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Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD. Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions. Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25-1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23-1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81-1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.80-1.30) and psychological (ES = 1.43, 95% CI 0.50-2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66-0.91) and psychological control (ES = 0.94, 95% CI 0.36-1.52). Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.

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). 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. Euthymic adults with bipolar disorders who had been randomised to CRT ( = 23) or TAU ( = 21) underwent blood testing before and after a 12 week intervention period. Five cytokines and four growth factor proteins, selected , were examined in association with global cognition and psychosocial functioning outcomes. 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. 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.

Background A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects. Methods CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30–40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models. Discussion This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action. Trial registration Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331 . Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting.

BackgroundNeurobiological research frequently implicates inflammatory and neurogenic components with core aspects of bipolar disorder. Even in periods of symptom remission (euthymia), individuals with bipolar disorder experience cognitive impairments, which are increasingly being proposed as an outcome for interventions; identifying biomarkers associated with cognitive impairment in people with bipolar disorder could advance progress in this therapeutic field through identifying biological treatment targets.AimsWe aimed to identify proteomic biomarker correlates of cognitive impairment in individuals with euthymic bipolar disorder.MethodForty-four adults with a bipolar disorder diagnosis in euthymia underwent a battery of cognitive assessments and provided blood for biomarkers. We examined a comprehensive panel of inflammatory and trophic proteins as putative cross-sectional predictors of cognition, conceptualised according to recommended definitions of clinically significant cognitive impairment (binary construct) and global cognitive performance (continuous measure).ResultsA total of 48% of the sample met the criteria for cognitive impairment. Adjusting for potentially important covariates, regression analyses identified lower levels of three proteins as significantly and independently associated with cognitive deficits, according to both binary and continuous definitions (interleukin-7, vascular endothelial growth factor C and placental growth factor), and one positively correlated with (continuous) global cognitive performance (basic fibroblast growth factor).ConclusionsThis study identifies four candidate markers of cognitive impairment in bipolar disorder, none of which have been previously compared with cognitive function in participants with bipolar disorder. Pending replication in larger samples and support from longitudinal studies, these markers could have implications for treating cognitive dysfunction in this patient population.

People with bipolar disorder have moderate cognitive difficulties that tend to be more pronounced during mood episodes but persist after clinical remission and affect recovery. Recent evidence suggests heterogeneity in these difficulties, but the factors underlying cognitive heterogeneity are unclear. To examine whether distinct cognitive profiles can be identified in a sample of euthymic individuals with bipolar disorder and examine potential differences between subgroups. Cognitive performance was assessed across four domains (i.e. processing speed, verbal learning/memory, working memory, executive functioning) in 80 participants. We conducted a hierarchical cluster analysis and a discriminant function analysis to identify cognitive profiles and considered differences in cognitive reserve, estimated cognitive decline from premorbid cognitive functioning, and clinical characteristics among subgroups. Four discrete cognitive profiles were identified: cognitively intact (n = 25; 31.3%); selective deficits in verbal learning and memory (n = 15; 18.8%); intermediate deficits across all cognitive domains (n = 30; 37.5%); and severe deficits across all domains (n = 10; 12.5%). Cognitive decline after illness onset was greater for the intermediate and severe subgroups. Cognitive reserve scores were increasingly lower for subgroups with greater impairments. A smaller proportion of cognitively intact participants were using antipsychotic medications compared with all other subgroups. Our findings suggest that individuals with cognitively impaired profiles demonstrate more cognitive decline after illness onset. Cognitive reserve may be one of the factors underlying cognitive variability across people with bipolar disorder. Patients in the intermediate and severe subgroups may be in greater need of interventions targeting cognitive difficulties.

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. We considered data from a randomized controlled trial comparing CR ( = 40) to treatment-as-usual (TAU; = 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. 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). 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.

Euthymic bipolar disorder (BD) is associated with general and domain-specific cognitive impairment, which predicts poor occupational and social functioning. We searched Embase, Medline, and PsycInfo for articles published between database inception and June 2024, examining cognitive domains in euthymic BD. We conducted meta-analysis, meta-regressions, including premorbid IQ, demographic, and clinical variables. Newcastle Ottawa Scale, statistic, and funnel plots/Egger's and Begg's Test were used to assess quality, heterogeneity, and publication bias, respectively. The Benjamini-Hochberg (BH) procedure was utilised for multiple comparisons. We identified 95 groups from 75 studies ( = 4,404 BD & 4,037 HC). BD showed significant impairment in general cognitive functioning (Hedge's = -0.58, 95%CI: -0.79, -0.37, <.01), verbal memory (Hedge's = -0.70, 95%CI: -0.79, -0.60, <.01), executive function (Hedge's = -0.69, 95%CI: -0.78, -0.60, <.01), visuo-spatial memory (Hedge's = -0.68, 95%CI: -0.83, -0.53, <.01), attention/processing speed (Hedge's = -0.64, 95%CI: -0.75, -0.54, <.01), working memory (Hedge's = -0.61, 95%CI: -0.74, -0.49, <.01), and premorbid IQ (Hedge's = -0.24, 95%CI: -0.36, -0.12, <.01). Demographic and clinical factors were not associated with cognitive performance, except for a statistically significant, but small positive correlation between years of education and lower impairment in verbal memory, = .066, adjusted <.05. Our findings highlight cognitive domains impaired in euthymic BD, indicating targets for interventions. Substantial variance is unexplained, warranting focus on larger samples of individual-level data.