Most cognitive studies of bipolar disorder (BD) have examined case–control differences on cognitive tests using measures of central tendency, which do not consider intraindividual variability (IIV); a distinct cognitive construct that reliably indexes meaningful cognitive differences between individuals. In this study, we sought to characterize IIV in BD by examining whether it differs from healthy controls (HCs) and is associated with other cognitive measures, clinical variables, and white matter microstructure.

Two hundred and seventeen adults, including 100 BD outpatients and 117 HCs, completed processing speed, sustained attention, working memory, and executive function tasks. A subsample of 55 BD participants underwent diffusion tensor imaging. IIV was operationalized as the individual standard deviation in reaction time on the Continuous Performance Test-Identical Pairs version.

BD participants had significantly increased IIV compared to age-matched controls. Increased IIV was associated with poorer mean performance scores on processing speed, sustained attention, working memory, and executive function tasks, as well as two whole-brain white matter indices: fractional anisotropy and radial diffusivity.

IIV is increased in BD and appears to correlate with other cognitive variables, as well as white matter measures that index reduced structural integrity and demyelination. Thus, IIV may represent a neurobiologically informative cognitive measure for BD research that is worthy of further investigation.

There are few economic evaluations of adjunctive psychosocial therapies for bipolar disorder.

Estimate the cost–utility of in-person psychosocial therapies for adults with bipolar disorder added to treatment as usual (TAU), from an Australian Government perspective.

We developed an economic model, estimating costs in 2021 Australian dollars (A$) and outcomes using quality-adjusted life-years (QALYs) gained and disability-adjusted life-years (DALYs) averted. The model compared psychoeducation, brief psychoeducation, carer psychoeducation, cognitive–behavioural therapy (CBT) and family therapy when added to TAU (i.e. pharmacotherapy) over a year for adults (18–65 years) with bipolar disorder. The relative risk of relapse was sourced from two network meta-analyses and applied to the depressive phase in the base case. Probabilistic sensitivity analysis and one-way sensitivity analyses were conducted, assessing robustness of results.

Carer psychoeducation was preferred in the base case when the willingness-to-pay (WTP) threshold is below A$1000 per QALY gained and A$1500 per DALY averted. Brief psychoeducation was preferred when WTP is between A$1000 and A$300 000 per QALY gained and A$1500 and A$450 000 per DALY averted. Family therapy was only preferred at WTP thresholds above A$300 000 per QALY gained or A$450 000 per DALY averted. In sensitivity analyses, brief psychoeducation was the preferred therapy. Psychoeducation and CBT were dominated (more costly and less effective) in base-case and sensitivity analyses.

Carer and brief psychoeducation were found to be the most cost-effective psychosocial therapies, supporting use as adjunctive treatments for adults with bipolar disorder and their families in Australia.

Psychotic disorders, including schizophrenia (SZ), schizoaffective disorder (SZA), bipolar disorder (BD), psychotic depression (PD), and other nonaffective psychoses (ONAP), are associated with increased risk of suicidal acts. Few studies have compared suicidal act prevalence across psychotic disorders using both self-report and register data. The impact of hospitalization duration on subsequent suicidal acts is unclear.

We used data from the SUPER-Finland study, involving 7067 participants with register-based ICD-10 diagnoses of psychotic disorders (SZ, SZA, BD, PD, ONAP). Lifetime suicidal acts were identified through self-report and register-based records of intentional self-harm events requiring medical treatment. Associations between diagnostic categories and suicidal acts were assessed using logistic regression, adjusted for sex, duration of illness, socioeconomic status, childhood abuse, and substance use. Survival analysis was used to examine the impact of hospital stay length on postdischarge self-harm.

Lifetime suicide attempts (39.1%) and register self-harm (19.3%) were prevalent. of those with self-reported suicide attempts, 40.5% also had register-based self-harm. Self-harm and suicide attempts were significantly more prevalent in SZA, BD, and PD compared to schizophrenia, with large differences between groups (24.1–46.4% for suicide attempts, 11.1–23.9% for self-harm). Adjusted odds of self-harm were higher for disorders with a mood component. Shorter hospitalizations were associated with an elevated hazard ratio for subsequent self-harm.

Prevalence of register-based self-harm and self-reported suicide attempts differ markedly. Suicidal acts are common in psychotic disorders, particularly in those with a mood component. Very short inpatient stays may not be adequate in these disorders.

Bipolar depression remains difficult to treat, and people often experience ongoing residual symptoms, decreased functioning and impaired quality of life. Adjunctive therapies targeting novel pathways can provide wider treatment options and improve clinical outcomes. Garcinia mangostana Linn. (mangosteen) pericarp has serotonogenic, antioxidant anti-inflammatory and neurogenic properties of relevance to the mechanisms of bipolar depression.

The current 28-week randomised, multisite, double-blind, placebo-controlled trial investigated mangosteen pericarp extract as an adjunct to treatment-as-usual for treatment of bipolar depression.

This trial was prospectively registered on the Australia New Zealand Clinical Trials Registry (no. ACTRN12616000028404). Participants aged 18 years and older with a diagnosis of bipolar I or II and with at least moderate depressive symptoms were eligible for the study. A total of 1016 participants were initially approached or volunteered for the study, of whom 712 did not progress to screening, with an additional 152 screened out. Seventy participants were randomly allocated to mangosteen and 82 to a placebo control. Fifty participants in the mangosteen and 64 participants in the placebo condition completed the treatment period and were analysed.

Results indicated limited support for the primary hypothesis of superior depression symptom reduction following 24 weeks of treatment. Although overall changes in depressive symptoms did not substantially differ between conditions over the course of the trial, we observed significantly greater improvements for the mangosteen condition at 24 weeks, compared with baseline, for mood symptoms, clinical impressions of bipolar severity and social functioning compared with controls. These differences were attenuated at week 28 post-discontinuation assessment.

Adjunctive mangosteen pericarp treatment appeared to have limited efficacy in mood and functional symptoms associated with bipolar disorder, but not with manic symptoms or quality of life, suggesting a novel therapeutic approach that should be verified by replication.

Diagnostic accuracy is an unmet need for major depressive disorder (MDD) and major depressive episode (MDE) in bipolar disorder. Very limited research has evaluated bipolar disorder/MDE and MDD using ecological momentary assessment (EMA) time-series data.

We aimed to examine differentiating phenomenological characteristics in positive affect dynamics, and temporal relationships with pleasure towards current activity and meaning in life (MIL), among MDD, MDE/bipolar disorder and healthy controls using EMA.

Participants (N = 88, mean age 28.7 years, 69% female), including individuals with MDD (n = 29) and MDE/bipolar disorder (n = 29) and healthy controls (n = 30), were assessed for positive affect, pleasure and MIL 5 times daily over a 2-week period. Multilevel modelling analysis was conducted, with estimation of first-order autoregressive model structure and time-lagged relationship between pleasure and positive affect.

From 4632 EMA observations, positive affect dynamics (inertia, variability and instability) did not differ significantly across groups (all P > 0.05). Although all groups demonstrated a bidirectional relationship between positive affect and pleasure, for MDE/bipolar disorder, both pleasuret − 1 (β = −0.11, t[51.09] = −2.31, P = 0.025) and positive affectt − 1 (β = −0.13, t[56.54] = −2.30, P = 0.025) predicted subsequent MIL less significantly than for MDD and healthy controls.

Individuals with MDE/bipolar disorder, but not MDD, had less self-reported MIL from positive affect and pleasure. There is little evidence that emotional experience alone characterises the pathophysiology between MDD and MDE/bipolar disorder; such investigation may be limited by within-group heterogeneity. Our findings provide a new perspective on using a time-series approach beyond bimodal measures in EMA to differentiate bipolar disorder/MDE and MDD.

Bipolar disorders are a major cause of disability worldwide, with most of the disease burden attributed to those in low- and middle-income countries, including Nigeria. There is limited evidence on culturally appropriate interventions for bipolar disorders in Nigeria.

The study aims to examine the feasibility, and acceptability of culturally adapted psychoeducation (CaPE) for treating bipolar disorders.

A randomised controlled trial (RCT) compared CaPE plus treatment as usual (TAU) with TAU alone among 34 persons with bipolar disorders in Jos, Nigeria. CaPE comprised 12 group sessions of in-person psychoeducation lasting approximately 90 min each, delivered on a weekly basis by clinical researchers supervised by clinical psychologists and consultant psychiatrists. The primary outcome was feasibility, measured by participants’ recruitment and retention rates. Other outcomes included acceptability as measured by the Service Satisfaction Scale (SSS), Brief Bipolar Disorder Symptom Scale (BBDSS), Patient Health Questionnaire (PHQ-9) and Quality-of-Life scale (EQ5D). Outcomes were assessed at baseline and weeks 12 and 24. Focus group (n = 10) and individual interviews (n = 5) were conducted with the CaPE + TAU group, recorded, transcribed verbatim and analysed using interpretative phenomenological analysis.

The CaPE+TAU group (n = 17) recorded a high participant recruitment and retention rate of 86% across 12 sessions, and also recorded a higher level of satisfaction with SSS compared with the TAU alone group; 87.5% indicated very satisfied compared with 66.7% indicated not sure in the TAU group. In terms of clinical outcomes, for PHQ-9 scores the intervention group showed a reduction from baseline to end of intervention (EOI) and follow-up, with differences of −12.01 and −7.39, respectively (both P < 0.001). The EQ5D index showed a notable improvement in the intervention group at both EOI and follow-up (P < 0.001). Lastly, BBDS scores decreased significantly in the CaPE+TAU group at both EOI and follow-up, with differences of −21.45 and −15.76 (both P < 0.001).

The RCT of CaPE is a feasible, acceptable and culturally appropriate treatment option for bipolar disorders in Nigeria. Further adequately powered RCTs evaluating the intervention’s clinical and cost-effectiveness are warranted.

Bipolar disorder (BD) affects over 1% of the population and is characterized by deficits in response inhibition. Response inhibition, a crucial component of executive functions, involves the ability to suppress or withhold a planned or ongoing response that is no longer required or appropriate in a given context. Response inhibition may be dissociated into three subcomponents: interference inhibition, action withholding, and action cancellation. These subcomponents are assessed using the hybrid response inhibition (HRI) task. Previous research has shown that inhibitory control is strongly lateralized to the right hemisphere. Specifically, the right inferior frontal gyrus (rIFG) is a key node underpinning response inhibition and might be amenable to neuromodulation using repetitive transcranial magnetic stimulation (rTMS). This proof-of-concept study aimed to investigate the effects of rTMS targeting the rIFG on response inhibition in individuals with BD and controls.

We investigated HRI performance scores in individuals with BD (n = 12) and sex-/age-matched controls (n = 12) immediately before and after intermittent theta-burst stimulation (iTBS) and continuous TBS to modulate cortical excitability of the rIFG.

The response inhibition subcomponent “action withholding” was significantly improved in the HRI task following iTBS in the BD group. No other significant effects were observed in the results.

Our study is the first to show that iTBS to the rIFG neuromodulated a specific subcomponent of response inhibition in BD. Further research investigating the potential therapeutic effect of neuromodulation of the rIFG in BD is warranted.

Despite evidence of associations between glucocorticoid treatment and adverse psychiatric and suicidal behaviour outcomes, large-scale observational evidence for serious outcomes is lacking.

To assess the risk of psychiatric and suicidal behaviour outcomes during glucocorticoid treatment.

Using Swedish population registers, we identified 1 105 964 individuals aged 15–54 years who collected a glucocorticoid prescription in oral form between 2006 and 2020. We investigated associations with a range of psychiatric outcomes: unplanned specialist healthcare contacts due to depressive, bipolar, anxiety or schizophrenia-spectrum disorders; and deaths by suicide or unplanned specialist healthcare contacts due to self-harm (‘suicidal behaviour’). We estimated hazard ratios from Cox proportional hazards models in a medication-only cohort by comparing outcome rates during and outside treated periods within individuals. We further identified individuals with an autoimmune or gastrointestinal autoimmune disorder diagnosis and compared hazards of the outcomes between those who did and did not initiate a glucocorticoid using a target trial emulation approach.

We found increased risks for psychiatric outcomes, with within-individual hazard ratios ranging from 1.08 (95% CI, 1.00–1.16) for depressive disorders to 1.23 (95% CI, 1.12–1.36) for bipolar disorder and 1.25 (95% CI, 1.20–1.31) for anxiety disorders. We found no clear association with suicidal behaviour (hazard ratio: 1.06; 95% CI, 0.96–1.17). These findings were similar when stratified by age and gender. Within-individual associations were attenuated in those diagnosed with an autoimmune disorder. The risk of anxiety and bipolar disorder outcomes appeared particularly elevated in the first weeks of treatment. Absolute rates were modestly elevated during treatment, and higher in those with a history of psychiatric disorders.

Glucocorticoid treatment is associated with elevated risks of serious psychiatric outcomes, including the onset and relapse of common psychiatric disorders. Individuals with psychiatric histories may require additional monitoring during glucocorticoid treatment.

Previous studies have estimated the lifetime incidence, age of onset and prevalence of mental disorders, but none have used nationwide data covering both primary and secondary care, even though mental disorders are commonly treated in primary care. We aimed to determine lifetime incidence, age-specific incidence, age of onset and service utilization for diagnosed mental disorders.

This register-based cohort study followed the entire population of Finland from 2000 to 2020. We estimated the cumulative incidence of diagnosed mental disorders with the Aalen–Johansen estimator, accounting for competing risks such as death and emigration. We also calculated age-specific incidence and 12-month service utilization as of 31 December 2019, providing diagnosis-, age- and gender-specific estimates.

We followed 6.4 million individuals for 98.5 million person-years. By age 100, lifetime incidence of any diagnosed mental disorder was 76.7% (95% CI, 76.6–76.7) in women and 69.7% (69.6–69.8) in men; in psychiatric secondary care, it was 39.7% (39.6–39.8) and 31.5% (31.4–31.6). At age 75, stricter estimates for non-organic disorders (ICD-10: F10–F99) were 65.6% (65.5–65.7) for women and 60.0% (59.9–60.1). Anxiety disorders (F40–F48) had the highest cumulative incidence. Median age of onset of non-organic mental disorders was 24.1 (interquartile range, 14.8–43.3 years) in women and 20.0 (interquartile range, 7.3–42.2 years) in men. Service utilization within 12 months was 9.0% for women and 7.7% for men.

Most, though not all, individuals experience at least one type of mental disorder, often during youth. Capturing the overall occurrence of mental disorders requires including both primary and secondary care data.

People with severe mental illness (SMI) have a higher risk of premature mortality than the general population.

To investigate whether the life expectancy gap for people with SMI is widening, by determining time trends in excess life-years lost.

This population-based study included people with SMI (schizophrenia, bipolar disorder and major depression) alive on 1 January 2000. We ascertained SMI from psychiatric hospital admission records (1981–2019), and deaths via linkage to the national death register (2000–2019). We used the Life Years Lost (LYL) method to estimate LYL by SMI and sex, compared LYL to the Scottish population and assessed trends over 18 3-year rolling periods.

We included 28 797 people with schizophrenia, 16 657 with bipolar disorder and 72 504 with major depression. Between 2000 and 2019, life expectancy increased in the Scottish population but the gap widened for people with schizophrenia. For 2000–2002, men and women with schizophrenia lost an excess 9.4 (95% CI 8.5–10.3) and 8.2 (95% CI 7.4–9.0) life-years, respectively, compared with the general population. In 2017–2019, this increased to 11.8 (95% CI 10.9–12.7) and 11.1 (95% CI 10.0–12.1). The life expectancy gap was lower for bipolar disorder and depression and unchanged over time.

The life expectancy gap in people with SMI persisted or widened from 2000 to 2019. Addressing this entrenched disparity requires equitable social, economic and health policies, healthcare re-structure and improved resourcing, and investment in interventions for primary and secondary prevention of SMI and associated comorbidities.

To understand the pathogenetic mechanisms shared among schizophrenia (SCZ), bipolar disorder (BP), and major depression (MDD), we investigated the pleiotropic mechanisms using large-scale genome-wide and brain transcriptomic data.

We analyzed SCZ, BP, and MDD genome-wide association datasets available from the Psychiatric Genomics Consortium using the PLEIO framework and characterized the pleiotropic loci identified using pathway and tissue enrichment analyses. Pleiotropic and disorder-specific loci were also assessed.

Our pleiotropy-informed genome-wide analysis identified 553 variants that included 192 loci not reaching genome-wide significance in input datasets. These were enriched for five molecular pathways: cadherin signaling (p = 2.18 × 10−8), Alzheimer’s disease-amyloid secretase (p = 4 × 10−4), oxytocin receptor-mediated signaling (p = 1.47 × 10−3), metabotropic glutamate receptor group III (p = 5.82 × 10−4) and Wnt signaling (p = 1.61 × 10−11). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex (p = 5.8 × 10−28), frontal cortex (p = 3 × 10−31), and cerebellar hemisphere (p = 9.8 × 10−28). SCZ-BP-MDD pleiotropic variants were also enriched for neurodevelopmental brain transcriptomic profiles related to the second-trimester post-conception (week 21, p = 7.35 × 10−5; week 17, p = 6.36 × 10−4) and first year of life (p = 3.25 × 10−5).

Genetic mechanisms shared among SCZ, BP, and MDD appear to be related to early neuronal development. Because the genetic architecture of psychopathology transcends diagnostic boundaries, pleiotropy-focused analyses can lead to increased gene discovery and novel insights into relevant pathogenic mechanisms.

Brain morphological alterations in bipolar disorder are well documented, particularly in chronic cases. This study focuses on first-episode mania (FEM) to quantify neuroanatomical changes at early stages of the disorder.

To assess deviations from normative brain morphometry and age-related brain changes in patients with FEM.

Pretrained models, based on large, independent healthy samples, were applied to structural brain images from FEM patients (n = 83) and healthy individuals (n = 61). Normative deviation z-scores were computed for regional brain morphometry, along with global and voxel-level brain–age-gap estimates (G-brainAGE and L-brainAGE, respectively). The proportions of infranormal (z < −1.96) and supranormal (z > 1.96) deviations were measured for both groups. Ridge regression and support vector machine models were used to evaluate whether z-scores predicted symptom severity, IQ or diagnosis. Case-control differences in L-brainAGE and correlations between G-brainAGE and clinical features were analysed.

Both FEM and healthy individuals showed similar proportions of infra- and supranormal deviations in regional measures. Morphometric data, whether observed or normative, did not significantly predict clinical outcomes or diagnosis. Mean G-brainAGE in FEM was −1.04 (s.d. 3.26) years and negatively correlated with age of onset, while L-brainAGE did not differ significantly between groups.

Regional morphometry and local brain-ageing metrics in FEM patients aligned with normative ranges, suggesting minimal abnormalities in early bipolar disorder. However, subtle delays in global brain ageing may reflect variation based on the age of onset, highlighting a potential area for further exploration.

The duration of undiagnosed or untreated bipolar disorder (DUBD) has become a focus of research interest. However, its relationship with clinical characteristics and outcomes remains poorly understood.

The objective of this systematic review and meta-analysis was to examine DUBD and explore its relationships with clinical characteristics and outcomes in bipolar disorder.

We conducted a systematic search of the literature to identify studies reporting on DUBD and its relationships with clinical characteristics and outcomes including frequency of relapse into mood episodes, severity and persistence of mood symptoms, functional and cognitive measures, suicidality, hospital admission rate, and comorbidities such as substance use disorders.

Thirty articles met inclusion criteria for the systematic review, and 23 studies were included in the three different sets of meta-analyses. The pooled mean DUBD across all studies was 9.10 years. Early onset, depression as the polarity of the first mood episode, lifetime suicide attempts, comorbid anxiety and alcohol use disorders, and family history of bipolar disorder were associated with significantly longer DUBD, whereas diagnosis of bipolar I disorder and lifetime psychotic symptoms were associated with shorter DUBD. Studies that investigated outcomes subsequent to the diagnosis of bipolar disorder yielded conflicting results.

DUBD may be associated with certain adverse outcomes. This association indicates the importance of adopting a more comprehensive approach to assessing mood disorders, with an emphasis on prioritising early screening for bipolar disorder. The significant heterogeneity among included studies suggests a need for improved methodological rigour in future research.

Lamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks in healthy volunteers, previously shown to be sensitive to antidepressant drug action in similar experimental designs.

Healthy volunteers (n = 36) were randomized in a double-blind design to receive a single dose of placebo or 300 mg lamotrigine. Mood and subjective effects were monitored throughout the study period, and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post-administration.

Participants receiving lamotrigine showed increased accurate recall of positive versus negative self-descriptors, compared to those in the placebo group. There were no other significant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience.

Lamotrigine did not induce widespread changes in emotional processing. However, there was increased positive bias in emotional memory, similar to the effects of antidepressants reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.

Offspring of parents with bipolar disorder (BD offspring) face elevated risks for emotional dysregulation and cognitive deficits, particularly in working memory. This study investigates working memory deficits and their neural correlates in BD offspring.

We assessed 41 BD offspring and 25 age-matched healthy controls (HCs) using a spatial N-back task and task-related functional magnetic resonance imaging (fMRI).

Compared to HCs, BD offspring exhibit reduced accuracy and lower signal-detection sensitivity (d′) on the 1-back task. fMRI reveals hyperactivation in the right intracalcarine cortex/lingual gyrus (ICC/LG) in BD offspring, particularly during the 1-back condition. Psychophysiological interaction (PPI) analyses show reduced connectivity between the right ICC/LG and the left postcentral gyrus in BD offspring as task load increases from 0-back to 1-back. This connectivity positively correlates with 1-back task performance in HCs but not in BD offspring. Additionally, using bilateral dorsolateral prefrontal cortex (DLPFC) as regions of interest, PPI analyses show diminished condition-dependent connectivity between the left DLPFC and the left superior frontal gyrus/paracingulate cortex, and between the right DLPFC and the left postcentral gyrus/precentral gyrus in BD offspring as the task load increases.

These findings suggest that BD offspring exhibit working memory deficits and impaired neural connectivity involving both sensory processing and higher-order cognitive systems. Such deficits may emerge at a genetically predisposed stage of bipolar disorder, underscoring the significance of early identification and intervention strategies.

The identification of early warning signs is of great importance for identifying individuals at risk for mental disorders. Especially in the case of bipolar disorder, these research endeavours are imperative considering that the frequently delayed diagnoses and longer illness duration are associated with symptom exacerbation and lower recovery rates.

To multimodally investigate associations between hypomanic personality traits and altered social affect and social cognition to probe their role as early warning signs of bipolar disorder.

In a community sample (n = 140; 50.71% female), we investigated associations between hypomanic personality traits and both behavioural and neural activity measures of empathy and theory of mind (ToM) based on data from a functional magnetic resonance imaging paradigm.

Although analyses revealed no significant associations between behavioural or neural correlates of empathy and hypomanic personality traits, these traits were significantly associated with elevated ToM-related neural activity in the anterior rostral medial prefrontal cortex and anterior cingulate cortex. These neural activation differences were not accompanied by differences in behavioural ToM performance, suggesting more intense recruitment of task-relevant brain regions but unaffected behavioural outcomes.

Our findings indicate hypomanic personality traits to be positively associated with ToM-related neural activity but not with behavioural ToM performance. Prospectively, our study contributes to driving towards a more comprehensive and potentially neurobiologically grounded phenotype of bipolar disorder risk that contributes to a more differential understanding of risk and resilience mechanisms.