European Neuropsychopharmacology

Psychedelic drugs are emerging as potentially efficacious tools for treating psychiatric conditions and probing the neural basis of consciousness. Although drug administration context is widely believed to shape psychedelic effects, it remains unclear whether it can independently generate placebo and nocebo effects resembling psychedelic experiences and side effects. In a pre-registered experiment, 78 non-clinical participants inhaled inert medical air under placebo and control conditions while completing a time perception task and a resting-state period. In the placebo condition, the gas was presented as nitrous oxide, whereas in the control, it was correctly identified. Placebo administration increased altered states of consciousness, ego dissolution, dissociation, and side effects, but did not significantly impact time perception. Predictive modelling indicated that placebo-induced psychedelic effects were predicted by trait responsiveness to verbal suggestion and absorption. These findings demonstrate that context alone can induce psychedelic effects, with implications for its causal role in psychedelic action.

Background: The incidence of antidepressant withdrawal reactions in longer-term users and the influence of dosage is insufficiently understood. Objectives: Informed by neuropharmacological models and user surveys, this study examined symptom change during tapering and if increases were specifically associated with reductions below 75% of the minimum effective dose. Design: This was a prospective longitudinal cohort study with seven assessments over six months. Methods: Altogether 32 Swiss adult primary care patients who were on antidepressants for at least six months and in stable remission were assessed at baseline (week 0) before they started tapering and after 2, 4, 6, 8, 16, and 26 weeks. Withdrawal symptoms were measured repeatedly using an adapted version of the Discontinuation-Emergent Signs and Symptoms Scale (DESS) and the main outcome was intra-individual symptom change during intervals. Antidepressant dose was standardized relative to the minimum effective dose in the treatment of depressive and anxiety disorders. Results: Across intervals, reductions below 75% of the minimum effective dose were associated with symptom increases, while reductions above that threshold or no reductions were associated with symptom decreases. After adjusting for potential confounders, the rate of clinically relevant symptom increases contingent on dose reductions below 75% of the minimum effective dose was 33%, as compared to 13% during intervals with no dose reductions (OR=3.2, 1.4 to 7.4). We thus estimated that 60% of the risk of clinically relevant symptom increases was attributable to pharmacological withdrawal effects. The adjusted incidence rates for clinically relevant and severe withdrawal reactions were 32% and 11%, respectively. Conclusions: Consistent with neuropharmacological research findings, we found that antidepressant withdrawal symptoms emerge mostly following reductions below 75% of the minimum effective dose, affecting about one-third of patients. Even small reductions may trigger clinically relevant withdrawal reactions in this lowest dose-range, stressing the need for personalized tapering plans.

Amitriptyline is commonly prescribed for chronic pain, yet treatment response and tolerability vary substantially. Genetic variation in CYP2C19 and CYP2D6 influences amitriptyline metabolism, but evidence linking pharmacogene status to clinical outcomes in chronic pain is limited. Amitriptyline is typically prescribed for chronic pain at lower doses than for depression, which may reduce pharmacogenomic effects on clinical outcomes. We analysed 1,146 participants with chronic pain from the Australian Genetics of Depression Study who reported amitriptyline use, treatment outcomes, and genotype data. Metaboliser phenotypes were assigned using PharmCAT. Associations with self-reported effectiveness and discontinuation due to side effects were examined using regression models adjusted for age and sex. Only CYP2C19 intermediate metabolisers showed nominally lower odds of discontinuation and reduced likelihood of reporting moderate effectiveness. Overall, pharmacogenetic phenotypes were not significantly associated with patient-reported amitriptyline outcomes in chronic pain, potentially reflecting the lower doses typically prescribed for pain management.

Abstract Background Ketamine has emerged as an effective rapid-acting treatment for treatment-resistant depression (TRD), producing significant antidepressant effects within hours of administration. Given ketamine's capacity to induce states of heightened neuroplasticity and psychological openness, psychotherapy may represent a meaningful complement to its pharmacological effects - facilitating emotional processing, cognitive restructuring, and the consolidation of therapeutic gains. However, the adjunctive potential of structured psychotherapeutic support in ketamine-based interventions remains largely unexplored. Methods This preliminary, non-randomized, open-label clinical trial evaluated the adjunctive effects of ketamine-assisted psychotherapy (KAP) in an outpatient setting. Forty-six patients with TRD received eight weekly sessions of subcutaneous esketamine (0.5-1.0 mg/kg) and were allocated into two groups: esketamine without psychotherapeutic support (n = 23) and esketamine combined with structured KAP encompassing preparation, dosing accompaniment, and post-session integration (n = 23). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory-II (BDI-II) at multiple timepoints during treatment and at follow-up assessments up to six months after protocol completion. Results Both groups showed significant reductions in depressive symptoms throughout treatment. The KAP group demonstrated greater clinical improvement by the end of treatment, with between-group differences on the MADRS emerging at sessions 7 and 8. MADRS response and remission rates were 52.2% and 34.8% in the KET group, and 78.3% and 78.3% in the KAP group, respectively. BDI-II scores indicated earlier subjective improvement in the KAP group, with between-group differences emerging as early as the second session and persisting across multiple timepoints. No significant between-group differences were observed during the six-month follow-up, with both groups maintaining symptom reductions comparable to end-of-treatment levels. Conclusions These findings suggest that structured psychotherapeutic support may be associated with early clinical response and remission rates in subcutaneous esketamine treatment for TRD, potentially through facilitation of emotional processing, psychological flexibility, and behavioural change. Further controlled studies are needed to clarify the specific contribution of psychotherapy, investigate the mechanisms underlying this interaction, and optimize integrated treatment approaches for TRD. The trial was registered at https://ensaiosclinicos.gov.br/rg/RBR-1072m6nv . Keywords: esketamine; treatment-resistant depression; ketamine-assisted psychotherapy; innovative therapies.

Background: The biological mechanisms linking generalized anxiety disorder (GAD) and COVID-19 remain poorly understood, despite substantial evidence of their comorbidity. To address this gap, we examined genetic and epigenetic factors underlying their co-occurrence. Methods: In a multi-ancestry sample of 893 participants, we conducted genome-wide and epigenome-wide analyses of GAD and COVID-19 severity. Integrating large-scale genome-wide datasets and information regarding methylation quantitative trait loci, complementary analytic approaches were used to identify regional methylation patterns, assess genetically regulated DNA methylation in blood and brain tissue, and evaluate causal loci shared between GAD and COVID-19. Results: GAD was associated with epigenome-wide significant variation in loci involved in chromatin regulation and synaptic signaling. Conversely, COVID-19-related epigenetic signals were enriched in immune-inflammatory and host-response pathways. Mild COVID-19 was epigenetically related to endothelial-inflammatory signals, while severe COVID-19 was linked to epigenetic changes implicated in myeloid and thrombo-inflammatory pathways. Epigenetic signals shared between GAD and COVID-19 implicated processes related to stress adaptation and tissue homeostasis. Genetically informed analyses identified 60 shared loci, including MAPT, ZFP57, and FBXL18, indicating pleiotropy between GAD and COVID-19 in genetically regulated DNA methylation variation. Brain-specific analyses further highlighted convergence in additional loci (i.e., MICB and HLA-DPB1), suggesting neuroimmune mechanisms underlying GAD-COVID-19 shared methylation patterns. Conclusions: These findings support that GAD and COVID-19 share epigenetic and genetic architecture involving pathways related to vascular integrity, immune function, and cellular adaptation, highlighting a potential neuroimmune basis for their co-occurrence.

Antidepressants are widely prescribed for major depressive disorder, yet only one-third of patients achieve remission after initial treatment. Previous genome-wide association studies (GWAS) of clinically assessed antidepressant response combined multiple antidepressant classes, potentially obscuring class-specific effects. This study focused on selective serotonin reuptake inhibitors (SSRIs), often first-line due to better tolerability. Data from 15 cohorts across four ancestries were integrated: European (N = 3887; 11 studies), East Asian (N = 1068; 4), African (N = 277; 1), and Admixed American (N = 250; 1). GWAS of non-remission and percentage improvement were conducted within cohorts, followed by ancestry-specific meta-analyses and trans-ancestry meta-regression. Single nucleotide polymorphism (SNP)-based heritability was estimated in European samples. Polygenic scores were used for leave-one-out prediction and to assess shared genetic architecture with psychiatric traits. Gene-level and gene-set enrichment analyses were also performed. No genome-wide significant variants were identified for either outcome in any ancestry-specific or trans-ancestry analyses. However, trans-ancestry meta-regression yielded eight independent loci with suggestive associations (p < 1 x 10-5) for non-remission and 17 for percentage improvement. Gene-set analyses revealed nominal enrichment of the serotonergic synapse pathway for non-remission. SNP-based heritability estimates were not significantly different from zero for either outcome. Better SSRI response was nominally associated with lower genetic predisposition to major depressive disorder, post-traumatic stress disorder, and schizophrenia. This study represents the largest trans-ancestry GWAS of SSRI response, highlighting emerging biological signals. Limited power emphasises the need for larger and ancestrally diverse cohorts to better characterise the genetic architecture of antidepressant response.

Mental illness poses a substantial global burden, yet existing psychotherapies and psychopharmacologies often produce limited outcomes. Psychedelic assisted therapies have emerged as potential transdiagnostic interventions. In particular, 3,4 methylenedioxymethamphetamine assisted therapy (MDMA AT) has generated interest for its rapid psychological effects and potential to enhance psychotherapy outcomes. However, the incremental efficacy of MDMA AT relative to control interventions across transdiagnostic outcomes remains unclear. Further, there have been emerging concerns regarding harm reporting quality in MDMA AT clinical trials. We conducted a systematic review and meta analysis of MDMA AT randomized controlled trials. Eleven publications representing eight controlled trials with 10 analyzed subgroups (n = 295 participants) were included in meta-analyses. Two additional secondary publications were included for harm reporting syntheses (k = 13 total). Across 114 extracted effect sizes, MDMA AT demonstrated a significant moderate-to-large incremental reduction in psychopathology relative to controls (g = 1.03, 95% CI [0.46, 1.60]), though heterogeneity was high (I squared = 76%). Incremental effects were larger versus inert placebos (g = 1.27) than active controls (g = 0.75). Symptom specific analyses indicated strong incremental effects for trauma reduction (g=1.46 [95% CI: 0.67, 2.25]) and smaller non-significant effects for depression (g=0.51 [95% CI: -0.06, 1.08]). Harm reporting quality synthesis showed only 23% of publications met high-quality reporting standards. Overall, MDMA AT demonstrates potential transdiagnostic efficacy, but small samples, confounding factors, and mediocre harm reporting highlight the need for larger more transparent clinical trials.

Background: Generalized anxiety disorder (GAD) is associated with substantial psychological burden, autonomic dysregulation, and limitations of existing pharmacological and psychotherapeutic treatments. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a promising non-invasive neuromodulation approach, but evidence regarding home-based application in GAD remains limited. Objective: To evaluate the feasibility, safety, and preliminary clinical and physiological outcomes of a home-based taVNS intervention in adults with psychologist-confirmed moderate-to-severe GAD. Methods: In this prospective single-arm feasibility study, 48 participants initiated a 4-week home-based taVNS intervention consisting of two daily stimulation sessions performed five days per week. Clinical assessments were conducted at baseline, Week 2, Week 4, and follow-up visits at Weeks 6 and 8. Ambulatory electrocardiographic monitoring was performed before treatment initiation, at Week 2, and at the end of treatment to assess heart rate variability (HRV) using the root mean square of successive differences (RMSSD). Primary outcomes included feasibility, safety, adherence, and change in clinician-rated anxiety severity (HAM-A). Results: Thirty-four participants completed the study and were included in the primary analyses. HAM-A scores decreased significantly from baseline to Week 4 ([EMD] -6.9, 95% CI -10.4 to -3.4, p = 0.001), with partial maintenance during follow-up. Improvements were also observed in Beck Anxiety Inventory scores, whereas changes in GAD-7, perceived stress, depressive symptoms, and sleep quality were not statistically significant. RMSSD increased significantly from baseline to Week 4 (EMD 6.7 ms, 95% CI 2.1-11.3, p = 0.009). Greater increases in RMSSD were associated with larger reductions in HAM-A (R^2 = 0.18, p = 0.031) and BAI scores (R^2 = 0.21, p = 0.019). No serious adverse events occurred. Mean adherence was 79.8%, and 73.5% of participants completed at least 70% of prescribed stimulation sessions. Conclusions: Home-based taVNS was feasible and generally well tolerated in adults with moderate-to-severe GAD. Preliminary improvements in clinician-rated anxiety severity and autonomic physiological measures were observed; however, the single-arm design precludes causal inference. These findings support further evaluation of home-based taVNS in adequately powered randomized sham-controlled trials.

Background: Participants in the ReINVEST randomised placebo-controlled trial of sertraline, conducted among men with high trait impulsivity and histories of violent offending, received structured clinical contact throughout the trial, including psychiatric assessments, nursing consultations, crisis support, and referrals to mental health and external services. We estimated the effect of placebo trial participation, compared with non-participation after baseline and single-blind run-in, on violent and domestic-violence reoffending. Methods: This prespecified secondary analysis included men from the ReINVEST trial pathway who completed baseline assessment and entered the single-blind run-in phase but did not proceed to randomisation, to inform the counterfactual. Violent and domestic-violence offences were identified from linked administrative records over 12- and 24-month follow-up periods. The adjusted difference in offending was estimated using two independent analytical approaches accounting for baseline differences. Additional analyses examined whether the effect varied by baseline clinical and criminal-history characteristics, whether pre-randomisation external referrals explained selection into placebo participation, and whether post-randomisation external referrals accounted for any part of the estimated effect. Results: Placebo trial participation was associated with lower offending across both outcome domains and follow-up periods. Placebo-standardised mean count differences for violent offending were -0.19 (95% confidence interval [CI] -0.38, -0.04) at 12 months and -0.22 (95% CI -0.51, -0.05) at 24 months. Corresponding differences for domestic-violence offending were -0.37 (95% CI -0.81, -0.14) at 12 months and -0.49 (95% CI -0.92, -0.22) at 24 months. The association was more apparent among men with a documented psychiatric history and, for domestic-violence offending, among those with higher baseline anger, irritability and aggression. Pre-randomisation referrals did not explain selection into placebo participation or materially alter the estimates. Post-randomisation referrals were observed in both groups, remained more common in the placebo group, and did not account for the observed association. Conclusion: Placebo participation in this trial involved sustained clinical contact and psychosocial support beyond exposure to inactive medication, and these non-pharmacological components may have contributed to lower reoffending. In placebo-controlled trials involving populations with high psychiatric morbidity and limited continuity of coordinated care, the clinical content of placebo participation should be explicitly characterised in trial design and interpretation.

Hoarding disorder (HD) affects approximately 2-3% of adults and is associated with substantial functional disability and limited access to evidence-based care. The aim of the current analysis was to examine the naturalistic effectiveness of therapist-delivered video cognitive-behavioral therapy (CBT) for HD in a large real-world sample, and to characterize individual-level treatment response, time-to-response, and moderators of outcome. This retrospective, observational analysis examined clinical data from 305 adults diagnosed with HD who received therapist-delivered video CBT through an online specialty therapy platform between September 2021 and February 2026. Hoarding symptom severity was assessed using the Hoarding Rating Scale-Self Report (HRS-SR). Linear mixed models examined symptom change from baseline to three timepoints: session 10, session 20, and each patient's final session. HRS-SR scores decreased from M = 22.4 (SD = 7.6) at baseline to M = 16.4 (SD = 8.2) at final session (Hedges' g = 0.81, 95% CI: 0.68-0.94). By the final session, median percent improvement was 25.0% [IQR: 3.0-46.7%]. A total of 39.3% of patients achieved [&ge;]35% HRS-SR reduction, 27.4% of patients who began above the clinical threshold achieved remission, 36.4% demonstrated reliable improvement, and 22.9% of eligible patients achieved clinically significant change. Among patients who achieved and maintained [&ge;]35% reduction through their final session (n = 120), median time to first response was session 9, with 54.2% responding within 10 sessions. Analyses of secondary outcomes showed significant improvements in clutter severity, depressive and anxiety symptoms, stress, quality of life, and functional disability (Hedges' g = 0.21-0.47). Greater baseline severity, more sessions, and longer treatment duration significantly moderated outcomes; prior OCD treatment history did not. Findings suggest that therapist-delivered video CBT for HD, delivered remotely in a real-world setting, produces outcomes consistent with controlled trials and may be a clinically effective and scalable approach for a condition historically underserved by mental health systems.

Background: Schizophrenia, bipolar disorder, and depression share substantial genetic liability. However, the molecular mechanisms underlying this shared architecture remain poorly characterized. In particular, the role of circulating proteins as potential mediators and therapeutic targets is not well understood. Methods: Based on large-scale genome-wide association studies, we constructed a latent psychiatric common factor using genomic structural equation modeling. We then performed proteome-wide Mendelian randomization to estimate the associations between circulating proteins and this shared liability, based on four independent proteomic cohorts. Protein-psychiatric common factor associations were prioritized through comprehensive sensitivity analyses and colocalization. We additionally performed tissue- and single-cell expression enrichment analyses and a systematic druggability assessment. Results: We identified 36 circulating proteins with evidence of association with the psychiatric common factor that withstood multiple sensitivity analyses. Several proteins showed distinct tissue-specific expression patterns, with enrichment in brain, immune, or liver tissues, highlighting convergent neuroimmune and systemic pathways. For instance, genetically predicted higher levels of MAPK3, FES, MRE11A, HS6ST3, OLFM1, BTN3A1, BTN3A2 and BTN3A3 were associated with increased psychiatric risk, whereas higher levels of CD40, ITIH3, and ITIH4 were associated with decreased risk. Druggability assessment identified CD40, MAPK3, FES, MRE11A and BTN3A1 as established or potential therapeutic targets. Conclusions: By integrating genetic, proteomic, and transcriptomic data, this study identifies circulating proteins that associated with the shared genetic effects on three major psychiatric disorders. These findings provide biologically grounded candidates for therapeutic targeting and offer insights into shared disease mechanisms.

In a single-blind randomized controlled trial, we investigated the effectiveness of real-time fMRI neurofeedback delivered in 7 runs over three sessions across two weeks in N = 65 patients with alcohol use disorder. The intervention targeted modulation of ventral striatal cue reactivity to alcohol-related cues as well as enhancement of prefrontal control mechanisms in the right inferior frontal gyrus. The study design incorporate three experimental groups that either were instructed to downregulate a ventral striatum signal, upregulate the right inferior frontal gyrus, or upregulate negative functional connectivity between these two structures. In two active control groups participants were instructed to either up- or downregulate the primary auditory cortex. We did not find an effect of ventral striatal downregulation or negative connectivity feedback, and a reduced striatal activation in the right inferior frontal gyrus upregulation group was accompanied by concurrent lower activation in the target structure, suggesting that our intended modulation approaches were not effective. Identified problems that might have contributed to this unexpected outcome might have been the use of continuous feedback presentation that potentially confuses regulation target and reward processing in the ventral striatum, counterintuitive regulation directions, a lack of explicit strategy guidance and transparency about the targeted process, and generally the difficulty to recruit a sufficient number of eligible voluntary participants for a well-powered study with a complex design. These insights emphasize the complex challenges of real-time fMRI neurofeedback interventions for the treatment of substance use disorders and could provide guidance for the development of more effective future approaches.

Despite their prevalence, the pathophysiology of depression and anxiety remains poorly understood. Although adversity is a known risk factor, the mechanisms and biological contexts through which it contributes to mood disorder symptoms remain unclear. Immune and mitochondrial adaptations have both been implicated in mood disorders, suggesting the biological embedding of adversity may involve both systems. However, inconsistencies in the literature remain, partly due to reliance on mixed peripheral blood mononuclear cell (PBMC) populations despite substantial variability in mitochondrial biology across immune cell subtypes. We therefore investigated associations between adversity, mood disorder symptoms, immune cell proportions, and immune cell-specific mitochondrial bioenergetics (enzyme activities and respirometry) in participants from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study (n=105, age 18-60, 68% female, 35% with mitochondrial disease). Depressive and anxiety symptoms were positively associated with the monocyte-to-lymphocyte ratio, suggesting a shift toward greater innate relative to adaptive immunity. Associations between mood disorder symptoms and immune cell count were stronger in those exposed to greater early life adversity. Mood disorder symptoms were negatively associated with lymphocyte maximal mitochondrial respiratory capacity (MRC). As expected, the associations between mood disorder symptoms and lymphocyte mitochondrial bioenergetics (enzyme-based MRC and respiratory measurements) were stronger and more consistent among individuals exposed to higher lifetime adversity compared to those with lower lifetime adversity. Overall, these results suggest a complex interplay between adversity, immune cell mitochondrial bioenergetics, and mood disorder symptoms, highlighting immune mitochondrial biology as a potential allostatic pathway linking adversity to psychiatric disorders.

The ability to adjust to changing environments (cognitive flexibility) and optimal decision-making are pivotal brain functions that govern successful human behavior. Anxiety and depressive disorders are strongly pervasive psychiatric conditions across the lifespan that profoundly disrupt mechanisms of attention, working memory, and decision-making. Although existing task evidence documents impaired decision-making and flexibility outcomes for both anxiety and depression, there is a growing need to systematically evaluate the role of anxiety and depression and to quantitatively compare the effects of these disorders on these domains. In the present study, we conducted a meta-analysis of anxiety and depression on decision-making and cognitive flexibility. We utilized a random-effects approach, given that a large amount of between-subject heterogeneity was anticipated. Given the scope of this meta-analysis, we used the machine learning tool asReview to more efficiently conduct a meta-analytic search. Across all outcomes, results showed anxiety and depression were associated with reduced cognitive flexibility and decision-making. These effect sizes were then tested for significance using a fixed-effects (plural) model. Subgroup analyses revealed no significant differences between anxiety and depression for either decision-making or flexibility outcomes, consistent with a transdiagnostic perspective. Results are contextualized in light of the biopsychosocial model and potential transdiagnostic factors.

Background: Aberrations in neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways are implicated in major depressive disorder (MDD). First-episode simple dysmood disorder (FE-SDMD) without metabolic syndrome offers a unique model to investigate early lipid alterations underlying NIMETOX pathophysiology. Methods: Plasma samples were collected from 88 university students (44 FE-SDMD, 44 healthy controls). Participants underwent comprehensive psychiatric and psychological assessments, including adverse childhood experiences (ACEs), negative life events (NLEs), depression, anxiety, suicidal behaviors, and insomnia. Untargeted lipid profiling was performed using LC-QTOF-MS, while indices of oxidative and nitrosative stress (ONS) and lecithin-cholesterol acyltransferase (LCAT) activity were assessed. Data was analyzed using machine learning approaches with recursive feature elimination and cross-validation. Results: FE-SDMD was characterized by increased ceramides (CER), diacylglycerides (DAG), triacylglycerides (TG), sphingomyelins (SM), bis-monoacylglycerol phosphates (BMP), cholestone, and fatty-acyl amino acids (FAAA). DAG, CER, and BMP were the strongest predictors of depression severity and physiosomatic symptoms, whereas cholestone, CER, and SM predicted suicidal behaviors. These lipid modules, together with lowered LCAT and increased ONS, explained substantial variance in depression severity (46.4%), physiosomatic symptoms (42.4%), cognitive-affective symptoms (37.9%), suicidal behaviors (30.1%), insomnia (32%), and anxiety (19.5%). ACEs and NLEs were strongly associated with CER (p<0.001), DAG (p<0.01), and cholestone (p<0.01). Conclusion: Early-stage MDD is characterized by distinct lipid dysregulations linked to psychosocial stress exposure, oxidative and nitrosative stress, and an indicant of impaired reverse cholesterol transport. These lipid modules may serve as early biomarkers and therapeutic targets in vulnerable populations.

Prader-Willi syndrome (PWS) is a rare multisystemic disorder characterized by obesity, endocrine dysfunctions, and psychiatric comorbidities, which imply frequent use of psychotropic medications. They account for atypical responses to standard dosages of psychiatric drugs. Pharmacogenetics could be part of the reason for this situation, potentially offering a valuable tool for individualized treatment. This study analyzed allelic and phenotypic frequency distributions of five of the main cytochrome P450 enzymes (CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A4) involved in psychiatric drug metabolism in 47 patients with genetically confirmed diagnosis of PWS and compared them to reference frequencies in the general European population. Allelic frequency comparisons between the European reference population and the overall PWS cohort revealed a significant global difference for CYP2B6, with CYP2C19 and CYP2D6 showing trends toward significance. Although no global allelic differences remained significant after false discovery rate correction, post-hoc analyses consistently identified an enrichment of reduced- or non-functional alleles CYP2B619 and CYP2D610 in patients with PWS. Predicted metabolizer phenotype analyses showed a significant shift toward intermediate metabolizers of CYP3A4 in the PWS cohort, with corresponding depletion of normal metabolizers. Subgroup analyses indicated that allelic differences were more pronounced in maternal uniparental disomy and non-deletion subtypes, particularly for CYP2B6, although no significant differences were observed between PWS genetic subtypes. Overall, results imply potential differences in metabolizing activity in PWS patients, and subsequent implications in drug efficacy and tolerability. These results support the idea that pharmacogenetic testing may improve therapeutic decision-making in PWS for psychiatric treatment. Larger studies are needed to confirm these preliminary results.

Abstract Introduction: Over 30% of adults with Attention-Deficit/Hyperactivity Disorder (ADHD) show an insufficient response to standard pharmacological treatments, which underscores the need for evidence-based alternative interventions. Methods: In this sham-controlled study, 30 adult outpatients with ADHD were randomized to 12 weeks of active or sham transcranial direct current stimulation (tDCS) as add-on to a digital cognitive behavioral therapy application (dCBT app). Participants received either active (2 mA, 20 min/day, 5 days/week) or sham tDCS with anodal (left) and cathodal (right) stimulation applied over the dorsolateral prefrontal cortex (DLPFC). In parallel, access to the dCBT app was provided for three months. ADHD symptoms were measured before and after treatment and after a three-month follow-up using the Adult Self-Report Scale (ASRS v1.1). Results: All scales showed an improvement over time with medium-to-large within-subjects effects (Cohens d: -.48 to -.75), irrespective of group allocation. Two additional sensitivity analyses including (1) participants with over 75% of planned (sham)-tDCS sessions and (2) those who logged into the dCBT app on at least 5 days (median split) confirmed results. Response was observed in 1/15 (6.7%) of the tDCS group and 2/15 (13.3%) of the sham-tDCS group, with no difference between groups (p = .543, phi = -.111). Compliance to (sham-)tDCS was high. tDCS usability was rated marginally lower in the tDCS group. Conclusions: tDCS as an add-on therapy could not produce additional improvement in ADHS symptoms. The results are discussed in terms of contextual and patient-related aspects. ClinicalTrials.gov Identifier: NCT06766214.

Background: While counterfactual thinking ('what could have been') guides adaptive decision-making, it remains unclear how this process is altered by the negative biases and motivational deficits characteristic of Major Depressive Disorder (MDD). Methods: We used a sequential economic decision-making task designed to emulate a volatile stock market to assess choice behavior in adults with or without MDD (Total N=178); a subset of these participants completed the task during functional MRI (N=53). The task allowed participants to make either positive ('invest') or negative ('short') bets, under either positive or negative contextual valence, defined by whether the immediately preceding stock price change was positive or negative. Fictive errors were defined as the difference between realized and best-possible outcomes. Results: Across the full cohort, group differences in behavioral adjustments to fictive error signals emerged exclusively under negative contextual valence, when stock prices decreased. Compared with controls, participants with MDD showed heightened sensitivity to invest-and-loss fictive errors, reflected in a greater reduction in subsequent bets (interaction beta = -0.63, p < .001), but blunted adjustment to short-and-gain fictive errors (beta = -0.86, p < .001). In the imaging cohort, blunted short-and-gain adjustment was accompanied by heightened anterior cingulate (ACC) activity and attenuated ventromedial prefrontal (vmPFC)-to-ACC coupling in MDD. vmPFC activity following negative market returns also tracked depression symptom severity. Conclusions: Depression selectively disrupts the use of counterfactual outcomes to guide adaptive choice under negative contextual valence, implicating altered frontocingulate function in maladaptive decision-making.

Background: Internet-based cognitive behavioral therapy (iCBT) is efficacious for panic disorder (PD), yet the mechanisms of change remain underspecified. Anxiety sensitivity (AS) is theoretically central to PD maintenance, but its role as a mediator has not been formally tested in Spanish-speaking populations using minimal-contact formats. This study evaluates the efficacy of the "Free from Anxiety" iCBT program and examines AS as a mediator of clinical outcomes. Methods: In a randomized controlled trial, 95 adults meeting DSM-IV-TR criteria for PD were assigned to an 8-week iCBT program with optional email support (n = 49) or a waiting-list control (n = 46). Primary outcome was PD severity (PDSS); secondary outcomes included anxiety sensitivity (ASI-3), general anxiety (BAI), and depression (BDI-II). Mediation was assessed via Baron and Kenny's framework with bootstrapping (5,000 resamples) to estimate the indirect effect of ASI-3 change on PDSS reduction. Results: The treatment group showed significant improvements across all measures compared to controls (PDSS: d = 0.76, 95% CI [0.10, 1.42]; mean d = 1.30). Mediation analysis confirmed that ASI-3 change partially mediated the treatment effect on PDSS (indirect effect = 1.85, 95% CI [0.36, 3.70]), accounting for 27.4% of the total effect. The direct effect remained significant (b = 4.89, p < .001). Intent-to-treat (ITT) analyses supported robustness (d = 0.47 to 1.47). Gains were maintained at 6-month follow-up (d = 1.19 to 1.26). Conclusions: iCBT reduces anxiety sensitivity as a partial mechanism of change, aligning with cognitive models of panic. These findings support Free from Anxiety as an evidence-based, viable first-step intervention for Spanish-speaking clinical populations within stepped-care pathways.

Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32E-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27E-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50E10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43E-237) and opioid use disorder (rg=1.01, P=4.40E-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.