Background:We examined the course of cognitive performance in first-episode psychosis (FEP) compared to healthy controls (HC), and whether this varied across subgroups of patients defined by premorbid functioning (PMF) trajectories, using a clustering approach. Methods:Data were collected in 302 FEP and 136 HC subjects participating in PSYSCAN (HEALTH.2013.2.2.1-2-FEP). K-means clustering (Euclidean distance) was used to cluster longitudinal trajectories of different PMF domains simultaneously. Since PMF was assessed retrospectively using the Premorbid Adjustment Scale (PAS), findings should be interpreted with caution, although PAS ratings have shown reasonable validity against prospective data. Results:As expected, FEP showed impaired performance across all cognitive domains compared to HC. We identified four trajectories of PMF: a normal premorbid developmental trajectory (globally-normal, 21 %), stable intermediate PMF across domains (stable-intermediate, 29 %), stable poor or deteriorating PMF in the academic domain (normal-social/poor-academic, 29 %), and a globally impaired group with poor/deteriorating PMF across domains (globally-poor, 21 %). These clusters showed distinct levels of post-onset impairments in sustained visual attention, visual working memory and emotion recognition. Conclusions:This study confirms a positive association between PMF and cognitive performance in the early years following psychosis onset. It aligns with findings that individuals later diagnosed with schizophrenia already show developmental deficits/lags from childhood to early adolescence compared to normally developing children. As PMF can be considered a proxy for cognitive reserve, our results suggest that higher reserve acts as a buffer against cognitive decline and supports better performance on sustained visual attention, complex visual working memory, and aspects of emotion recognition.

BACKGROUND: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. METHODS: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7-90 years, 54% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). RESULTS: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. CONCLUSIONS: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.

BACKGROUND:22q11.2 deletion syndrome (22q11DS) is a genetic disorder characterised by a wide range of physical, cognitive, and psychiatric symptoms. Current knowledge on 22q11DS highlights considerable variation in cognitive outcomes, but the role of environmental factors in shaping these trajectories over time remains poorly understood. AIMS:This study investigates how environmental factors contribute to variability in intelligence quotient (IQ) among individuals with 22q11DS across three European cohorts. By examining these influences over time, the research aims to identify potential drivers of IQ differences and uncover modifiable factors that may support improved cognitive outcomes in individuals with 22q11DS. METHODS:Data were collected from 297 individuals with 22q11DS across three European cohorts. Cognitive assessments included full-scale IQ (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ). Environmental measures encompassed parental education, sleep, stress and substance use, gathered through questionnaires and interviews. Baseline associations between environmental measures and IQ were evaluated with ANOVA at the first assessment. To examine within-person IQ change across three visits, we used linear mixed-effects models. RESULTS:We found a significant decline in FSIQ, VIQ and PIQ over time, with linear trends observed for all three measures. Parental education, particularly the father's education, explained a significant proportion of the variance of all IQ-based measures. CONCLUSIONS:Parental education emerged as a key predictor of IQ, suggesting that socioeconomic factors contribute to cognitive performance variability in individuals with 22q11DS. Even in high-penetrance genetic variants, such as the 22q11.2 deletion, environmental factors and gene-environment interactions may make significant contributions to the severity of phenotypes.

The aims of the Reward Task Optimisation Consortium (RTOC) study (Bilderbeck et al., 2020) were to explore the validity, reliability, and feasibility of a battery of reward processing tasks for the development of new treatments for anhedonia. We report our findings from the Grip Strength Effort Task (GSET), an effort-based decision-making task in which participants chose to either perform easy trials that required less physical effort for low monetary reward or hard trials that required more effort for potentially larger rewards. Thirty-seven participants with schizophrenia (SZ), 40 with major depressive disorder (MDD), and 59 age- and sex-matched healthy controls were administered the task across four European sites. 19% of participants (8.5% HC, 27% SZ, 27.5% MDD) were 'inflexible responders' who always chose hard trials irrespective of the reward amount. MDD participants showed less willingness to exert physical effort for high reward than controls, when inflexible responders were excluded, but no statistically significant differences were observed between SZ participants and controls. Across all participants, willingness to exert effort for high reward negatively correlated with measures of anhedonia. Inflexible responders exhibited higher depressive symptoms and higher anticipation of punishment than other participants. Forty-three participants performed the GSET again after 3-5 weeks and moderate-to-high test-retest reliability was observed. Minimal site effects confirmed operational feasibility of the task in multi-site studies. We conclude that the GSET can provide objective behavioural biomarkers of reward processing dysfunction, but further investigation is needed to understand inflexible responding and its implications on the task's design and interpretation.

BACKGROUND AND HYPOTHESIS:Young people (YP) with psychotic experiences (PE) have an increased risk of developing a psychiatric disorder. Therefore, knowledge on continuity of care from child and adolescent (CAMHS) to adult mental health services (AMHS) in relation to PE is important. Here, we investigated whether the self-reported trajectories of persistent PE were associated with likelihood of transition to AMHS and mental health outcomes. STUDY DESIGN:In this prospective cohort study, interviews and questionnaires were used to assess PE, mental health, and service use in 763 child and adolescent mental health service users reaching their service's upper age limit in 8 European countries. Trajectories of self-reported PE (3 items) from baseline to 24-month follow-up were determined using growth mixture modeling (GMM). Associations were assessed with auxiliary variables and using mixed models. Study results. At baseline, 56.7% of YP reported PE. GMM identified 5 trajectories over 24 months: medium increasing (5.2%), medium stable (11.7%), medium decreasing (6.5%), high decreasing (4.2%), and low stable (72.4%). PE trajectories were not associated with continuity of specialist care or transition to AMHS. Overall, YP with PE reported more mental health problems at baseline. Persistence of PE or an increase was associated with poorer outcomes at follow-up. CONCLUSIONS:PE are common among CAMHS users when reaching the upper age limit of CAMHS. Persistence or an increase of PE was associated with poorer mental health outcomes, poorer prognosis, and impaired functioning, but were less discriminative for continuity of care.

Predicting outcomes in individuals at clinical high risk (CHR) of developing psychosis remains challenging using clinical metrics alone. The PSYSCAN project aimed to enhance predictive value by integrating data across clinical, environmental, neuroimaging, cognitive, and peripheral blood biomarkers. PSYSCAN employed a naturalistic, prospective design across 12 sites (Europe, Australia, Asia, Americas). Assessments were conducted at baseline, 3, 6, and 12 months, with follow-ups at 18 and 24 months to evaluate clinical and functional outcomes. The study included 238 CHR individuals and 134 healthy controls (HC). At baseline, CHR and HC groups differed significantly in age, education, IQ, and vocational and relationship status. Cannabis and tobacco use did not significantly differ between groups, however CHR individuals had higher proportion of moderate to high risk of tobacco abuse. A substantial portion of the CHR sample met DSM criteria for anxiety (53.4%) and/or mood disorders (52.9%), with some prescribed antidepressants (38.7%), antipsychotics (13.9%), or benzodiazepines (16.4%). Over the follow-up period, 25 CHR individuals (10.5%) transitioned to psychosis. However, the CHR group as a whole showed improvements in functioning and attenuated psychotic symptoms. Similar to other recent multi-centre studies, the CHR cohort exhibits high comorbidity rates and relatively low psychosis transition rates. These findings highlight the clinical heterogeneity within CHR populations and suggest that outcomes extend beyond psychosis onset, reinforcing the need for broader prognostic models that consider functional and transdiagnostic outcomes.

Access to large patient cohort data and biobanked resources is a catalyst for progress in genomics and biomedical research, increasing statistical power, and unlocking deeper insights—especially in areas like rare diseases and mental health. Responsible research necessitates maintenance of data privacy, regulatory compliance, and research standardization. It can appear that these guiding principles oppose each other and present barriers to responsible Open science. To address these critical challenges, we developed MINDDS-Connect, a federated data collaboration platform that integrates a web-based interface with decentralized Docker instances via a REST API. This architecture allows registered users to securely query samples across the platform’s network, and offers a tool to facilitate the formation of virtual multi-centric meta-cohorts and research collaboration. MINDDS-Connect allows institutions to retain data control while enabling collaborative research and meta-cohort analysis through standardized metadata fields. Its implementation across five European centers enhanced the accessibility of 900 samples, demonstrating its effectiveness in enabling cohort construction and promoting collaborative research. The platform provides a secure, open-source solution consistent with EU Open Science policies, advancing large-scale mental health research.

Pharmacogenetics in psychiatry may have benefits for medication treatment success. However, medication regimes leading to drug-drug interactions and potential phenoconversion of actionable pharmacogenetic phenotypes challenge the application of pharmacogenetics. Although polypharmacy is common, its impact in patients with psychosis is understudied, even though these patients might benefit from pharmacogenetics-guided medication adjustment. Here, we investigated the impact of two pharmacogenes relevant in psychiatric practice, CYP2C19 and CYP2D6, and the effect of sex and age. Medication use and predicted occurrence of phenoconversion was examined in a sample of patients with psychosis over a period of approximately six years. Bayesian statistics were applied to examine longitudinal effects. Our results show that women used more medications, including CYP2C19 and CYP2D6 inhibitors and (actionable) substrates. No significant sex or age differences were found for phenoconversion of either enzyme. A sex-effect on CYP2C19 inhibitor use was found but appeared to be driven by weakly inhibiting oral contraceptives, which were reported only in women. The phenoconversion rate for both enzymes appeared to change over time, suggesting that phenoconversion is a dynamic state that may affect patients differently over their lifetime. To further improve treatment in this patient population, long-term and regular updated medication monitoring in (pharmacogenetic) research as well as application in practice are recommended.

Extinction learning is regarded as a core mechanism underlying exposure therapy. Under this assumption, studies have looked at the predictive value of the extinction learning paradigm for exposure therapy outcomes. However, predicting factors of long-term exposure therapy success have not been established. Participants with a specific phobia (SP) for spiders were included in a double-blind randomized controlled trial. Participants were randomly assigned to receive exposure therapy (n = 25, 24 females) or an active control intervention, progressive muscle relaxation (PMR; n = 18, 15 females). Symptom levels were measured with the Fear of Spiders questionnaire (FSQ) at baseline (T0), after the intervention (T1), and at six- (T2) and twelve (T3) months follow-up. At baseline, participants completed a three-day fMRI fear conditioning, extinction learning, and extinction recall paradigm. Indices of extinction were defined as self-reported threat expectancy and fear, and neural activation during stimulus presentations and threat omission in the ventromedial prefrontal cortex and nucleus accumbens, based on prior data. Mixed model analysis revealed that the exposure therapy group had an overall stronger decrease in phobic symptoms over time than the PMR group (β = 10.95, p < .001). However, none of the indices of extinction learning were predictive for FSQ scores after exposure therapy at the longest follow-up measurement (T3). In sum, the current results show the long-term effectiveness of a single session of exposure therapy for reducing a specific fear of spiders but no baseline characteristics were identified that predicted individual differences in exposure therapy success after one year.

ACT in Daily Life (ACT-DL) is a blended-care Ecological Momentary Intervention that extends ACT into the daily life of individuals, improving psychotic distress, negative symptoms, and global functioning. However, it remains unclear whether ACT-DL works equally for everyone. We investigated whether moderators (i.e., sociodemographic information, personality, and trauma history) determine clinical outcomes in individuals with early psychosis receiving ACT-DL. Seventy-one participants from the INTERACT trial, using ACT-DL, were analyzed. Outcomes included psychotic distress, negative symptoms, global functioning, and psychological flexibility. Using multivariate-multilevel models, we evaluated the effects of sociodemographics, personality, and childhood trauma across baseline, post-intervention, and six- and 12-month follow-ups. Sociodemographic characteristics and personality predicted clinical outcomes. Higher education demonstrated more substantial improvement in global functioning at 6- (B = 7.43, p = 0.04) and 12-FU (B = 10.74, p = 0.002) compared to lower education. Higher extraversion showed less improvement in negative symptoms at 12-FU (B = 1.24, p = 0.01) and more improvement in global functioning at post-intervention (B = 0.39, p = 0.046) and 6-FU (B = 1.40, p = 0.02) compared to lower extraversion. Higher negative affectivity showed more improvement in negative symptoms at 12-FU (B = −1.59, p = 0.001) and higher psychological flexibility at 12-FU (B = 8.38, p = 0.001) compared to lower negative affectivity. Our findings suggest that while ACT-DL improves clinical outcomes in individuals with early psychosis, the improvement rate is dissimilar for individuals and predictable by baseline characteristics. If replicated, these findings enable precision medicine approaches in allocating ACT-DL for early psychosis.

The objective of this article was to examine basic psychometric properties of the Maastricht Memory Recall and Recognition Task (MMRRT), which was designed to assess the influence of emotionally colored words on recall and recognition. One hundred eighteen Dutch adults participated. A recall task consisting of three presentations was administered. Fifteen and forty-five minutes after the recall task, participants completed a recognition task. The investigated dependent variables included the yes/no reproduction and recognition of a word, as well as occurrence of a false positive of a new, content-matched word. The validity of the MMRRT was assessed by evaluation of the known effects of age, gender, educational level, word length, presentation number, retesting (6 months later) and the primacy and recency phenomenon on reproduction. Using multilevel regression analyses for dichotomous outcomes, all these predictors were statistically significant and independent of each other. These results provide evidence in favor of the validity of the MMRRT. When evaluating cognition, the MMRRT seems to have similar psychometric properties compared to other memory tasks. Contrary to our expectations, emotionally loaded words appear to have a lower likelihood of being remembered and reproduced. Future research is necessary to shed more light on this unexpected finding.

BACKGROUND:22q11.2 deletion syndrome (22q11.2DS) has been associated with increased risk of early-onset Parkinson's disease (PD). OBJECTIVE:To determine the prevalence and predictors of PD in a large international 22q11.2DS sample. METHODS:The sample comprised 856 adults (median age 28 (range 16-76) years; 53.0% female). PD was defined as clinical diagnosis by a neurologist (including bradykinesia, rest tremor and/or rigidity). Age-specific risk and predictors of PD were analyzed using Kaplan-Meier curve and Cox regression. RESULTS:PD was present in 1.8% (95% CI: 0.9-2.6%) of the sample, 3.4% (95% CI: 2.2-4.6%) when including uncertain PD (clinical diagnosis or suspicion, but not meeting all criteria), and 14.0% (95% CI: 6.9-21.0%) of those aged ≥50 years. Median age at motor onset was 45 (range 20-66) years. None of the factors considered were associated with PD. CONCLUSIONS:Given high PD prevalence and young onset, we propose periodic motor evaluations from age 40 years in 22q11.2DS.

BackgroundA significant proportion of mental health care professionals (MHCPs) hold stigmatizing attitudes about their patients. When patients perceive and internalize these beliefs, self-stigmatization can increase. Acceptance and Commitment Therapy (ACT) may decrease stigmatizing attitudes by changing the ‘us’ versus ‘them’ thinking into continuum beliefs. In the present study MHCPs were given an ACT-based training, aiming to decrease stigmatization, hypothesizing that self-stigmatization of their patients will subsequently decrease.MethodsAn RCT with a 2 (pre-test/post-test) x 2 (no training/training) design was conducted. A total of 41 MHCPs participated, 20 were randomized to the experimental and 21 to the control condition respectively. The MHCPs in the experimental condition received an ACT-based training, MHCPs in the control condition received no training. From every MHCP, one of their patients participated in the pre- and post-measurement. As the primary outcome, patients’ awareness, agreement, application and hurt-self, was measured using the Self Stigma of Mental Illness Scale - Short Form (SSMIS-SF), before and after the MHCPs’ ACT-based training.ResultsSignificant group x time interaction effects were found for ‘application’ (internalization of mental illness stereotypes) in patients after the ACT-based training of their MHCP: F (1,39) = 9.33, p < 0.01, ηp2 = .85. On the contrary, no effect was found on the subscales ‘awareness’, ‘agreement’ and ‘hurt-self’.ConclusionPreliminary results suggest that a brief ACT training for MHCP might heighten their awareness and contribute to reduction of their stigmatizing attitudes and behavior, leading to less application of self-stigmatizing beliefs in their patients.

OBJECTIVES:We investigated the association between adverse childhood events, personality disorders and multimorbidity in older adults. METHODS:This is a cross-sectional analysis in a population of older adults including 40 people with a personality disorder and 75 healthy controls. The Childhood Traumatic Events Scale was used to assess adverse childhood events. Multimorbidity was defined as the presence of 2 or more predetermined chronic somatic and psychiatric disorders. Logistic regression analysis was used to assess the association between adverse childhood events, personality disorders and multimorbidity. RESULTS:No significant association was found between adverse childhood events and multimorbidity (OR = 1.03, 95% CI = 0.96-1.09). The presence of a personality disorder was significantly associated with multimorbidity (OR = 12.95, 95% CI = 4.28-39.14). CONCLUSIONS:Overall, we did not find an association between adverse childhood events and multimorbidity in older adults. Multimorbidity was more prevalent in subjects with personality disorders compared to healthy controls. CLINICAL IMPLICATIONS:The findings suggest that personality disorders are associated with both mental and physical health challenges, underscoring the importance of integrated care approaches to address both aspects in clinical practice.

Altered sensory feedback processing and attention control are assumed to contribute to auditory verbal hallucinations, which are experienced by the general population and patients with psychosis, implying a continuum of hallucination proneness (HP). However, the interaction of altered sensory feedback processing and attention control along this HP continuum remains unclear. We tested this interaction using electroencephalography while forty participants varying on HP, self-generated (via a button-press) and passively listened to their own voices. These voices were created by first recording each participant's neutral and angry voice and then morphing them to create final five types of voice stimuli differing in voice quality per participant (100 % neutral, 60-40 % neutral-angry, 50-50 % neutral-angry, 40-60 % neutral-angry, 100 % angry). Regardless of the voice quality, the N100 and P200 suppression effects decreased with increase in HP. This may indicate increased error awareness and attention allocation in high HP individuals for self-voice generation stemming from altered sensory feedback processing, and/or attentional control. The current findings suggest that alterations of the sensory feedback processing and/or attentional control in self-voice production are fundamental characteristics of the continuum of HP, regardless of the clinical status of voice hearers.

Social media use has rapidly increased over the past decade, especially among young people. To obtain more insight into the potential negative associations with problematic social media use in Dutch early adolescents, we assessed its relation to self-reported well-being. We conducted a cross-sectional study with 585 students in their final year of primary school (11–12 years old) who completed a questionnaire during school hours. We examined the association between problematic social media use and psychosomatic complaints, as well as general life satisfaction and whether perceived social support and sex moderated these associations. Problematic social media use was associated with lower general life satisfaction, as well as all psychosomatic complaints, with the strongest association for having a bad mood or feeling irritated (OR = 3.08, 99% CI = 2.05–4.63). Most associations were not moderated by perceived social support or sex. Our findings indicate that the well-being of early adolescents may be affected by problematic social media use already in primary school. The association persisted regardless of the amount of perceived social support, and without strong gender differences. This suggests that the potential for limiting the potential negative consequences of problematic social media use through increasing social support is limited.