The debate on euthanasia for mental suffering in young people in The Netherlands has become highly polarised, with a novel, apparently epidemiological argument taking centre stage: that psychiatric euthanasia is necessary to prevent suicide. This article evaluates that claim. Using data from 353 young applicants (annual suicide risk 2.9%) and optimistic assumptions (80% sensitivity and specificity), the number needed to treat was 10 and the number needed to harm 9. Thus, ten youths would need to undergo assisted dying to prevent one suicide, and nine would die without a preventive purpose having been served. Empirically and ethically, the prevention argument does not appear to hold; real prevention requires other, previously well-debated factors such as relational continuity, trauma-informed care and social inclusion in response to mental suffering.

BACKGROUND:Sex differences in psychosis pathoetiology are insufficiently understood. This study explores how childhood adversity (CA) and coping mechanisms relate to psychosis expression (PE) across males and females in the general population. METHODS:Data from the TwinssCan project (males: n = 312; females: n = 478) were used. The Childhood Trauma Questionnaire assessed CA domains. The Utrecht Coping List assessed coping strategies. Psychosis expression was assessed using the Community Assessment of Psychic Experiences (CAPE). Mixed linear regression analyses examined sex-stratified associations of CAPE scores with CA, coping strategies, and their interactions. RESULTS:Emotional abuse (EA) was associated with increased total CAPE scores (T-CAPE), explaining the greatest variance among CA across sexes. Sex-specific effects showed that sexual abuse (SA) and physical abuse (PA) were linked to higher T-CAPE in females, whereas physical neglect (PN) was linked to higher T-CAPE in males. Passive-reacting was associated with increased T-CAPE, explaining the greatest variance among coping styles across both sexes. Sex-specific effects showed that, in females, seeking social support was linked to decreased T-CAPE, while emotional expression increased it. The only sex-shared interaction effect was between reassuring thoughts and emotional neglect (EN), associated with decreased T-CAPE. In females, social support (× PA/PN/EA), reassuring thoughts (× PA/PN), and palliative-reacting (× PN/PA) were associated with decreased T-CAPE, while passive-reacting (× EN) increased it. In males, avoidance (× SA/PA) and passive-reacting (× PN) were associated with increased T-CAPE. CONCLUSIONS:Sex differences in the associations of PE with CA and coping underscore the necessity for sex-specific interventions that promote adaptive coping strategies.

Instead of trying to refine diagnoses, we should focus on how best to give people the care that they need. Instead of trying to refine diagnoses, we should focus on how best to give people the care that they need.

Background The vulnerability-stress framework guiding gene-environment interaction (GxE) research overlooks the role of positive experiences. The Differential Susceptibility (DS) model offers a broader perspective, suggesting that individuals vary in sensitivity to both negative and positive environments. This study aimed at replicating previous DS research by examining interactions between polygenic scores for environmental sensitivity (PGS-ES) and positive and negative early exposures on subclinical psychosis and internalizing psychopathology, functioning, and wellbeing.Methods The sample consisted of 638 twins from the first wave of the TwinssCan study, a general population twin cohort. PGS-ES and adversity, bullying and positive experiences in childhood were collected, along with assessments of psychotic, affective, functioning, and positive mental health. GxE interactions were tested under a competitive-confirmatory approach.Results DS effects were found for the interactions between PGS-ES and all environmental exposures on schizotypic eccentricity and functioning. Adolescents with high genetic sensitivity were rated as more eccentric and less functional under childhood adversity but were rated as less eccentric and better adjusted under childhood favorable conditions. DS also resulted from the interaction between PGS-ES and positive childhood on social coping. No significant models emerged for internalizing or wellbeing.Conclusion Findings overall supported DS, indicating that genetic sensitivity to the environment operates in a "for better and for worse" manner depending on the quality of environmental exposures. It extends initial evidence that DS applies to nonclinical psychosis expression and highlights the importance of considering the full spectrum of environmental conditions to understand both risk and opportunity factors in GxE.

Introduction: Despite the growing interest in complementary healthcare, limited data are available about professionals' perceptions of collaboration with complementary healthcare providers in mental healthcare. This study aims to gain insight into the feasibility of collaboration between general practitioners and practice nurses and complementary healthcare providers in the Amsterdam Southeast region for persons with mental health concerns. Methods: A qualitative exploratory study was conducted using grounded theory procedures. Participants were recruited through a combination of purposive and snowball sampling strategies. Four general practitioners and 11 practice nurses participated in two focus groups and 4 individual interviews. Data collection continued until no substantially new themes emerged within the achieved sample. The constant comparative method was used for data analysis. Findings are reported in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. Results: The analysis yielded one central category, 'Person-centred care', supported by two related categories, 'Accessibility' and 'Trust'. Together, these categories reflected the needs, experiences, and value judgements of general practitioners and practice nurses regarding collaboration with complementary healthcare providers. Conclusion: To tailor mental healthcare to people from non-Western cultural backgrounds, practitioners and participants perceived mind-body interventions as compatible with non-Western health concepts, suggesting a possible role in bridging communication barriers. General practitioners and practice nurses indicated a need for more training and information about complementary and alternative medicine in this context. Referrals to complementary healthcare providers are influenced by professional experience and established networks. Complementary healthcare providers have a responsibility to improve accessibility, including contributing to upto-date regional social mapping and integration within referral systems. This study highlights that the affordability of complementary medicine in lower-income regions, such as Amsterdam Southeast, remains a significant barrier. Funding: This research was supported by Regieorgaan SIA, part of the Dutch Research Council (NWO) under grant number PD01.003 and RBCZ organisation for complementary health practitioners in the Netherlands.

Social isolation and loneliness are associated with schizophrenia, yet their distinct genetic contributions and developmental pathways across the psychosis spectrum remain poorly understood. Using data from the EU-GEI study (2045 patients and 2456 healthy controls), we examined whether genetic liability to loneliness and social isolation increases psychosis risk through a two-step strategy: first testing whether polygenic scores (PGS) for loneliness and four isolation-related traits (derived from UK Biobank GWAS) were associated with first-episode psychosis (FEP), schizophrenia-spectrum disorders (SSD), symptom dimensions, and retrospectively reported loneliness and social isolation during childhood and adolescence; and second testing whether these developmental experiences mediated the relationship between genetic liability and psychosis. Genetic liability to loneliness (LNL-PGS) was associated with increased psychosis risk in the combined sample and specifically with FEP, independent of schizophrenia and depression genetic risk, with stronger effects in males. In contrast, a PGS indexing frequency of family and friends’ visits (VISITS-PGS), as a proxy for objective isolation, was associated with SSD diagnosis—particularly in females—and greater negative symptom severity. At the developmental level, LNL-PGS predicted prolonged loneliness during adolescence (ages 12–16) among patients, especially males, while VISITS-PGS only predicted lower sociability in childhood in healthy controls. Mediation analyses revealed that adolescent loneliness partially mediated the association between LNL-PGS and psychosis risk, accounting for 21% of the total effect and up to 27% in males. Together, these findings support partially distinct genetic and developmental mechanisms—with sex-specific contributions—linking perceived loneliness and objective social isolation to psychosis risk, and highlighting adolescent loneliness as a potential target for early preventive interventions.

BACKGROUND AND HYPOTHESIS:Previous research in both clinical and non-clinical populations has suggested an association between intelligence quotient (IQ) and psychosis. The social defeat hypothesis posits that low status and repeated humiliation increase the risk of psychosis. The present study investigated the relationship between IQ and subclinical psychosis in the general population, while also examining the potential mediating and confounding roles of psychosocial stressors and core schemata. STUDY DESIGN:We analyzed data from 1497 healthy controls in the EU-GEI dataset, a multicenter study conducted across six countries. IQ and the positive dimension of subclinical psychosis (measured by the positive dimension of the Community Assessment of Psychic Experiences questionnaire) were analyzed using linear regression models adjusting for age, sex, childhood trauma, stressful life events, and core schemata (positive and negative schemata). Mediation analysis was conducted to explore indirect effects. STUDY RESULTS:IQ was associated with subclinical psychosis. The results remained statistically significant after adjustment for several confounders. In the mediation analysis, IQ had no total or direct effect, but a small negative indirect effect through negative-other schemata (ß = -0.040; 95% Confidence Interval: -0.55, -0.024), childhood trauma (ß = -0.029; 95% CI -0.042, -0.016), negative-self schemata (ß = -0.009; 95% CI -0.017, -0.001), and stressful life events (ß = -0.012; 95% CI -0.021, -0.003). CONCLUSION:These findings support the idea that cognitive vulnerability is associated with an increased risk of subclinical psychotic symptoms, with psychosocial stressors and core schemata possibly playing a mediating role, in line with the social defeat hypothesis.

OBJECTIVE:Autistic traits (ATs) are associated with difficulties in social functioning, but their impact on the quantity and the quality of daily-life social interactions is not yet fully understood. Hereby, we examined the relationship between AT and daily-life social interactions in adolescents and young adults. METHODS:Data were derived from the TwinssCan cohort (N = 593). ATs were assessed using the Autism Spectrum Quotient (AQ), while the quantity and the quality of daily-life social interactions were evaluated using the Experience Sampling Methodology. Multilevel regressions were performed, with the AQ as the independent variable and each social/solitary quantity/quality variable as the dependent variable. Models were adjusted for age, sex, and general psychopathology, measured with the Symptom Checklist-90. RESULTS:No significant association was found between AQ total scores and quantity of social interactions. However, AQ total scores were significantly associated with quality of social interactions. Higher ATs were associated with an increased preference to be alone (B = 0.04, 95% CI 0.01-0.07), less pleasure while in-company (B = -0.02, 95% CI -0.04 to -0.01), less feeling of safety while in-company (B = -0.02, 95% CI -0.04 to -0.002), and less feeling of belongingness (B = -0.02, 95% CI -0.03 to -0.001). ATs were differently associated with the quality of social interactions depending on the familiarity. No significant associations were found between ATs and solitary qualities. CONCLUSIONS:Our findings highlight the importance of evaluating ATs during clinical assessments, especially in adolescents and young adults, to evaluate the impact on social interactions and the potential psychopathological consequences.

Background:Adolescent interpersonal stress increases depression risk, and chronic low-grade inflammation may act as a potential underlying biological mechanism. Methods:We explored longitudinal associations between interpersonal stress, inflammation, and depressive symptoms from adolescence to young adulthood, using DNA methylation (DNAm) indices of C-reactive protein (CRP) from saliva. Data were collected from N = 434 adolescents (RADAR-Y study, 56.4% male) and analyzed in preregistered structural equation models. Interpersonal stress was estimated from repeated measures of parent-adolescent conflict, parental psychological control, parental criticism, and peer victimization. Results:Interpersonal stress was not associated with DNAm indices of CRP at age 17 or age 25, nor with depressive symptoms at age 27. In exploratory analyses examining parent versus peer-related stress separately, higher negative parenting-but not peer victimization-was nominally associated with one out of three DNAm indices of CRP at age 17 (Hillary index, β = .15, p = .035), with no association at age 25. Conclusion:This study did not show an association of either interpersonal stress or inflammation with later depressive symptoms and thereby could not identify inflammation as a potential mediator. Our findings tentatively suggest timing-dependent differential effects of family versus peer-related stress on epigenetic indices of inflammation, which may be further explored in future studies.

Importance:Dose reduction or discontinuation (DRD) early after remission from first-episode psychosis (FEP) increases short-term relapse risk. Controversy remains regarding potential benefits in functioning over the longer term because studies with long-term outcomes show conflicting findings. Objective:To compare short- and long-term effects between DRD and maintenance medication over a 4-year period in a large sample of patients with FEP. Design, Setting, and Participants:The Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment (HAMLETT) study is a single-blind pragmatic randomized (1:1) clinical trial conducted in 26 specialized psychosis units in the Netherlands from September 2017 to March 2023. Patients remitted for FEP from in- and outpatient services were included. Interventions:DRD within 12 months after remission compared with 12 months maintenance treatment. Main Outcomes and Measures:The primary outcome was patient-rated functioning, measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2). Secondary outcomes were researcher-rated global assessment of functioning (GAF), quality of life, relapse, symptom severity (measured by the Positive and Negative Syndrome Scale [PANSS]), serious adverse events, and adverse effects. Results:A total of 347 patients (241 male [69.5%]; mean [SD] age, 27.9 [8.7] years) were included, with 168 randomized to early DRD and 179 to maintenance. WHODAS-2 showed no time × condition interaction. In the first year, DRD was associated with higher risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66; P = .04) and lower quality of life (β = -3.31; 95% CI, -6.34 to -0.29; P = .03). At 3 years (β = 3.61; 95% CI, 0.28 to 6.95; P = .03) and 4 years (β = 6.13; 95% CI, 2.03 to 10.22; P = .003), a nonlinear effect of time occurred, showing significantly better GAF for patients in the DRD condition, with a similar trend for PANSS at 4 years (P for trend = .06). Although SAEs and adverse effects were similar between groups, 3 confirmed deaths by suicide occurred in the DRD group, against 1 death by suicide in the maintenance group. Conclusions and Relevance:This randomized clinical trial found that DRD posed risks of relapse and worse quality of life over the first year but yielded better researcher-rated functioning at the third and fourth year, with a similar trend for symptom severity; because antipsychotic medication doses were comparable in the 2 groups from 1 year onwards, this finding is not a direct result of lower medication but may reflect a learning experience to use antipsychotics to better handle psychotic vulnerability. These findings suggest that the potential learning and empowering element of DRD needs to be weighed carefully against short-term risks. Trial registration:EudraCT number: 2017-002406-12.

Most genetic variants associated with complex heritability phenotypes lie in non-coding regions and are thought to influence disease risk by regulating gene expression. However, most transcriptome-wide association approaches primarily model local (cis) genetic effects, leaving much of gene regulation unexplained. Here, we show that incorporating distal (trans) regulatory effects improves the prediction of gene expression and the identification of disease-associated genes. Using RNA sequencing data from six human post-mortem brain regions, we developed INGENE and MODULE, two models capturing the combined influence of candidate trans-acting variants within gene coexpression networks. Integrating these models with conventional cis-based predictors improved gene expression imputation (maximum likelihood estimation, α = 0.05) for 18,744 genes across regions. Applying this framework to Psychiatric Genomics Consortium wave 3 genotypes identified 766 genes associated with schizophrenia (PFDR < 0.01), including 641 not previously reported by transcriptome-wide analyses. These findings highlight the contribution of distal regulatory mechanisms and gene network interactions to schizophrenia risk.

Background: This study aimed to gain insight into patient-reported experiences with tapering of mood stabilizers among patients with a self-reported bipolar spectrum disorder diagnosis in the Netherlands. Methods: A digital survey on experiences with tapering of mood stabilizers and the Functioning Assessment Short Test (FAST) was distributed via multiple online platforms to reach adult patients with a bipolar spectrum disorder diagnosis. Results: A total of 104 respondents shared their experiences with tapering mood stabilizers, of whom 86 completed the FAST. Lithium was the most reported mood stabilizer ever used (74% [76/103]) and currently used (47% [32/68]). Almost all respondents attempted tapering or discontinuation (95% [97/102]), of whom 29% (28/97) completely discontinued and no longer used a mood stabilizer. Tapering was often done gradually (85% [82/97]), frequently following a linear (34% [28/82]) or hyperbolic approach (11% [9/82]), and usually under clinician guidance (77% [75/97]). Duration of tapering varied widely, ranging from four weeks to several years. Most patients who have tapered their mood stabilizer(s) completely, do not experience functional impairment (65% [15/28]). Limitations: This study relied on self-reported data and a cross-sectional design, which may limit generalizability and prevent causal conclusions. Conclusions: Tapering of mood stabilizers is typically done gradually and the duration varies greatly. Most patients who have discontinued their mood stabilizer(s) seem to have no functional impairment. Trials comparing tapering versus continuation of maintenance treatment in euthymic patients diagnosed with a bipolar spectrum disorder are needed, with outcomes such as relapse risk, withdrawal symptoms and functioning.

Most mental disorders emerge before age 24, yet the mechanisms shaping youth mental health trajectories remain poorly understood. Here, we present the Youth-GEMs consortium performing a multidisciplinary, multisite research project funded by a European Union Horizon-Staying-Healthy-2021 grant. The Youth-GEMs project (Gene Environment interactions in Mental health trajectorieS of Youth) has an integrated, developmental framework that examines how genetic, epigenetic, and environmental factors dynamically interact to influence risk and resilience across adolescence and young adulthood. The project combines developmental (epi)genomic mapping of the human brain, genomic analyses of trans-syndromal phenotypes, exposome-wide environmental assessment, and Artificial Intelligence-based modelling to identify predictive and actionable markers of mental health trajectories of young people. By harmonizing multimodal data from existing population-based cohorts and by establishing the first international, trans-syndromal clinical cohort of help-seeking young people, Youth-GEMs is generating biologically informed polygenic and exposomic scores, cell-type-specific regulatory annotations, and interpretable machine-learning models. Continuous engagement with young people, clinicians, and stakeholders ensures that findings translate into tools for early detection, monitoring, and personalized intervention. Together, these efforts aim to advance mechanistic understandings of youth mental health, improve prediction of emerging illness, and support the development of evidence-based, developmentally sensitive approaches to prevention and care.

BACKGROUND AND HYPOTHESIS:Persistent distressing psychotic-like experiences (PLE) are associated with impaired functioning and future psychopathology. Prior research suggests that physical activities may be protective against psychopathology. However, it is unclear whether physical activities may interact with genetics in the development of psychosis. STUDY DESIGN:This study included 4679 participants of European ancestry from the Adolescent Brain Cognitive Development Study. Persistent distressing PLE was derived from the Prodromal-Questionnaire-Brief Child Version using four years of data. Generalized linear mixed models tested the association between polygenic risk score for schizophrenia (PRS-SCZ), physical activities, and PLE. The models adjusted for age, sex, parental education, income-to-needs ratio, family history of psychosis, body mass index, puberty status, principal components for PRS-SCZ, study site, and family. STUDY RESULTS:PRS-SCZ was associated with a greater risk for persistent distressing PLE (adjusted relative risk ratio (RRR) = 1.14, 95% CI [1.04, 1.24], P = .003). Physical activity was associated with less risk for persistent distressing PLE (adjusted RRR = 0.87, 95% CI [0.79, 0.96], P = .008). Moreover, physical activities moderated the association between PRS-SCZ and persistent distressing PLE (adjusted RRR = 0.89, 95% CI [0.81, 0.98], P = .015), such that the association was weaker as participants had greater participation in physical activities. CONCLUSIONS:These findings demonstrate that the interaction between genetic liability and physical activities is associated with trajectories of distressing PLE. Further research is needed to understand the mechanisms of physical activities and genetic liability for schizophrenia in the development of psychosis.

BACKGROUND AND HYPOTHESIS:Psychosis prevention can be supported by tools that facilitate the early detection of individuals at clinical high risk (CHR-P) and predicting their clinical outcomes. We aimed to use clinical, genetic, and environmental data to: (1) predict case-control status as a proof-of-concept for CHR-P detection, and (2) predict transition to psychosis. STUDY DESIGN:We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions: a multicenter cohort study comprising 344 CHR-P individuals and 67 healthy controls. To predict CHR-P status, we used environmental (Psychosis Polyrisk Score [PPS]) and genetic (polygenic risk score for schizophrenia [PRS]) measures with logistic regression (LR) and random forest (RF). To predict transition to psychosis, we used clinical, environmental, and genetic measures with Cox proportional hazards model and random survival forest. Primary outcomes were discrimination (C-index) and calibration (intercept and slope) in repeated nested cross-validation. Clinical utility was assessed with decision curve analysis. STUDY RESULTS:For detection of CHR-P, both PPS (LR:C = 0.91, 95% CI, 0.87-0.94, intercept = 1.46, slope = 0.73; RF:C = 0.77, 95% CI, 0.61-0.90, intercept = -0.53, slope = 0.42) and PPS + PRS (LR:C = 0.89, 95% CI, 0.85-0.92, intercept = 1.45, slope = 0.73; RF:C = 0.78, 95% CI, 0.65-0.89, intercept = -0.24, slope = 0.44) had excellent discrimination performance, whereas PRS performed substantially worse (LR:C = 0.60, 95% CI, 0.52-0.67, intercept = 1.63, slope = 0.81; RF:C = 0.57, 95% CI, 0.41-0.72, intercept = -0.84, slope = 0.10). All models over-estimated risk in individuals with low observed risk. Prognosis model performance was poor (C ≤ 0.65). CONCLUSIONS:CHR-P detection may be improved by using the PPS, though evidence is needed from more representative detection settings. However, we did not find evidence that baseline clinical, environmental and/or genetic data enhanced the prediction of psychosis onset.