BACKGROUND:The perinatal period represents risk for the development of postpartum obsessive-compulsive symptoms (POCS) but the variables of risk that lead to symptom development are not well understood. The goal of the current study was to evaluate the longitudinal, cross-lagged associations between obsessive beliefs and subsequent postpartum symptom onset, in the context of genetic and personality vulnerability, from early pregnancy to approximately 20 weeks postpartum. The study also tested cognitive specificity, namely whether obsessive beliefs are uniquely predictive of POCS compared to general mood and anxiety symptoms, and conversely, whether cognitive vulnerabilities thematically congruent to mood and anxiety symptoms are predictive of POCS. METHODS:In a prospective study with a community perinatal sample (N = 599), women completed a genetic assay and a test battery of measures assessing personality, stress, symptom functioning and cognitive vulnerability in early pregnancy (Time 1), and symptom and cognitive measures again in the early postpartum period (Time 2), and in the later postpartum period (Time 3). RESULTS:The model fit was acceptable, and the results supported the hypothesized cross-lagged associations between elevated obsessive beliefs about inflated responsibility/threat and subsequent POCS development at each phase of the study. Obsessive beliefs were not associated with the development of mood and anxiety symptoms in the postpartum period, nor were thematically congruent cognitive vulnerabilities for depression and anxiety symptoms predictive of POCS onset. CONCLUSIONS:Obsessive beliefs focusing on inflated responsibility/threat demonstrate specificity and temporal salience in predicting POCS onset longitudinally.

Background Venlafaxine is commonly prescribed for older adults with depression, yet the relationship between venlafaxine-related exposure and treatment outcomes remains unclear. We aimed to assess the association of exposure to venlafaxine, its active metabolite O-desmethylvenlafaxine (ODV) and its active moiety (i.e., venlafaxine + ODV) with treatment response and adverse effects in late-life depression. Method We analyzed data from 325 participants from the Incomplete Response in Late-Life Depression: Getting to Remission (IRL-GRey) study. Participants were >= 60 years old, treated openly with venlafaxine (up to 300 mg/day) for 12 weeks. Treatment response was assessed with the Montgomery-Asberg Depression Rating Scale and adverse effects were evaluated with the Udvalg for Kliniske Unders & oslash;gelser (UKU) rating scale. Venlafaxine-related exposures were derived from a published population pharmacokinetic model based on the IRL-GRey study, and their associations with treatment outcomes were assessed using regression analyses. Result At week 4, the primary endpoint, higher venlafaxine-related exposures were not associated with greater symptom improvement. While at the end of treatment (week 12), we did not observe additional antidepressant benefit with increased venlafaxine-related exposures, higher ODV and active moiety exposures were associated with the occurrence of at least one adverse effect (odds ratio [OR] = 1.6 [1.1, 2.3], p = 0.02 and 1.8 [1.2, 2.6], p = 0.003, respectively). Also, higher venlafaxine and active moiety exposures were associated with nausea/vomiting (OR = 1.1 [1.0, 1.2], p = 0.02 and 2.3 [1.3, 4.0], p = 0.006); while higher active moiety exposure was associated with orthostatic dizziness (OR = 1.9 [1.1, 3.2], p = 0.02). Conclusion Our findings suggest a potential threshold effect, where venlafaxine-related exposure past a certain level did not enhance antidepressant response but increased adverse-effect burden. These results support incorporating exposure measures from therapeutic drug monitoring in antidepressant studies to address the heterogeneity of safety and tolerability outcomes.

Hand grip strength (HGS) is a predictor of cognitive decline in aging. To understand the direct and indirect mechanisms underlying this association, we performed integrative analyses of genetic, cognitive, and autopsy data. A polygenic risk score for HGS (PRSHGS) was calculated in two independent studies of aging (total n = 25,227). Cross-sectional and longitudinal modeling, including mediation with physical activity, assessed the effects of PRSHGS on cognitive performance and postmortem neuropathology. In both cohorts, higher PRSHGS predicted better global cognitive performance (p = 7.77 × 10-4 and p = 0.025) and improved the predictive performance of an Alzheimer's disease PRS (likelihood ratio test p = 2.5 × 10-5 and p = 0.007). PRSHGS was not associated with levels of any postmortem neuropathology. PRSHGS effects on cognition were only partially and inconsistently mediated by physical activity. Genetic predisposition for greater HGS predicts better cognitive performance in late life, independent from Alzheimer's disease-related neuropathology.

BACKGROUND:Late-life depression (LLD) and chronic low back pain frequently co-occur and exacerbate one another. Outcomes with antidepressant treatment in this population are often suboptimal. Pharmacogenetic factors may help explain variability in antidepressant response. Building on prior findings suggesting that SLC6A2 variation predicts venlafaxine response in LLD, we examined whether such genetic associations extend to older adults with chronic low back pain in the ADAPT study (Addressing Depression and Pain Together). METHODS:Older adults with LLD and chronic low back pain received venlafaxine treatment over 20 weeks. The primary analysis focused on the SLC6A2 rs2242446 variant, whereas secondary analyses evaluated 37 variants across 14 candidate genes implicated in depression or pain. Outcomes included percentage improvement in PHQ-9 scores, remission, and time to remission. RESULTS:Genotype data were available for 101 participants. Primary analyses showed no association between SLC6A2 rs2242446 and any outcome measure. In secondary analyses, the serotonin 1A receptor gene (HTR1A) variant rs6295 emerged as the most consistent nominal genetic signal. CONCLUSION:Previously reported pharmacogenetic signal involving SLC6A2 did not extend to a more clinically complex population, whereas exploratory serotonergic variation showed a nominal association. Findings inform pharmacogenetic research in late-life depression with comorbid pain.Clinical trial registration identifier is NCT01124188.

BackgroundVenlafaxine is commonly prescribed for older adults with depression, yet the relationship between venlafaxine-related exposure and treatment outcomes remains unclear. We aimed to assess the association of exposure to venlafaxine, its active metabolite O-desmethylvenlafaxine (ODV) and its active moiety (i.e., venlafaxine + ODV) with treatment response and adverse effects in late-life depression.MethodWe analyzed data from 325 participants from the Incomplete Response in Late-Life Depression: Getting to Remission (IRL-GRey) study. Participants were ≥ 60 years old, treated openly with venlafaxine (up to 300 mg/day) for 12 weeks. Treatment response was assessed with the Montgomery-Asberg Depression Rating Scale and adverse effects were evaluated with the Udvalg for Kliniske Undersøgelser (UKU) rating scale. Venlafaxine-related exposures were derived from a published population pharmacokinetic model based on the IRL-GRey study, and their associations with treatment outcomes were assessed using regression analyses.ResultAt week 4, the primary endpoint, higher venlafaxine-related exposures were not associated with greater symptom improvement. While at the end of treatment (week 12), we did not observe additional antidepressant benefit with increased venlafaxine-related exposures, higher ODV and active moiety exposures were associated with the occurrence of at least one adverse effect (odds ratio [OR] = 1.6 [1.1, 2.3], p = 0.02 and 1.8 [1.2, 2.6], p = 0.003, respectively). Also, higher venlafaxine and active moiety exposures were associated with nausea/vomiting (OR = 1.1 [1.0, 1.2], p = 0.02 and 2.3 [1.3, 4.0], p = 0.006); while higher active moiety exposure was associated with orthostatic dizziness (OR = 1.9 [1.1, 3.2], p = 0.02).ConclusionOur findings suggest a potential threshold effect, where venlafaxine-related exposure past a certain level did not enhance antidepressant response but increased adverse-effect burden. These results support incorporating exposure measures from therapeutic drug monitoring in antidepressant studies to address the heterogeneity of safety and tolerability outcomes.

Introduction Drug metabolism is primarily carried out by the cytochrome P450 (CYP) family of enzymes in the liver. Based on an individual's diplotype, they can be classified into poor (PM), intermediate (IM), normal (NM), rapid (RM) or ultrarapid (UM) metabolizers. Here, we show the distribution of allele frequency and metabolizer status across ancestries for CYP2D6, CYP2C19, CYP2C9, CYP2B6, CYP3A4 and CYP1A2 in a cohort from Ontario, Canada.Methods Patients currently taking or starting a psychotropic drug (N = 8,280) were enrolled. Patients self-reported their ancestry, and DNA was analysed for the CYP2D6, CYP2C19, CYP2C9, CYP2B6, CYP3A4 and CYP1A2 genes using a commercial pharmacogenetic test and metabolizer status was assigned using ClinPGx as a reference.Results The cohort was primarily of European ancestry (70%), followed by individuals with mixed ancestry (9.3%). The combined frequency of PMs and UMs, representing the extremes of enzyme activity, was highest for CYP2C19 and CYP2D6, with this frequency being approximately 8% for each enzyme. The frequency varied considerably by ancestry, with up to 24% of individuals of Caribbean descent being CYP2C19 PMs or UMs, for example, compared to only 7% among those of Latin, Central and South American ancestry. Of the entire sample, only 5.1% were NMs across all enzymes, meaning 94.9% of individuals had a non-NM status and would benefit from pharmacogenetic testing.Conclusion Overall, this study provides a useful reference for variations in the CYP family of genes in the population of Ontario, Canada.

Background Antipsychotic-induced weight gain (AIWG) is a major clinical concern, affecting approximately 30% of patients. Clinical predictors explain only part of AIWG risk. Genetic and molecular variations are hypothesized to contribute to susceptibility. The purpose of this review is to summarize recent results to identify replicated and novel findings. Study Design Applying PRISMA guidelines, we searched MEDLINE, Embase, and PsycINFO (May 2018–May 2026) for studies on genetic and molecular associations with AIWG, extending our prior review. Reviews, editorials, and conference abstracts were excluded. We extracted study characteristics (design, diagnosis, antipsychotic exposure, sample size, ancestry, genetic variants, and AIWG outcomes) (e.g., ≥7% weight gain, BMI change). Results Fifty-three studies met inclusion criteria. In candidate gene studies, the most consistently replicated genes associated with AIWG were observed for DRD2, HTR2C, and MC4R. Multiple novel associations were identified by genome-wide association studies (GWAS) (e.g., MAP2K1, ZDBF2, PEPD), polygenic risk scores (PRS) (e.g., body mass index PRS), gene expression (e.g., CYP3A4, EP300), and epigenetic analyses (e.g., cg12034943 at CRTC1). Conclusions Polymorphisms in candidate genes related to neurotransmission and appetite regulation continue to be investigated for associations with AIWG, while novel findings have emerged from GWAS, gene expression, and epigenetic studies. Evidence remains inconsistent due to limited replication, methodological variability, sparse ancestry data, and geographical underrepresentation. No single genetic variant is ready for clinical use, and multi-omic and multi-ancestry models are needed to improve prediction and clinical utility.

BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment (β(SE) = 0.17(0.08), p = 0.04, padj = 0.11, f2 = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up (χ2LRT(3) = 24.9, p < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.

The perinatal period represents uniquely elevated risk for the development of obsessive-compulsive symptoms compared to any other period in the lifespan but the variables of risk and the specific pathways that lead to symptom development are not well understood. The goal of the current study was to evaluate an integrated, theoretically-derived model of risk focusing on a pathway from genes through personality vulnerability to dysfunctional beliefs to symptom development in the postpartum period. It was hypothesized that women with elevated stress reactivity, via genetic and personality vulnerability, and elevated dysfunctional obsessive beliefs would be at risk of developing postpartum obsessive-compulsive (OC) symptoms. This pathway model for postpartum OC symptom development was evaluated in relation to hypothesized pathways for the development of mood and anxiety symptoms based on shared (genes, personality, stress) and unique risk (specific dysfunctional beliefs). In a prospective study with a community perinatal sample (N = 196), women completed a test battery in late pregnancy (Time 1) and again at six weeks postpartum (Time 2). All indicators of the measurement and structural models with genes, personality, and obsessive beliefs demonstrated good fit for the pathway of risk to the development of OC symptoms, and this pathway differed from the paths to the development of mood and anxiety symptoms. In addition to the established role of obsessive beliefs, genetic and personality vulnerability related to stress reactivity need to be considered in contributing to risk and can be modelled effectively on the same pathway to predicting postpartum OC symptom onset.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat-response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

Abstract Neuroticism, a personality trait characterized by the predisposition to experience intense and frequent negative emotions, has been associated with an increased risk of Alzheimer’s disease (AD). However, the mechanisms underlying this association remain unclear. Our study investigated two potential pathways: (1) whether the relationship between neuroticism and AD is causal, and (2) whether it is mediated by health and behavioral factors associated with both neuroticism and AD risk. To assess causality, a two-sample Mendelian randomization (MR) was employed using publicly available genome-wide association studies (GWAS) for neuroticism (Nagel et al., 2018) and AD (Bellenguez et al., 2022). Mediation analysis was conducted in a subset of UK Biobank participants aged 60 and older, including 121,825 controls (mean age = 63.9 ± 2.81; 61,993 females or 50.9%) and 1,277 individuals with AD (mean age = 65.6 ± 2.71; 628 females or 49.2%). All participants had complete data on neuroticism and the potential mediators. MR analysis suggested that the neuroticism-AD relationship is unlikely to be causal. However, depression (β=0.048, p=3×10⁻⁴), hypertension (β=0.005, p=2×10⁻⁴), and alcohol consumption (β=0.001, p=1×10⁻ 5 ) were identified as significant mediators of the relationship between higher neuroticism and increased AD risk. Overall, the association between neuroticism and AD may be largely explained by modifiable health and behavioral factors rather than a direct causal effect. A better understanding of these mediating pathways may inform targeted prevention and therapeutic strategies to reduce AD risk.

Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries. This research identified six areas in the genome that are associated with binge eating, and eight areas that are associated with anorexia nervosa, in people of European ancestry. Binge eating has both shared and distinct genetic features compared with anorexia nervosa.

Tardive dyskinesia (TD) is a potentially irreversible movement disorder that emerges in a proportion of schizophrenia patients who are prescribed antipsychotic medications. These movements affect mostly the orofacial regions, but may also affect the limbs and other body areas, resulting in significant functional impairment and decreased quality of life. While uncertainty about the pathophysiology of TD persists, studies on families support a genetic component. Over the years, a number of genes have emerged as potential candidates for TD, but evidence supporting their involvements remain inconclusive. Here, we performed a literature search for articles related to genetics of TD from 2015 to 2025 on PubMed and Scopus and reviewed the progress in TD genetic research over the past decade.

Pharmacogenomic (PGx) testing is an evidence-based strategy to optimize the selection and dosing of certain psychotropic medications. An individual's genetics play a role in medication response through pharmacokinetic and pharmacodynamic mechanisms. The current evidence base of psychiatric PGx mainly focuses on the metabolism of psychotropics through the cytochrome P450 (CYP) system. PGx testing and decision support tools are not yet standardized, resulting in variations in interpretation and prescribing recommendations. Clinicians are encouraged to use PGx results as part of the clinical picture, in addition to the patient's overall clinical profile, in determining a personalized treatment plan for their patients.

BACKGROUND:Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with a strong genetic component. Previous studies have suggested a role for the dopamine receptor genes in OCD with the dopamine D3 receptor (DRD3) gene being relatively overlooked. There is neurobiological evidence that D3 may be involved in the striatal-cortical circuits that affect compulsive behaviour and anxiety. Thus, we investigated genetic variants of DRD3 in association with OCD and serotonin reuptake inhibitor (SRI) response. METHODS:We examined nine polymorphisms across DRD3 in 318 individuals with OCD (comprised of 129 small nuclear families, and 196 independent singleton cases) compared to 196 healthy controls matched for age, gender, and ethnicity using the family-based association test (FBAT) and case-control analysis respectively. Quantitative analyses were performed with age at onset (AAO) and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) severity scores. RESULTS:Nominally significant biased transmission of alleles in polymorphic sites rs2399504, rs7611535, rs1394016, Ser9Gly, rs167770, and rs2087017 was observed with FBAT. The rs2399504, rs7611535, rs1394016, Ser9Gly, and rs167770 polymorphisms were associated with AAO but not with Y-BOCS scores using FBAT. Five polymorphisms (rs2399504, rs7611535, rs1394016, Ser9Gly, and rs167770) showed a trend in case-control analyses for allele/genotype distributions. Haplotype analyses of the polymorphisms using Haploview revealed several combinations of markers associated with OCD. Nominally positive association between rs167770 and rs11721264 and sertraline response remained significant after correction for multiple testing. CONCLUSION:This is the first report to our knowledge of involvement of DRD3 in OCD, which requires further research.

Abstract Background Our understanding of the interplay between genetic and environmental factors (Gene x Environment Interaction, or GxE) determining mental health disorders has improved through the proliferation of genome-wide interaction association studies (GWIAS) and targeted GxE analyses. Moreover, multivariate modelling approaches, such as structural equation modelling (SEM) and polygenic risk scores (PRS), offer opportunities for the integration of clinical and genome-wide genotype data in building improved biopsychosocial models of mental illness aetiology and their response to treatment. Aims & Objectives We propose to construct a SEM framework to uncover the inter-correlation and directed structure of mental health phenotypes by leveraging the joint predictive capacity of PRS for comorbid traits that share underlying biological and environmental risk pathways. The proposed model will be capable of linking latent constructs to their observed measurements; these will include disease severity, comorbidities and clinical histories, and behaviours and lifestyle factors such as physical and social activity. Method Our gene-by-environment SEM (GESEM) will be initially developed and tested using four well- characterized clinical cohorts for older adults diagnosed with late-life depression and treated with antidepressants (CAN-BIND, IRL-GREY, STOP-PD II and IMPACT; n =1,238). The primary outcome will be antidepressant remission. Multiple PRS will be calculated to capture underlying genetic risk across vulnerable pathways which contribute to comorbidities. This selection will be made based on new, largely unpublished work from our group on the impact of PRS and targeted GxE studies on psychiatric outcomes across the lifespan. Each PRS will be calculated using both clumping and thresholding (PRSice-2) and continuous shrinkage (PRS-CS-auto) methods across selected cohorts using well-powered publicly available GWAS summary statistics. The multilevel GESEM model will include interactions between symptoms and comorbidities (i.e., observed measurements), which are caused by unobserved factors (i.e.,latent constructs), and are subject to modification by background PRS. We will compare our GESEM model against existing SEM-based approaches to GxE, including local SEM (LOSEM). Discussion & Conclusion An open-source R package of the analytical code will be created and shared with the research community. This work has the potential to improve upon existing PRS-based predictive models in a clinical setting.

The brain requires a large amount of energy, primarily obtained through glucose metabolism, which appears to be disrupted in various neuropsychiatric disorders. The etiology of neuropsychiatric disorders is complex and involves genetic factors that are slowly being identified. To investigate whether glucose metabolism-related genes are associated with major psychiatric disorders, we conducted secondary analyses using genome-wide association study (GWAS) summary statistics for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). Based on predefined glucose metabolism pathway genes, we conducted a multi-layer integrative analysis using gene-level approaches including multi-marker analysis of genomic annotation (MAGMA), transcriptome-wide association studies (TWAS) with joint-tissue imputation (JTI), and summary-based Mendelian randomization (SMR). We further explored gene expression patterns across tissues, druggability, and applied gene network analysis to evaluate the interactions. MAGMA identified 1 significant gene for MDD, 19 for BD, and 32 for SCZ, with gene RBKS shared across all three disorders. TWAS-JTI detected 17 and 35 transcriptome-wide significant genes for BD and SCZ, respectively, while SMR prioritized 2 and 9 putatively causal genes. For MDD, no convergent evidence emerged from TWAS-JTI or SMR analyses. Integrated analysis highlighted NDUFS2, NDUFS7, and NDUFC2 in the oxidative phosphorylation pathway as potential therapeutic targets. Finally, gene network analysis highlighted enrichment in mitochondrial respiratory chain complex I biogenesis, NADH dehydrogenase complex assembly, and ATP synthesis. Our results reinforce the role of energy metabolic disturbance in psychiatric disorders, particularly in BD and SCZ. These findings open avenues for targeted therapeutic interventions, warranting further validation across populations.