Polygenetic risk scores and phenotypic constellations of obsessive–compulsive disorder in clozapine-treated schizophrenia

Obsessive–compulsive symptoms (OCS) are frequently observed in individuals with schizophrenia (SCZ) treated with clo- zapine (CLZ). This study aimed to analyze prevalence of OCS and obsessive–compulsive disorder (OCD) in this subgroup and find possible correlations with different phenotypes. Additionally, this is the first study to examine polygenetic risk scores (PRS) in individuals with SCZ and OCS. A multicenter cohort of 91 individuals with SCZ who were treated with CLZ was recruited and clinically and genetically assessed. Symptom severity was examined using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), Global Assessment of Functioning Scale (GAF) and Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Participants were divided into subgroups based on phenotypic OCS or OCD using Y-BOCS scores. Genomic-wide data were generated, and PRS analyses were performed to evaluate the association between either phenotypic OCD or OCS severity and genotype-predicted predisposition for OCD, SCZ, cross-disorder, and CLZ/norclozapine (NorCLZ) ratio, CLZ metabolism and NorCLZ metabo- lism. OCS and OCD were frequent comorbidities in our sample of CLZ-treated SCZ individuals, with a prevalence of 39.6% and 27.5%, respectively. Furthermore, the Y-BOCS total score correlated positively with the duration of CLZ treatment in years (r = 0.28; p = 0.008) and the PANSS general psychopathology subscale score (r = 0.23; p = 0.028). A significant cor- relation was found between OCD occurrence and PRS for CLZ metabolism. We found no correlation between OCS severity and PRS for CLZ metabolism. We found no correlation for either OCD or OCS and PRS for OCD, cross-disorder, SCZ, CLZ/NorCLZ ratio or NorCLZ metabolism. Our study was able to replicate previous findings on clinical characteristics of CLZ-treated SCZ individuals. OCS is a frequent comorbidity in this cohort and is correlated with CLZ treatment dura- tion in years and PANSS general psychopathology subscale score. We found a correlation between OCD and PRS for CLZ metabolism, which should be interpreted as incidental for now. Future research is necessary to replicate significant findings and to assess possible genetic predisposition of CLZ-treated individuals with SCZ to OCS/OCD. Limitations attributed to the small sample size or the inclusion of subjects on co-medication must be considered. If the association between OCD and PRS for CLZ metabolism can be replicated, it should be further evaluated if CYP1A2 alteration, respectively lower CLZ plasma level, is relevant for OCD development

Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapineassociated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n=698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4% of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6%), weight gain (69.3%), and increased sleep necessity (65.9%), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10%). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being

Genetic determinants associated with response to clozapine in schizophrenia:an umbrella review

OBJECTIVE: Clozapine response varies widely from person to person, which may be due to inter-individual genetic variability. This umbrella review aims to summarize the current evidence on associations between pharmacodynamic genes and response to clozapine treatment. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis methodology, a systematic literature search was conducted in the PubMed and EMBASE databases from inception to November 2021 to identify systematic reviews and meta-analyses of studies that examined genetic determinants of clozapine response. The quality of the reviews was assessed with the AMSTAR-2 tool. RESULTS: From a total of 128 records, 10 studies representing nine systematic reviews and one meta-analysis met our inclusion criteria. The overall quality of the included studies was poor. All systematic reviews concluded that the results of primary studies were largely negative or conflicting. Most evidence was found for an association with clozapine response and rs6313 and rs6314 within HTR2A and rs1062613 within HTR3A in the serotonergic system. CONCLUSIONS: Conclusive evidence for associations between genetic variants and clozapine response is still lacking. Hypothesis-generating genetic studies in large, well-characterized study populations are urgently needed to obtain more consistent and clinically informative results. Future studies may also include multi-omics approaches to identify novel genetic determinants associated with clozapine response

Lifestyle interventions for people with a severe mental illness living in supported housing:A systematic review and meta-analysis

Although supported housing facilities (SHF) appear to be an ideal setting for supporting people with severe mental illness (SMI) to obtain a healthier lifestyle, little is known about the effects of lifestyle interventions in SHF and the factors contributing to successful implementation. We performed a systematic review and meta-analysis to assess the effect of lifestyle interventions on mental and physical health in people with SMI in SHF, and reviewed which intervention factors contribute to successful implementation. A meta-analysis using a random effects model was undertaken. Discussions were reviewed to identify factors that foster successful implementation. Of 7401 identified studies, 9 RCTs (n = 1260) were included for the systematic review and 8 (n = 1187) for the meta-analysis. Improvements in weight (n = 3), BMI (n = 1), 6-Min Walk Test (n = 1) and metabolic criteria (n = 2) were seen. In the meta-analysis we only found a small effect for a decrease in waist circumference. Reviewing factors involved with the implementation showed that the most successfully implemented interventions were multidisciplinary and integrated into standard care. In conclusion, we found limited evidence for the effectiveness of lifestyle interventions on physical health for those living in SHF. To reliably examine the effects on mental and physical health, more studies with high involvement of staff and participants are needed

Guidelines on genetic testing in psychiatry:an overview

Background In recent years, technological advances have led to the identification of numerous genetic variations that are associated with psychiatric symptoms. Establishing a genetic cause may provide patients and family members with an explanation for the problems and in specific cases allows targeted treatment of psychiatric and somatic (co)morbidity. At present, patients with psychiatric disorders are rarely referred for genetic testing. Aim To provide an overview of literature and (inter)national guidelines in the field of genetic testing for patients with psychiatric disorder, and to present guidance on indications for genetic testing in clinical practice. Method A systematic search was conducted in PubMed and Embase focusing on articles with recommendations on genetic testing in psychiatric disorders. In addition, national and international guidelines on genetic testing in psychiatry were studied. The main findings were summarized in an infographic. Results Based on the current literature and (inter)national guidelines, patients with (comorbid) intellectual disability should always be referred to a clinical geneticist. Psychiatrists should consider genetic testing in patients with other psychiatric disorders if there are 'red flags' such as a positive family history, congenital abnormalities, developmental delay, dysmorphic features, movement disorders or cognitive decline. Psychiatrists may request genetic testing themselves or refer patients to clinical geneticists. Conclusion Psychiatric disorders may be underpinned by a genetic anomaly, particularly in patients presenting with psychiatric as well as somatic symptomatology. Psychiatrists should recognize symptoms and warning signs indicative of an underlying genetic abnormality, and know when to refer their patients for genetic testing

Genetic risk of mental illness:What do we know and how do we communicate this?

Background Insights from psychiatric genetics research and large international psychiatric genetics consortia are promising but still remain outside the realm of clinical practice. Aim To provide an overview of developments in the field of psychiatric genetics; and to offer guidance for health professionals how to assess and manage clinical implications of these developments. Method In this review, we address: recent developments in psychiatric genetics, with a focus on polygenic risk scores (PRS); ethical dilemmas associated with clinical application of PRS; and basic principles of genetic counseling for psychiatric disorders. Results PRS are not yet ready for implementation in clinical practice because of limited predictive value and poor generalizability. In addition, it is still unclear how genetic risk and PRS can be communicated clearly to patients and families. Conclusion Advances in psychiatric genetics and increased availability of genetic risk scores may lead to questions from patients and families coping with psychiatric illness. These questions may be best addressed using psychiatric genetic counseling techniques. We recommend that psychiatrists have some basic knowledge of psychiatric genetics and know how to refer their patients to a clinical geneticist. Implementing a psychiatric genetics theme in training and education may be helpful

Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapine-associated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n = 698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4 % of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6 %), weight gain (69.3 %), and increased sleep necessity (65.9 %), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10 %). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being

Associations between polygenic risk score loading, psychosis liability, and clozapine use among individuals with schizophrenia

Importance: Predictors 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. Objective: To examine associations between PRS-SCZ loading and groups with different liabilities to SSD: individuals with SSD on clozapine, individuals with SSD on 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: Six-year follow-up and cross-sectional observational cohort study. Setting: Multi-center. Participants: Individuals diagnosed with SSD using clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Exposure: PRS-SCZ. Main Outcomes and Measures: We used multinomial logistic regression to examine possible differences between groups by computing risk ratios (RRs), i.e., 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. Results: PRSs-SCZ were generated for 2344 participants (mean age: 36.95 years; 42.4% female) remaining after quality control (557 individuals with SSD on clozapine, 350 individuals with SSD on other antipsychotics during six-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 on clozapine (RR=3.24 [95%CI 2.76-3.81], p=2.47x10-46), followed by individuals with SSD on other antipsychotics (RR=2.30 [95%CI 1.95-2.72], p=3.77x10-22), parents (RR=1.44 [95%CI 1.25-1.68], p=1.76x10-6), and siblings (RR=1.40 [95%CI 1.21-1.63], p=8.22x10-6). PRS-SCZ was positively associated with clozapine versus other antipsychotic use (OR=1.41 [95%CI 1.22-1.63], p=2.98x10-6), suggesting a higher likelihood of clozapine prescriptions in individuals with higher PRS-SCZ. Conclusions and Relevance: PRS-SCZ loading differs between groups of individuals with SSD, their relatives, and unrelated healthy controls, with clozapine users being at the far end of PRS-SCZ loading. Additionally, PRS-SCZ is associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies into the value of PRS-SCZ for personalized antipsychotic treatment