European Neuropsychopharmacology

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with changes in motivation to work for rewards being a core symptom. Transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising therapy but its effects on the core features of MDD, such as changes in motivation, remained relatively unexplored. In this randomised, single-blind, cross-over, controlled trial, we used a grip strength effort task to investigate how tVNS impacted choices to exert different levels of physical effort for varying monetary rewards in MDD patients (n=53) and a non-depressed control group (n=45). Compared to sham stimulation, tVNS enhanced the efficiency with which participants with severe depressive symptoms allocated physical effort for rewards (reward-effort efficiency). These effects were not seen in participants with less severe symptoms. Specifically, we found that the effect of tVNS on reward-effort efficiency was driven by reduced unnecessary effort, i.e., a reduction in choices to exert additional effort when this was not required to gain a larger reward. These findings suggest a potential motivational mechanism by which tVNS exerts its therapeutic effects in MDD. Determining whether the effects of tVNS are linked to broader changes in executive functioning, such as improvements in cognitive flexibility in MDD, should be a key aim for future work.

Esketamine is a fast-acting antidepressant drug which induces acute psychoactive effects. The most frequent is a dissociative state which seems unrelated to therapeutic efficacy. Other esketamine-induced effects, including psychedelic-like mystical experiences, have been poorly studied in terms of phenomenology and frequency, and may carry specific therapeutic relevance. In this study, we characterised esketamine-induced mystical experiences in relation with clinical outcomes. We conducted a longitudinal observational study and systematically measured acute subjective effects in patients receiving esketamine for treatment-resistant depression after each administration across the induction phase. A total of 45 patients were included, from two independent centres, totalling 352 esketamine administrations. Principal Component Analysis (PCA) supported the validity of the Mystical Experience Questionnaire (MEQ-30) for assessing esketamine-induced subjective effects, with components recovering dimensions previously validated with classic psychedelics. Mystical experiences (MEQ-30 score above 60) occurred in 58% of patients, with high inter- and intra-individual variability in frequency, intensity, and phenomenology across sessions. Higher mean and peak MEQ scores were associated with greater improvement in Montgomery-Asberg Depression Rating Scale scores from pre- to post-treatment, whereas the intensity of dissociative or other non-mystical effects was not. Positive mood and mystical MEQ dimensions in particular predicted therapeutic outcomes. Baseline spirituality also significantly predicted treatment outcomes and peak MEQ scores in the first week of treatment. These findings add to the growing body of evidence suggesting that psychedelic-like mystical experiences may be associated to therapeutic efficacy, not only in classic psychedelic-assisted therapy, but also in esketamine treatment.

Importance: Conventional repetitive transcranial magnetic stimulation (rTMS) can be ineffective in individuals who have previously failed brain stimulation, ketamine and/or multiple lines of therapies. Modern accelerated rTMS protocols using image-guided targets have not been systematically investigated in these individuals. The goal of this study was to assess the feasibility and efficacy of personalized, connectivity-guided, accelerated intermittent theta-burst stimulation (iTBS) in patients with treatment-resistant depression (TRD) of varying refractoriness. Objective: To assess whether connectivity-guided, accelerated iTBS produces significant reductions in depression severity, and to what extent this benefit extends to ultra treatment-resistant depression (UTRD). Design: This was an open-label feasibility trial of connectivity-guided, accelerated iTBS in patients with TRD. Two distinct groups of participants were recruited from a neurosurgical-psychiatry clinic with UTRD and an interventional psychiatry clinic with TRD. Patients were stratified into a priori treatment-resistance subgroups. Patients received five days of open-label treatment. Outcome measures were collected immediately prior to and after treatment, as well as at 4- and 12-weeks post-treatment. Setting: This trial (NCT05813093) was conducted between November 2023 and July 2025 at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. Participants: Patients with major depressive disorder. A total of 96 participants were screened, with 73 meeting eligibility criteria (UTRD=30, TRD=43). One withdrew due to inability to tolerate the baseline MRI, and the other withdrew voluntarily prior to treatment. Intervention: Participants underwent a neuronavigated accelerated iTBS (600 pulses) protocol using personalized left dorsolateral prefrontal cortex (dlPFC) targets derived from functional magnetic resonance imaging (fMRI), comprising eight daily treatments, repeated over five days. Main Outcomes: Primary outcomes were i) change in Hamilton Depression Rating Scale (HAM-D17) from baseline to the end of the fifth day of treatment, and ii) the difference in change in HAM-D17 between UTRD and TRD subgroups. Results: Connectivity-guided fMRI targeting yielded personalized targets clustered around the anterolateral dlPFC. Accelerated iTBS elicited rapid antidepressant effects ({Delta}HAM-D17 -9.01 [SD 6.06], t = -12.45, p < 0.001) regardless of treatment-resistance group ({Delta}HAM-D17 -9.64 [SD 5.94] vs -8.10 [SD 6.12], t = -1.05, p = 0.299), which were sustained up to 12 weeks after treatment. Overall response and remission rates at the end of treatment were 40.8% and 16.9%. Self-report scales revealed broad symptomatic relief outside of core depressive symptoms. Conclusions & Relevance: This study demonstrated that fMRI connectivity-guided, accelerated iTBS induces sustained antidepressant effects and broader psychiatric benefits in patients across the spectrum of TRD. In a cohort unlikely to respond to most antidepressant therapies, connectivity-guided, accelerated iTBS offers a safe, well-tolerated option that can achieve benefit, or when ineffective, allow patients to expeditiously proceed with subsequent therapies than conventional rTMS. Trial Registration: This clinical trial was registered at clinicaltrials.gov with NCT05813093.

BackgroundPsilocybin is a classic psychedelic that acutely alters brain functional connectivity. These changes are linked to therapeutic doses and subjective effects, with some evidence that changes persist beyond acute drug administration. However, the effects of lower doses on sustained connectivity changes remain unclear. MethodsTen healthy volunteers received three psilocybin doses (between 5 and 20 mg) in a randomized and blinded order, with at least one week between doses. Resting-state functional magnetic resonance imaging was completed at baseline and one week after a single dose. Functional connectivity changes were analyzed in relation to dose and altered conscious states at both the level of individual brain region connections (edges) and resting-state networks. ResultsDose-dependent changes in 77 edges (76 increases, 1 decrease, of 1275 possible) were observed, but none survived multiple-comparison correction. At the network level, we observed one dose-dependent between-network increase (of 21 possible), and one dose-dependent within-network increase (of seven possible); the latter surviving correction. Alterations in conscious state were positively associated with widespread connectivity changes (dose-adjusted), with many network-level associations surviving correction. These directional patterns showed that lower doses and smaller conscious state alterations were linked to decreased connectivity, whereas higher doses and greater conscious state alterations were linked to increased connectivity. ConclusionsDose level and acute subjective effects were positively associated with multiple functional connectivity changes one week after a low-to-moderate psilocybin dose. Further research is warranted to characterize these sustained effects and their therapeutic relevance to inform studies adopting similar dosing regimens in clinical cohorts. Trial RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621000560897 Date registered: 12 May 2021 URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381526&isReview=true

Background: The etiology and nosological status of seasonal affective disorder (SAD) as a specifier of depressive episodes versus a transdiagnostic disorder are the subject of debate. In this study, we investigated the underlying etiology of SAD and dimensional seasonality by examining their association with latitude and genetic risk for a range of traits, and investigated gene-environment interactions. Methods: This study included 12,460 adults aged 18-90 with a history of depression from the Australian Genetics of Depression Study. Regression models included predictors for latitude (distance from equator) and polygenic scores for eight traits; major depressive disorder, bipolar disorder, anxiety disorders, chronotype, sleep duration, body mass index, vitamin D levels, and educational attainment. Outcomes were SAD status and general seasonality score. Results: SAD was positively associated with latitude (OR[95%CI] = 1.05[1.03-1.06], padjusted<0.001), and there was nominal evidence of additive and multiplicative interactions between chronotype genetic risk and latitude (OR = 0.99[0.99-0.99], padjusted=0.381; OR=0.98[0.97-0.99], padjusted=0.489). General seasonality score was associated with latitude (IRR=1.01[1.01-1.01], padjusted 0.001) and genetic risk for major depressive disorder (IRR =1.02[1.01-1.03], padjusted<0.001), bipolar disorder (IRR=1.02[1.01-1.03], padjusted=0.001), anxiety disorders (IRR=1.03[1.01-1.04], padjusted<0.001), vitamin D levels (OR=0.89[0.80-0.95], padjusted=0.048), and educational attainment (IRR=0.97[0.96-0.99], padjusted<0.001). Conclusions: These findings enhance understanding of SAD etiology, highlighting contributions of psychiatric genetic risk and geographic measures on seasonal behavior, and support examining seasonality as a continuous dimension.

Polygenic risk scores (PRS) have shown increasing utility for risk stratification across complex diseases, but for psychiatric disorders such as bipolar disorder (BD), current PRS explain only a fraction of disorder liability (~1-9%), with predictive performance further diminished in non-European populations and real-world clinical cohorts. To explore the potential of integrating social and environmental risk factors alongside genetic liability to improve risk prediction, we evaluated the relationship between a PRS for BD (PRSBD) and six social risk measures - perceived stress, discrimination in medical settings, neighborhood social cohesion, perceived neighborhood disorder, cost-related medication nonadherence, and adverse childhood experiences - to BD case status in 115,275 participants (7,000 cases; 108,275 controls) from the All of Us Research Program. PRSBD was associated with BD case status across ancestry groups, though liability-scale variance explained was attenuated relative to what has been reported for curated research cohorts (R2 = 1.86% in European, 0.60% in African, 1.65% in Latino/Admixed American ancestries). Each social risk factor tested exhibited a larger effect size than PRSBD, with perceived stress (OR = 2.05 per SD) and adverse childhood experiences (OR = 2.68 for [&ge;]4 ACEs) demonstrating the strongest associations. Individuals in the lowest genetic risk decile with high social burden exhibited BD prevalence comparable to or exceeding those in the highest genetic risk decile with low social burden. These findings demonstrate the substantial explanatory power of social risk factors and support the development of integrated genetic-social risk frameworks for more accurate and equitable psychiatric risk prediction.

Background Chronic pain and depression are common disorders and leading causes of disability worldwide. They frequently co-occur and show substantial genetic correlation, indicating a shared genetic basis. However, the locus-specific architecture of this overlap remains poorly characterised and may yield important insights into the pathophysiology of their comorbidity. Methods Using the largest currently available European-ancestry genome-wide association studies of major depressive disorder (MDD) (n = 1,639,572) and multisite chronic pain (MCP) (n = 387,649), we estimated the polygenic overlap between traits using the bivariate causal mixture model (MiXeR), identified shared loci via conjunctional false discovery rate (conjFDR), and tested colocalisation with each trait and genetically regulated gene expression in 13 brain tissues. Results MiXeR analysis demonstrated a high degree of directionally consistent polygenic overlap between MDD and MCP. Subsequent conjFDR analysis identified 375 shared loci, 22 of which showed cross-trait colocalisation between the MDD and MCP signals. Gene mapping and enrichment of shared loci implicated several biological processes, including cadherin-mediated cell-cell adhesion and translational initiation. Gene expression colocalisation in brain tissue highlighted protein phosphatase 6 catalytic subunit (PPP6C) and suppressor of cancer cell invasion (SCAI) in both disorders. Conclusion Overall, these findings have enhanced our understanding of the complex relationship between chronic pain and depression by identifying shared molecular mechanisms that warrant further study as targets for prevention and treatment.

BackgroundLoneliness is a psychosocial stressor associated with elevated risk of severe mental illness (SMI), including major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). Loneliness is theorized to become biologically embedded via inflammation-related mechanisms, yet its causal relationship with SMI and the role of inflammatory signaling remain unclear. AimsTo investigate whether loneliness causally influences SMI risk and whether inflammatory cytokines mediate this relationship. MethodWe applied univariable Mendelian randomization (MR) to estimate the causal effect of loneliness on SMI and multivariable MR (MVMR) to assess mediation by inflammatory signaling. We integrated genome-wide association study (GWAS) summary statistics for loneliness and SMI with genetic instruments for inflammatory cytokines. MVMR models estimated the direct effect of loneliness after accounting for inflammatory signaling using eQTL and pQTLs for interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), IL-6 receptor (IL-6R), tumor necrosis factor alpha (TNF-), and TNF receptors (TNF-R1/2). Bidirectional MR examined potential reverse causal pathways between inflammation, SMI, and loneliness. ResultsMR provided evidence consistent with a causal effect of loneliness on SCZ and MDD. Results were also consistent with inflammatory cytokine pathways for IL-1RA, IL-6R, and TNF-R1, partially mediating the loneliness-SCZ and loneliness-MDD causal effect. No significant effects were identified for BD in UVMR or MVMR models. Bidirectional MR suggested evidence of reverse causation between SCZ and loneliness. ConclusionsThe findings support a causal risk-increasing effect of loneliness on SCZ and MDD, partially mediated by systemic inflammatory signaling, implicating pathways as a plausible mechanistic link between psychosocial stress and mental illness risk and highlighting potential opportunities for prevention and targeted intervention through inflammation and social pathways.

Severe mental disorders (SMDs), including bipolar disorder, schizophrenia, and major depressive disorder, are highly complex conditions associated with a substantial clinical burden and an increased suicide risk. Here, we present the Madrid Manic Cohort (MadManic), a large-scale initiative from Spain designed to integrate genomic, multi-omics, clinical, and digital phenotyping data to investigate the biological basis and clinical heterogeneity of SMDs. The cohort is still expanding and currently includes over 4,400 participants (~2,300 psychiatric patients and ~2,100 controls) and >11,000 biospecimens. Genotyping, transcriptomic and epigenetic data are available for different subsets of the cohort. By establishing the MadManic cohort we aim to integrate molecular data with detailed clinical and longitudinal digital information, allowing a more precise characterization of patient subgroups based on biological and phenotypic profiles. The MadManic cohort is well positioned to contribute to major international efforts in psychiatric genetics by enhancing the representation of Southern European populations, and advancing the identification of genetic risk, clinical predictors, and pharmacogenomic markers of treatment response. This cohort represents a valuable resource for advancing precision psychiatry, with the potential to improve risk prediction and guide personalized interventions in SMDs.

3,4-methylenedioxymethamphetamine (MDMA) has emerged as a potential treatment for post-traumatic stress disorder (PTSD), generating considerable enthusiasm in the field. However, rapidly changing evidence in a fast-moving field can be challenging to integrate. Here, we present a living systematic review and open-data meta-analytic resource on MDMA treatment for PTSD. In this initial release, six randomized controlled trials comprising 286 participants are included in the database. Our primary model uses inverse-variance random-effects meta-analysis of standardized mean differences on primary outcomes of PTSD. Compared to control conditions, MDMA showed a greater reduction in PTSD symptoms (Hedges' g = -0.71). Meta-regression on both the number of dosing sessions and cumulative dose showed that a higher number of dosing sessions and a higher cumulative dose was related to larger effects of MDMA. Treatment with MDMA as compared to placebo also resulted in higher response (risk ratio (RR) = 1.35) and remission (RR = 2.25) rates. Most studies included in the database had a low risk of bias according to Cochrane guidelines, though these fail to capture pertinent challenges in the field such as expectancy, functional unblinding, potential issues with study conduct, and safety. The current findings were assigned an overall low certainty rating using the GRADE approach. Together, this systematic review and meta-analysis suggests that MDMA-assisted therapy results in short-term decreases in PTSD symptoms across studies to date, though more trials are needed. This living systematic review, meta-analysis, database, and online dashboard (sypres.io) will continue to be updated as evidence emerges, providing a valuable, open, and transparent resource for researchers in a rapidly evolving field.

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

Background: Substance use disorders (SUDs), including alcohol and drug dependence, and smoking, pose a public health threat with their high prevalence and comorbidity with other diseases, and contribution to mortality. SUDs are highly correlated, and their genetic background is shared to some degree. Objectives: We aimed to investigate the genetic associations of previously reported loci for a wide range of SUDs in an unstudied Ukrainian population. Methods: We collected data from 595 individuals (339 women, 253 men), including 321 participants from two rehab centres. Based on clinical review and questionnaire data we defined drug dependence, alcohol dependence, alcohol abuse, binge drinking, smoking, opiate, amphetamine, cannabis, and hallucinogen use, along with several intermediary alcohol use and smoking variables considering the amount of use and the level of dependence. We genotyped COMT-rs4680, ADH1B-ADH1C-rs1789891, and HTR2A-rs6313, and applied logistic and ordered logistic regression assuming an additive inheritance model, controlling for the recruitment group, other substance uses, age, and sex, in the association analyses. Results: We replicate (P<0.05) the associations at COMT-rs4680 with smoking status (OR[95% CI]=1.56[1.01-2.41], P=0.047) and heaviness (1.37[1.04-1.80], P=0.026), and at ADH1B-ADH1C-rs1789891 and HTR2A-rs6313 with alcohol dependence (1.69[1.03-2.76], P=0.038 and 0.66[0.47-0.92, P=0.016], respectively). Furthermore, we provide evidence for an association at HTR2A-rs6313 with hallucinogen use (0.58[0.35-0.98], P=0.040). Conclusion: In this study on multiple SUDs we shed light on the genetic background of SUDs in Ukrainians and provide further evidence that variation at COMT is mainly associated with smoking, at ADH1B-ADH1C with alcohol-related variables, whereas HTR2A is a more general SUD-associated locus.

Background Chronic pain and depression are leading causes of disability and frequently co-occur. Depression presents with diverse symptoms, but despite this variability, the prevalence of individual depressive symptoms in chronic pain and the genetic and causal associations linking these traits remain poorly characterised. Methods Using data from 142,688 age- and sex-matched UK Biobank participants, we compared depressive symptom severity levels and item-level Patient Health Questionnaire-9 (PHQ-9) prevalences, spanning affective, cognitive and somatic domains, between participants with and without chronic pain. Using genome-wide association study (GWAS) summary statistics of multisite chronic pain (MCP), major depressive disorder (MDD), and individual symptoms of depression, genetic correlations and bidirectional causal effects between MCP and depressive phenotypes (MDD and individual symptoms) were estimated via linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomisation (MR), respectively. Results Depression (at every severity level) was more common in the chronic pain group compared to controls, with the largest between-group difference for severe symptoms (7.50-fold increase). All individual depressive symptoms were at least 2.79 times as prevalent in chronic pain. Additionally, chronic pain had a significant and positive genetic correlation with MDD (rg = 0.59) and all depressive symptoms (rg = [0.24, 0.55]). MR supported a bidirectional causal association between MCP and MDD (MCP[-&gt;]MDD: OR = 1.85, pFDR < 0.001, MDD[-&gt;]MCP: {beta} = 0.17, pFDR < 0.001). At the symptom level, MR indicated bidirectional effects between MCP and anhedonia (MCP[-&gt;]anhedonia: OR = 1.60, pFDR < 0.001, anhedonia[-&gt;]MCP: {beta} = 0.08, pFDR = 0.005), and unidirectional effects of MCP on appetite/weight gain (OR = 1.90, pFDR = 0.022) and appetite/weight loss (OR = 1.63, pFDR = 0.005), concentration problems (OR = 1.63, pFDR = 0.044), and suicidal thoughts (OR = 1.46, pFDR = 0.021). Additionally, genetic liability to concentration problems was associated with a lower risk of MCP ({beta} = -0.04, pFDR = 0.022). Conclusion Chronic pain is associated with a marked depressive burden spanning all symptom domains. Shared genetic architecture and symptom-specific causal pathways, particularly involving anhedonia, highlight potential targets for improved treatment of comorbid chronic pain and depression.

Alternative-splicing events (ASE) increase transcriptomic variability and play key roles in biological functions. The contribution of ASE to bipolar disorder (BD) remains largely unexplored. We performed a Transcriptome-Wide Alternative-Splicing Analysis (TWASA) to identify ASEs and genes potentially involved in BD. The study comprised 635 individuals: a discovery sample (DS) of 31 individuals from eight multiplex BD families (16 BD cases; 15 unaffected relatives), and a replication sample (RS) of 604 subjects (372 BD cases; 232 controls). Sequencing was conducted on RNA from lymphoblastoid cell lines (DS) and whole blood (RS). TWASA was performed using VAST-TOOLS (VT), rMATS (RM), and MAJIQ/MOCCASIN (MCC). Gene-set association analyses of genes containing ASEs were performed across six psychiatric disorders. Novel ASE (nASE) were investigated in the DS using FRASER. Limited gene overlap was observed across TWASA tools. MCC identified 2,031 complex ASEs involving 1,508 genes, showing the strongest genetic association with BD across psychiatric phenotypes. Prioritization of MCC-identified ASE genes yielded 441 candidates, including DOCK2 as top candidate from the DS. Replication was obtained for 98 genes, five with an identical ASE, and four (RBM26, QKI, ANKRD36, and TATDN2) showing a concordant percentage-spliced-in direction with the DS. Finally, 578 nASE were identified in the DS, with no evidence of familial segregation or differences in ASE types. This first TWASA in BD reveals tool-specific variability, complex ASE for genes specifically associated with BD, and novel candidate genes for BD. Alternative transcript isoform abundance may represent a mechanism contributing to BD pathophysiology.

Progress in pharmacological treatment development for neurodevelopmental disorders is hindered by a misalignment between targeted mechanisms, outcome measures, and trial designs. This study was initiated as a post-trial access pathway for bumetanide and later expanded with treatment-naive participants. Within this framework, we implemented a parent-cocreated sensory outcome measure set (PROMset) in an unmasked, multiple-baseline single-case experimental design with randomized baseline periods of 2-12 weeks, followed by 6 months of bumetanide treatment (up to 1.5 mg twice daily). Participants (7-19 years) had atypical sensory reactivity and a diagnosis of ASD, ADHD, epilepsy, or TSC. The primary outcome was a PROMset comprising seven PROMIS item banks assessing anxiety, depressive symptoms, sleep disturbance, fatigue, sleep-related impairment, cognitive function, and peer relationships. Secondary outcomes included SSP, SRS-2, RBS-R, and ABC. Of 113 enrolled participants (mean age 13.2 [SD 2.7], 64% male), 102 completed the trial and 95 had analyzable PROMsets. At baseline, PROMset scores showed substantial impairment across domains (mean deviation =9.0 T-score points, p<.001) and correlated with sensory reactivity (SSP; r=-0.40, p<.001). Individual-level analyses showed improvement in 24-41% of participants per PROM domain, most frequently in anxiety and depressive symptoms (41% and 38%; mean across-case Cohen's d=-1). Overall, 83% improved on at least one domain. Group-level analyses showed improvement across all secondary outcomes (p<.001), with superiority over historic placebo for RBS-R and SSP. Integrating PROMsets with individualized trial designs can reveal clinically meaningful changes, supporting a more sensitive and patient-centered framework for treatment evaluation in heterogeneous populations.

Nicotine use disorder shows heterogeneity in treatment response, potentially reflecting differences in underlying neural circuitry, particularly in the presence of depression. We examined real-time neural dynamics during nicotine inhalation in two chronic users - one with depression and one without - using simultaneous hippocampal recordings from responsive neurostimulation (RNS) electrodes and scalp EEG. Oscillatory activity and hippocampal-cortical connectivity were analyzed in relation to mood and craving. Oscillatory activity tracked mood in the non-depressed individual but was attenuated or reversed in the depressed individual, suggesting reduced reward-related neural responsiveness. In contrast, both participants showed reduced alpha hippocampal-cortical connectivity following nicotine use, suggesting a shift from reward-seeking to reward and relief processing. These findings support a network-based framework of nicotine-driven neural dynamics and provide preliminary evidence that depressive status may modulate these processes. Although limited to two cases, this work highlights the potential for identifying neurophysiological subtypes of nicotine users and informs future efforts toward personalized treatment approaches.

ImportanceBlood-based biomarkers hold promise for psychiatric diagnosis and prognosis, yet clinical translation is constrained by poor reproducibility. Psychiatric biomarker studies are typically small, and demographic, behavioral, and temporal covariates often go undetected or cannot be adequately modeled. This may lead to residual confounding and unstable associations. ObservationsLeveraging UK Biobank data (N=~500,000), we systematically quantified how technical, demographic, behavioral, and temporal covariates influence 29 blood biomarkers commonly measured in research studies in psychiatry. Variance analyses showed substantial differences across biomarkers. Technical factors explained 1-6% and demographic factors explained 5-15% of the variance, with pronounced age-by-sex interactions for lipids and sex hormones. Behavioral covariates, particularly body mass index (BMI) and smoking, strongly influenced inflammatory markers. Temporal factors introduced systematic confounding. Chronotype was associated with blood collection time, multiple biomarkers exhibited marked diurnal rhythms (including testosterone, triglycerides, and immune markers), and inflammatory markers showed seasonal peaks in winter. In association analysis of biomarkers with major depression, bipolar disorder and schizophrenia, covariate adjustments attenuated or eliminated a substantial proportion of the biomarker-disorder associations, with BMI emerging as the dominant confounder. These findings demonstrate that such confounding structures exist and can be characterized in large cohorts, though specific biomarker-disorder relationships require validation in clinical samples. Conclusions and RelevancePoor reproducibility of biomarkers may not only stem from insufficient biological signal but also from inconsistent handling of confounders. We propose a systematic framework distinguishing technical factors (to be removed), demographic factors (addressed through adjustment or stratification), temporal factors (ideally controlled at design stages), and behavioral factors (requiring explicit causal reasoning). Associations robust to multiple adjustment strategies should be prioritized for clinical biomarker development. Standardized collection protocols, comprehensive covariate measurement, and transparent reporting across models are essential to improve reproducibility and identify biomarkers that reflect genuine illness-related pathophysiology.

BackgroundMajor depressive disorder (MDD), a leading cause of disability worldwide, exhibits substantial heterogeneity in treatment outcomes. Patients who do not respond to standard antidepressant therapy account for the majority of MDDs disease burden. Risk factors have been implicated in treatment response, including genes impacting on how antidepressants are metabolised. Yet, despite its clinical importance, risk factors for treatment-resistant depression (TRD) remain unexplored in low- and middle-income countries (LMIC). We used data from the DIVERGE study on MDD to investigate the risk factors of TRD in Pakistan. MethodsDIVERGE is a genetic epidemiological study that recruited adult MDD patients ([&ge;]18 years) between Sep 27,2021 to Jun 30, 2025, from psychiatric care facilities across Pakistan. Detailed phenotypic information was collected by trained interviewers and blood samples taken. Infinium Global Diversity Array with Enhanced PGx-8 from Illumina was used for genotyping followed by DRAGEN calling to infer metaboliser phenotypes for Cytochrome P450 (CYP) enzyme genes. We defined TRD as minimal to no improvement after [&ge;]12 weeks of adherent antidepressant therapy. We conducted multi-level logistic regression to test the association of demographic, clinical and pharmacogenetic variables with TRD. FindingsAmong 3,677 eligible patients, polypharmacy was rampant; 86% were prescribed another psychotropic drug along with an antidepressant. Psychological therapies were uncommon (6%) while 49% of patients had previously visited to a religious leader/faith healer in relation to their mental health problems. TRD was experienced by 34% (95%CI: 32-36%) patients. The TRD group was characterised by more psychotic symptoms and suicidal behaviour (OR=1.39, 95%CI=1.04-1.84, p=0.02; OR=1.03, 95%CI=1.01-1.05, p=0.005). Social support (OR=0.55, 95%CI=0.44-0.69, p=1.4x10-7) and parents being first cousins (OR=0.81, 95%CI=0.69-0.96, p=0.01) were associated with lower odds of TRD. In 1,085 patients with CYP enzyme data, poor (OR=1.85, 95%CI=1.11-3.07, p=0.01) and ultra-rapid (OR=3.11, 95%CI=1.59-6.12, p=0.0009) metabolizers for CYP2C19 had increased risk of TRD compared with normal metabolisers. InterpretationThere was an excessive use of polypharmacy in the treatment of depression while psychological therapies were uncommon highlighting the need for more evidence-based practice. This first large study of MDD from Pakistan uncovered the importance of culture-specific forms of social support in preventing TRD, highlighting opportunities for interventions in low-income settings. Pharmacogenetic markers can be leveraged to predict TRD.

Background: Gamma oscillation dysfunction has been implicated in neuropsychiatric disorders. Restoring gamma oscillations via brain stimulation represents an emerging therapeutic approach. However, the strength of its clinical effects and treatment moderators remain unclear. Method: We conducted a systematic review and meta-analysis to examine the clinical effects of gamma neuromodulation in neuropsychiatric disorders. A literature search for controlled trials using gamma stimulation was performed across five databases up until April 2025. Effect sizes were calculated using Hedge's g. Separate analyses using the random-effects model examined the clinical effects in schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism spectrum disorder. For SZ and MDD, subgroup analyses evaluated the effects of stimulation modality, stimulation frequency, treatment duration, and pulses per session. Result: Fifty-six studies met the inclusion criteria (NSZ = 943, NMDD = 916, NBD = 175, NASD = 232). In SZ, gamma stimulation was associated with improvements in positive (k = 10, g = -0.60, p < 0.001), negative (k = 12, g = -0.37, p = 0.03), depressive (k = 8, g = -0.39, p < 0.001), anxious symptoms (k = 5, g = -0.59, p < 0.001), and overall cognitive function (k = 7, g = 0.55, p < 0.001). Stimulation frequency and treatment duration moderated therapeutic effects. In MDD, reductions in depressive symptoms were observed (k = 23, g = -0.34, p = 0.007). Conclusion: Gamma neuromodulation showed moderate therapeutic benefits in SZ and MDD. Substantial heterogeneity likely reflects protocol differences, highlighting the need for well-powered future trials.

BackgroundContemporary research indicates that psychedelics induce notable neurophysiological changes, some lasting weeks to months after a single dose. However, most evidence derives from acute administration studies and limited post-acute follow-ups. Long-term naturalistic psychedelic users remain critically underexamined, yet may exhibit distinct neurobiological profiles informing our understanding of persistent alterations following repeated exposure. MethodsWe recorded resting-state EEG in 57 long-term psychedelic users (abstinent [&ge;]30 days) and 49 matched non-users across two independent sites under eyes-open and eyes-closed conditions. We analyzed oscillatory power, signal complexity, and source-localized effective connectivity, focusing on five canonical frequency bands and regions of the Default Mode, Salience, and Central Executive Networks. Analyses included linear mixed-effects modeling for power spectra and complexity results and a rank-based approach combining ordinary least squares regression with randomization inference for effective connectivity. ResultsWe observed predominantly null findings. No significant between-group differences emerged for oscillatory power. Complexity comparison yielded results contrary to our hypothesis: psychedelic users exhibited lower complexity values in the eyes-open condition. Effective connectivity revealed no within- or between-network differences that would survive statistical corrections. Additionally, we report a few small-magnitude effects uncovered by exploratory analyses. Conclusions Long-term naturalistic psychedelic users showed largely non-significant differences in oscillatory power, complexity, and network connectivity compared to non-users -- across several measures commonly reported as altered in acute administration studies. These findings raise the question of whether psychedelics neurophysiological signatures persist during abstinence despite repeated prior use, or whether they reflect homeostatic receptor adaptation, individual variability, or contextual factors. Null, incongruous, or subtle effects contribute to the existing evidence base, yet underscore the need for replication in larger, more ecologically valid populations to advance the emerging field of psychedelic neuroscience.