European Neuropsychopharmacology

BackgroundAttention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by attentional deficits, hyperactivity and impulsivity that often persists into adulthood. While dysfunction of dopaminergic neurotransmitter systems has been observed, underlying mechanisms remain incompletely understood. Current treatments with methylphenidate and amphetamines show limited long-term effectiveness and do not address broader clinical needs. The endocannabinoid system represents a promising therapeutic target. Cannabinoid type 1 (CB1) receptors are highly concentrated in the prefrontal cortex and striatum, brain regions central to ADHD pathophysiology. The "dual pathway model of ADHD" describes deficits in inhibition-related executive functions and reward-related functions, both mediated by fronto-striatal networks. Striatal CB1 receptor availability correlates negatively with impulsivity. Given the interaction between dopaminergic and endocannabinoid systems, CB1 receptors may play a key role in ADHD pathogenesis. MethodsThis controlled study will investigate CB1 receptor availability in ADHD using positron emission tomography (PET) with the CB1-selective radiotracer [18F]MK-9470. The primary outcome is the CB1 receptor distribution volume (VT) in the striatum. Secondary outcomes include CB1 receptor availability in prefrontal cortex and other ADHD-relevant brain regions, plasma concentrations of endocannabinoids (anandamide, 2-arachidonoylglycerol), and validated neuropsychological assessments of attention and impulsivity. We will compare three groups (n=34 each): medication-naive participants with ADHD, methylphenidate-treated participants with ADHD, and healthy controls. Statistical analysis will employ ANOVA with post-hoc comparisons and correlation analyses between neuroimaging and behavioral measures. DiscussionThis first investigation of the endocannabinoid system in ADHD will provide crucial insights into disease mechanisms and identify potential therapeutic targets. Results may inform development of novel cannabinoid-based treatments and improve evidence-based therapeutic strategies for ADHD management. Trial registration: German Clinical Trials Register (DRKS-ID: DRKS00037526, Registration date: 25 September 2025)

BackgroundAntidepressants exert their therapeutic effects through ameliorating negative emotional biases that underpin depression. However, therapeutic gains may depend upon restructuring how emotional information is processed. This can be achieved through Cognitive Bias Modification (CBM), a technique for positively shifting recognition of emotional facial expressions. Here, we examined how CBM modifies emotional processing circuits in individuals with depression who were taking Selective Serotonin Reuptake Inhibitors (SSRIs). MethodsA double-blind Randomised Controlled Trial was conducted in 84 participants with depression who had recently started SSRI medication. Participants received five sessions of active or sham CBM over one week before fMRI scanning where they viewed emotional faces (happy, fearful, sad). ResultsAcross all emotional expressions, greater Blood Oxygen Level Dependent (BOLD) signal was observed in the inferior occipital gyrus for the active compared to sham CBM. Emotional-specific effects were observed in the medial Prefrontal Cortex (mPFC), with reduced BOLD signal in the active (compared to sham) group for viewing happy vs. fearful faces. Changes in BOLD signal were also associated with individual differences in response to CBM. Enhanced functional connectivity between mPFC and right Dorsolateral Prefrontal Cortex (rDLPFC) predicted improvement in depressive symptoms four weeks later. ConclusionsThese results indicate that CBM modifies the neural circuits involved in emotion processing in people with depression currently taking antidepressants. Converting these changes in emotional perception to improved depressive symptoms was related to changing mPFC-rDLPFC connectivity. Future trials are needed to test CBMs clinical utility as a simple, affordable and accessible adjunct therapy for depression.

IntroductionMechanism-of-action studies on Eye Movement Desensitization and Reprocessing have so far focused mainly on the presumed active component of bilateral stimulation (BLS). In this pilot study, a further potential working mechanism was examined for the first time, involving stimulation-induced changes in emotional valence. MethodsTwenty-five patients with posttraumatic stress disorder and 25 healthy controls between 19 and 64 years of age underwent a simulated intervention based on components of Eye Movement Desensitization and Reprocessing (EMDR). Each participant was presented with 18 individual script pairs, simulating different valence shifts (valence switch into neutral, valence switch into positive, no valence shift), whereas BLS vs. no BLS were applied. During the intervention, subjective and physiological emotional responses were measured. ResultsWhen valence shifted to positive or neutral, a significant change in treatment-relevant subjective and physiological effect measures was found compared to scripts without a valence shift. For stimulation type, no subjective, but significant physiological effects were observed: The controls showed a physiological de-arousal under BLS, indicated by a decreased skin conductance level, and the patients showed an accelerated heart rate and an increased M. zygomaticus activity. Significant interaction effects were observed: Under BLS, the arousal-reducing and valence-changing effects of negative to neutral switches increased. Interestingly, these BLS effects became conscious to the participants only when valence switches were applied. DiscussionThe findings provide new insights into the potential emotion-modulating physiological effects of BLS and its interplay with changes in emotional valence.

Isolating specific cognitive effects of antidepressant drugs is crucial to develop targeted and individualized treatment selection in psychiatry. In this double-blind, placebo-controlled study in healthy controls, we used computational modeling to characterize the cognitive effects of two classes of drugs for depression, escitalopram, a typical SSRI which increases serotonergic transmission, and agomelatine, which activates melatonin receptors and antagonizes 5-HT2C serotonergic receptors. 128 healthy participants were randomized to receive either escitalopram (20 mg), agomelatine (25 mg or 50 mg) or placebo for 8 weeks and performed two complementary learning tasks at three time-points allowing to measure early (3 days), intermediate (2 weeks) and delayed (8 weeks) treatment effects. The first task was a simple probabilistic instrumental learning task evaluating how participants learned from positive and negative feedback. The second task was a more complex reversal learning task devised to assess learning from positive and negative feedback in an unstable environment. At 8 weeks, both drugs improved accuracy in task 1 and decreased choice stochasticity in task 2 compared to placebo. Agomelatine 25 and 50 mg had an additional early beneficial effect on reward processing at 3 days whereas agomelatine 50 mg showed maximal effects at 2 weeks. Our study provides one of the very first cognitive evaluations of the delayed effects of antidepressant drugs in healthy volunteers. It reveals that they share common beneficial effect on learning along with pharmacological-specific effects. All observed effects varied highly over time, highlighting the non-linearity of the cognitive impact.

Evidence-based psychotherapies are first-line treatments for psychiatric disorders, yet response rates remain suboptimal. Noninvasive brain stimulation (NIBS) may augment psychotherapy by modulating treatment-engaged circuits. We conducted a systematic review and meta-analysis of randomized controlled trials comparing active NIBS plus evidence-based psychotherapy versus sham NIBS plus psychotherapy. Following Cochrane methods, we searched six databases through February 2025, screening 1,017 records. Twenty-eight trials (31 treatment arms; 1,506 participants) met inclusion criteria. Active NIBS combined with psychotherapy produced significantly greater symptom improvement than sham NIBS with psychotherapy (standardized mean difference = -0.38, 95% confidence interval [-0.68, -0.08]), with substantial heterogeneity. Moderator analyses revealed critical implementation parameters: repetitive transcranial magnetic stimulation (rTMS) showed significant benefit while transcranial direct current stimulation did not. Non-concurrent delivery--stimulation before or after psychotherapy sessions--was significantly effective, whereas concurrent administration was not. Among psychotherapy modalities, cognitive behavioral therapy combined with NIBS produced significant benefit. Human-delivered psychotherapy, but not computerized formats, significantly enhanced outcomes. By diagnosis, significant effects were observed only for anxiety disorders. Secondary analyses revealed significant anxiety symptom reduction specific to rTMS. Treatment integrity was under-reported: only 39.3% of studies used fully manualized protocols and 10.7% documented therapist adherence. Non-concurrent rTMS paired with human-delivered, manualized cognitive behavioral therapy emerges as the most effective strategy, particularly for anxiety disorders. These findings provide an evidence-based framework for optimizing combined treatment protocols and highlight the need for standardized psychotherapy fidelity monitoring in future trials.

BackgroundThe Antidepressant Medications: Biology, Exposure & Response (AMBER) research programme was established to investigate the biological mechanisms underlying antidepressant action and variability in treatment response. Generation Scotland holds detailed genomic, clinical, and health information with recontacting consent, making this cohort ideal for investigating these aims. MethodsWe deployed a questionnaire, developed with input from a Lived Experience panel, to the Generation Scotland cohort to gather data on their depressive symptoms, medication history, efficacy, and side effects to develop clinically meaningful phenotypes of antidepressant response. Invitations were sent to 15,117 Generation Scotland participants who were 18 years or older and consented to be recontacted. Between July and November 2025, 1,180 participants with a history of antidepressant treatment for depression completed the questionnaire. ResultsThe sample was predominantly female (78.1%), self-identified as White (98.6%), and older (median age 57 years) than the wider Generation Scotland cohort (median 49 years) and Scottish population (median 41.3 years). Participants reported heterogeneous depressive symptom profiles spanning mood, anxiety, cognitive, sleep, behavioural, and physical domains. One-third of participants (31.1%) had taken three or more different antidepressants. Selective serotonin reuptake inhibitors (SSRIs) were the most common class (89.1%). Using self-reported treatment duration, discontinuation patterns, and efficacy, we developed a stringent classification system to capture treatment response extremes, where 23.8% were classified as responders and 1.5% as non-responders, with the majority unclassified. ConclusionsQuestionnaire data will be linked with electronic health records to validate antidepressant response classifications. Following validation, 25 responders and 25 non-responders will provide biological samples for DNA methylation profiling and generation of patient-derived cell lines. These models will be exposed to SSRIs to identify gene expression signatures and biological pathways distinguishing treatment response, integrating with genomic and clinical data across the AMBER project. These findings will provide a valuable resource for future antidepressant response research. Plain Language SummaryDepression is a common mental health condition affecting millions of people worldwide. Antidepressant medications are the primary medication treatment, but response is highly variable with only about one-third of individuals achieving full symptom remission after their first medication trial. We dont fully understand why some people respond well while others dont. To help answer this question, the Antidepressant Medications: Biology, Exposure & Response (AMBER) research programme was established. This study utilised the Generation Scotland cohort, a large health study in Scotland. Between July and November 2025, we invited 15,117 Generation Scotland participants to complete a detailed questionnaire about their experiences with antidepressant medications. A total of 1,180 participants answered detailed questions about their depression symptoms, which medications they tried, how long they were on a medication, how well the medications worked, and what side effects they experienced. We found that peoples experiences with depression and antidepressants varied considerably. About one-third had tried three or more different antidepressants. Using strict criteria based on treatment duration, effectiveness ratings, and medication changes, we identified 281 people (24%) who responded very well to SSRIs (the most common type of antidepressant) and 18 people (1.5%) who did not respond despite trying multiple SSRIs. A key limitation is that all information was self-reported, so we will validate findings by linking questionnaire responses with medical records. In the future, we will collect blood samples from some participants to study the biological differences between responders and non-responders. This research will help us better understand why antidepressants work for some people but not others, which could lead to more personalised treatment approaches for depression.

Classical psychedelics have regained interest for their potential to treat psychiatric and neurological disorders, and explore neural mechanisms supporting perception, cognition, and mood. Acute psychedelic effects have been linked to increases in brain complexity and entropy, but it is unclear if these changes are specific to psychedelics or reflect more general psychoactive effects. Here, we examined whether brain complexity and entropy metrics can identify features specific to the psychedelic state. Using resting-state fMRI from three placebo-controlled crossover trials (N=79; 255 sessions), we compared LSD, psilocybin, and mescaline with psychostimulants MDMA and d-Amphetamine. Compared to stimulants, psychedelics produced significant increases in meta-state complexity, short-timescale multiscale entropy, and dynamic conditional correlation entropy. Both drug classes increased Lempel-Ziv and spatial complexity, and decreased absolute modularity. Our findings highlight psychedelic-specific effects on brain signals that distinguish the acute psychedelic state from other psychoactive drug effects and may be relevant for understanding their therapeutic potential.

Background At present, there are no approved pharmacological treatments for people at clinical high risk for psychosis (CHR-P). We sought to assess the acceptability of cannabidiol (CBD): a promising candidate treatment for this population. Methods CHR-P individuals completed a survey which assessed their views on the acceptability of CBD, its expected effectiveness and side effects, and on formulation preferences. Results The sample comprised 55 CHR-P individuals (24.3 years and 69% female). Most (91%) were familiar with CBD, and had previously used cannabis (64%), and around half (42%) had tried over-the-counter CBD. 75% were willing to take CBD as an intervention for mental health problems. Most participants anticipated fewer side effects with CBD than with existing medications, and preferred tablet or capsule formulations over liquids. Discussion CBD is perceived as a highly acceptable treatment among CHR-P individuals.

BackgroundBorderline personality disorder (BPD) involves emotional instability and stress sensitivity linked to oxytocinergic and HPA-axis dysregulation. This study examined oxytocin and cortisol responses to acute psychosocial stress and the modulatory effects of SSRIs and hormonal contraception. Methods93 female participants (45 with BPD with/without SSRIs and 48 healthy controls) underwent the Trier Social Stress Test. Linear and generalized linear mixed-effects models were applied to assess time, group, and hormonal contraception effects, and their interactions. ResultsDuring the stress task, both BPD groups reported significantly higher subjective anxiety and anger than controls. All participants showed increased salivary oxytocin (OXT) during stress anticipation, but post-task trajectories diverged: BPD participants without SSRIs exhibited a sharp OXT decline, whereas those on SSRIs mirrored the stable trajectory of controls. Hormonal contraception reversed the OXT decline in untreated BPD participants, resulting in a progressive increase during recovery. Cortisol (CORT) analyses revealed hyporeactivity in BPD participants without SSRIs, a pattern unaffected by hormonal contraception. A significant three-way interaction indicated that higher OXT levels were associated with higher CORT concentrations during late recovery specifically in the BPD SSRI group, a relationship that was marginal in untreated patients and absent in controls. ConclusionsOur findings confirm that neuroendocrine dysregulation in BPD is context-dependent and sensitive to pharmacological modulation. The ability of SSRIs and hormonal contraception to influence stress-response patterns, despite limited efficacy on core symptoms, highlights the importance of controlling for medication and hormonal status in future BPD biomarker research.

BackgroundIn 2020, Oregon became the first U.S. state to establish a regulated framework for adults to access psilocybin services using naturally-derived mushroom products. No studies have examined mental health outcomes among individuals receiving psilocybin in this context. AimsTo evaluate changes in self-reported symptoms of depression, anxiety, and well-being 30-days post-psilocybin session under the Oregon state-regulated model , and document session-related adverse events and doses consumed. MethodsThis was a naturalistic study (March 2024-April 2025) among adults [&ge;]21 years participating in a legal psilocybin services program. Online surveys were completed pre-session, 1-day, and 30-days post-session. Primary outcomes were change in depression, anxiety, and well-being symptoms pre-session to 30-days post-session evaluated using linear mixed-effects models (random effect: timepoint; fixed effects: sex, concurrent psychiatric medication use, age, session dose [total psilocybin equivalents, TPE, mg: psilocybin mg + 1.39 * psilocin mg]). Adverse events (e.g., hallucinogen persisting perception disorder [HPPD]) were assessed at 1-day and 30-days post-session. ResultsParticipants (n=88; median age 43 years; 52% male) were predominantly Oregon residents (53.4%), psychedelic-experienced (64.8%), and concurrently using psychiatric medication (46.6%). All outcomes improved significantly at 30-days post-session (p<0.001), including in sensitivity analyses stratified by concurrent psychiatric medication usage (p<0.001 all outcomes, both groups). Two participants (2.3%) reported symptoms consistent with HPPD at 1-day post-session, but none at 30-days. Mean dose was 27.8 mg (SD 8.2) TPE. ConclusionsPsilocybin sessions delivered under the Oregon regulatory model were associated with clinically meaningful improvements in depression, anxiety, and well-being 30-days post-session, supporting therapeutic effectiveness of legal psilocybin services.

Deficits in inhibitory control are common across a wide range of psychiatric disorders and are closely linked to symptom severity, including emotional dysregulation, anxiety, substance misuse, and self-harm, making them an appealing target for intervention. Cognitive training offers a low-cost, scalable, and non-invasive strategy to strengthen inhibitory control; however, most existing paradigms target only a single facet of inhibition and rarely account for environmental influences, such as affective context. To address these gaps, we developed a computerized inhibitory control training paradigm to simultaneously engage three components of inhibition: preemptive, proactive, and reactive, while embedding trials within positive and negative affective contexts to assess the impact of emotional stimuli. Across two online experiments, participants completed the GAMBIT task in one session (Experiment 1, N = 300) or repeated over three sessions (Experiment 2, N = 65). The task included No-Go trials to train preemptive inhibition, stop-signal trials for reactive inhibition, and stop-signal anticipation trials to train proactive inhibition. Affective images of differing valence were presented as background stimuli to evaluate their impact on inhibitory performance. In Experiment 1, participants showed higher accuracy on No-Go versus reference Go trials ({beta}=1.45, SE=0.09, p<.001), confirming successful manipulation of preemptive inhibition. Reaction times were slower during anticipation trials across two different conditions ({beta}=0.16, SE=0.04, p<.001; {beta} = 0.07, SE = 0.04, p = 0.047), consistent with proactive slowing when anticipating a potential stop signal. Additionally, positive affective images ({beta} = 0.10, SE= 0.009, p < 0.001) further slowed RTs, indicating emotional interference with proactive control. In Experiment 2, the pattern of higher No-Go accuracy was replicated ({beta} = 0.91, SE = 0.11, p < .001) and accuracy generally improved over sessions ({beta} = 0.38, SE = 0.06, p < .001). In anticipation trials, RTs become shorter across sessions (session 2: {beta} = -0.25, SE = 0.06, p < .001; session 3: {beta} = -0.45, SE = 0.06, p < .001), reflecting practice-related gains, and SSRTs decreased over time (F(2,56) = 6.26, p = .004), consistent with enhanced reactive inhibition. Proactive inhibition was modulated by affective images, with both negative ({beta} = 0.04, SE = 0.02, p = .039) and positive ({beta} = 0.16, SE = 0.02, p < .001) affective images associated with slower RTs. Participants also reported reductions in self-assessed temper control by the last session (W = 25.5, p = .007, q = .037, d = -0.51) and usability ratings were high (all means [&ge;] 3.87/5). Together, these findings show that this paradigm recruits multiple forms of inhibitory control and yields training-related improvements in both performance and affective outcomes. This provides preliminary validation of a scalable, fully online inhibitory control training tool targeting multiple dissociable inhibitory processes within affective contexts. The approach holds promise as an accessible transdiagnostic intervention to support symptom improvement across psychiatric disorders, with future work needed to evaluate clinical efficacy in patient populations.

BackgroundPsychedelics exert widespread effects on brain activity, but their impact on motor function is unclear. This is clinically relevant given the emerging interest in psychedelic-assisted physical therapy for disorders of motor function. This studys primary objectives examined the feasibility and safety of administering movement tasks following low-to-moderate doses of psilocybin in healthy volunteers. MethodsHealthy participants were randomly assigned three psilocybin doses consisting of either (1) 5mg, 10mg, and 15mg, or (2) 10mg, 15mg, and 20mg, with at least one week between doses. Movement tasks were administered during the acute drug effects. Participants, physiotherapists, and statisticians were blinded to the dosing order. Feasibility was assessed by evaluating completion of the de Morton Mobility Index and Functional Movement Exploration (measures of gross motor function). Safety outcomes included vital signs and adverse events. Additional exploratory motor outcomes included the Action Research Arm Test (assessing dexterity), Box and Block Test (Original and Modified versions) (combining dexterity with motor speed), Digit Symbol Substitution Test (combining motor speed with intellectual functions), and Reaction Time Ruler Drop Test (assessing reaction time). The 5-Dimensional Altered States of Consciousness and Ego-Dissolution Inventory assessed changes in states of consciousness. Blinding efficacy was assessed by asking participants and physiotherapists to guess the doses administered. ResultsThirteen participants were randomised: seven to 5mg, 10mg, and 15mg; six to 10mg, 15mg, and 20mg. One participant was unable to complete several movement tasks at 20mg. Nausea (n=8, 62%) and headache (n=7, 54%) were the most common adverse events. No serious adverse events or adverse events related to movement task administration occurred. Median values [interquartile ranges] remained near-perfect across doses for the de Morton Mobility Index (92.5-100.0 [85.0-100.0]), Functional Movement Exploration (100.0 [96.0-100.0]), and Action Research Arm Test (56.0-57.0 [52.0-57.0]). Baseline Box and Block Test (Original) median scores (65.0 [60.0-67.0]) improved to 79.0 [70.0-83.0] at 5mg and 4.5 hours post-dose (5mg-4.5H), and worsened to 57.5 [51.0-64.0] at 20mg-1.5H. Baseline Box and Block Test (Modified) median scores (48.0 [47.0-53.0]) worsened to 43.0 [35.0-45.0] at 20mg-1.5H. Baseline Digit Symbol Substitution Test median scores (73.0 [66.0-77.0]) improved to 87.0 [81.0-90.0] at 10mg-4.5H, and worsened to 62.0 [54.0-86.0] at 20mg-1.5H. Reaction Time Ruler Drop Test scores lacked consistent dose-related changes across participants. Changes in states of consciousness were greatest at 20mg. Participants and physiotherapists correctly guessed the administered dose 53% and 50% of the time, respectively. ConclusionsMovement tasks were feasible during psilocybin dosing up to 15mg. Impairments emerged at 20mg in tasks that combined motor and additional cognitive functions. These findings support the feasibility of performing complex movement tasks during psilocybin dosing and will inform the conduct of trials utilising psilocybin-assisted physical rehabilitation in neuropsychiatric disorders. 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 Key FindingsO_LIThere is growing interest for psychedelic-assisted physical therapy in neuropsychiatric disorders of motor dysfunction, however, the impact of psychedelics on motor function remains unclear. C_LIO_LIThis study investigated the feasibility, safety, and impact on motor function of administering movement tasks following low-to-moderate doses of psilocybin in healthy volunteers. C_LIO_LIThese findings support the feasibility of performing complex movement tasks during psilocybin dosing up to 15mg and will inform the conduct of trials utilising psilocybin-assisted physical therapy in neuropsychiatric disorders. C_LI

BackgroundNeuropsychological deficits are common in obsessive-compulsive disorder (OCD) and may influence functional and treatment outcomes. Only a few studies have effectively targeted these deficits, with most failing to show broad transfer of training. This study aimed to evaluate the efficacy of an integrated cognitive control training (ICCT) program on neuropsychological functioning in OCD patients and assess related changes in clinical and socio-occupational functions. MethodA single-group open-label design with pre-, mid-, post-treatment, and follow-up assessments was employed with 38 participants diagnosed with OCD, who were on stable doses of serotonin reuptake inhibitors (SRIs). The ICCT program, integrating task- and game-based cognitive stimulation with metacognitive strategy training and generalization exercises, included 24 hours of training over eight weeks across therapist-guided and homework sessions. The intervention was systematically adapted and validated, and its efficacy was examined across neuropsychological, clinical, and socio-occupational domains. ResultsThe intervention demonstrated moderate to large improvements in neuropsychological functioning (R{superscript 2}M range = .15 to .27) and self-reported cognitive difficulties (R{superscript 2}M = .58) and further demonstrated transfer to untrained domains such as OCD symptom reduction (R{superscript 2}M = .54), anxiety (R{superscript 2}M = .61), depression (R{superscript 2}M = .60), metacognitive regulation (R{superscript 2}M = .30), and socio-occupational functioning (R{superscript 2}M = .26). However, response inhibition saw only small improvements (R{superscript 2}M = .11). ConclusionThe ICCT program achieved both near and far transfer of cognitive training, improving neuropsychological, clinical, and socio-occupational outcomes. This contrasts with prior interventions with limited transfer of training. The small effect on response inhibition may reflect the trait nature of the deficit, assessment limitations, or gaps in the intervention. Future studies should use randomized control designs to validate and compare ICCT with other interventions.

Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to "any anxiety diagnosis". Additional genome-wide evidence to discern genetic differences between fear and distress is required. We conducted GWAS meta-analyses of fear (panic, agoraphobia, specific phobia, social anxiety disorder) and generalised anxiety disorder (GAD), measured using brief single-item and detailed symptom-based diagnoses from three datasets. We explored two control group criteria: phenotype-specific (fear/GAD) or broader anxiety/depression screening. We identified one SNP-based independent locus and three gene-level genome-wide significant (GWS) associations with fear (up to 35,523 Ncases; 157,447 Ncontrols). Four GWS SNP-based loci and three gene-level loci were associated with GAD (up to 60,879 Ncases; 117,064 Ncontrols). The genetic correlation between fear and GAD was significantly different from unity only when excluding a depression-enriched dataset and using phenotype-specific control screening (rg = 0.87; P = 9.32 x 10-3). Most complex traits had statistically similar genetic correlations with fear and GAD, including depression. Exceptions included general cognitive ability, educational attainment, and coronary artery disease, showing statistically stronger genetic correlations with fear than GAD, while bipolar disorder type I, anorexia nervosa, and neuroticism displayed the opposite pattern. Our findings partially support a distress-fear genetic distinction, but show stronger evidence for an overarching genetic liability to internalising psychopathology driving comorbidity across anxiety disorders and depression.

Externalizing spectrum disorders--spanning attention-deficit/hyperactivity disorder, conduct disorder, substance use disorders, and other disorders characterized by disinhibition--frequently co-occur within individuals due, in part, to shared genetic etiology. To advance understanding of this genetic architecture, we conducted a multi-ancestry, multivariate genome-wide association analysis of more than 4 million individuals, identifying 1,294 genomic regions linked to an externalizing factor. Fine-mapping and gene prioritization efforts identified 961 effector genes, with the putative causal variant associations showing robust replication in the All of Us Research Program sample. Bioinformatic analyses revealed a broadly distributed neural architecture with early and sustained involvement of GABAergic and glutamatergic neurons. Drug repurposing analyses further highlighted the role of GABAA receptors, as well as dopaminergic signaling, excitatory-inhibitory balance, and neurosteroid pathways. A genome-wide polygenic index predicted [~]12% of the variance in externalizing in independent cohorts of individuals with European-like ancestry, compared to [~]3% in individuals with African-like ancestry, and was associated with myriad health and life outcomes. Together, these findings map the shared genetic etiology of externalizing psychopathology and identify neurodevelopmental and synaptic mechanisms with translational relevance.

ObjectiveTo identify immunomodulatory drug targets with genetic evidence in major depressive disorder (MDD), probe symptom-level heterogeneity in their effects, and identify drug repurposing opportunities. MethodsWe used cis-Mendelian randomisation to evaluate the targets of 204 immunomodulatory compounds, including immunosuppressants, cytokine inhibitors, and anti-infectives. As exposures, we selected genetic instruments from nine genome-wide association studies (GWASs) of protein or gene transcript levels in blood and six brain regions, capturing peripheral and central inflammatory processes. As outcomes, we used summary statistics from GWASs of MDD and eight individual depressive symptoms. We prioritised targets based on consistency across tissues and robustness of Mendelian randomisation estimates, and prioritised compounds based on predicted therapeutic effects. ResultsWe prioritised 13 drug targets (C1S, CRBN, CUL4A, DEPE1, FCGRT, FKBP1A, HRH1, IL1RL2, IMPDH1, MMP7, POLE2, PRIM1, and S1PR4) associated with MDD risk. These are targeted by 46 compounds - mostly inhibitory - including doxycycline, sutimlimab, and pomalidomide, which may have therapeutic benefits for MDD. In symptom-level analyses, most targets showed heterogeneity across symptoms. Among prioritised targets, three showed consistent effects across more than half the symptoms, while the remainder showed symptom-specific or opposing effects between symptoms. ConclusionWe provide genetic evidence supporting the repurposing of immunomodulatory drugs for MDD, including compounds acting on novel therapeutic targets. Effects differ across depressive symptoms, suggesting that symptoms respond to different drug mechanisms. These findings highlight the importance of considering individual symptoms, rather than MDD as a unitary condition, when developing treatments with a broad spectrum of action or targeting specific symptom profiles.

ObjectiveThe most common forms of migraine are complex disorders characterized by significant clinical diversity. The genetic basis of migraine has been the subject of many studies but remains largely unknown. We present the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility risk loci through a case-control study, in order to unravel population-specific variants. MethodsGenotyping was conducted on 380 individuals using the Applied Biosystems Axiom PMDA array. A vast dataset of 8,031,293 single-nucleotide polymorphisms (SNPs) was available, providing a comprehensive scope for GWAS analysis. PRS models were created and tested on subsets of the genotyping data, and the optimal statistical significance threshold was assessed. ResultsWe detected nine risk loci corresponding to nine lead SNPs (ZNF385D, YTHDF3, NPS, RAP1A/INKA2, CTA-481E9.4/CTA-481E9.3, AC092079.1, PPHLN1, SMYD3 and AL355597.1 (near ADARB2)). Additionally, eleven variants, without any previous association to pathogenicity in migraine, were highlighted by the chosen PRS model. Among our results, a new locus within the NPS gene, representing a novel association with migraine, is a potential new target directly related to recent and effective migraine treatments. ConclusionsThese findings reinforce the importance of neurotransmitter release and synaptic transmission, as well as the involvement of vascular components, in migraine pathophysiology. This work underscores that GWAS can provide novel, clinically valuable insights into populational and disease-associated genetic landscapes, enabling therapeutic developments and bolstering personalized medicine strategies.

Major depressive disorder (MDD) is characterized by both physiological and psychological changes that impact daily function and quality of life. Despite advancements in treatment approaches, clinical outcomes remain variable, highlighting the need for reliable biomarkers to guide treatment selection and to monitor treatment responses. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) allows for the characterization of local cortical excitation and inhibition through TMS-evoked potentials (TEPs). However, interindividual variability and various artifacts have previously limited the utility of TEPs for biomarker development. We applied single-pulse TMS to the left dorsolateral prefrontal cortex (L-DLPFC), and recorded EEG responses in 28 individuals with MDD and 8 healthy controls. An individualized mapping procedure identified stimulation sites and intensities that minimized artifacts and ensured early TEP (<60 ms) deflections exceeded the predefined threshold of 6 V. We quantified the ratio between the second and first peak-to-peak amplitudes of the TEP, as excitatory and inhibitory mechanisms have been identified to contribute to these peaks. The TEP peak ratio differed significantly between MDD participants and healthy controls (p = 0.003), and correlated with depression symptom severity quantified with the Quick Inventory of Depressive Symptomatology Self-Report (r = 0.459, p < 0.05), Ruminative Response Scale (r = 0.656, p < 0.001), Patient Health Questionnaire (r = 0.368, p < 0.05), and Positive Valence Systems Scale (r = 0.332, p < 0.05). These correlations were not observed when an anatomy-based targeting method (Beam F3) was applied with the conventional stimulation intensity of 120% of the resting motor threshold. Our findings highlight the utility of a novel individualised mapping technique in capturing high-quality early TEPs through a real-time EEG readout for minimisation of artifacts and ensuring a minimum TMS-evoked response. The altered TEP peak ratio adds to the growing body of evidence that the excitation/inhibition imbalance plays a role in MDD neurophysiology and serves as a promising candidate biomarker that warrants further investigation.

ObjectivesTrauma-focused cognitive behavioural therapy (TF-CBT) is the established first-line treatment for paediatric posttraumatic stress disorder (PTSD), but access to evidence-based care remains limited. This study aimed to evaluate the feasibility and acceptability of a therapist-guided, 12-week, internet-delivered TF-CBT (iTF-CBT) programme for adolescents with PTSD, and to explore preliminary changes in PTSD symptoms. DesignSingle-group feasibility trial. SettingSave the Children, Sweden. ParticipantsTwenty-two adolescents (13-17 years, 82% female) with primary PTSD. InterventionsA 12-week, therapist-guided, internet-delivered TF-CBT comprising eight modules and parallel caregiver modules with joint child-caregiver activities. OutcomesFeasibility measures included recruitment pace, participant retention, treatment adherence (module completion), and therapist time. Acceptability was evaluated through satisfaction, credibility, negative effects, and reported adverse events. Preliminary treatment effects were evaluated as within-group changes in PTSD severity using independent evaluator-rated Clinician-Administered PTSD Scale (CAPS-CA-5) and the self-reported Child and Adolescent Trauma Screen 2 (CATS-2). Assessments occurred at baseline, during treatment, post-treatment, and at 1-month follow-up (primary endpoint). ResultsRecruitment was completed after seven months of active enrolment. Retention and adherence were high, satisfaction and credibility ratings were favourable, and no intervention-related serious adverse events occurred. Clinically meaningful within-group improvements were observed at the primary endpoint, with large reductions on CAPS-CA-5 (Cohens d = 1.27) and CATS-2 (Cohens d = 1.51). ConclusionsTherapist-guided iTF-CBT for adolescents with PTSD was safe, feasible, acceptable, and associated with clinically meaningful symptom improvements. These findings support further evaluation in larger, controlled trials to determine efficacy, cost-effectiveness, and long-term outcomes. Trial registrationClinicalTrials.gov NCT06185244. Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIFirst internet-delivered TF-CBT trial for young people with PTSD C_LIO_LIUse of clinician-rated PTSD symptoms (CAPS-CA-5) in combination with validated self-report measures. C_LIO_LIThe intervention was developed in close collaboration with clinicians, alongside contributions from young people. C_LIO_LIAbsence of a control group. C_LI

BackgroundThe frontoparietal network (FPN) has been strongly implicated in both the development of and recovery from major depressive disorder (MDD), making it a promising target for transcranial magnetic stimulation (TMS) therapy of MDD. However, commonly used TMS targeting approaches often co-stimulate multiple neighboring functional brain networks to varying degrees across individuals. We therefore aimed to develop a clinically feasible, standardized TMS coil placement that enables stronger and more selective stimulation of the FPN without requiring individual neuroimaging or neuronavigation. MethodsWe optimized the placement of a prototypical figure-of-eight coil in a population-based brain template by maximizing simulated electric field (E-field) strength within a representative FPN cluster. Based on this optimized placement, we derived a practical heuristic using EEG electrode positions and simple scalp measurements. The FPN-optimized placement and its heuristic were validated by comparing E-field hotspot coverage of the FPN and other functional networks against a clinically established, standard coil placement (Beam F3 method) in precisely mapped brains of 20 healthy individuals (15 female) and 20 patients with MDD (7 female). We further assessed robustness of FPN stimulation to coil tilt inaccuracies and the role of coil orientation. ResultsThe optimized heuristic places the center of the coil over the F5 electrode and orients its handle along the F5-AF7 axis. This placement yielded significantly stronger and more selective FPN coverage than the established clinical approach. Targeting was largely robust to tilt inaccuracies but sensitive to rotational deviations. DiscussionThis scalp-based F5-AF7 TMS coil placement enables selective and reliable targeting of the frontoparietal depression network in routine clinical settings. Whether it improves antidepressant efficacy compared to established targeting strategies should be evaluated in future clinical trials.