BACKGROUND:C-reactive protein (CRP) has emerged as a promising peripheral biomarker of neuroinflammatory processes implicated in the pathophysiology of major depressive disorder (MDD). We combined structural magnetic resonance imaging (MRI) with resting-state functional MRI to examine plasma CRP-related cortical thickness and resting-state functional connectivity (RSFC) changes. METHODS:Seventy-six patients with MDD and 65 healthy controls (HCs) were included in this study. The association between whole-brain cortical thickness and plasma CRP levels in the total sample (MDD+ HC, n = 141) was investigated. Seed-to-voxel RSFC analysis was performed using plasma CRP level-related cortical regions as seeds. RESULTS:Compared to the HC group, the MDD group showed significantly higher plasma CRP levels (p = 0.039). Higher plasma CRP levels were associated with cortical thinning in the prefrontal cortices and precentral gyrus, and cortical thickening in the left postcentral and right medial orbitofrontal gyrus. RSFC analysis showed a lower RSFC between the left dorsolateral prefrontal cortex and bilateral insula and between the precentral gyrus and superior parietal cortex, and higher RSFC between the dorsomedial prefrontal cortex and postcentral gyrus in MDD compared to HCs. CONCLUSIONS:Our findings suggest that systemic inflammation may be associated with structural and functional disruption of emotion regulation and cognitive control networks in MDD.
BACKGROUND:The long-term effects of antipsychotic treatment on brain structure in schizophrenia remain uncertain. Previous meta-analyses have primarily compared patients with controls rather than examining dose-related associations between cumulative exposure and brain structure. OBJECTIVE:To quantify the association between cumulative antipsychotic exposure (chlorpromazine equivalents) and structural brain changes measured by MRI in patients with schizophrenia. METHODS:Following prospective registration (PROSPERO CRD420261352526), 19 studies involving 1607 patients were included. Pearson's r or standardized β coefficients were pooled using random-effects models with the DerSimonian-Laird estimator. Subgroup analyses were conducted for the primary outcome. RESULTS:Higher cumulative antipsychotic exposure was associated with lower global gray matter volume (10 studies, n = 993; r = -0.259, 95% CI -0.337 to -0.179; p < 0.001). Publication bias was detected for this outcome (Egger's test p = 0.00574). Negative associations were also observed for global cortical thickness (r = -0.293), frontal lobe volume (r = -0.339), temporal lobe volume (r = -0.351), and total brain volume (r = -0.310). Lateral ventricular volume showed a positive association (r = 0.228), whereas white matter volume was not significantly associated. The dose-related association with gray matter volume was consistent across study designs and illness stages, with no significant subgroup differences. CONCLUSIONS:Higher cumulative antipsychotic exposure was modestly associated with greater structural brain alterations. However, these observational findings do not establish causality because medication exposure is closely linked to illness progression. Interpretation is further limited by publication bias, the small number of studies, and heterogeneity across secondary outcomes. Well-designed prospective longitudinal studies are needed to better distinguish medication effects from disease-related changes.
INTRODUCTION:Real-world evidence on desvenlafaxine effectiveness and tolerability in Major Depressive Disorder (MDD) remains limited, particularly in clinically heterogeneous populations. This multicentre observational study evaluated the real-world effectiveness and tolerability of desvenlafaxine, focusing on depressive and anxiety symptoms, response, remission, and side-effects burden. METHODS:This multicentre prospective observational study included 197 outpatients with DSM-5-TR Major Depressive Episode initiating desvenlafaxine. Assessments were conducted at baseline (T0), one month (T1), and three months (T2). Depressive symptoms (MADRS) were the primary outcome; anxiety (HAM-A), manic symptoms (YMRS), and tolerability (ASEC) were secondary outcomes. Response was defined as ≥50% MADRS reduction and remission as MADRS <10. RESULTS:Participants (mean age 46.1 ± 14.6 years; 55.3% female) showed clinically relevant baseline severity (MADRS 30.8 ± 7.3). MADRS scores decreased significantly over time in both unadjusted and adjusted models (both p < 0.005), with greater reductions at T2. A significant time × dose association was observed at T1 (p = 0.013), although no dose-related difference persisted at T2; prior hospitalisation was associated with attenuated improvement (p < 0.005). Anxiety symptoms improved significantly across follow-up (p < 0.005). Response and remission rates increased markedly from T1 to T2 (response: 12.4% to 66.7%; remission: 3.9% to 32.6%; both p < 0.005). Overall side-effect burden decreased significantly (p < 0.005), with reduced prevalence of most adverse events. Mean YMRS scores remained low throughout follow-up, with no clinically meaningful increase from baseline. CONCLUSIONS:In this multicentre real-world cohort, desvenlafaxine was associated with substantial improvements in depressive and anxiety symptoms, increasing response and remission rates, favourable tolerability. These findings support desvenlafaxine as an effective and well-tolerated treatment option in routine clinical practice.
BACKGROUND:Agoraphobia has traditionally been grouped with panic disorder in clinical and research settings. However, it has recently been acknowledged as a distinct condition which can and does occur in the absence panic disorder. The genetic heritability of agoraphobia is high. It can be impractical or impossible to contact parents directly to assess their psychiatric history, often leading to the use of single item measures of parental psychiatric history (e.g., has your mother/father ever had agoraphobia?). This study examined the agreement between responses of adult children (n = 1193) on a single item measure of parental agoraphobia history and their parents' own responses on a single item measure of their own agoraphobia history. DESIGN:Data came from the Lifelines Cohort Study, which is a community-based study in the Netherlands. Parents self-reported if they had a history of agoraphobia. Kappa, sensitivity, selectivity, positive predictive value, and negative predictive value were calculated. RESULTS:There was weak to moderate agreement between adult children's reports of parental agoraphobia history and parents' own reports of agoraphobia history (κmothers = 0.47, κfathers = 0.40). Sensitivity ranged from 66.7% for fathers to 95.2% for mothers. Specificity was high for both mothers (91.8%) and fathers (97.8%). CONCLUSION:Findings suggest that adult children may somewhat underestimate their fathers' history of agoraphobia, while successfully identifying with high accuracy their mothers' history of agoraphobia. This is the first study to examine the agreement between adult children's reports of parental agoraphobia history and their parents' own self-reports of agoraphobia history.
Background Oxidative imbalance and inflammatory processes have been implicated in major psychiatric disorders, yet data on personality disorders remain scarce. This study evaluated peripheral redox balance and inflammatory status in men with antisocial personality disorder (ASPD) and examined their associations with aggression and impulsivity. Methods In this single-center cross-sectional case–control study, 51 men with ASPD and 51 healthy men were included. Fasting blood samples were analyzed for total antioxidant status (TAS), total oxidant status (TOS), total thiol (TT), native thiol (NT), disulfide (DIS), and interleukin-1β (IL-1β). The oxidative stress index (OSI) and thiol–disulfide ratios were calculated. Aggression and impulsivity were assessed using the Buss–Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale-11 (BIS-11). Results Compared with controls, the ASPD group showed significantly higher TOS, OSI, DIS, DIS/NT, and DIS/TT, and lower TAS, TT, NT, and NT/TT. These group differences remained significant after adjustment for age, body mass index, smoking status, alcohol use, and substance use. Attentional impulsivity correlated moderately with TAS (r = −0.376) and OSI (r = 0.354). IL-1β levels did not differ between groups. Conclusion ASPD in men was associated with peripheral redox imbalance, reflected by increased oxidative burden and disrupted thiol–disulfide homeostasis. The observed redox alterations may reflect peripheral biological changes associated with ASPD, although their clinical significance requires further investigation. A single peripheral measurement of IL-1β did not reveal a significant inflammatory difference between groups. Larger studies incorporating broader biomarker panels are warranted.
BACKGROUND:Non-adherence to antidepressants contributes to relapse and recurrence in major depressive disorder (MDD). Existing risk-prediction models are drawn largely from chronic conditions in high-income settings; none exist for Pakistani outpatient psychiatry. METHODS:We analysed cross-sectional, patient-reported data from 2513 adults with MDD attending outpatient clinics in Lahore, Rawalpindi and Quetta. The outcome was an Urdu Morisky-Green-Levine score of 3 or higher, with 31 binary predictors from the Urdu Drug Attitude Inventory and Urdu Antidepressant Side-Effect Checklist. Six classifiers were compared within a pre-specified pipeline (leakage audit, nested cross-validation, bootstrap confidence intervals, calibration, SHAP, decision-curve analysis), reported per TRIPOD+AI. A sensitivity analysis re-fitted the primary model with available covariates. RESULTS:Non-adherence was present in 23.2% of patients. The four strongest models showed similar discrimination (AUC 0.771-0.779), with no significant DeLong difference. Penalised logistic regression, the primary model, achieved AUC 0.774 (95% CI 0.710-0.821), average precision 0.585, Brier score 0.136, calibration slope 1.17, requiring no recalibration. Permutation importance, SHAP, and standardized coefficients showed side-effect burden as the main predictor, with attitude items providing a smaller, mostly protective, contribution. Net benefit remained positive across thresholds 0.10-0.40. Adding covariates did not improve discrimination (AUC 0.759) and did not change adverse-effect coefficients. CONCLUSIONS:A parsimonious, well-calibrated logistic-regression model can identify MDD patients at risk of antidepressant non-adherence, and is to our knowledge the first TRIPOD+AI-compliant adherence model from South Asian psychiatry. Because predictors and outcomes were measured simultaneously and no external validation was performed, the findings only show correlations, not causation; the model isn't ready for deployment as a triage tool.
Anhedonia is a transdiagnostic disturbance of reward processing, yet the comparative efficacy and certainty of available interventions remain unclear. We searched PubMed, Embase, Web of Science, and MEDLINE for controlled trials reporting quantitative anhedonia outcomes. The protocol was registered in PROSPERO under CRD42025630784. Random-effects frequentist network meta-analyses were conducted overall and by population, including major depressive disorder, schizophrenia, and healthy individuals with trait anhedonia. Randomized trials were assessed with the Cochrane Risk of Bias 2 (RoB 2) tool, and the single non-randomized trial was assessed with the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. Certainty of evidence was assessed using the Confidence in Network Meta-Analysis framework. Sixty reports representing 61 independent trials, 5794 participants, and 80 contrasts were included. The primary network comprised 35 trials, 39 contrasts, and 17 treatment nodes. In the overall transdiagnostic network, estimates versus the pooled control node favoured vortioxetine 10 mg/day, left dorsolateral prefrontal cortex-targeted transcranial magnetic stimulation (left DLPFC-targeted TMS), behavioural activation, and meditation. The corresponding standardized mean differences were -0.90, -0.55, -0.52, and -0.49. Heterogeneity was substantial at I² = 71.90%, but the design-by-treatment test did not indicate global inconsistency. Left DLPFC-targeted TMS showed the most consistent evidence pattern across the overall and major depressive disorder networks, supported by five direct trials in the overall network and stable leave-one-trial-out estimates. These findings clarify the comparative evidence across pharmacological, neuromodulatory, and psychological approaches and provide a structured basis for future diagnosis-specific trials and treatment development.
First-episode schizophrenia (FES) presents with substantial heterogeneity in cognitive performance, yet this variability is frequently overlooked in studies investigating disease pathology and treatment. This study aimed to quantify cognitive heterogeneity across domains and individuals, and to identify distinct cognitive subtypes in FES. We assessed cognitive performance using the MATRICS Consensus Cognitive Battery (MCCB) and clinical symptoms with the Positive and Negative Syndrome Scale (PANSS) in 271 patients with FES and 133 healthy controls (HC). Domain-specific impairment was quantified using Hedges' g, whereas quantile-based analyses were performed to characterize distributional heterogeneity in overall cognitive performance. Gaussian mixture clustering was subsequently applied to identify latent subtypes within FES group. Compared with HC, patients with FES demonstrated significant impairments across all assessed cognitive measures. However, the magnitude of impairment varied across measures, with Attention/Vigilance as the domain with the greatest impairment. Quantile-based analyses demonstrated that the FES-HC difference was significantly greater at the lower than at the upper end of the cognitive distribution, indicating that cognitive impairment was not uniformly distributed across patients. Clustering analysis identified two cognitive subtypes: one subgroup with severe global cognitive deficits and another with relatively preserved cognitive functioning. Crucially, these subtypes also differed significantly in their clinical symptom profiles. In conclusion, specific cognitive impairments may reflect the underlying pathology of early schizophrenia, and individuals can be reliably stratified into distinct cognitive phenotypes. These findings provide critical clinical insights that can directly inform targeted, stratified strategies in early psychosis from a cognitive perspective.
OBJECTIVES:Excessive alcohol consumption is a major public health concern. Protective behavioral strategies (PBS) are widely incorporated into alcohol interventions, but their effectiveness and role as mechanisms of behavior change remain unclear. This systematic review and meta-analysis evaluated the effects of PBS-based interventions on alcohol consumption, alcohol-related harms, and PBS use. METHODS:PubMed, Embase, Scopus, CINAHL, and ProQuest were searched from inception to December 2025 for randomized controlled trials (RCTs) of adults (≥18 years) delivering PBS as an active intervention component. Random-effects meta-analyses using Hedges' g examined alcohol quantity, drinking frequency, alcohol-related problems, and PBS use. RESULTS:Fifteen RCTs were included, predominantly involving young adults attending U.S. universities. PBS interventions increased protective strategy use (g=0.23, p=0.005 after outlier removal), but alcohol effects were modest: no change in quantity (g=-0.05, p=0.162), small reduction in frequency (g=-0.09, p=0.014), and marginal reduction in problems (g=-0.07, p=0.052; significant in sensitivity analysis). Subgroup findings suggested greater effects at longer follow-up and when PBS was incorporated into multi-component interventions. Evidence supporting PBS as a mechanism of change was limited and inconsistent. CONCLUSIONS:PBS-based interventions produce modest, context-dependent effects on alcohol outcomes. Most evidence comes from young U.S. university students, underscoring the need for studies in more diverse adult populations and further mechanistic research.
Background Posttraumatic stress disorder (PTSD) research has largely focused on exposure to DSM-defined traumatic events, while comparatively little attention has been paid to the role of ongoing socioeconomic stressors. Few contemporary, population-based studies have examined how lifetime trauma (e.g., physical violence) and recent socioeconomic stressors jointly relate to PTSD risk, or whether the association between socioeconomic stressors (e.g., losing a job) and PTSD differs by trauma burden among trauma-exposed individuals. Methods We analyzed data from the Global Social Determinants of Health Survey (2023–2024), a population-based cross-sectional survey conducted in eight countries (Brazil, France, India, Indonesia, Nigeria, the Philippines, Turkey, and the United States). Analyses were restricted to adults reporting at least one lifetime traumatic event (N = 5,525). PTSD was assessed using the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5). We assessed the relationship between trauma burden, socioeconomic stressor burden, and PTSD using survey-weighted Rao–Scott chi-square tests and logistic regressions. We estimated marginal predicted probabilities for PTSD by socioeconomic stressor burden for each trauma exposure level. Findings PTSD prevalence increased from 5.1% (95% CI: 4.3%, 5.9%) among those with mild trauma to 23.9% (95% CI: 19.3%, 29.1%) among those with severe trauma. Similarly, PTSD prevalence rose from 0.6% (95% CI: 0.3%, 1.0%) among those with no recent socioeconomic stressors to 17.9% (95% CI: 15.6%, 20.4%) among those with severe exposure. The association between socioeconomic stressors and PTSD was modified by trauma burden (joint Wald test p<0.001). Among those with mild trauma, each additional stressor increased PTSD odds by 41% (OR: 1.41 [95% CI 1.32,1.51]), while this association was attenuated among moderate (interaction OR: 0.83; combined association OR: 1.17) and severe trauma (interaction OR: 0.85; combined association OR: 1.20). PTSD prevalence was also markedly higher for specific exposures, with the largest exposed-unexposed contrasts observed for sexual violence (19.9% vs 4.6%), physical assault (17.4% vs 3.9%), forced displacement (16.2% vs 4.4%), housing insecurity (17.0% vs 4.7%), divorce or separation (14.0% vs 4.7%), and social isolation (12.2% vs 1.5%). Interpretation We found strong evidence that PTSD risk among trauma-exposed adults is shaped by both lifetime traumatic exposure and ongoing socioeconomic stressors. These findings highlight the importance of contextual adversity in shaping PTSD burden.
BACKGROUND:Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD), yet specific molecular targets remain to be fully characterized. METHODS:A summary-data-based Mendelian randomization (SMR) framework integrated AD genome-wide association study (GWAS) statistics (39,918 cases) with blood DNA methylation quantitative trait loci (mQTL), gene expression (eQTL), and protein (pQTL) data for 1136 mitochondria-related genes. Associations were assessed using Bayesian colocalization and HEIDI testing. Tissue relevance was evaluated in four brain regions (hippocampus, amygdala, cortex, frontal cortex) using GTEx and external transcriptomic datasets. RESULTS:Screening identified eight candidates supported across blood mQTL and eQTL layers. Stepwise central nervous system (CNS) evaluation singled out biphenyl hydrolase-like (BPHL) as the consistent candidate. Higher genetically predicted BPHL expression was associated with reduced AD risk across the hippocampus (OR=0.920, 95% CI 0.873-0.970), amygdala (OR=0.925, 95%CI 0.880-0.973), cortex (OR=0.943, 95% CI 0.908-0.978), and frontal cortex (OR=0.938, 95%CI 0.901-0.976). These findings aligned with protein-protein interactions connecting BPHL to respiratory complexes and lower BPHL expression in independent AD brains. Functional enrichment converged on oxidative phosphorylation pathways. CONCLUSIONS:By integrating multi-omics data with tissue-specific validation, this study nominates BPHL as a consistent protective candidate in the brain. These findings provide genetic support for mitochondrial molecular perturbations in AD, offering insights for future validation.
Background Prior studies show that inaccurate disclosure of suicidal thoughts is common in health care settings. Little is known about disclosure in the context of universal suicide risk screening programs. This project sought to characterize the frequency of inaccurate disclosure of suicidal ideation during universal suicide risk screening and immediate follow-up in Veterans Health Administration (VHA) mental health settings and to identify predictors of inaccurate disclosure. Methods We conducted a national survey study with linkage to VHA electronic medical records. Analyses incorporated weighting for response and patient characteristics. Seven hundred ninety-two veterans receiving VHA mental health specialty care participated. The survey included questions inquiring about the extent to which participants had responded accurately when asked about suicidal thoughts during screening visits. Results In weighted analyses, 38.1% of screen-negative and 45.8% of screen-positive participants reported responding less than “very accurately” to screening questions. Characteristics associated with less accurate disclosure in both groups included lower beliefs that suicide is not a way out (screen-positive: OR=0.46; 95% CI=0.28-0.77; screen-negative: OR=0.40; 95% CI=0.2-0.79) and greater concern for overreaction (screen-positive: OR=2.36; 95% CI=1.35-4.11; screen-negative: OR=3.73; 95% CI=1.71-8.13). Conclusions Inaccurate disclosure during VHA universal suicide risk evaluation occurs with modest frequency. The results highlight that mental health clinicians and care systems should not overly rely on screening results and suggest that screening accuracy may be improved using a patient-centered approach including orientation of patients to the screening process.
BACKGROUND:Cognitive-behavioral therapy (CBT) is the well-established standard treatment for young people with an ultra high-risk (UHR) state for psychosis. While CBT has been shown to reduce the risk of transition to psychosis, early treatment discontinuation is highly prevalent. This study examines the impact of attenuated psychotic symptoms on change mechanisms and therapy attendance. METHODS:65 young people at UHR (confirmed with the Structured Interview for Psychosis-Risk Syndromes, SIPS) received a specialized, 12-session CBT intervention at an Early Recognition and Intervention Centre (FETZ Bern) between 2018 and 2023. They provided demographic information, pre and post therapy measures of psychopathology (including psychotic, depressive, and anxiety symptoms), functioning, and quality of life. The Scale for the Multiperspective Assessment of General Change Mechanisms in Psychotherapy (SACiP) was rated regularly by patients and therapists. RESULTS:Of 65 participants (71% female, mean age 18 years), 43 (66%) completed the intervention and experienced improvements in psychotic, depressive and anxiety symptoms, functioning, and quality of life. Psychotic symptoms were negatively associated with patient-rated resource activation and problem actuation early in therapy. Mastery and resource activation improved significantly over the course of therapy. Neither psychotic symptoms nor SACiP scores predicted attendance. CONCLUSION:CBT for UHR is associated with improved clinical symptoms and functioning. Nevertheless, even in specialized early intervention services like FETZ Bern, a substantial proportion of young people discontinue treatment early. The interplay between psychotic symptoms and change mechanisms can help to understand the subjective experience of psychotherapy in UHR cohorts and should be studied further.
OBJECTIVE:Major depressive disorder (MDD) is one of the most prevalent and debilitating health conditions worldwide; unfortunately, numerous patients are "treatment-resistant" to traditional therapies. Deep transcranial magnetic stimulation (Deep TMS) has emerged as an effective treatment for such cases; however, the precise mechanisms by which Deep TMS alters neurophysiological patterns and attenuates depressive symptoms are still ambiguous. METHODS:In the current study, resting-state quantitative electroencephalography (QEEG) measures of power, coherence, and asymmetry were assessed pre-and-post treatment in a sample of 75 participants with MDD. RESULTS:The 36-session protocol yielded a response rate of 82.6 percent and an overall significant reduction in depressive symptoms. Further, slow-frequency delta activity was reduced in the left prefrontal cortex while frontal beta asymmetry shifted leftward. Coherence (brain connectivity) was also improved between the left prefrontal and temporal lobes. CONCLUSIONS:These findings provide additional support for the utility of Deep TMS in altering aberrant neurophysiological patterns pertaining to depression. SIGNIFICANCE:Deep TMS paired with qEEG should continue to be utilized for the treatment of MDD as well as other treatment-resistant conditions.
