Little is known regarding the shared genetic architecture underlying the phenotypic associations between depression and preterm birth (PTB). We aim to investigate the genetic overlap and causality of depression with PTB.

Leveraging summary statistics from the largest genome-wide association studies for broad depression (Ntotal = 807,533), major depression (Ntotal = 173,005), bipolar disorder (Ntotal = 414,466), and PTB (Ntotal = 226,330), we conducted a large-scale genome-wide cross-trait analysis to assess global and local genetic correlations, identify pleiotropic loci, and infer potential causal relationships

Positive genetic correlations were observed between PTB and broad depression (rg = 0.242), major depression (rg = 0.236), and bipolar disorder (rg = 0.133) using the linkage disequilibrium score regression, which were further verified by the genetic covariance analyzer. Local genetic correlation was identified at chromosome 11q22.3 (harbors NCAM1-TTC12-ANKK1-DRD2) for PTB with depression. Cross-trait meta-analysis identified two loci shared between PTB and broad depression, two loci shared with major depression, and five loci shared with bipolar disorder, among which three were novel (rs7813444, rs3132948 and rs9273363). Mendelian randomization demonstrated a significantly increased risk of PTB for genetic liability to broad depression (odds ratio [OR]=1.30; 95% confidence interval [CI]: 1.11-1.52) and major depression (OR=1.27; 95%CI: 1.08-1.49), and the estimates remained significant across the sensitivity analyses.

Our findings demonstrate an intrinsic link underlying depression and PTB and shed novel light on the biological mechanisms, highlighting an important role of early screening and effective intervention of depression in PTB prevention, and may provide novel treatment strategies for both diseases.

Immunomodulatory effects of psychotropic agents used to treat severe mental disorders (SMDs) have been suggested. We investigated associations between immune marker levels and antipsychotic- (AP), antidepressant- (AD), and mood stabilizing agents (MS) use in SMDs.

We included 1215 participants with SMDs (777 with schizophrenia spectrum disorders and 438 with bipolar disorders). Circulating levels of 45 immune markers were determined by enzyme-immunoassay or immunoturbidimetry and analyzed for associations with use, doses, and serum concentrations of AP, AD, and MS. Extensive adjustments for potential confounders were performed. Immune marker levels of 1008 healthy controls served as a reference.

AP use was significantly associated with higher plasma levels of beta defensin 2 (BD-2) (β = 0.094, p = 0.8E-4), AD use with higher serum levels of CRP (β = 0.072, p = 0.8E-3), and MS use with higher plasma levels of soluble interleukin 2 receptor (sIL-2R) (β = 0.063, p = 0.9E-4). These findings were paralleled by positive associations with psychotropic agent dose and serum concentrations: AP dose was associated with BD-2 levels (β = 0.045, p = 2.3E-4), AD dose with CRP levels (β = 0.039, p = 0.001), MS dose with sIL-2R levels (β = 0.048, p = 0.001), and serum concentration of AD was nominally positively associated with CRP (β = 0.072, p = 0.002).

The findings suggest that AP and MS use affect pathways involved in immune homeostasis and inflammatory regulation in individuals with SMDs, while AD use augments low-grade systemic inflammation reflected by CRP.

MicroRNAs (miRNAs) alterations in patients with bipolar disorder (BD) are pivotal to the disease’s pathogenesis. Since obtaining brain tissue is challenging, most research has shifted to analyzing miRNAs in peripheral blood. One innovative solution is sequencing miRNAs in plasma extracellular vesicles (EVs), particularly those neural-derived EVs emanating from the brain.

We isolated plasma neural-derived EVs from 85 patients with BD and 39 healthy controls (HC) using biotinylated antibodies targeting a neural tissue marker, followed by miRNA sequencing and expression analysis. Furthermore, we conducted bioinformatic analyses and functional experiments to delve deeper into the underlying pathological mechanisms of BD.

Out of the 2,656 neural-derived miRNAs in EVs identified, 14 were differentially expressed between BD patients and HC. Moreover, the target genes of miR-143-3p displayed distinct expression patterns in the prefrontal cortex of BD patients versus HC, as sourced from the PsychENCODE database. The functional experiments demonstrated that the abnormal expression of miR-143-3p promoted the proliferation and activation of microglia and upregulated the expression of proinflammatory factors, including IL-1β, IL-6, and NLRP3. Through weighted gene co-expression network analysis, a module linking to the clinical symptoms of BD patients was discerned. Enrichment analyses unveiled these miRNAs’ role in modulating the axon guidance, the Ras signaling pathway, and ErbB signaling pathway.

Our findings provide the first evidence of dysregulated plasma miRNAs within neural-derived EVs in BD patients and suggest that neural-derived EVs might be involved in the pathophysiology of BD through related biological pathways, such as neurogenesis and neuroinflammation.

Identifying key areas of brain dysfunction in mental illness is critical for developing precision diagnosis and treatment. This study aimed to develop region-specific brain aging trajectory prediction models using multimodal magnetic resonance imaging (MRI) to identify similarities and differences in abnormal aging between bipolar disorder (BD) and major depressive disorder (MDD) and pinpoint key brain regions of structural and functional change specific to each disorder.

Neuroimaging data from 340 healthy controls, 110 BD participants, and 68 MDD participants were included from the Taiwan Aging and Mental Illness cohort. We constructed 228 models using T1-weighted MRI, resting-state functional MRI, and diffusion tensor imaging data. Gaussian process regression was used to train models for estimating brain aging trajectories using structural and functional maps across various brain regions.

Our models demonstrated robust performance, revealing accelerated aging in 66 gray matter regions in BD and 67 in MDD, with 13 regions common to both disorders. The BD group showed accelerated aging in 17 regions on functional maps, whereas no such regions were found in MDD. Fractional anisotropy analysis identified 43 aging white matter tracts in BD and 39 in MDD, with 16 tracts common to both disorders. Importantly, there were also unique brain regions with accelerated aging specific to each disorder.

These findings highlight the potential of brain aging trajectories as biomarkers for BD and MDD, offering insights into distinct and overlapping neuroanatomical changes. Incorporating region-specific changes in brain structure and function over time could enhance the understanding and treatment of mental illness.

Lithium treatment is associated with reduced mortality in bipolar disorder (BD), but the role of treatment continuity remains underexplored. This study investigated the association between patterns of lithium exposure and all-cause mortality in a population-based cohort.

We analyzed electronic health records from 15,384 individuals with BD in Catalonia, Spain (2010–2019). Patients were classified as having sustained, partial/intermittent, or no lithium exposure based on annual defined daily doses (DDDs). All-cause mortality was the primary outcome. Kaplan–Meier and Cox regression analyses (adjusted for sociodemographic, clinical, and treatment-related variables) estimated hazard ratios (HRs) for mortality risk. Interaction and sensitivity analyses were conducted to assess the role of comorbidity burden and dose effects.

Over the study period, 715 deaths were recorded. In fully adjusted models, sustained lithium exposure was associated with a significantly lower mortality risk compared to no exposure (HR = 0.69, 95% confidence interval [CI]: 0.51–0.93, p = 0.016). In the lithium-exposed subgroup, sustained use was also protective compared to partial/intermittent exposure (HR = 0.70, 95% CI: 0.51–0.97, p = 0.03). No significant interaction was observed between sustained lithium use and comorbidity burden. Sensitivity analyses confirmed this effect at lower dose thresholds but not at higher ones.

Sustained lithium use is associated with improved survival in BD. Discontinuous exposure does not confer the same benefit. Ensuring treatment continuity may maximize lithium’s protective effect and improve long-term outcomes.

Lurasidone is a second-generation antipsychotic with antidepressant properties, but its effect on depressive symptoms across diagnostic domains is not known.

This systematic review aims to synthesise the evidence for the transdiagnostic efficacy of lurasidone in reducing depressive symptoms.

Electronic databases were searched up to October 2024 to identify randomised controlled trials comparing the effects of lurasidone and placebo on depressive symptoms, as measured by any standardised scale, in populations with different psychiatric diagnoses. Acceptability, tolerability and safety were also measured. The Cochrane risk of bias tool was used to assess study quality, and the GRADE tool to evaluate certainty of evidence. A random-effects meta-analysis was performed to estimate standardised mean differences (SMDs, for continuous outcomes) or relative risks (for dichotomous outcomes) with 95% CI.

Fourteen trials met inclusion criteria. Pooled analysis of 5239 participants found lurasidone to be more efficacious than placebo in improving depression scores (SMD −0.26, 95% CI −0.37, −0.15) across multiple diagnoses (including schizophrenia, bipolar disorder and major depressive disorder). Secondary analyses showed better acceptability (relative risk 0.55, 95% CI 0.43, 0.71) and safety (relative risk 0.73, 95% CI 0.58, 0.91) and comparable tolerability (relative risk 0.74, 95% CI 0.54, 1.02) between lurasidone and placebo. The main limitations were the high risk of bias of several included studies and the high heterogeneity observed in our findings.

Lurasidone is a potentially efficacious and safe strategy for reducing depressive symptomatology across a range of psychiatric diagnoses. Further long-term, robust trials employing precision psychiatry methods are needed to support its broader use to target depressive symptoms transdiagnostically.

We investigate whether, in Swedish national registers, social and psychiatric outcomes for six major psychiatric and substance disorders – drug use disorder (DUD), alcohol use disorder (AUD), major depression (MD), bipolar disorder (BD), anxiety disorder (AD), and schizophrenia (SZ) – reflect the primary genetic risk for each disorder and the level of genetic heterogeneity.

We utilize Genetic Risk Ratios – defined as the ratio of the genetic risk for secondary disorders to the genetic risk for the primary disorder – derived from Family Genetic Risk Scores. Poor social outcome was defined by a common factor of four variables: receipt of social welfare, sick leave, early retirement pension, and residence in a socially deprived area. Psychiatric outcome was defined as days of inpatient psychiatric hospitalization.

With poorer social outcomes, the primary genetic risks rose robustly for all disorders except SZ, as did the secondary genetic risks for DUD, AUD, and attention-deficit hyperactivity disorder. With poorer psychiatric outcomes, available only for BD and SZ, the primary genetic risks increased sharply. Overall, MD, AD, and BD became substantially more genetically heterogenous as their social outcomes became poorer, while for AUD, DUD, and SZ, the increase in heterogeneity was more modest. By contrast, with poorer psychiatric outcome, genetic risks for SZ became substantially more genetically homogeneous, with a similar but less robust trend seen for BD.

Despite important differences between our primary disorders, social and psychiatric outcomes are often robust indices of genetic risk and can reflect the levels of genetic heterogeneity.

Suicidal behaviors (SB) in bipolar disorder (BD) are major adverse outcomes that may influence disease progression. While staging models exist for psychiatric disorders, none include suicide. This study aims to stratify suicidal risk in BD, propose a staging model for SB, and assess its clinical utility.

Participants from the FondaMental Advanced Centers of Expertise for Bipolar Disorder (FACE-BD) cohort were categorized into five stages (St) based on SB: St0 (no suicidal ideation [SI]), St1 (SI but no suicide attempt [SA]), St2a (non-severe/violent SA), St2b (severe /violent SA), and St3 (multiple SAs). Stages were analyzed based on demographic, clinical, cognitive, and biological characteristics using logistic regression.

Key differences emerged between stages. St1 showed longer untreated illness and higher lability and lower functioning than St0. St2a was linked to anxiety, substance use disorders, and longer disorder duration, while male gender and lithium bitherapy were protective. St2b exhibited shorter untreated illness and higher childhood trauma (CTQ) scores, with male gender and alcohol use as risk factors. St3 was associated with BD-II, alcohol use, longer disorder duration, and more depressive episodes, but less anxiety. No biochemical or cognitive differences were found across stages. The model was significantly associated with SA occurrence (LRT = 28.74, p < 0.0001).

This staging model for suicidality in BD provides a multifaceted approach to risk stratification and predictive insights, although further refinement is needed.

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.