PsyCog: A computerised mini battery for assessing cognition in psychosis.

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.

Turning 18 in mental health services: a multicountry qualitative study of service user experiences and views.

BACKGROUND: Worldwide, the division between Child and Adolescent Mental Health Services (CAMHS) and Adult Mental Health Services (AMHS) has frequently resulted in fragmented care with an unprepared, non-gradual transition. To improve continuity of care and other service transition experiences, service user input is essential. However, such previous qualitative studies are from a decade ago or focused on one mental disorder or country. The aim of the present study was to learn from service users' transition experiences and suggested improvements. METHODS: Semi-structured interviews were held with young people aged 18-24 and/or parents/caregivers in the United Kingdom, Ireland, the Netherlands and Croatia. Inclusion was based on the experience of specialist mental health care before and after turning 18. Thematic analysis of transcribed and translated interview transcripts was performed using ATLAS.ti 9. RESULTS: Main themes of service user experiences included abrupt changes in responsibilities, various barriers and a lack of preparation, communication and ongoing care. Young people expressed a great need for continuity of care. Their suggestions to improve transitional care included early and adequate preparation, joint working, improved communication from and between services, overlapping services, staying at CAMHS for longer and designated youth mental health teams. CONCLUSIONS: Young people who experienced care before and after turning 18 suggested either altering the age limits of services or ensuring early preparation and communication regarding the transition and finding AHMS. This communication should include general changes when turning 18. Further considerations include increasing collaboration and overlap between CAMHS and AMHS.

Influence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review.

Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.

Sexual exploitation of young men: Background characteristics and needs from a life-course perspective.

BACKGROUND: Sexually exploited young men are prevalent, yet underrepresented in clinical practice, policy and research. There are multiple barriers that often prevent young men to disclose and to seek or receive support, such as gender norms, limited awareness of victimization and feelings of guilt and shame. OBJECTIVE: By gaining more insight into the background characteristics of young men who experienced sexual exploitation and their needs, this study aims to raise awareness and to better inform policymakers, care- and educational professionals on adequate prevention and intervention efforts. METHODS: Twenty-six young men (age 14-32) who experienced sexual exploitation or other forms of sexual violence in their youth or were at high-risk, participated in this qualitative study that was conducted in The Netherlands. By means of semi-structured interviews and case-file analyses, data was collected to identify risk and protective factors in their life-course and support needs. RESULTS: Several vulnerabilities (e.g. previous experiences of abuse and neglect, household dysfunction, social rejection, running away, substance use) and a lack of positive and supportive relationships led young men into high-risk situations. Among these were involvement in pay dates, criminality and having to survive from day to day, which contributed to victimization. Prevailing gender norms and experiences of stigmatization were often a barrier to express vulnerabilities and to disclose victimization. There was a wide variety in support needs, including peer-to-peer support, therapy, support with day-to-day practices and anonymous support. CONCLUSIONS: These results will contribute to adequate prevention and trauma-informed intervention strategies that meet the unique needs of young men at risk for, or victim of sexual exploitation.

Looking for the good in times of adversity: Examining the interplay of temperament and social schemas in shaping resilience in youth.

AIM: Resilience is a broad and dynamic concept that can be seen as being constituted by the combination of internal factors, for example, temperament profiles, and external factors, for example, social support. This paper aimed to identify temperament profiles in help-seeking youth exposed to adverse childhood experiences, and to investigate whether temperament (putative internal protective factor) interacts with social schemas (as proxy for the putative external protective factor social support) such that their combination is associated with (a) reduced mental health problems and (b) attenuated decrease in positive affect following daily life stressors. METHODS: Self-report questionnaires were used to measure temperament, social schemas and mental health problems. The experience sampling method was used to assess stress and positive affect (i.e., stress-sensitivity as a potential daily life resilience mechanism). Temperament profiles were identified by latent profile analysis and regression analyses were used to examine (interaction) effects. RESULTS: In 138 subjects, three temperament profiles were identified, that is, a moderate, volatile and persevering profile, of which the latter was negatively associated with mental health problems. Neither mental health problems nor stress sensitivity were found to be affected by the interaction between temperament and social schemas. However, positive social schemas were found to be independently associated with reduced mental health problems (b = -4.41; p = <.001) and reduced stress sensitivity (b = .10, p = .044). CONCLUSIONS: Findings are relevant for both practice and research, and contribute to improving our understanding of putative protective factor in the development of mental ill-health, thereby further unravelling the construct of resilience.

A naturalistic cohort study of first-episode schizophrenia spectrum disorder: A description of the early phase of illness in the PSYSCAN cohort.

BACKGROUND: We examined the course of illness over a 12-month period in a large, international multi-center cohort of people with a first-episode schizophrenia spectrum disorder (FES) in a naturalistic, prospective study (PSYSCAN). METHOD: Patients with a first episode of schizophrenia, schizoaffective disorder (depressive type) or schizophreniform disorder were recruited at 16 institutions in Europe, Israel and Australia. Participants (N = 304) received clinical treatment as usual throughout the study. RESULTS: The mean age of the cohort was 24.3 years (SD = 5.6), and 67 % were male. At baseline, participants presented with a range of intensities of psychotic symptoms, 80 % were taking antipsychotic medication, 68 % were receiving psychological treatment, with 46.5 % in symptomatic remission. The mean duration of untreated psychosis was 6.2 months (SD = 17.0). After one year, 67 % were in symptomatic remission and 61 % were in functional remission, but 31 % had been readmitted to hospital at some time after baseline. In the cohort as a whole, depressive symptoms remained stable over the follow-up period. In patients with a current depressive episode at baseline, depressive symptoms slightly improved. Alcohol, tobacco and cannabis were the most commonly used substances, with daily users of cannabis ranging between 9 and 11 % throughout the follow-up period. CONCLUSIONS: This study provides valuable insight into the early course of a broad range of clinical and functional aspects of illness in FES patients in routine clinical practice.

Endocannabinoid levels in plasma and neurotransmitters in the brain: a preliminary report on patients with a psychotic disorder and healthy individuals.

BACKGROUND: Interactions between the endocannabinoid system (ECS) and neurotransmitter systems might mediate the risk of developing a schizophrenia spectrum disorder (SSD). Consequently, we investigated in patients with SSD and healthy controls (HC) the relations between (1) plasma concentrations of two prototypical endocannabinoids (N-arachidonoylethanolamine [anandamide] and 2-arachidonoylglycerol [2-AG]) and (2) striatal dopamine synthesis capacity (DSC), and glutamate and y-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC). As anandamide and 2-AG might reduce the activity of these neurotransmitters, we hypothesized negative correlations between their plasma levels and the abovementioned neurotransmitters in both groups. METHODS: Blood samples were obtained from 18 patients and 16 HC to measure anandamide and 2-AG plasma concentrations. For all subjects, we acquired proton magnetic resonance spectroscopy scans to assess Glx (i.e. glutamate plus glutamine) and GABA + (i.e. GABA plus macromolecules) concentrations in the ACC. Ten patients and 14 HC also underwent [18F]F-DOPA positron emission tomography for assessment of striatal DSC. Multiple linear regression analyses were used to investigate the relations between the outcome measures. RESULTS: A negative association between 2-AG plasma concentration and ACC Glx concentration was found in patients (p = 0.008). We found no evidence of other significant relationships between 2-AG or anandamide plasma concentrations and dopaminergic, glutamatergic, or GABAergic measures in either group. CONCLUSIONS: Our preliminary results suggest an association between peripheral 2-AG and ACC Glx levels in patients.

A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study.

(1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.

Corrigendum: Usability, feasibility, and effect of a biocueing intervention in addition to a moderated digital social therapy-platform in young people with emerging mental health problems: a mixed-method approach.

[This corrects the article DOI: 10.3389/fpsyt.2022.871813.].

The temporal association between social isolation, distress, and psychotic experiences in individuals at clinical high-risk for psychosis.

BACKGROUND: Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis. METHODS: We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models. RESULTS: SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs. CONCLUSIONS: Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

The association between childhood trauma and tobacco smoking in patients with psychosis, unaffected siblings, and healthy controls.

In patients with psychosis, rates of tobacco smoking and childhood trauma are significantly higher compared to the general population. Childhood trauma has been proposed as a risk factor for tobacco smoking. However, little is known about the relationship between childhood trauma and smoking in psychosis. In a subsample of the Genetic Risk and Outcome of Psychosis study (760 patients with psychosis, 991 unaffected siblings, and 491 healthy controls), tobacco smoking was assessed using the Composite International Diagnostic Interview and childhood trauma was measured with the Childhood Trauma Questionnaire. Logistic regression models were used to assess associations between trauma and smoking, while correcting for confounders. Positive associations were found between total trauma, abuse, and neglect, and an increased risk for smoking in patients, while correcting for age and gender (ORtrauma 1.77, 95% CI 1.30-2.42, p < 0.001; ORabuse 1.69, 95% CI 1.23-2.31, p = 0.001; ORneglect 1.48, 95% CI 1.08-2.02, p = 0.014). In controls, total trauma and abuse were positively associated with smoking, while correcting for age and gender (ORtrauma 2.40, 95% CI 1.49-3.88, p < 0.001; ORabuse 2.02, 96% CI 1.23-3.32, p = 0.006). All associations lost their significance after controlling for additional covariates and multiple testing. Findings suggest that the association between childhood trauma and tobacco smoking can be mainly explained by confounders (gender, cannabis use, and education) in patients with psychosis. These identified aspects should be acknowledged in tobacco cessation programs.

Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Hearing loss and history of otolaryngological conditions in adults with microdeletion 22q11.2.

Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16-74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full-scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high-frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that  in 22q11.2DS, high-frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high-frequency ranges.

Transdiagnostic Ecological Momentary Intervention for Improving Self-Esteem in Youth Exposed to Childhood Adversity: The SELFIE Randomized Clinical Trial.

Importance: Targeting low self-esteem in youth exposed to childhood adversity is a promising strategy for preventing adult mental disorders. Ecological momentary interventions (EMIs) allow for the delivery of youth-friendly, adaptive interventions for improving self-esteem, but robust trial-based evidence is pending. Objective: To examine the efficacy of SELFIE, a novel transdiagnostic, blended EMI for improving self-esteem plus care as usual (CAU) compared with CAU only. Design, Setting, and Participants: This was a 2-arm, parallel-group, assessor-blinded, randomized clinical trial conducted from December 2018 to December 2022. The study took place at Dutch secondary mental health services and within the general population and included youth (aged 12-26 years) with low self-esteem (Rosenberg Self-Esteem Scale [RSES] <26) exposed to childhood adversity. Interventions: A novel blended EMI (3 face-to-face sessions, email contacts, app-based, adaptive EMI) plus CAU or CAU only. Main Outcomes and Measures: The primary outcome was RSES self-esteem at postintervention and 6-month follow-up. Secondary outcomes included positive and negative self-esteem, schematic self-beliefs, momentary self-esteem and affect, general psychopathology, quality of life, observer-rated symptoms, and functioning. Results: A total of 174 participants (mean [SD] age, 20.7 [3.1] years; 154 female [89%]) were included in the intention-to-treat sample, who were primarily exposed to childhood emotional abuse or neglect, verbal or indirect bullying, and/or parental conflict. At postintervention, 153 participants (87.9%) and, at follow-up, 140 participants (80.5%), provided primary outcome data. RSES self-esteem was, on average, higher in the experimental condition (blended EMI + CAU) than in the control condition (CAU) across both postintervention and follow-up as a primary outcome (B = 2.32; 95% CI, 1.14-3.50; P < .001; Cohen d-type effect size [hereafter, Cohen d] = 0.54). Small to moderate effect sizes were observed suggestive of beneficial effects on positive (B = 3.85; 95% CI, 1.83-5.88; P < .001; Cohen d = 0.53) and negative (B = -3.78; 95% CI, -6.59 to -0.98; P = .008; Cohen d = -0.38) self-esteem, positive (B = 1.58; 95% CI, 0.41-2.75; P = .008; Cohen d = 0.38) and negative (B = -1.71; 95% CI, -2.93 to -0.48; P = .006; Cohen d = -0.39) schematic self-beliefs, momentary self-esteem (B = 0.29; 95% CI, 0.01-0.57; P = .04; Cohen d = 0.24), momentary positive affect (B = 0.23; 95% CI, 0.01-0.45; P = .04; Cohen d = 0.20), momentary negative affect (B = -0.33; 95% CI, -0.59 to -0.03, P = .01, Cohen d = -0.27), general psychopathology (B = -17.62; 95% CI, -33.03 to -2.21; P = .03; Cohen d = -0.34), and quality of life (B = 1.16; 95% CI, 0.18-2.13; P = .02; Cohen d = 0.33) across postintervention and follow-up. No beneficial effects on symptoms and functioning were observed. Conclusions and Relevance: A transdiagnostic, blended EMI demonstrated efficacy on the primary outcome of self-esteem and signaled beneficial effects on several secondary outcomes. Further work should focus on implementing this novel EMI in routine public mental health provision. Trial Registration: Dutch Trial Register Identifier:NL7129(NTR7475).

The Effects of a Digital, Transdiagnostic, Clinically and Peer-Moderated Treatment Platform for Young People With Emerging Mental Health Complaints: Repeated Measures Within-Subjects Study.

BACKGROUND: To address the growing prevalence of youth mental health problems, early intervention is crucial to minimize individual, societal, and economic impacts. Indicative prevention aims to target emerging mental health complaints before the onset of a full-blown disorder. When intervening at this early stage, individuals are more responsive to treatment, resulting in cost-effective outcomes. The Moderated Online Social Therapy platform, which was successfully implemented and proven effective in Australia, is a digital, peer- and clinically moderated treatment platform designed for young people. The Netherlands was the first country outside Australia to implement this platform, under the name Engage Young People Early (ENYOY). It has the potential to reduce the likelihood of young people developing serious mental health disorders. OBJECTIVE: This study aims to investigate the effects on young people using the ENYOY-platform in relation to psychological distress, psychosocial functioning, and positive health parameters. METHODS: Dutch-speaking young people with emerging mental health complaints (N=131) participated in the ENYOY-platform for 6 months in a repeated measures within-subjects study. Psychological distress, psychosocial functioning, and positive health parameters were assessed at baseline and 3, 6, and 12 months. Repeated measures ANOVA was conducted and adjusted for age, sex, therapy, and community activity. The Reliable Change Index and Clinically Significant Index were computed to compare the baseline with the 6- and 12-month measurements. The missing data rate was 22.54% and the dropout rate 62.6% (82/131). RESULTS: The primary analysis (77/131, 58.8%) showed that psychological distress decreased and psychosocial functioning improved over time with large effect sizes (P<.001 in both cases; ηp2=0.239 and 0.318, respectively) independent of age (P=.76 for psychological distress and P=.48 for psychosocial functioning), sex (P=.24 and P=.88, respectively), therapy activity (P=.49 and P=.80, respectively), or community activity (P=.59 and P=.48, respectively). Similarly, secondary analyses (51/131, 38.9%) showed significant effects of time on the quality of life, well-being, and meaningfulness positive health parameters (P<.05; ηp2=0.062, 0.140, and 0.121, respectively). Improvements in all outcome measures were found between baseline and 3 and 6 months (P≤.001-.01; d=0.23-0.62) and sustained at follow-up (P=.18-.97; d=0.01-0.16). The Reliable Change Index indicated psychological distress improvements in 38% (39/102) of cases, no change in 54.9% (56/102) of cases, and worsening in 5.9% (6/102) of cases. Regarding psychosocial functioning, the percentages were 50% (51/102), 43.1% (44/102), and 6.9% (7/102), respectively. The Clinically Significant Index demonstrated clinically significant changes in 75.5% (77/102) of cases for distress and 89.2% (91/102) for functioning. CONCLUSIONS: This trial demonstrated that the ENYOY-platform holds promise as a transdiagnostic intervention for addressing emerging mental health complaints among young people in the Netherlands and laid the groundwork for further clinical research. It would be of great relevance to expand the population on and service delivery of the platform. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-021-03315-x.

The association between clinical, sociodemographic, familial, and environmental factors and treatment resistance in schizophrenia: A machine-learning-based approach.

BACKGROUND: Prediction of treatment resistance in schizophrenia (TRS) would be helpful to reduce the duration of ineffective treatment and avoid delays in clozapine initiation. We applied machine learning to identify clinical, sociodemographic, familial, and environmental variables that are associated with TRS and could potentially predict TRS in the future. STUDY DESIGN: Baseline and follow-up data on trait(-like) variables from the Genetic Risk and Outcome of Psychosis (GROUP) study were used. For the main analysis, we selected patients with non-affective psychotic disorders who met TRS (n = 200) or antipsychotic-responsive criteria (n = 423) throughout the study. For a sensitivity analysis, we only selected patients who met TRS (n = 76) or antipsychotic-responsive criteria (n = 123) at follow-up but not at baseline. Random forest models were trained to predict TRS in both datasets. SHapley Additive exPlanation values were used to examine the variables' contributions to the prediction. STUDY RESULTS: Premorbid functioning, age at onset, and educational degree were most consistently associated with TRS across both analyses. Marital status, current household, intelligence quotient, number of moves, and family loading score for substance abuse also consistently contributed to the prediction of TRS in the main or sensitivity analysis. The diagnostic performance of our models was modest (area under the curve: 0.66-0.69). CONCLUSIONS: We demonstrate that various clinical, sociodemographic, familial, and environmental variables are associated with TRS. Our models only showed modest performance in predicting TRS. Prospective large multi-centre studies are needed to validate our findings and investigate whether the model's performance can be improved by adding data from different modalities.

Exploring pathway interactions to detect molecular mechanisms of disease: 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of clinical phenotypes including autistic spectrum disorder, schizophrenia, congenital heart defects, and immune deficiency. Many characteristics of the disorder are known, such as the phenotypic variability of the disease and the biological processes associated with it; however, the exact and systemic molecular mechanisms between the deleted area and its resulting clinical phenotypic expression, for example that of neuropsychiatric diseases, are not yet fully understood. RESULTS: Using previously published transcriptomics data (GEO:GSE59216), we constructed two datasets: one set compares 22q11DS patients experiencing neuropsychiatric diseases versus healthy controls, and the other set 22q11DS patients without neuropsychiatric diseases versus healthy controls. We modified and applied the pathway interaction method, originally proposed by Kelder et al. (2011), on a network created using the WikiPathways pathway repository and the STRING protein-protein interaction database. We identified genes and biological processes that were exclusively associated with the development of neuropsychiatric diseases among the 22q11DS patients. Compared with the 22q11DS patients without neuropsychiatric diseases, patients experiencing neuropsychiatric diseases showed significant overrepresentation of regulated genes involving the natural killer cell function and the PI3K/Akt signalling pathway, with affected genes being closely associated with downregulation of CRK like proto-oncogene adaptor protein. Both the pathway interaction and the pathway overrepresentation analysis observed the disruption of the same biological processes, even though the exact lists of genes collected by the two methods were different. CONCLUSIONS: Using the pathway interaction method, we were able to detect a molecular network that could possibly explain the development of neuropsychiatric diseases among the 22q11DS patients. This way, our method was able to complement the pathway overrepresentation analysis, by filling the knowledge gaps on how the affected pathways are linked to the original deletion on chromosome 22. We expect our pathway interaction method could be used for problems with similar contexts, where complex genetic mechanisms need to be identified to explain the resulting phenotypic plasticity.

Risk and Protective Factors for Sexual Exploitation in Male and Female Youth From a Cross-Cultural Perspective: A Systematic Review.

Youth are at elevated risk of becoming victims of sexual exploitation, which has a detrimental impact on their physical and psychological well-being. Understanding factors associated with sexual exploitation is key for prevention efforts and adequate and timely treatment. This systematic review sheds more light on this by providing an overview of both risk and protective factors for sexual exploitation in male and female youth from a cross-cultural perspective. In all, 65 studies were selected meeting the inclusion criteria: qualitative or quantitative peer-reviewed studies in English, Dutch, or German with findings on risk and protective factors associated with sexual exploitation in youth aged up to 24 years. Results show that there are common risk factors in male and female youth worldwide (e.g., adverse childhood experiences, lack of a social network, substance use, and running away). Positive and supportive relationships are an important protective factor in mitigating the risk of sexual exploitation. Geographic differences were found. In non-Western continents, more environmental factors (e.g., economic vulnerabilities, residential instability) were cited. Research in countries outside the United States is limited and protective factors and males are underexamined. To fully understand vulnerabilities in youth, their interactions, and possible gender differences and to address the needs of diverse populations, more insight should be gained into the broader range of risk and protective factors worldwide. This systematic review has made a valuable contribution to this by providing practice, policy, and research guidance in the establishment of more targeted prevention efforts, adequate treatment, and areas to address in future research.

Risk factors for suicidality across psychosis vulnerability spectrum.

BACKGROUND: Suicide is a leading cause of death in individuals with psychotic disorders. Risk factors for suicidality across the psychosis vulnerability spectrum are insufficiently known. METHODS: For patients (n = 830), siblings (n = 664) and controls (n = 444), suicidality was assessed by the use of a clinical interview. Multilevel modelling was used to investigate risk factors of suicidality. Lastly, risk factor × familial risk interaction effects were examined. RESULTS: Multivariable models revealed a significant relation between suicidality and depressive symptoms across all three groups, and childhood trauma in patients and siblings. The association between suicidality and psychotic-like experiences is more pronounced in siblings compared to controls. CONCLUSION: Across the psychosis vulnerability spectrum, depressive symptoms and childhood trauma have been associated with suicidality. Clinicians should pay attention to suicidality in individuals at high familial risk for psychosis with psychotic-like experiences.

Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis.

BACKGROUND AND HYPOTHESIS: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.