engagement reporting framework; (b) broader application of alternative clinical trial designs; and (c) directed efforts to build upon an initial parsimonious conceptual model of DMHI engagement.

Digital Mental Health Interventions for Depression: Scoping Review of User Engagement.

BACKGROUND: While many digital mental health interventions (DMHIs) have been found to be efficacious, patient engagement with DMHIs has increasingly emerged as a concern for implementation in real-world clinical settings. To address engagement, we must first understand what standard engagement levels are in the context of randomized controlled trials (RCTs) and how these compare with other treatments. OBJECTIVE: This scoping review aims to examine the state of reporting on intervention engagement in RCTs of mobile app-based interventions intended to treat symptoms of depression. We sought to identify what engagement metrics are and are not routinely reported as well as what the metrics that are reported reflect about standard engagement levels. METHODS: We conducted a systematic search of 7 databases to identify studies meeting our eligibility criteria, namely, RCTs that evaluated use of a mobile app-based intervention in adults, for which depressive symptoms were a primary outcome of interest. We then extracted 2 kinds of information from each article: intervention details and indices of DMHI engagement. A 5-element framework of minimum necessary DMHI engagement reporting was derived by our team and guided our data extraction. This framework included (1) recommended app use as communicated to participants at enrollment and, when reported, app adherence criteria; (2) rate of intervention uptake among those assigned to the intervention; (3) level of app use metrics reported, specifically number of uses and time spent using the app; (4) duration of app use metrics (ie, weekly use patterns); and (5) number of intervention completers. RESULTS: Database searching yielded 2083 unique records. Of these, 22 studies were eligible for inclusion. Only 64% (14/22) of studies included in this review specified rate of intervention uptake. Level of use metrics was only reported in 59% (13/22) of the studies reviewed. Approximately one-quarter of the studies (5/22, 23%) reported duration of use metrics. Only half (11/22, 50%) of the studies reported the number of participants who completed the app-based components of the intervention as intended or other metrics related to completion. Findings in those studies reporting metrics related to intervention completion indicated that between 14.4% and 93.0% of participants randomized to a DMHI condition completed the intervention as intended or according to a specified adherence criteria. CONCLUSIONS: Findings suggest that engagement was underreported and widely varied. It was not uncommon to see completion rates at or below 50% (11/22) of those participants randomized to a treatment condition or to simply see completion rates not reported at all. This variability in reporting suggests a failure to establish sufficient reporting standards and limits the conclusions that can be drawn about level of engagement with DMHIs. Based on these findings, the 5-element framework applied in this review may be useful as a minimum necessary standard for DMHI engagement reporting.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

Comparing continuous and harmonized measures of depression severity in older adults with bipolar disorder: Relationship to functioning.

OBJECTIVE: Harmonizing different depression severity scales often requires creation of categorical variables that may decrease the sensitivity of the measure. Our aim was to compare the associations between categorical and continuous and harmonized measures of depression and global functioning in a large dataset of older age patients with bipolar disorder (OABD). METHOD: In the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) the 17-item Hamilton Depression scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) or the Center for Epidemiological Studies Depression scales (CES-D) was used to assess current depressive symptoms, while the Global Assessment of Functioning (GAF) assessed functional status. Data were harmonized from 8 OABD studies (n = 582). In each subsample, the relationship of depression severity as a continuous and categorical measure was compared to GAF. In the total sample, harmonized ordinal depression categories were compared to GAF. RESULTS: Effect size and variance explained by the model for the categorical measure in the total sample was higher than both the categorical and continuous measure in the CES-D subsample, higher than the categorical but lower than the continuous measure in the HAM-D subsample, and lower than both the categorical and continuous measures in the MADRS subsample. LIMITATIONS: All included studies have different inclusion and exclusion criteria, study designs, and differ in aspects of sociodemographic variables. CONCLUSIONS: Associations were only slightly larger for the continuous vs categorical measures of depression scales. Harmonizing different depression scales into ordinal categories for analyses is feasible without losing statistical power.

Cognitive subgroups and their longitudinal trajectories in bipolar disorder.

INTRODUCTION: Cognitive functioning in bipolar disorder is heterogeneous with evidence for multiple subgroups. However, cognitive subgroup change patterns over time remains unknown. While prior work suggests minimal differences in cognitive functioning patterns over time between those with bipolar disorder and controls, group-based analyses may obscure unique subgroup-based changes. MATERIAL AND METHODS: Participants diagnosed with bipolar disorder (I, II, NOS; n = 568) and unaffected controls (n = 234) completed baseline, one- and five-year neuropsychological assessments. Data reduction techniques were used to limit the number of neuropsychological variables. Bipolar disorder participant baseline neuropsychological data were entered into hierarchical cluster analyses and resultant clusters were entered in multilevel models, which tested for differences in baseline and longitudinal cognitive changes in cognition among the cluster groups and with controls. RESULTS: Results were consistent with bipolar disorder participants forming three subgroups with high (n = 209), mid (n = 259), and low (n = 100) cognition. These groups were associated with unique clinical characteristics. Multilevel models demonstrated that over a five-year period, the low group improved, relative to the high and mid groups, and with controls, in auditory memory. Over the five-year period, the mid group, in comparison with the high group, improved in visual memory; additionally, the high group remained stable, in comparison with a slight decline in the control group, in inhibitory control. CONCLUSION: These results demonstrate that cognition-based subgroups of bipolar disorder participants have minimal differences in their longitudinal course in relation to each other and with unaffected controls.

Predictors of functional impairment in bipolar disorder: Results from 13 cohorts from seven countries by the global bipolar cohort collaborative.

OBJECTIVES: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. METHODS: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. RESULTS: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. CONCLUSIONS: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Strategies and foundations for scientific discovery in longitudinal studies of bipolar disorder.

Bipolar disorder (BD) is a complex and dynamic condition with a typical onset in late adolescence or early adulthood followed by an episodic course with intervening periods of subthreshold symptoms or euthymia. It is complicated by the accumulation of comorbid medical and psychiatric disorders. The etiology of BD remains unknown and no reliable biological markers have yet been identified. This is likely due to lack of comprehensive ontological framework and, most importantly, the fact that most studies have been based on small nonrepresentative clinical samples with cross-sectional designs. We propose to establish large, global longitudinal cohorts of BD studied consistently in a multidimensional and multidisciplinary manner to determine etiology and help improve treatment. Herein we propose collection of a broad range of data that reflect the heterogenic phenotypic manifestations of BD that include dimensional and categorical measures of mood, neurocognitive, personality, behavior, sleep and circadian, life-story, and outcomes domains. In combination with genetic and biological information such an approach promotes the integrating and harmonizing of data within and across current ontology systems while supporting a paradigm shift that will facilitate discovery and become the basis for novel hypotheses.

C-reactive protein and affective inhibition in bipolar disorder.

BACKGROUND: Individuals with bipolar disorder (BD) experience cognitive and affective processing deficits that often persist beyond the remission of acute mood symptoms. One possible biological mechanism for these deficits involves the potential effects of chronic low-grade peripheral inflammation on brain function. Peripheral inflammation has been associated with reduced executive functioning and memory performance, as well as altered reward processing in BD, but whether it is also implicated in cognitive-affective processing remains unknown. METHOD: Peripheral inflammation was measured by serum C-reactive protein (CRP) in 119 adults with BD I or II, age 18-65. All participants completed the Affective Go/No-Go Task, a measure of cognitive-emotional processing. Correlations of CRP with discrimination of and response times to Negative, Positive, and Neutral words were performed before and after adjustment for severity of residual depressive symptoms and other demographic and clinical characteristics associated with inflammation. RESULTS: Increased CRP was significantly associated with reduced negative target discriminability, which was also significantly reduced compared to positive and neutral target conditions. Additionally, greater CRP was associated with faster response times for both negative hits and commissions, as well as positive commissions. CONCLUSIONS: This study adds to existing research demonstrating associations between inflammation and cognition or reward sensitivity and motivation separately in BD, by raising the possibility that inflammation is also implicated in the integration of cognitive-affective processing. Assessment of these associations over time is warranted to determine involvement of inflammation and cognitive-emotional processing in course of illness and identify critical periods for possible modulation of inflammation.