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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.

Background: England's primary care service for psychological therapy (Improving Access to Psychological Therapies [IAPT]) treats anxiety and depression, with a target recovery rate of 50%. Identifying the characteristics of patients who achieve recovery may assist in optimizing future treatment. This naturalistic cohort study investigated pre-therapy characteristics as predictors of recovery and improvement after IAPT therapy. Methods: In a cohort of patients attending an IAPT service in South London, we recruited 263 participants and conducted a baseline interview to gather extensive pre-therapy characteristics. Bayesian prediction models and variable selection were used to identify baseline variables prognostic of good clinical outcomes. Recovery (primary outcome) was defined using (IAPT) service-defined score thresholds for both depression (Patient Health Questionnaire [PHQ-9]) and anxiety (Generalized Anxiety Disorder [GAD-7]). Depression and anxiety outcomes were also evaluated as standalone (PHQ-9/GAD-7) scores after therapy. Prediction model performance metrics were estimated using cross-validation. Results: Predictor variables explained 26% (recovery), 37% (depression), and 31% (anxiety) of the variance in outcomes, respectively. Variables prognostic of recovery were lower pre-treatment depression severity and not meeting criteria for obsessive compulsive disorder. Post-therapy depression and anxiety severity scores were predicted by lower symptom severity and higher ratings of health-related quality of life (EuroQol questionnaire [EQ5D]) at baseline. Conclusion: Almost a third of the variance in clinical outcomes was explained by pre-treatment symptom severity scores. These constructs benefit from being rapidly accessible in healthcare services. If replicated in external samples, the early identification of patients who are less likely to recover may facilitate earlier triage to alternative interventions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Improving Access to Psychological Therapies (IAPT) is a primary care therapy service commissioned by England's National Health Service (NHS) for people with unipolar depression and anxiety-related disorders. Its scope does not extend to 'severe mental illness', including bipolar disorders (BD), but evidence suggests there is a high BD prevalence in ostensibly unipolar major depressive disorder (uMDD) samples. This study aimed to indicate the prevalence and characteristics of people with BD in a naturalistic cohort of IAPT patients. Methods: 371 participants were assessed before initiating therapy. Participants were categorised by indicated diagnoses: BD type-I (BD-I) or type-II (BD-II) as defined using a DSM diagnostic interview, bipolar spectrum (BSp, not meeting diagnostic criteria but exceeding BD screening thresholds), lifetime uMDD or other. Information about psychiatric history and co-morbidities was examined, along with symptoms before and after therapy. Results: 368 patients provided sufficient data to enable classification. 10% of participants were grouped as having BD-I, 20% BD-II, 40% BSp, 25% uMDD and 5% other. BD and uMDD participants had similar demographic characteristics, but patients meeting criteria for BD-I/BD-II had more complex psychiatric presentations. All three 'bipolar' groups had particularly high rates of anxiety disorders. IAPT therapy receipt was comparable between groups, as was therapy response (F 9704 = 1.113, p = 0.351). Conclusions: Notwithstanding the possibility that bipolar diathesis was overestimated, findings illustrate a high prevalence of BD in groups of people notionally with uMDD or anxiety. As well as improving the detection of BD, further substantive investigation is required to establish whether individuals affected by BD should be eligible for primary care psychological intervention. [ABSTRACT FROM AUTHOR]

Background: Reserpine is an effective antihypertensive drug, but its role in routine practice has declined such that it is rarely used. This is largely based on the assumption that reserpine causes depression. This assumption was a foundation for the original monoamine hypothesis of depression. However, there remains conflicting evidence as to whether reserpine causes depression, and no systematic review of available evidence. Aims: We systematically reviewed evidence on effects of reserpine on depressive and related symptoms (e.g. anxiety, suicidal ideation). Method: Electronic searches of MEDLINE, Embase and PsycINFO were conducted to identify studies up to 14 February 2021. Studies of any methodological design involving reserpine-treated and reserpine-untreated conditions, in any adult human population, were included and a narrative synthesis of findings was undertaken. Risk of bias (RoB) was examined using ROBINS-I. Results: Of the 35 studies meeting inclusion criteria, 9 were randomised controlled trials. Eleven studies reported some depressogenic effects, 13 reported no effect and 11 reported putative antidepressant effects. Studies identifying depressive effects were more likely to examine people without psychiatric disorders at baseline, while studies identifying a potential antidepressant effect tended to treat fewer participants for shorter durations, at higher doses. Around one-third of studies conducted in people with psychiatric disorders showed beneficial effects on depression symptoms. 30/35 studies were at high RoB. Conclusions: Associations between reserpine and depression are inconsistent and limited by a lack of high-quality evidence. Due to reserpine's apparently complex effects, we urge nuance rather than simplicity surrounding the monoamine hypothesis of depression. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below). Methods: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions. Results: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09–2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23–1.73) and risperidone (ES = 1.42, 95% CI: 1.29–1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81–0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses. Conclusions: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) is associated with cognitive and functional difficulties, persistent beyond mood episodes. Cognitive remediation (CR) is a psychological therapy targeting cognitive and functioning difficulties. Recent evidence suggests that CR may enhance long-term functioning but transfer mechanisms on functional outcomes have not been explored. We aim to investigate whether and how cognitive gains after CR transfer to functional improvement. Methods: We considered data from a randomized controlled trial comparing CR (n = 40) to treatment-as-usual (TAU; n = 40) in euthymic people with BD. Treatment outcomes included individual cognitive domains and global cognition, psychosocial functioning, and goal attainment. Regression-based mediation and moderation modelling were used to assess whether and how post-treatment cognitive changes translate into functional improvement at follow-up, three months after treatment end. Results: Cognitive gains after CR transferred to functional changes three months later: improvement in post-treatment global cognition partially mediated the effect of CR on psychosocial functioning (standardized indirect effect: −0.23, 95% CI −0.51 to −0.04). Goal attainment was not significantly mediated by changes in cognition, but post-treatment cognitive performance moderated the effect of CR on the GAS at follow-up (interaction effect: 0.78, 95% CI 0.08–1.55). Conclusions: Our findings suggest that cognitive improvements contribute to functional improvement but transfer mechanisms differ between psychosocial functioning and idiosyncratic recovery goals. Cognition accounted for only a proportion of the total CR effect on functional outcomes. Future studies should consider other variables, such as metacognition, that may drive the transfer of CR effects to functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Immune dysregulation appears involved in affective disorder pathophysiology. Inflammatory biomarkers have been linked with the cognitive impairment observed in people with bipolar disorders and as such are candidate markers that may improve with, and/or predict outcomes to, cognitive remediation therapies (CRT)., Aims: Nine candidate biomarkers were examined as putative mediators and/or moderators to improvements following CRT compared with treatment as usual (TAU) from a randomised controlled trial., Method: Euthymic adults with bipolar disorders who had been randomised to CRT ( n = 23) or TAU ( n = 21) underwent blood testing before and after a 12 week intervention period. Five cytokines and four growth factor proteins, selected a priori , were examined in association with global cognition and psychosocial functioning outcomes., Results: CRT attenuated a reduction in the brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor and vascular endothelial growth factor-C compared to TAU. For the BDNF, lower baseline levels predicted better functional outcomes across the sample but was more pronounced in TAU versus CRT participants and indicated larger CRT effects in those with a higher BDNF. A moderation effect was also apparent for tumour necrosis factor-β and interleukin-16, with greater CRT versus TAU effects on functioning for participants with lower baseline levels., Conclusions: Although preliminary, results suggest that CRT may exert some protective biological effects, and that people with lower levels of neurotrophins or cytokines may benefit more from CRT. We note an absence of associations with cognitive (versus functional) outcomes. These findings require further examination in large well-controlled studies.