Externalizing and internalizing behaviours capture heritable, transdiagnostic dimensions of psychopathology, but their genetic architecture and links to societal outcomes remain incompletely understood. This study applied a multivariate framework to population-based, non-clinical traits to explore simultaneous genetic associations across externalizing and internalizing behaviours to elucidate their biological underpinnings and genetic relation to clinical diagnoses. Using genomic structural equation modelling, we built a two-factor model for externalizing (EXT) and internalizing (INT) behaviour utilizing 13 genome-wide association study (GWAS) summary statistics from population-based cohorts (n=64,000-1,200,000). We tested genetic correlations of EXT and INT with 12 psychiatric diagnoses (n=14,000-2,000,000) using linkage-disequilibrium score regression, and we studied genetic relation to emotional well-being with polygenic score analyses (PRS-CS) in an independent cohort (n= 4,565). Multivariate GWAS revealed 184 genome-wide significant loci for EXT and 31 for INT. Gene-level analyses identified 52 novel genes for EXT and 18 for INT. Enrichment analyses using single-cell-RNA-sequencing data showed significant enrichment in neuronal and non-neuronal populations, with strongest signals in hippocampal CA4 for EXT and amygdalar excitatory neurons for INT. EXT correlated with attention-deficit/hyperactivity disorder and substance-use disorders, INT showed significant genetic correlations with obsessive-compulsive disorder and anorexia nervosa. EXT and INT also exhibited overlap in genetic correlations with posttraumatic stress disorder, major depressive disorder, schizophrenia, and anxiety disorder. PRS-CS demonstrated association of INT liability with emotional well-being. Overall, these findings advance our understanding of the genetic architecture underlying transdiagnostic externalizing and internalizing behaviours and underscore their relevance for both psychiatric risk and emotional well-being.
Evidence of clozapine’s transdiagnostic benefits beyond schizophrenia spectrum disorders (SSDs) is increasing. Whether this has impacted clozapine usage patterns in practice is yet to be assessed. This study aims to examine the range of indications associated with clozapine prescribing internationally and explore cross-country variation in the distribution of utilisation across diagnostic categories. Information on prescribing indication was obtained using the IQVIA Multinational Integrated Data Analysis System (MIDAS) Disease Insights database. The database contained information on indications recorded for clozapine prescribing in 55 countries and 15 regions. Prescribing indications for clozapine were obtained by IQVIA through a combination of (1) electronic medical records, (2) prescription and claims data, and (3) patient medication records. Results were analysed descriptively. Collectively, prescribing of clozapine was most commonly recorded within SSDs (82.3%). Clozapine prescribing within non-SSDs accounted for approximately 18% of all indications recorded; mood disorders (13.6%), anxiety disorders (2.5%), movement disorders (1.1%), epilepsy (0.4%), and dementia (0.1%). Bipolar disorder (59.3%) was the most commonly recorded prescribing indication within mood disorder management. Substantial interregional variation in utilisation trends were apparent. Recorded clozapine prescribing within non-SSDs was highest in African and Asian regions, accounting for an average of 34.3% and 21% of all recorded indications within each region respectively. In conclusion, substantial use of clozapine outside of SSDs was identified, with approximately 1 in 5 recorded indications occurring for a non-SSD indication. International guidance considering the availability and quality of evidence supporting clozapine use more broadly in psychiatry is now required to promote rationale, evidence-based use.
Anhedonia, or the lack of interest and pleasure, is a transdiagnostic feature of mental health disorders with emerging links to physical health. This exploratory literature review investigated evidence of anhedonia's association with physical health and somatic diseases. A citation chaining approach was applied to 20 papers identified through targeted searches conducted from September to October 2024 on PubMed and Google/Google Scholar. Studies published in English and reporting outcomes in adults with anhedonia were included. Quality assessments were performed using the Centre for Evidence-Based Medicine critical appraisal tool for prognostic studies. Data on study characteristics, assessment and definition of anhedonia, and clinical outcomes were extracted. 41 publications on 40 unique studies were included. Most studies included patients with cardiac conditions, and 14 reported a psychiatric diagnosis, predominantly depression. Anhedonia was significantly associated with all-cause mortality, risk of major adverse cardiovascular events and worse physical health-related quality of life. Moreover, high positive affect was correlated with lower risk of functional decline, reduced inflammatory biomarkers and protective effects against conditions like diabetes and hypertension, compared with low positive affect. To our knowledge, this is the first exploratory review to gather evidence that anhedonia, whether occurring as a symptom of depression, another psychiatric disorder, or a somatic condition, may be associated with poorer health and somatic disease outcomes. Conversely, positive affect may confer protective benefits. These insights emphasise the need to prioritise development of treatment modalities that have proven impacts on hedonic tone.
Esketamine nasal spray (NS) is an established treatment for patients with treatment resistant depression (TRD). To further optimise real-world outcomes, consensus is needed regarding strategies to enhance patient outcomes and decision-making factors for pivotal timepoints in esketamine NS treatment. This modified Delphi panel (3 rounds) established expert consensus (≥80% agreement) from 30 European psychiatrists experienced in management of patients with TRD receiving esketamine NS. During the acute phase (4-12 weeks), modest/subjective reductions in core symptoms important to both patients and physicians supported esketamine NS continuation, especially with long disease course/resistance to multiple therapies. Consensus was reached that such a modest improvement during the acute phase should justify esketamine NS continuation (and supplementation of other treatment modalities with esketamine NS). Esketamine NS dose/frequency maximisation (84 mg weekly) was advocated for, to enhance acute phase outcomes, alongside strategies reflective of individual clinical characteristics. Monitoring in the continuation phase (6-9 months) should prioritise residual/fluctuating symptoms, changes in symptom severity, functional recovery status and comorbidity management/emergence. Should residual symptoms persist, dose/frequency escalation, among other all-phase options, were supported. Prolonging maintenance phase treatment (≥12 months) depended on the degree of clinical worsening when tapering, the risks/consequences of relapse, chronicity of the last depressive episode, residual symptoms and recurrence history. Across all phases, recommended treatment plans included integration of psychotherapy, optimisation of concomitant antidepressants/augmentation strategies, comorbidity management and strengthening support networks. Overall, the consensus advocated for an approach reflective of TRD complexities, prioritising meaningful outcomes for individual patients.
Suicide remains a leading cause of premature mortality worldwide. Current treatments are limited by delayed onset, durability, or poor tolerability. This narrative review, informed by a structured literature search, summarises the last decade of evidence on pharmacological and neuromodulation interventions for suicidal ideation (SI) or suicide attempt (SA) that are not approved for these indications. We searched PubMed for studies enrolling adults with SI or SA, including controlled trials and naturalistic/observational studies. Thirty-four studies were included: 22 pharmacological (13 efficacy, nine effectiveness) and 12 using neuromodulation (nine efficacy, three effectiveness). Across controlled trials, SI commonly improved within days to weeks. Some trials reported SI reduction beyond concurrent depression score changes, suggesting partial independence, but evidence remains inconsistent and method-dependent. Encouraging results were reported for NMDA-related drugs (NRX-101 and high-dose d-cycloserine; amantadine in Borna disease virus-1-positive depression), opioid-system modulation (buprenorphine at ultra-low and high doses in distinct populations), ayahuasca in major and treatment-resistant depression, and adjunctive pimavanserin. Smaller effects were observed for vortioxetine augmentation and insomnia-targeted zolpidem. Large observational datasets reported associations between lower suicidality and folic acid, benztropine, testosterone initiation in transgender adults, and non-vitamin K oral anticoagulants versus warfarin, whereas non-medical cannabis use was associated with worse SI trajectories. Neuromodulation evidence implicated accelerated or targeted repetitive transcranial magnetic stimulation, theta-burst stimulation, and magnetic seizure therapy for SI reduction, with longer-term observational support for vagus nerve stimulation. Future trials should prespecify suicide-related outcomes, test independence from mood change, and assess durability and high-risk transition periods to advance suicide-specific treatment development.
Women with bipolar disorder (BIP) have a higher risk of developing polyendocrine metabolic ovarian syndrome (PMOS). Shared genetic architecture may underlie this comorbidity. Valproate, a mood-stabilizer commonly used to treat BIP, increases the risk of PMOS. Still, the mechanism underlying PMOS in BIP remains unknown. Here, we aimed to identify genetic variants shared between BIP and PMOS, as well as their interaction with valproate. We used the results of large-scale genome-wide association studies of BIP (41,510 cases and 354,340 controls), and PMOS (3609 cases and 229,788 controls). Using conditional false discovery rate, we discovered genetic variants jointly associated with BIP and PMOS. Gene mapping of identified variants was performed using the Open Targets platforms. We analyzed the tissue-specific expression, interaction with valproate, and involvement in biological pathways of the mapped genes. We identified two loci shared between BIP and PMOS. Among the 10 genes mapped to the locus on chromosome 8:11,444,837-11,463,015, GATA4, NEIL2, and FDFT1 showed expression profiles suggesting their role in the observed comorbidity. Mapped to the locus on chromosome 12:2499,849-2514,270, CACNA1C, FKBP4, DCP1B, and ITFG2 are expressed in both the ovaries and the brain. Valproate interacts with CACNA1C, and CACNA1C is part of biological pathways that also include other genes interacting with valproate. We identified shared genetic underpinnings of BIP and PMOS and highlighted genes that may potentially contribute to the biological mechanisms underlying their comorbidity and to a hypothesized role of valproate in these mechanisms.
Inflammation and depression have been consistently associated, with elevated C-reactive protein (CRP) levels observed in a significant subset of affected individuals. However, the genetic mechanisms underlying this association remain poorly understood. We integrated results from large-scale genome-wide association studies (GWAS) of depression and CRP levels in a cross-trait analysis specifically focusing on identifying horizontally pleiotropic loci. Identified variants were stratified as concordant versus discordant based on their direction of effects on the two traits and followed up using functional annotation, gene set enrichment, and colocalization analyses. We also explored causal relationships using Mendelian Randomization (MR) analysis with extensive sensitivity analyses, including adjustment for body mass index (BMI). We identified 9 novel loci. Functional analyses revealed that concordant loci were enriched in genes linked to immune and inflammatory processes, while discordant loci mostly mapped to metabolic pathways, including lipid regulation. MR provided strong evidence for body mass index driving a causal relationship between the genetic liability of depression on CRP levels. Our findings suggest that the association between depression and CRP levels is partly driven by shared genetic influences, pointing to different biological pathways depending on whether genetic effects are concordant or discordant. These results underscore the importance of considering effect direction when assessing the genetic overlap between depression and inflammatory processes. In addition, they highlight BMI as a key factor in the causal relationship between depression and systemic inflammation.
BACKGROUND:Post-traumatic stress disorder is a leading driver of distress and premature mortality. OBJECTIVE:To provide contemporary, nationally representative estimates of post-traumatic stress disorder in Australia using data from the Australian population-based 2020-2022 National Study of Mental Health and Wellbeing, including sex-specific prevalence, remission and comparisons with the 2007 National Study of Mental Health and Wellbeing. METHODS:Post-traumatic stress disorder and 14 other Diagnostic and Statistical Manual of Mental Disorders (4th ed.) disorders were assessed with the World Mental Health Composite International Diagnostic Interview 3.0. Kaplan-Meier survival analysis estimated projected lifetime risk and time to remission. Cox regression tested for projected lifetime remission. Logistic regression tested associations between post-traumatic stress disorder and demographic, mental health, and physical health variables, and prevalence changes between the 2007 and 2020-2022 surveys. RESULTS:Lifetime post-traumatic stress disorder prevalence (n = 15,893) was 7.1%. Females had higher odds than males (odds ratio = 2.3, confidence interval = [2.0, 2.7]) of post-traumatic stress disorder diagnosis. Projected lifetime risk was 9.6% and higher for females (12.3%) than males (6.4%; hazard ratio = 2.2, standard error = 0.10). Projected lifetime remission was 63.3%, with higher remission for males than females (68.7% vs 61.2%; hazard ratio = 0.81; standard error = 0.10). Three quarters entered remission after 10 years for males and 20 years for females. Individuals with post-traumatic stress disorder had higher odds of experiencing any anxiety disorder (adjusted odds ratio = 6.0, confidence interval = [5.0, 7.3]), any mood disorder (adjusted odds ratio = 4.8, confidence interval = [3.9, 5.9]), sedative use disorder (adjusted odds ratio = 7.9, confidence interval = [3.9, 15.9]), suicidality (adjusted odds ratio = 5.0, confidence interval = [4.2, 5.9]), asthma (adjusted odds ratio = 2.0, confidence interval = [1.7, 2.4]) and diabetes (adjusted odds ratio = 1.8, confidence interval = [1.2, 2.6]). No differences in post-traumatic stress disorder diagnosis were observed between the 2007 and 2020-2022 surveys. CONCLUSION:Post-traumatic stress disorder remains a prevalent and chronic condition in Australia, frequently co-occurring with other mental and physical health conditions and characterised by significant sex differences in risk and remission.
Altered brain structural connectivity has been implicated in the pathophysiology of Major Depressive Disorder (MDD), yet its stability over time and responsiveness to treatment remain unclear. This study utilized network science to analyze the white matter connectome based on longitudinal magnetic resonance imaging data in MDD. In MDD patients (n = 109) undergoing various in-patient treatments (including n = 50 receiving electroconvulsive therapy (ECT)), we compared pre-treatment and six-week follow-up data to that of healthy controls (HC; n = 43). There was a significant group (MDD vs. HC)-by-time (pre vs. post) interaction (pFWE < 0.05; network based statistic t-threshold = 1.5, component size: 404 edges; Cohen's d = 0.104, 95% CI [0.102, 0.106]), which was driven by MDD patients showing significantly increased connectivity strength post-treatment in a widespread brain network. The observed changes in connectivity were not found in HC and were not confined to any specific treatment, indicating a general effect unrelated to particular therapies like ECT. Furthermore, the level of connectivity increase was linked to a reduction of depression symptoms (pFWE < 0.05; network based statistic t-threshold = 1.5, component size: 304 edges, partial η2 = 0.041, 95% CI [0.038, 0.044]), suggesting a link between neuroplastic effects and effective treatment. Brain connectome alterations show a dynamic pattern during treatment in MDD, indicative of a potential new biomarker for treatment response in MDD. Results underline the importance of considering brain connectome changes and neuroplastic mechanisms as potential treatment targets in MDD.
Cognitive impairment is a core feature across mood disorders (MD) and schizophrenia spectrum disorders (SSD), but effective replicated pro-cognitive treatments are lacking. Identifying neuroimaging biomarkers that predict treatment efficacy can aid development of more effective and personalized treatment strategies. Virtual reality-based cognitive remediation therapy (VR-CRT) improves cognition and increases task-related neurocircuitry activity in the dorsal prefrontal cortex (dPFC) in MD or SSD. This study investigates if pre-treatment functional and structural neuroimaging features can predict cognitive benefits after VR-CRT. Thirty-six cognitively impaired individuals with clinically stable MD or SSD underwent neuropsychological assessment and magnetic resonance imaging (MRI) at baseline and after completion of either a four-week VR-CRT intervention (n = 20) or VR control treatment (n = 16). Linear regression analyses were conducted to assess if pre-treatment dPFC neurocircuitry activity and thickness were associated with greater VR-CRT-related benefits on global cognition. Lower baseline activity in the left superior frontal gyrus during memory encoding was associated with greater VR-CRT-related improvements in global cognition at treatment completion (β = -1.40, 95% CI [-2.45; -0.35], p = 0.01) but not at three-months follow-up (p = 0.16). Cortical thickness in the dPFC was not related to treatment effects on cognition (ps≥0.28). In conclusion, lower pre-treatment dPFC neurocircuitry activity is associated with greater cognitive benefits after VR-CRT across individuals with MD or SSD. If replicated, dPFC hypoactivation may represent a transdiagnostic neural biomarker predicting enhanced cognitive gains from VR-based cognitive training.
Childhood maltreatment is a transdiagnostic risk factor, whose distributed neural correlates are most timely and urgently assessed in young adults in the earliest stages of emerging mental disorders. Here, we applied a data-driven multivariate approach to identify distributed brain structural signatures associated with childhood maltreatment, with a particular focus on limbic regions, and to examine their relevance for later functional outcomes. In a transdiagnostic sample of 251 individuals (mean age 24.9 ± 4.3, 51.8% male) with early affective or anxiety syndromes, we used a multivariate sparse partial least squares algorithm to investigate multi-layered associations between grey-matter volume and the Childhood Trauma Questionnaire. We identified signatures linking age-dependent physical abuse and minimization/denial to widespread cortical thinning (ρ=0.424, p=.007; R2 = 18%), as well as female-specific emotional abuse to smaller left amygdala nuclei (ρ =0.566, p=.014; R2 = 32% shared variance). In females, emotional abuse predicted poorer functioning at 1- (β=-0.45, p<.001) and 2-year (β=-0.48, p<.001) follow-up, while smaller amygdala nuclei predicted better outcomes at 2 years (β=0.26, p=.04), although sensitive to including baseline functioning (β=0.17, p=.071). Support-vector machine (SVM) analyses further showed that females with higher trauma-related loadings and larger left amygdala nuclei could be identified using clinical features, although only in the extreme tertile split (BAC=69.2%, p=.038, AUC=0.62, 95%-CI=0.40-0.84). These findings suggest that trauma-reactive amygdala alterations may reflect heterogeneous sex-specific adaptation trajectories. This highlights the potential of age-, sex-, and trauma type-sensitive assessment at the earliest point of care, and proposes that early identification of such neurobiological signatures can inform more individualised approaches to treatment and recovery.
OBJECTIVE:The objective is to investigate associations between anxiety accessing mental health services and structural stigma as self-reported by people with borderline personality disorder. METHODS:A retrospective cohort design was used to investigate data from the 2017 National Consumer Survey undertaken in Australia between June and July 2017. Analyses were performed using multivariate binary logistic regression models. RESULTS:Data comprised 423 people with borderline personality disorder aged 18 years and above, where 384 (93.7%) were females. Associations were found between anxiety and stigma in relation to mental health service access for borderline personality disorder. Strikingly, most people with borderline personality disorder reported experiencing anxiety accessing mental health services irrespective of having anxiety disorder/s, indicative of stigma leading to anxiety rather than a by-product of anxiety disorder/s. People with borderline personality disorder and anxiety disorder/s were 9.8 times more likely to feel very anxious about not being taken seriously in mental health services, than respondents with no anxiety disorder/s. Contrastingly, people with borderline personality disorder and anxiety disorder/s were 79% less likely to feel anxious about cost of services, than respondents with no anxiety disorder/s. People with borderline personality disorder previously refused public hospital admission were 8.7 times more likely to feel very anxious about cost of services and 5.3 times more likely to feel very anxious about long wait lists for services than people with borderline personality disorder not refused hospital admission. CONCLUSION:Associations were observed for people with borderline personality disorder experiencing anxiety accessing mental health services, attributed to stigma in health systems. Findings provide nuanced understanding of structural mechanisms and system-level problems affecting services and advances knowledge on the impact of borderline personality disorder-related stigma in healthcare.
Adaptive functioning has been shown to be an important determinant of outcome in autistic individuals, determining the level of independence. This must be one of the main therapeutic objectives when working with autistic individuals and for this it is needed valid and easy tools to evaluate both, functioning of individuals and causes of failure to achieve it. A sample of 319 autistic adults from the population monitored within the Comprehensive Care Program for autistic individuals (PAITEA) of the Vall d'Hebron Hospital Psychiatry Service was included. An EFA was used to explore the factorial structure of the FAST-A. Posteriorly, an CFA was performed. Independent samples t-tests were performed comparing men (n = 203) and women (n = 116) and patients aged 18-25 years (n = 155) with those aged 25 years and older (n = 164) on the FAST-A scores. An EFA with a 'Maximum likelihood' extraction method was used in combination with an 'oblimin' rotation to explore the factorial structure of the FAST-A. We retained 4 factors due to the convergence of the analysis of the inflexion point of the scree plot and Kaiser's criterion (eigenvalues greater than 1,00), explaining almost 61% of the total variance. 5 items were eliminated in an iterative process used to improve the structure, reliability, and validity of the scale. This new test with 4 factors and 19 items will be called FAST-A from now on. An CFA was performed using the diagonally weighted least squares method. The analysis of the internal structure of the FAST-A demonstrated a satisfactory model fit to the EFA four-factor structure. The model yielded favourable fit indices, including RMSEA value of 0.060 (95% IC [0.051-0.069]), SRMR value of 0.071, a CFI value of 0.999 and a TLI value of 0.999. In the t-student test, men had significantly higher scores than women in the autonomy factor (M_men = 5.27; M_women = 4.15), t(317) = 3.16, p = .002 and in the social participation factor (M_men = 9.42; M_women = 8.15), t(317) = 2.72, p = .007. On the other hand, women had significantly higher scores than men in the Cognitive factor (M_women = 4.78; M_men = 4.05), t(317) = -2.09, p = .038. But the 18-25 year group had significantly higher scores than the >25 year group (M = 5.90 vs. 3.88), t(317) = 6.11, p < .001. in the autonomy factor, meaning that young adult patients present greater impairment than older adults in the autonomy factor. The FAST-A appears to be a valid instrument for the rapid assessment of adaptive functioning in the autistic adult population.
The global rise in mental health problems has outpaced the availability of trained professionals, prompting interest in digital solutions such as mobile mental health applications (apps). These apps offer potential benefits including cost-effectiveness, accessibility, and personalized care. Here we provide expert consensus recommendations for evaluating mental health apps, developed by a taskforce of the European College of Neuropsychopharmacology (ECNP) Digital Network using a Delphi process. The consensus group agreed that minimum evaluation criteria should include measures of efficacy, usability, acceptability, user satisfaction, and monitoring of potential adverse effects. Dropout rates were identified as a critical indicator of real-world app use. Accordingly, the task force emphasized the importance of examining barriers to user engagement, as well as patterns of app usage and attrition, as essential components of evaluation. App assessments must also address data security and explicitly report any breaches or other iatrogenic effects. Where feasible, evaluations should track time spent on the app and frequency of use. In addition, app development should incorporate equity and psychosocial considerations that may restrict access to digital technologies, highlighting the importance of co-design with end users. By establishing minimum standards and promoting evidence-based evaluation, this consensus seeks to support the responsible integration of mental health apps into care systems, ensuring they are safe, effective, and equitable tools within the mental health landscape.
