Psychological Medicine

There is a wealth of phenotypic literature on the interplay between mental health and social connections. However, how genetic propensity to mental health traits may be associated with distinct social connections phenotypes (i.e., structural, functional and quality aspects) is largely unexplored. Using polygenic scores (PGSs), we explored the associations between genetic propensity for five mental health traits (PGSdepressive-symptoms, PGSanxiety, PGSbipolar- disorder, PGSschizophrenia, PGSwellbeing) and four social connection phenotypes (social isolation, loneliness, social support and relationship strain). Linear regressions were conducted in a representative sample of unrelated older adults living in the UK, and analyses were controlled for age, sex, and principal components to account for population stratification. The results show that higher PGSdepressive-symptoms was associated with greater loneliness (B=0.11, CI-95%=0.07, 0.15) and relationship strain (B=0.09, CI-95%=0.05, 0.13) and lower social support (B=-0.07, CI-95%=-0.13, -0.01). Higher PGSanxiety was associated with higher social isolation (B=0.05, CI-95%=0.00, 0.10) and greater relationship strain (B=0.05, CI-95%=0.01, 0.09). Higher PGSbipolar-disorder was associated with greater loneliness (B=0.05, CI-95%=0.01, 0.09) and relationship strain (B=0.06, CI-95%=0.02, 0.10). Higher PGSwellbeing was associated with lower loneliness (B=-0.07, CI-95%=-0.11, -0.03), relationship strain (B=- 0.07, CI-95%=-0.11, -0.03), and social isolation (B=-0.07, CI-95%=-0.12, -0.02), and greater social support (B=0.14, CI-95%=0.08, 0.21). This suggests differential associations between different mental health PGSs and distinct aspects of social connections, indicating a nuanced picture. Our findings confirm that genetics play a role in having adequate social connections, which can be supported through social, community, and cultural schemes. They also highlight that genetic confounding is important when using observational data assessing the associations between mental health and social connections.

Altered affect and cognitive dysfunction are transdiagnostic, burdensome, and pervasive features of many psychiatric conditions which remain poorly understood and have few efficacious treatments. Research on the genetic architecture of these phenotypes and causal relationships between them may provide insight into their aetiology and comorbidity. Using data from the Lifelines Cohort Study, we conducted genome-wide association studies (GWAS) on positive and negative affect and four cognitive domains (working memory, reaction time, visual learning and memory, executive function). Using publicly available large GWAS on related - albeit distinct-phenotypes (depression, anxiety, wellbeing, general cognitive ability [GCA]) we conducted genetic correlation and Mendelian randomization (MR) analyses to examine genetic overlap and causal relationships. We identified one genome-wide hit (p<5x10-8) for reaction time, and many loci with suggestive associations (p<5x10-6; N range= 11-20 independent hits) for other phenotypes. For most phenotypes, gene mapping and tissue expression analysis of suggestive hits from the GWAS showed increased gene expression in brain tissue compared to other tissues. As predicted, negative affect is genetically correlated with mental health phenotypes (depression rg=0.51; anxiety rg=0.70; wellbeing rg = -0.71) and cognitive domains are genetically correlated with GCA and brain volume (rg [&le;] 0.66). Genetic correlations between negative and positive affect suggest that they are dissociable constructs (rg = -0.18) with negative affect having higher genetic overlap with GCA than positive affect (rg =-0.19 vs -0.06). This could indicate that negative affect has a higher shared neural basis with GCA than positive affect and/or GCA and negative affect may exhibit causal relationships. MR analyses suggest potential causal effects of higher GCA on reduced negative affect, reduced risk of depression and anxiety, and higher wellbeing, but little impact on positive affect. We also report evidence for potential causal effects of depression and lower wellbeing on reduced GCA. Taken together, these results suggests that GCA may be a valid target for negative affect (but not positive affect) and depression and wellbeing may be valid targets for GCA.

BackgroundAccess to evidence-based psychosocial interventions for adults with Attention-Deficit/Hyperactivity Disorder (ADHD) remains limited, despite strong patient demand for non-pharmacological options such as cognitive behavioral therapy (CBT). Digital interventions may offer a scalable, low-threshold solution to meet this need and complement existing care. MethodsThis pragmatic randomized controlled trial evaluated the effectiveness of attexis, a fully self-guided digital intervention based on CBT and mindfulness principles, as an adjunct to treatment as usual (TAU). A total of 337 adults with confirmed ADHD were randomized to either attexis + TAU or TAU alone. The primary outcome was ADHD symptom severity (Adult ADHD Self-Report Scale total score) at 3 months post-randomization (T1). Secondary outcomes included functional impairment, depressive symptoms, self-esteem, and health-related quality of life. Follow-up was conducted at 6 months (T2). ResultsIntent-to-treat analyses showed significantly lower ADHD symptom severity in the intervention group at T1 (baseline-adjusted mean difference = -5.0 points; d = 0.85, p < .001). Significant improvements were also observed across all secondary outcomes, and effects remained stable at T2. Responder analyses confirmed the clinical relevance of the findings. Subgroup analyses demonstrated consistent effects across sex, medication use, psychotherapy status, and treatment changes. No adverse events related to attexis were reported. Conclusionsattexis was effective in reducing ADHD symptoms and improving a broad range of functional and psychosocial outcomes. As a safe, low-threshold, fully self-guided intervention, it may serve as a valuable adjunct to routine care and help address existing gaps in access to psychosocial treatment for adults with ADHD.

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.

Background: Diminished Expression (DE) and Amotivation/Apathy (AA) are widely recognized as two main factors of negative symptoms. This study aimed to 1) examine the longitudinal stability of the DE-AA structure and its variation throughout a 5-year follow-up in people with first-episode psychosis (FEP), and 2) investigate whether DE and AA have distinct predictive value compared with the unitary construct of negative symptoms. Study Design: 227 participants from the EUropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and Genetics and Psychosis (GAP) studies were included at FEP and were followed up 5 years later. One-factor (global negative symptoms), uncorrelated two-factor (DE-AA), and correlated two-factor structures were modelled using confirmatory factor analysis. Regression analyses were applied to examine the associations between these factors and negative symptom trajectories, functioning, and quality-of-life outcomes. Study Results: The correlated two-factor model composed of DE and AA best fitted the data and exhibited 5-year stability. The regression model adjusted for AA accounted for more variance (59.2%) than global negative symptoms (52.8%) in explaining the enduring course of negative symptoms. Baseline AA was the only negative symptom factor that significantly predicted individuals' functional outcome at follow-up (B=-1.76, p=0.037). All negative symptom dimensions negatively predicted employment status, whereas lower educational attainment was primarily related to AA severity at baseline. Conclusions: Our findings support the validity and longitudinal stability of the two-dimensional (DE-AA) approach to negative symptoms in individuals with FEP. AA in particular exhibited distinctive predictive value, underscoring its potential clinical utility for early identification and the development of targeted interventions.

When the brain and body misalign, emotional experience and sense of reality can be disrupted. Although such atypical experiences are central to schizophrenia spectrum disorders (SSD), interoception, processing of internal bodily signals, remains poorly understood in individuals with SSD, particularly across subjective, behavioural, and neural domains. We tested whether SSD is associated with convergent alterations across interoceptive domains and whether these relate to clinical symptoms in a cross-sectional observational design. Patients with SSD (n = 53) and matched healthy controls (HC; n = 60) completed an EEG experiment comprising eyes-closed and eyes-open resting-state recordings and a heartbeat counting task (HCT), followed by self-report measures. Interoceptive accuracy was derived from the HCT, while cortical responses to afferent cardiac signals were indexed by heartbeat evoked potentials (HEP). In individuals with SSD, subjective interoceptive awareness was altered, characterised by impaired regulation and negative bodily appraisal, alongside elevated depersonalization. At the behavioral level, interoceptive accuracy was marginally lower. HEP positivity was attenuated, most clearly during HCT and, to a lesser extent, in eyes-open rest, over centro-parietal regions, consistent with context-dependent alterations in cortical processing of afferent bodily signals. Symptom-interoception links were largely modest, with depersonalization emerging as the most consistent correlate of clinical severity, suggesting that interoceptive disturbances in SSD may reflect a trait-like, disorder-central alteration. Together, these findings indicate that SSD involves pervasive disturbances in bodily self-experience, marked by impaired interoceptive regulation and by context-dependent neural attenuation during interoceptive engagement. This profile highlights interoceptive dysfunction as a disorder-central feature with potential prognostic and therapeutic relevance.

Background: Emerging evidence suggests that alterations in the gut microbiome may contribute to mental health outcomes through the gut-brain axis. However, older adults with post-traumatic stress disorder (PTSD) remain underrepresented in microbiome research. This pilot study investigated associations between PTSD symptoms, dietary fibre intake, cognitive function, and gut microbiome functional capacity in adults aged 50 years and older. Methods: Participants with PTSD symptoms and trauma-exposed controls (TEC) completed validated assessments of mental health, trauma exposure, and dietary fibre intake. A subset of participants provided stool samples for microbiome analysis and undertook cognitive function assessment. Quantitative PCR was used to assess phylum-level taxonomy and butyrate-producing bacterial pathways (terminal butyrate generating enzyme), with abundances normalised to the 16S rRNA gene. Results: Participants with PTSD demonstrated significantly greater mental health symptom burden and poorer performance on cognitive tasks related to executive function, working memory, and learning. Dietary fibre intake did not differ significantly between PTSD and TEC groups and no significant differences in overall microbial composition were identified at the phylum level. In contrast, differences were more apparent when assessing functional microbiome pathways, with butyrate kinase abundance significantly lower in PTSD participants than TEC participants. When stratified by fibre intake, a greater butyrogenic capacity was observed in the High fibre TEC participants compared to the Low fibre TEC participants, while little difference was observed in the PTSD fibre-stratified groups. Substantial inter-individual variation was also evident across both taxonomic and functional measures. Conclusions: These findings suggest that functional characteristics of the gut microbiome may provide greater insight into PTSD-related biological processes than broad taxonomic measures alone. Dietary fibre intake may be associated with greater butyrate-producing capacity in trauma-exposed older adults without PTSD symptoms, although this relationship appeared less evident among older adults living with PTSD symptoms. These findings support further investigation of microbiome function, diet, and cognition within the gut-brain axis. Larger studies incorporating metagenomic and metabolomic approaches are warranted.

BackgroundWe investigated treatment effects of Acceptance and Commitment Therapy in Daily Life (ACT-DL) on psychological flexibility (PF) and the moderating role of the therapeutic working alliance on these effects in patients with early psychosis. MethodsACT-DL is an ecological momentary intervention (EMI) combining face-to-face ACT with a smartphone app. In the multi-center INTERACT randomized controlled trial, n=148 early psychosis individuals were randomized to either treatment as usual (TAU as the control condition, n=77) or to ACT-DL in addition to TAU (ACT-DL + TAU as the experimental condition, n=71). We assessed global PF and the therapeutic alliance with self-report questionnaires. In addition, we used the experience sampling methodology (ESM) to assess PF with a momentary (in-the-moment and since-the-previous-beep openness) and an evening (daily PF) questionnaire. Assessments took place at baseline, post-intervention (POST), six (FU6), and twelve months (FU12) follow-up. ResultsGlobal (B=19.49 to 33.14; all P-values<.001) and daily PF (B=0.68; P-value<.001) improved equally in both conditions at each time point. Individuals in the ACT-DL condition improved more than those in TAU on momentary openness (in-the-moment openness at POST (B=0.32; P-value=0.007) and since-the-previous-beep openness at POST (B=0.33; P<.001) and FU6 (B=0.23; P-value=0.025). Client-perceived working alliance moderated in-the-moment openness such that larger improvements in openness at POST (B=0.05; P-value<.001) were found in ACT-DL in individuals with higher working alliance scores. ConclusionOur results provide partial support for the capability of ACT-DL to improve daily life measures of openness, and emphasize the importance of the therapeutic relationship in supporting processes of change.

Stroboscopic light stimulation (SLS) is a candidate non-pharmacological intervention that induces transient visual and affective experiences, with potential application in depression. Before efficacy testing, clinical development requires safety, tolerability and feasibility data. We report a staged, single-site programme in adults reporting depressive symptoms. Work Package (WP) 1 tested 11 SLS parameter sets for safety and tolerability. An interim bridge study assessed whether a low-phenomenology SLS control reduced subjective visual effects while preserving session context. WP2 randomised 84 participants to four weekly supervised 31-minute sessions of the intervention or a low-phenomenology control. In WP1, 31 participants were analysed; no severe adverse reactions occurred, mean discomfort was low (0.49/10), and the highest session-level upper 80% confidence limit was 1.13/10, well below the prespecified threshold. The interim study supported experiential separation between intervention and control. In WP2, endpoint data were available for 70/84 participants (83.3%): 39/42 in the intervention arm and 31/42 in the control arm. Overall retention met the criterion, but lower control-arm retention remains a design issue; protocol adherence was high, discomfort remained low, and no serious SLS-attributable adverse events occurred. Exploratory depressive-symptom changes suggested a possible BDI-II signal, but do not establish efficacy. Supervised SLS met key safety, tolerability, and feasibility criteria, and a lower visual-phenomenology active control can be carried forward, while masking and comparator credibility remain to be established. The next step is a diagnostically defined, CTU-governed Phase 2a feasibility trial that pre-registers a locked protocol and tests masking, credibility, retention and endpoint precision.

BackgroundThis study elucidates the intricate relationship between stressful life events and the development of ADHD symptoms in children, acknowledging the considerable variability in individual responses. By examining these differences, we aim to uncover the unique combinations of factors contributing to varying levels of vulnerability and resilience among children. MethodsUtilizing longitudinal data from the Adolescent Brain Cognitive Development study (baseline: N=6303, age=9.9), we applied Generalized Random Forest to model the non-linear relationships among genetic predispositions, brain features, and environmental factors. ResultsSignificant individual variability was observed in childrens ADHD symptoms post-stress, particularly at the 1-year and 2-year follow-ups. At the 1-year follow-up, increased vulnerability was indicated by heightened parental mental health problems and a lower polygenic risk score for smoking. By the 2-year follow-up, escalated parental mental health disorders, higher ADHD polygenic risk scores, and altered structural connectivity in the cognitive control network were significant contributors to individual differences. ConclusionsThese findings underscore the importance of integrating environmental, genetic, and neural variables to identify children vulnerable or resilient to developing ADHD symptoms following early-life stress. This study demonstrates how multimodal data combined with non-parametric machine-learning can advance precision psychology and psychiatry, aiding targeted support for affected children.

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 [&ge;]9.0 T-score points, p<.001) and correlated with sensory reactivity (SSP; r[&ge;]-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 Cohens d{approx}-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.

Accumulating evidence suggests alterations in neurocognitive, affective, interoceptive and autonomic processing in functional neurological disorder (FND), yet interventions targeting these processes remain underexplored. This study investigated the possible immediate and longer-term effects of a somatic yoga intervention on cognitive control, emotion regulation, state dissociation and affect, autonomic arousal, and interoceptive processing in FND. Twenty-three adults with FND completed six weeks of somatic yoga (N=12) or six weeks of a music-based relaxation control (N=11). At baseline, post-single session, and post-six weeks, participants completed laboratory measures of sustained attention, response inhibition, interoception, emotion regulation, and state dissociation and affect. Electrocardiography and galvanic skin conductance were recorded throughout. Linear mixed effects models assessed potential change on day one, immediately pre/post a single session, and from day 1 to the end of the six-week programme. After one session, stop signal reaction time, negative affect, and heartrate decreased in both groups ({Delta}=.69-.75). After one session and at six weeks, improved sustained attention, elevated positive affect, and reduced dissociation were seen in both groups, with a larger magnitude of change in yoga ({Delta}=.50-1.10). The yoga group exhibited fewer direction errors on the response inhibition task and shorter response times on the sustained attention task, with the opposite seen in the music group ({Delta}=.50-1.17). Both in the short- and longer-term, somatic yoga might lead to adaptive changes in attention and executive functioning, arousal, state affect and dissociation.

Background Multimorbidity is increasingly prevalent, and associated with worse clinical and psychosocial burdens. Interoception, the brain's ability to sense and interpret internal bodily signals, may contribute to multimorbidity, through its link with health behaviors, stress regulation, and mental health. This study examines whether self-reported interoceptive accuracy and attention is associated with multimorbidity, by identifying multimorbid subgroups and their interoceptive profiles. Methods Morbidity classes were identified through latent class analyses in two Dutch survey datasets, focusing on depression and alexithymia (DA-dataset; N = 671) and lifestyle factors (L-dataset; N = 1022). Linear regression analyses were used to assess interoceptive accuracy and attention (by the Interoceptive Accuracy Scale and Interoceptive Attention Scale respectively) among different subgroups. Results Multimorbid subgroups were characterized by older age, low socioeconomic position, and elevated physical, psychological, and behavioral problems. Multimorbid classes exhibited lower interoceptive accuracy (DA-dataset: B = -1.14, 95% CI = [-2.89, 0.62]; L-dataset: B = -2.36, 95% CI = [-3.83, -0.89]) and higher attention (DA-dataset: B = 3.62, 95% CI = [0.97, 6.27]; L-dataset: B = 1.07, 95% CI = [-1.42, 3.56]) compared to healthier classes. Conclusion Multimorbid populations demonstrated lower interoceptive accuracy and higher interoceptive attention. This highlights the psychosocial complexity of multimorbid populations which may impact their self-management and health behavior. These findings underscore the need to expand treatments to include psychosocial domains for multimorbid patients.

BackgroundEating behaviour and sleep changes are core diagnostic features of depression, contributing to the heterogeneity of symptoms. Depression demonstrates substantial phenotypic and genetic overlap with sleep disturbances and eating behaviours, yet previous genetic research has predominantly examined these relationships at the disorder level rather than investigating specific symptom patterns. MethodsWorst-episode depression symptoms and core eating behaviours from the UK Biobanks second Mental Health Questionnaire were investigated to uncover the underlying factor structure, indicating latent variables describing symptom clusters (i.e., weight/appetite, emotional symptoms, sleep disturbances). Genome-wide association studies were run for the derived latent variables. Linkage disequilibrium score regression estimated single nucleotide polymorphism heritability and genetic correlations between the latent variables and with other relevant psychiatric and metabolic phenotypes. ResultsA four-factor model best fit the data, identifying the symptom clusters of (1) increased appetite/weight (including binge eating), (2) fatigue/anhedonia, (3) decreased appetite/weight, and (4) negative self-perception. The two appetite/weight factors were negatively correlated both phenotypically and genetically, indicating distinct symptom pathways. Factor SNP-based heritabilities were around 6%, and GWAS identified one associated SNP in the FTO gene for increased appetite/weight. Genetic correlation analyses revealed distinct patterns across BMI, sleep traits (e.g., insomnia, short sleep), and psychiatric conditions, including PTSD and anxiety. ConclusionsThese findings demonstrate the multidimensional and heterogeneous nature of depression at both phenotypic and genetic levels and provide evidence for subtyping of depression. Symptom-level analyses provide valuable insight into the complex aetiology of depression.

Mind wandering has been linked to a wide range of psychiatric conditions, yet most studies have examined these associations in isolation. Given the substantial comorbidity across the psychopathological spectrum, it remains unclear whether elevated mind wandering reflects a general marker of psychopathology or a more specific attentional-control deficit shared across symptom dimensions. To address this, we adopted a dimensional, transdiagnostic approach in a non-clinical sample (N = 376), simultaneously modeling seven symptom dimensions: ADHD, depression, obsessive-compulsive tendencies, schizotypy, autistic traits, hypomania, and eating disorder symptoms. At the bivariate level, mind wandering correlated positively with all symptom dimensions. However, when the substantial shared variance across dimensions was accounted for in both frequentist and Bayesian multivariate regression models, only ADHD symptoms emerged as a unique predictor ({beta} = 0.53; BF{square}{square} > 1000), with all remaining predictors yielding negligible unique contributions and Bayes factors supporting the null hypothesis. These findings suggest that previously reported associations between mind wandering and diverse psychopathological symptom dimensions largely reflect a shared liability with ADHD-related attentional dysregulation, rather than disorder-specific mechanisms. This positions mind wandering as a marker of attentional dysregulation more closely tied to ADHD symptomatology than to general psychopathological burden.

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.

We evaluated whether oxytocin improves social-emotional reciprocity in children and adolescents with autism spectrum disorder (ASD) by conducting a secondary, hypothesis-driven reanalysis of the SOARS-B trial, the largest randomized clinical trial of intranasal oxytocin to date involving over 272 youth. We used a machine learning approach to construct data-driven composite outcome measures maximally sensitive to treatment from the Aberrant Behavior Checklist modified Social Withdrawal (ABC-mSW) and Social Responsiveness Scale-2 Emotion Recognition (SRS2-ER) subscales. Permutation testing rigorously controlled the Type I error rate under outcome learning. Oxytocin significantly increased emotional responsiveness in the learned ABC-mSW composite (mean Cohens d = -0.25, p = 0.014) and improved social-emotional reciprocity in the learned SRS2-ER composite (mean d = -0.43, p = 0.022) compared to placebo. Both effects replicated in the open-label phase, with prior placebo participants also improving on the ABC-mSW composite (mean d = -0.30, p = 0.039) and the SRS2-ER composite (mean d = -0.22, p = 0.041) after crossing over to oxytocin. We thus provide robust evidence that oxytocin enhances social-emotional reciprocity in ASD - a rare finding given that most pharmacologic trials for core ASD symptoms are negative. The findings also highlight the value of outcome learning for detecting nuanced treatment effects and support oxytocins potential as a targeted intervention in ASD. Prospective, preregistered trials should replicate these effects to strengthen the evidence base. Lay SummaryWe found that the hormone oxytocin may help children and teens with autism improve how they share and respond to emotions with others. Using new computer methods, we discovered that oxytocin helped increase social connection and emotional responsiveness in ways that previous studies often missed. These results should be confirmed in new studies but suggest that oxytocin could be useful for improving social skills in autism.

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 SRQ-20 screens common mental distress in low- and middle-income countries, yet its equivalence across groups, especially armed-conflict exposure, is rarely tested with methods that separate true invariance from an underpowered null. We evaluated its psychometric properties and measurement equivalence in Colombian adults. Methods. In 10,865 adults from the 2015 Colombian National Mental Health Survey, we assessed dimensionality, fitted a two-parameter logistic (2PL) model, and tested equivalence across armed-conflict exposure, sex, and region using multiple-group models with purified anchoring and freely estimated group means, separating true distress differences from item bias. Item functioning was equivalence-tested against a {+/-} 0.10 band on signed expected-score differences (SIDS), with test-level differential test functioning (DTF) plus severity-graded and design-weighted sensitivity analyses. Criterion validity used design-weighted ROC against 12-month CIDI diagnoses. Results. The scale was essentially unidimensional (one-factor CFI = .945, rising to .971 with four content-redundant item pairs modelled; explained common variance = .71) and fit the 2PL well, with high conditional reliability at the cut-points (.93-.94). Once true distress differences were separated from item bias, the SRQ-20 was equivalent across armed conflict exposure (all |SIDS| < .10, maximum .03; net DTF {approx} 0.1 points) and region, holding even among directly victimised adults; sex was partially invariant (three items; DTF {approx} 0.85 points). Design-weighted AUC was .88 (major depression) and .84 (any disorder). Conclusions. The SRQ-20 measures distress equivalently across armed-conflict exposure (including direct victimisation) and region in Colombian adults, supporting exposed-non-exposed comparisons within this population; raw-total sex comparisons carry a small, quantifiable bias. The 20-item form is recommended.

BackgroundPsychomotor retardation is characterised by slowed motor and cognitive processes. Although associated with greater illness severity in depression, its relationship with treatment response is unclear. We examined whether psychomotor retardation is associated with treatment outcomes in depression. MethodsWe conducted a secondary analysis of individual participant data from nine randomised controlled trials of pharmacological, psychological and exercise-based treatments for unipolar depression in primary care. Self-reported psychomotor retardation was assessed at baseline using the Revised Clinical Interview Schedule. The primary outcome was the standardised z-score of each trials validated self-report depression measure at 3-4 months post-randomisation; the secondary outcome was remission. Within-study regression models were adjusted for established prognostic factors, with secondary analyses additionally adjusting for baseline core depressive symptoms and depression severity. Effect estimates were pooled using random-effects meta-analysis. ResultsAmong 4,290 participants, 2,754 (64.2%) reported psychomotor retardation. Psychomotor retardation was associated with greater depression severity at follow-up (pooled z-score = 0.184, 95% CI 0.059-0.309, p = 0.004, I{superscript 2} = 68.7%) and lower odds of remission (pooled OR = 0.737, 95% CI 0.577-0.941, p = 0.015, I{superscript 2} = 57.7%), adjusting for age, sex, ethnicity, marital status, employment status and allocated treatment. Findings were robust to adjustment for baseline core depressive symptoms but not after adjustment for full baseline severity. ConclusionsPsychomotor retardation is associated with poorer treatment outcomes in depression, though this may reflect underlying severity. Recognition of psychomotor retardation may help identify patients at risk of poorer response and inform clinical management.