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ImportancePredictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices.ObjectiveTo examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics.Design, Setting, and ParticipantsThis genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022.ExposuresPolygenic risk scores for SCZ.Main Outcomes and MeasuresMultinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics.ResultsPolygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD taking clozapine (RR, 3.24; 95% CI, 2.76-3.81; P = 2.47 × 10−46), followed by individuals with SSD taking other antipsychotics (RR, 2.30; 95% CI, 1.95-2.72; P = 3.77 × 10−22), parents (RR, 1.44; 95% CI, 1.25-1.68; P = 1.76 × 10−6), and siblings (RR, 1.40; 95% CI, 1.21-1.63; P = 8.22 × 10−6). Polygenic risk scores for SCZ were positively associated with clozapine vs other antipsychotic use (OR, 1.41; 95% CI, 1.22-1.63; P = 2.98 × 10−6), suggesting a higher likelihood of clozapine prescriptions among individuals with higher PRS-SCZ.Conclusions and RelevanceIn this study, PRS-SCZ loading differed between groups of individuals with SSD, their relatives, and unrelated healthy controls, with patients taking clozapine at the far end of PRS-SCZ loading. Additionally, PRS-SCZ was associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies of the value of using PRS-SCZ to personalize antipsychotic treatment.

Oxford Mental Illness and Violence (OxMIV) addresses the need in mental health services for a scalable, transparent and valid tool to predict violent behaviour in patients with severe mental illness. However, external validations are lacking. Therefore, we have used a Dutch sample of general psychiatric patients with schizophrenia spectrum disorders (N = 637) to evaluate the performance of OxMIV in predicting interpersonal violence over 3 years. The predictors and outcome were measured with standardized instruments and multiple sources of information. Patients were mostly male (n = 493, 77%) and, on average, 27 (SD = 7) years old. The outcome rate was 9% (n = 59). Discrimination, as measured by the area under the curve, was moderate at 0.67 (95% confidence interval 0.61–0.73). Calibration-in-the-large was adequate, with a ratio between predicted and observed events of 1.2 and a Brier score of 0.09. At the individual level, risks were systematically underestimated in the original model, which was remedied by recalibrating the intercept and slope of the model. Probability scores generated by the recalibrated model can be used as an adjunct to clinical decision-making in Dutch mental health services.

Individuals at clinical risk for psychosis (CHR-P) and persons with a first episode of psychosis (FEP) are up to three-fold more likely to smoke than the general population, respectively1,2. Besides the general well-known consequences of tobacco consumption (lung cancer, COPD, etc.), smoking has also been associated with other profound effects in patients with psychotic disorders and CHR-P individuals. For example, worse psychiatric symptoms3 and an increased risk of relapse4. Besides smoking cigarettes, abuse of cannabis, and other illicit drugs is also common. To improve outcomes, it is essential to gain insight into the patterns of substance abuse in UHR and FEP. Several, non-mutually exclusive explanations of the relationship between smoking and psychosis exist. The shared vulnerability hypothesis5-7 postulates a shared genetic and environmental vulnerability of substance use and psychosis, which explains why patients with psychosis smoke so frequently and heavily compared to healthy controls. The misattribution hypothesis states that substance users experience depressive and anxiety symptoms when withdrawal occurs; these feelings are relieved by substance use thus creating the perception that, for example, smoking has beneficial and relaxing effects. Substance use can also be seen as a dysfunctional coping mechanism to deal with distress and affective symptoms, which are the most common comorbid symptoms in CHR-P8 and FEP9. However, other authors state that nicotine has indeed beneficial effects on symptom severity by stimulation of the acetylcholine receptor and reduce side effects through cyp-induction10,11, also known as self-medication. By contrast, the stress-induction model of smoking proposes that smoking actually causes stress and negative affect12. The aim of this study is to further explore whether substance use is associated with symptomatology, negative affect and stress in CHR-P and FEP. Substance use, symptomatology, negative affect and stress have been assessed with clinical interviews and Experience Sampling Methods (ESM) respectively. We therefore aim to investigate the following research objectives on a between and within-subject level: The objectives are: i. Investigate the associations between baseline substance use (tobacco smoking and cannabis use), and severity and course of symptoms, experienced stress and negative affect as assessed with clinical interviews and aggregated ESM-data over a one year period, while accounting for a-prior defined covariates. ii. Investigate causal effects of smoking on psychotic experiences, negative affect and stress (and vice versa) using a dynamic approach between these outcomes in a moment-to-moment analysis. iii. Explore the moderating role of stress on the smoking-negative affect relationship: since daily stressors are related to both smoking and negative affect, exposure to stress might be an important moderator of the smoking–negative affect relationship.

BackgroundCognitive alterations are a central and heterogeneous trait in psychotic disorders, driven by environmental, familial and illness-related factors. In this study, we aimed to prospectively investigate the impact of high familial risk for cognitive alterations, unconfounded by illness-related factors, on symptomatic outcomes in patients.MethodsIn total, 629 probands with non-affective psychosis and their sibling not affected by psychosis were assessed at baseline, 3- and 6-year follow-up. Familial cognitive risk was modeled by three cognitive subtypes (‘normal’, ‘mixed’ and ‘impaired’) in the unaffected siblings. Generalized linear mixed models assessed multi-cross-sectional associations between the sibling cognitive subtype and repeated measures of proband symptoms across all assessments. Between-group differences over time were assessed by adding an interaction effect of time and sibling cognitive subtype.ResultsProbands affected by psychosis with a sibling of the impaired cognitive subtype were less likely to be in symptomatic remission and showed more disorganization across all time points. When assessing differences over time, probands of siblings with the impaired cognitive subtype showed less remission and less improvement of disorganization after 3 and 6 years relative to the other subtypes. They also showed less reduction of positive, negative and excitement symptoms at 6-year follow-up compared to probands with a sibling of the normal cognitive subtype.ConclusionsCross-sibling pathways from higher levels of familial cognitive vulnerability to worse long-term outcomes may be informative in identifying cognition-related environmental and genetic risks that impact psychotic illness heterogeneity over time.

Background The high prevalence of obsessive-compulsive symptoms (OCS) among subjects at Ultra-High Risk (UHR) for psychosis is well documented. However, the network structure spanning the relations between OCS and symptoms of the at risk mental state for psychosis as assessed with the Comprehensive Assessment of At Risk Mental States (CAARMS) has not yet been investigated. This article aimed to use a network approach to investigate the associations between OCS and CAARMS symptoms in a large sample of individuals with different levels of risk for psychosis. Method Three hundred and forty-one UHR and 66 healthy participants were included, who participated in the EU-GEI study. Data analysis consisted of constructing a network of CAARMS symptoms, investigating central items in the network, and identifying the shortest pathways between OCS and positive symptoms. Results Strong associations between OCS and anxiety, social isolation and blunted affect were identified. Depression was the most central symptom in terms of the number of connections, and anxiety was a key item in bridging OCS to other symptoms. Shortest paths between OCS and positive symptoms revealed that unusual thought content and perceptual abnormalities were connected mainly via anxiety, while disorganized speech was connected via blunted affect and cognitive change. Conclusions Findings provide valuable insight into the central role of depression and the potential connective component of anxiety between OCS and other symptoms of the network. Interventions specifically aimed to reduce affective symptoms might be crucial for the development and prospective course of symptom co-occurrence.

ObjectivePeople at ultra-high risk (UHR) for psychosis have a high prevalence of tobacco smoking, and rates are even higher among the subgroup that later develop a psychotic disorder. However, the longitudinal relationship between the course of tobacco smoking and clinical outcomes in UHR subjects is unknown.MethodsWe investigated associations between tobacco smoking and clinical outcomes in a prospective study of UHR individuals (n = 324). Latent class mixed model analyses were used to identify trajectories of smoking severity. Mixed effects models were applied to investigate associations between smoking trajectory class and the course of attenuated psychotic symptoms (APS) and affective symptoms, as assessed using the CAARMS.ResultsWe identified four different classes of smoking trajectory: (i) Persistently High (n = 110), (ii) Decreasing (n = 29), (iii) Persistently Low (n = 165) and (iv) Increasing (n = 20). At two-year follow-up, there had been a greater increase in APS in the Persistently High class than for both the Persistently Low (ES = 9.77, SE = 4.87, p = 0.046) and Decreasing (ES = 18.18, SE = 7.61, p = 0.018) classes. There were no differences between smoking classes in the incidence of psychosis. There was a greater reduction in the severity of emotional disturbance and general symptoms in the Decreasing class than in the High (ES = −10.40, SE = 3.41, p = 0.003; ES = −22.36, SE = 10.07, p = 0.027), Increasing (ES = −11.35, SE = 4.55, p = 0.014; ES = −25.58, SE = 13.17, p = 0.050) and Low (ES = −11.38, SE = 3.29, p = 0.001; ES = −27.55, SE = 9.78, p = 0.005) classes, respectively.ConclusionsThese findings suggests that in UHR subjects persistent tobacco smoking is associated with an unfavorable course of psychotic symptoms, whereas decrease in the number of cigarettes smoked is associated with improvement in affective symptoms. Future research into smoking cessation interventions in the early stages of psychoses is required to shine light on the potential of modifying smoking behavior and its relation to clinical outcomes.

Corrigendum to "A Network of Psychopathological, Cognitive, and Motor Symptoms in Schizophrenia Spectrum Disorders" by Moura et al. Schizophr Bull. 2021; doi: 10.1093/schbul/sbab002. In the originally published version of this manuscript, there were a number of errors in the author list. The author "Hanneke Wigman" should have appeared as "Johanna T. W. Wigman" The author "Genetic Risk and Outcome of Psychosis (GROUP) investigators" have appeared as the fifth author, not the last author. Johanna T.W. Wigman should have had a second affiliation: "Rob Giel Onderzoekscentrum, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands ".