Little is known about how stigma is perceived within psychiatric genetics, a field increasingly central to public discussions about heredity, neurodiversity, and psychiatric risk. Understanding how stigma is perceived and experienced by psychiatric geneticists is important for guiding responsible communication and future stigma-reduction efforts. The International Society of Psychiatric Genetics (ISPG) Stigma Reduction Special Interest Group surveyed members' experiences and perceptions of mental health-related stigma (122 responses; response rate = 11.3%). Two-thirds believed that psychiatric genetics research reduces stigma, and there was a general consensus that researchers should consider stigma-related impacts when communicating research findings. Almost half of respondents perceived public stigma toward the field, and one-third reported avoiding certain research projects due to stigma-related concerns. Among respondents with a mental health diagnosis, 51% described selective disclosure at work shaped by fears of judgment or career impact. Respondents reported the persistence of stigmatizing attitudes within workplaces, despite reporting perceptions of meaningful cultural improvements in recent years. This first empirical assessment of stigma among psychiatric genetics professionals provides several key action points for the field: (1) developing stigma-sensitive research communication guidelines, (2) explicitly include individuals with lived experience, (3) reconsidering mentoring and hiring practices, and (4) evaluating organizational stigma-reducing efforts.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable neurodevelopmental disorder; however, its genetic architecture remains poorly explored in Indigenous populations. This study aimed to analyze and characterize genetic variation in 11 genes (ADGRL3, CDH8, DCC, DUSP6, FOXP1, FOXP2, MEF2C, PCDH7, SEMA6D, SORCS3, and ST3GAL3) previously implicated in ADHD, in an indigenous sample, comparing them with reference populations from the 1000 Genomes Project. Exome data from 64 individuals representing 12 Indigenous groups from the Brazilian Amazon were analyzed. Among the identified, 99 met the inclusion criteria. Four previously unreported variants in the developed reference datasets were identified in ADGRL3, DCC, and FOXP2. Significant differences in allele frequencies were observed for 56 variants compared with continental populations. Multidimensional scaling analysis indicated genetic differentiation of the Indigenous group in relation to other populations. This study highlights the distinct genetic profile of Amazonian Indigenous populations, likely shaped by demographic and evolutionary processes such as genetic drift and founder effects. The identification of exclusive variants and marked allele frequency differences reinforces the importance of including historically underrepresented populations in genomic studies related to ADHD and neurodevelopment, contributing to a broader understanding of human genetic diversity.
UBE3A is a dosage-sensitive HECT E3 ubiquitin ligase whose neuronal expression is shaped by genomic imprinting at the 15q11.2-q13 locus. Opposite directions of UBE3A dosage imbalance contribute to distinct neurodevelopmental phenotypes: loss of maternal UBE3A underlies Angelman syndrome, whereas maternally derived 15q11.2-q13 copy-number gains, including interstitial duplications and isodicentric inv. dup(15)/idic(15) rearrangements, contribute to Dup15q-associated syndromic autism phenotypes. This review synthesizes evidence across molecular architecture, isoform biology, neuronal imprinting, synaptic regulation, circuit excitability, and therapeutic development. The central argument is that UBE3A should not be interpreted as a general explanation for autism, but as a mechanistically informative model for a defined subset of neurodevelopmental disorders in which parent-of-origin effects and copy-number state are central. In Angelman syndrome, UBE3A loss disrupts proteostasis, synaptic plasticity, inhibitory circuit function, and neuronal excitability through distributed rather than single-pathway mechanisms. In the maternally derived Dup15q spectrum, increased UBE3A dosage is strongly implicated in neuronal and synaptic abnormalities, although interval-wide dosage effects also contribute. Therapeutically, the direction of dosage change creates opposite translational requirements: restoration or paternal reactivation in Angelman syndrome versus dosage normalization in Dup15q-associated overdosage states. A dosage-directionality framework may therefore clarify how UBE3A biology connects molecular mechanism, developmental timing, and precision therapeutic design.
A wide range of behavioral phenotypes has been described in PWS patients including autism spectrum disorder (ASD). The prevalence of behavioral disorders was studied in 292 participants over 3 years with genetically confirmed PWS (N = 164 females and N = 128 males) with deletion (N = 182) and mUPD (maternal uniparental disomy) (N = 99). The prevalence of ASD, and other behavioral disorders was tested for association with gender, genetic subtypes, and growth hormone (GH) treatment. The prevalence of ASD in PWS individuals was 19.5%, in concordance with previous studies at 25%. The frequency of ADHD was 10.7%. The mean age at diagnosis for ASD, ADHD, and disruptive behavior was 14.9 ± 10.5, 9.3 ± 5.9, and 19.6 ± 14 years, respectively. There was no statistically significant difference in the prevalence of ASD and ADHD between deletion and UPD subjects, and between GH-treated and non-treated subjects. Patients with mUPD had higher frequencies of anxiety than those with deletions (p = 0.001). GH-treated participants had a lower frequency of depression and a higher frequency of anxiety than non-treated participants (p = 0.04, p = 0.02, respectively). This is the largest study to evaluate an association between genetically confirmed PWS and ASD. We found no significant differences in the frequency of ASD and other behavioral disorders across the genetic groups and GH treatment.
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.
Maintaining effective blinding is a major methodological challenge in psychedelic research. This study provides a comprehensive evaluation of blinding integrity in 120 healthy volunteers who received either psilocybin, MDMA, or methylphenidate (active placebo) in a double-blind, randomized controlled trial. Using a multi-level assessment incorporating forced-choice substance guesses, certainty ratings, decision factors, and subjective substance effects, the analyses characterize blinding integrity and its relation to the substance experience. Results indicate that overall blinding was insufficient, with psilocybin showing the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest. As an active placebo, methylphenidate provided more effective blinding for MDMA than for psilocybin. Incorporating certainty levels of substance guesses revealed a more differentiated pattern, with lower functional unblinding rates. Decision factors and subjective substance experiences were associated with phenomenological substance effects. Prior substance experiences did not influence accuracy of forced-choice substance guesses. These findings provide empirical guidance for the design and reporting of blinding procedures in psychedelic trials and underscore the value of systematic, multi-level assessment of blinding integrity.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent late-onset neurodegenerative diseases worldwide. Both are influenced in part by genetic factors and are currently incurable. Tobacco and alcohol, the two most common substances used among the general adult population, are potential AD/PD risk factors and are also heritable. Although important progress has been made, most existing research on the genetics of AD and PD has been carried out in individuals of European genetic ancestry. Investigations in a broad range of groups are crucial to understand disease mechanisms. Given the current availability of ancestry-specific tobacco and alcohol use as well as AD and PD genome-wide association study summary statistics, we performed global and local genetic correlation analyses using East Asian datasets. Genes within the correlated genetic regions were subsequently used to identify potentially enriched biological pathways between substance use and neurodegenerative diseases. We identified a global genetic correlation between smoking cessation and PD, which we confirmed in complementary European genetic ancestry data. Gene set enrichment analyses highlighted potentially shared genetic mechanisms between breast cancer and AD, which warrants further exploration. This work aims to promote further analyses across genetic ancestry groups.
The present longitudinal study focuses on FMR1 premutation carrier women during midlife and early old age (n = 115). Bringing together the genetic risk factor of a family history of FXTAS and the environmental protective factor of higher education, the goal of the study was to determine how these factors potentially interact to predict self-reported FXTAS-type symptoms in women carrying the FMR1 premutation. We investigated age-related changes in symptoms, measured prospectively over a decade. Using an accelerated longitudinal design approach, we estimated trajectories of change extending from early midlife (starting at age 39) into older age (up to age 80) in a community-based cohort. Results indicated that women with the FMR1 premutation who have a family history of FXTAS are at greater risk for experiencing symptoms during late midlife and older age than those who do not have such a family history. Consistent with research on other neurodegenerative diseases, this family history risk may be moderated by completing a college education, suggesting that cognitive enrichment during a period of neuroplasticity might provide protection from the neurodegenerative symptoms that are experienced by some women with the premutation as they age.
There is a lack of consensus in the field about the indefinite use of psychostimulants for adult ADHD and the circumstances under which their deprescribing warrants consideration. To address this gap in knowledge, the American Society of Clinical Psychopharmacology (ASCP) convened a Task Force on the deprescribing of psychotropic medications, including stimulant medications for adult ADHD, which entailed a focused literature review and 2-round Delphi survey querying 45 international psychopharmacology experts on factors related to deprescribing. Consensus (≥75% agreement, defined by endorsements of “strongly agree” or “moderately agree”) was reached on 10 of 11 (91%) Delphi statements. Survey responses plus literature review suggest that stimulant deprescribing may be appropriate when 1) the diagnosis of ADHD is deemed incorrect upon reevaluation unless another stimulant-responsive condition is evident; 2) cognitive complaints have other more likely etiologies for which stimulant medications are inappropriate; 3) cognitive benefits are absent; 4) stimulant medications exacerbate medical or other psychiatric comorbidities; 5) adverse effects, if present, are non-remediable; 6) stimulant medications are misused; and 7) untreated comorbid non-cannabis substance use disorders are present. Panelists just fell short of consensus in perceiving regular use of cannabis as an insufficient reason to deprescribe stimulant medications in adult ADHD patients. In sum, clinical circumstances and rationales can be identified that support decisions to deprescribe stimulant medications for adult ADHD. Deliberate stimulant misuse or abuse, comorbid medical or psychiatric contraindications, and diagnostic inaccuracy pose strong reasons to consider deprescribing stimulants, potentially in favor of alternative pharmacotherapies and psychotherapies for adult ADHD.
Psychomotor slowing (PS) is common across mental disorders and has been linked to the clinical course of major depressive disorder (MDD). Prospective evidence as a predictor of treatment outcomes remains limited. We hypothesized that baseline PS severity would be associated with negative treatment outcomes in patients with MDD including the severity of acute suicidality. We analyzed data from a 6-month prospective, multicenter observational study of inpatients with MDD and acute suicidality. Depression (Montgomery-Asberg Depression Rating Scale), suicidality (Sheehan-Suicide Tracking Scale), Personal and Social Performance Scale (PSP), Work Productivity and Activity Impairment (WPAI, item #6) and quality of life (European Quality of Life Group, 5-Dimension) were assessed at baseline (T1), inpatient discharge (T2), and 3-months (T3) and 6-months (T4). Linear mixed models were fitted to examine associations between baseline PS (item #15 of the Quick Inventory of Depressive Symptomatology-Self-Report) and outcomes across timepoints, using Bonferroni correction. Among 235 participants (age = 36.4 ± 13.6 years; women = 57.9%), across all timepoints, baseline PS was significantly associated with greater depression symptom severity (p < 0.001), lower quality of life (p = 0.042), reduced leisure time productivity (p = 0.002), and higher suicidality (p = 0.001). The association of baseline PS with social functioning was negative (p = 0.043). Only for PSP, the association varied over time, i.e., T4 > T1 and T2 > T1. This first longitudinal study of PS in acutely suicidal MDD patients showed that baseline PS predicted a broad range of clinical and functional outcomes over six months. PS may serve as a prognostic marker and help identify distinct clinical trajectories in MDD.
We conducted a systematic search of observational studies published up to March 2026 in PubMed, Embase, and Web of Science. Meta-analyses were performed using robust variance estimation to pool adjusted estimates from included studies. Subgroup analyses were conducted to explore variations in risk by type of antidepressant (AD), study design, and geographic region. Dose-response analysis assessed the relationship between dose levels and colorectal cancer (CRC) risk. Fifteen studies involving millions of participants were included. The meta-analysis showed a significantly lower CRC risk associated with AD use with a pooled odds ratio (OR) of 0.88 (95% CI: 0.87, 0.95) and a pooled hazard ratio (HR) of 0.85 (95% CI: 0.74, 0.97). Specifically, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressant (TCAs) were associated with a lower CRC risk (both pooled OR estimated at 0.90; 95%CI: 0.84, 0.96), while results for other AD classes were non-significant and require cautious interpretation due to limited sample sizes. Furthermore, dose level stratification and exposure duration-response analyses identified no statistically significant relationship between AD exposure pattern and CRC risk. Findings suggest that AD use, particularly SSRIs and TCAs, may be associated with decreased CRC risk, highlighting the potential for ADs to serve a dual role in treating mental health conditions and a preventive effect against CRC.
Autistic traits and negative symptoms (NS) frequently co-occur in schizophrenia spectrum disorders (SSD), even in early stages such as first-episode psychosis (FEP), complicating both diagnosis and prognosis, as these dimensions strongly influence functional outcomes and may share etiological mechanisms. This study aims to explore the genetic architecture underlying autistic and NS dimensions, to support early stratification and personalised interventions. 203 non-affective FEP were analysed. Symptom severity was assessed using Positive and Negative Symptom Syndrome (PANSS) derived measures: PANSS-Autism Severity Score (PAUSS) for autistic traits and Marder-factors for NS (NSFS), including subdomains of social reciprocity, communication, restricted-repetitive behaviours (PAUSSsoc, PAUSScom, PAUSSrrb), and expressive deficits (EXP) and motivational/pleasure deficits (MAP). Polygenic scores (PGS) for autism spectrum disorder (PGSASD), schizophrenia (PGSSZ), educational attainment (PGSEA), and cognitive performance (PGSCP), including pathway-specific PGS (pPGS) targeting neurodevelopmental and immune-related processes, were used to examine associations with baseline and one-year autistic and NS dimensions. At baseline, PGSASD showed nominal associations (p < 0.05) with PAUSS-total and NSFS-total. At the subdomain level, PGSCP was significantly associated with PAUSScom (p = 0.019), while PGSASD showed significant associations with PAUSSsoc (p = 0.034), PAUSSrrb (p = 0.009, p.adj=0.038) and EXP (p = 0.044). At one-year follow-up, PGSASD remained associated with PAUSSrrb (p = 0.009; p.adj=0.048), but not EXP, and PGSEA with PAUSScom (p = 0.023). pPGS analyses showed nominal associations (p < 0.05) between neurodevelopmental and immune pathways and PAUSSrrb, PAUSScom, and EXP. Autistic traits and NS in FEP exhibit marked multidimensionality, with distinct subdomains showing differential genetic underpinnings. Neurodevelopmental and immune-mediated pathways appear particularly relevant to restricted-repetitive traits and expressive deficits, supporting subdomain-level phenotyping as a valuable tool for early patient stratification and for refining the clinical characterisation of SSD.
In antipsychotic trials for acute schizophrenia, dropout reasons are typically classified into inefficacy, adverse events (AEs), and other reasons. AEs can include not only somatic, but also psychiatric AEs, which may reflect inefficacy. However, studies seldom report them separately. We examined detailed reasons for dropouts attributed to AEs and assessed the impact of reclassification. We searched Vivli for randomized controlled trials with individual-participant-data on adults with acute schizophrenia (up to April 9, 2025). When dropout was attributed to an AE, we cross-checked reports and recategorized the corresponding dropouts into somatic, psychiatric, and other AEs using MedDRA(v28.1). We performed random-effects meta-analyses to compare antipsychotics and placebo for i) the study-reported dropouts due to AEs, and for ii) dropouts reclassified as due to somatic AEs. Seventeen trials (6823 participants; 70% male; mean age 40.9 years; mean Positive and Negative Syndrome Score 93.1) were included. Studies reported that 1369 dropouts due to inefficacy, 445 dropouts due to AEs, and 1173 dropouts due to other reasons. We reclassified the study-reported dropouts due to AEs as due to psychiatric (n = 223), somatic (n = 207), and other AEs (n = 15). We did not find evidence of difference between antipsychotics and placebo with respect to study-defined dropouts due to AEs (OR, 0.93 [95% CI; 0.72, 1.12]). However, we found evidence that dropouts reclassified as somatic AEs were more frequent with antipsychotics (OR, 1.54 [95% CI; 1.04, 2.27]). We conclude that combining somatic with psychiatric AEs may mask the true impact of antipsychotics on tolerability. Future trials should report these categories separately.
Mental disorders (MDs) are established risk factors for self-harm, yet disorder-, age-, and sex-specific risk estimates in population-representative samples are rarely studied. We conducted a territory-wide, population-based cohort study using Hong-Kong medical record database covering public hospitals, specialist and general outpatient clinics, identifying 322,922 people with a first-recorded diagnosis of any MDs and 888,031 primary-care controls without MDs (proxy general population) between 1-January-2006 and 31-December-2021. Outcomes were incident self-harm events. Cox proportional-hazards models estimated hazard ratios (HRs) adjusting for sex, age-group, physical-comorbidity, and calendar-year; incidence rates (IRs) and HRs by each diagnostic-group, age-group and sex were generated. Over 3031,600.9 person-years, the MD cohort had an IR of 60.2 per 1000 person-years (95%CI 59.5-61.0), with HR 10.59(10.31-10.89). Elevated self-harm risk was observed across all fourteen diagnostic-groups, highest for substance use disorders (SUD, 22.86[21.47-24.34]), followed by alcohol use disorders (AUD,14.59[13.49-15.79]), personality disorders (PD,7.81[5.60-10.89]), major depressive disorder (7.48[7.14-7.85]), eating disorders (6.56[4.07-10.58]), bipolar disorder (6.43[5.71-7.24]), attention deficit/hyperactivity disorder (ADHD,6.09[5.51-6.73]), schizophrenia (5.00[4.63-5.40]), autism-spectrum disorders (ASD, 4.88[4.35-5.48]), post-traumatic stress disorders (PTSD, 3.64[2.83-4.68]), dysthymia (3.43[3.12-3.78]), obsessive compulsive disorder (3.74[3.27-4.27]), anxiety disorders (2.26[2.09-2.44]), and organic mental disorders (2.01[1.84-2.19]). Further analyses identified substantially elevated risk of SUD (with their high standalone and compounding risk). Subgroup analyses showed the highest self-harm risks in youths (≤24 years), and female predominance across most MDs, notably in PTSD, PD, AUD, ASD and ADHD. Taken together, this territory-wide electronic-health-record study maps the transdiagnostic nature of self-harm across first-diagnosed MDs, and further research to confirm the special vigilance for the at-risk subgroups/diagnostic groups.
Treatment-resistant depression (TRD) represents a significant clinical challenge, yet data on its epidemiology and real-world therapy patterns remain limited. This study aimed to estimate TRD prevalence and analyze treatment patterns using claims data. This retrospective analysis used the German Analysis Database for Evaluation and Health Services Research (DADB), encompassing 2.47 million statutory health insurance beneficiaries in 2019. TRD was operationally defined as a claims-based proxy for patients with moderate-to-severe depression receiving at least three consecutive antidepressant prescriptions involving two or more changes of therapeutic strategy (switch, combination, augmentation, or ECT) using claims data. Among 360,344 individuals diagnosed with depressive episodes, 98,577 (27.36%) had moderate-to-severe depression and received pharmacological treatment. Of these, 12,054 patients met our operational TRD definition, representing 6.46% of all moderate/severe depression cases and 17.49% of those receiving continuous pharmacological treatment. Treatment patterns revealed suboptimal guideline adherence: only 27.20% of patients received combination or augmentation therapy after failure of first-line therapies, and 38.35% in third-line treatment. SSRIs dominated across all therapy lines, with frequent class-level cycling back to previously failed medication groups. ECT remained critically underused. This study provides the first large-scale, real-world evidence on epidemiology and treatment patterns of TRD in Germany. TRD affects a substantial proportion of patients with moderate-to-severe depression. As first large-scale, real-world evidence on TRD in Germany, these findings highlight urgent needs for improved clinical decision-making and better access to specialized care to address the substantial burden and suboptimal treatment trajectories of TRD in Germany.
Gene-environment correlations (rGE) may drive the clinical heterogeneity of major depressive disorder (MDD) through their effects on brain structure. However, previous literature focused on isolated components of these interplays. Here, we jointly investigate how rGE shape neurobiological profiles in MDD, and whether rGE-driven brain signatures can disentangle depression subtypes. In 5951 MDD patients with genetic, trauma-related and neuroimaging data from the UK Biobank, cross-validated sparse canonical correlation analysis was employed to assess multivariate associations between polygenic scores (PGSs) for mental health conditions and adverse childhood experiences (ACEs). Linear regressions tested the impact of the shared PGSs-ACEs dimensions on gray matter (GM) measures. Consensus clustering was applied to the neuroimaging features significantly associated with PGSs or ACEs to identify latent biotypes of MDD, and the emerged clusters were compared for depressive symptomatology and organic comorbidities. We found a significant canonical correlation between PGSs and ACEs (r = 0.11, p < 0.001). The most contributing PGSs were schizophrenia, attention deficit-hyperactivity disorder, autism (positive weights) and education (negative weight). Canonical variates of PGSs and ACEs associated with reduced GM in frontal, temporal, cingulate, parietal and subcortical regions (b = [-0.041; -0.021], pFDR<0.05). Such rGE-sensitive brain regions underpinned two clusters of patients, with one showing higher genetic/environmental risk, reduced GM integrity, and a worse clinical profile, including atypical symptoms, anhedonia, lethargy, sleep alterations and diabetes comorbidity. These findings indicate that rGE-driven neurobiological signatures contribute to the clinical heterogeneity of depression, supporting biologically informed subtyping in MDD.
Bipolar disorder (BD) typically manifests during adolescence and young adulthood, with unipolar depression (UD) being common initially. Concerns persist that antidepressants may increase the conversion risk from UD to BD. This study employed a target-trial-emulation framework, using an electronic-medical-record database of public-healthcare services in Hong-Kong, to examine BD-conversion risk, defined by two BD-diagnoses or one BD-diagnosis and a mood-stabilizer prescription, over 12-week and 52-week follow-up among individuals aged 6-30 years diagnosed with incident UD between 2002-2022. Participants initiating antidepressants within 90 days of UD were compared to those without antidepressant treatment, applying inverse-probability-weighting to balance baseline characteristics. We further identified factors associated with BD-conversion within both follow-up intervals using weighted-Cox-regression analyses with backward stepwise-selection. Among 10,801 individuals (mean-age=22.1±5.3 years; male=24.9%), 84.7% initiated antidepressants. The outcome occurred in 87 individuals by 12-weeks and in 257 by 52-weeks. Treatment group showed no significantly increased BD-conversion risk at 12-weeks compared to controls (hazard-ratio [HR]=2.94; 95% confidence interval (CI)=0.89-9.69), while a modestly increased risk at 52-weeks (HR=2.14; 95%CI=1.31-3.51). Presence of psychotic features and past psychiatric hospitalization were associated with BD-conversion. Findings were consistent in stratified analyses by age (6-17, 18-30 years) and secondary analyses repeated in a separate cohort of individuals aged >30 years. Our findings indicate no short-term risk of antidepressant-associated BD-conversion in people with UD regardless of age. Although a modest increase in risk was observed at extended 52-week follow-up, this association likely reflects the influence of risk factors rather than antidepressant exposure causally contributing to BD-conversion.
This retrospective cohort study aimed to compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus metformin for preventing type 2 diabetes mellitus (T2DM), reducing mortality, and improving body mass index (BMI) in antipsychotic-treated patients with overweight /obesity. We used data from the TriNetX Global Collaborative Network. Adults (aged ≥18 years) with overweight or obesity, antipsychotic exposure, and no prior T2DM diagnosis were identified. After propensity score matching, patients initiating GLP-1RA therapy were compared with those initiating metformin. The primary outcome was incident T2DM occurring between 1 and 5 years after treatment initiation. Secondary outcomes included all-cause mortality and BMI change. Among 9939 eligible patients, 3115 matched pairs were included. The incidence of T2DM was significantly lower in the GLP-1RA group compared with the metformin group (1.96% vs 7.26%; hazard ratio [HR]=0.34; 95% CI, 0.26-0.46; p < 0.001). All-cause mortality was also reduced in the GLP-1RA group (0.32% vs 1.96%; HR, 0.25; 95% CI, 0.13-0.49; p < 0.001). Regarding BMI change, patients receiving GLP-1RA experienced greater weight reduction than those receiving metformin. The mean (standard deviation) change in BMI was -2.66 (8.51) kg/m² in the GLP-1 group versus -1.36 (8.63) kg/m² in the metformin group (p < 0.001). In conclusion, in this large real-world cohort of antipsychotic-treated patients with overweight or obesity, GLP-1RA therapy was associated with significantly lower risks of T2DM and mortality, and greater BMI reduction compared with metformin. These findings suggest that GLP-1RAs may offer a more favorable profile against antipsychotic-induced glucose dysregulation.
Cross-disorder research and replication of neuroimaging findings remains scarce. Social dysfunction is an early manifestation across diverse neuropsychiatric disorders that may relate to altered default mode network (DMN) integrity. This study aimed to replicate previous findings linking social dysfunction with diminished resting-state DMN functional connectivity and altered task-based DMN functional activation in response to emotional faces across schizophrenia (SZ), Alzheimer’s disease (AD), and healthy controls (HC), and to extend these findings to major depressive disorder (MDD). Resting-state fMRI and task-based fMRI data on implicit facial emotional processing were acquired in an overlapping cohort (resting-state fMRI: N=167; SZ=32, MDD=44, AD=29, HC=62. Task-based fMRI: N=152; SZ=30, MDD=42, AD=26, HC=54). Additionally, mega-analyses (N=317 for resting-state fMRI; N=291 for task-based fMRI) of the current and a prior independent sample were conducted. Social dysfunction was indexed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness (LON) scale. The association between higher mean SFS+LON social dysfunction scores and diminished DMN connectivity within the dorsomedial prefrontal cortex across SZ/AD/HC participants was replicated, and extended to MDD patients. Similar observations within the dorsomedial and rostromedial prefrontal cortex were found in the mega-analysis. Associations between social dysfunction and DMN activation in response to sad and happy faces were not replicated or found in the mega-analysis. To conclude, diminished dorsomedial prefrontal cortex DMN connectivity emerged as a transdiagnostic neurobiological marker for social dysfunction, suggesting a potential treatment target for precision medicine approaches. DMN functional responses to emotional faces may not be a sensitive biomarker for social dysfunction.
