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 clozapine (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 metabolism. 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 correlation 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 duration 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.

The ethics of polygenic scores in psychiatry: minefield or opportunity for patient-centered psychiatry?

Recent advancements in psychiatric genetics have sparked a lively debate on the opportunities and pitfalls of incorporating polygenic scores into clinical practice. Yet, several ethical concerns have been raised, casting doubt on whether further development and implementation of polygenic scores would be compatible with providing ethically responsible care. While these ethical issues warrant thoughtful consideration, it is equally important to recognize the unresolved need for guidance on heritability among patients and their families. Increasing the availability of genetic counseling services in psychiatry should be regarded as a first step toward meeting these needs. As a next step, future integration of novel genetic tools such as polygenic scores into genetic counseling may be a promising way to improve psychiatric counseling practice. By embedding the exploration of polygenic psychiatry into the supporting environment of genetic counseling, some of the previously identified ethical pitfalls may be prevented, and opportunities to bolster patient empowerment can be seized upon. To ensure an ethically responsible approach to psychiatric genetics, active collaboration with patients and their relatives is essential, accompanied by educational efforts to facilitate informed discussions between psychiatrists and patients.

Clinical symptoms and psychosocial functioning in patients with schizophrenia spectrum disorders testing seropositive for anti-NMDAR antibodies: a case-control comparison with patients testing negative.

BACKGROUND: Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies. METHODS: In this case-control comparison, by combining new and existing studies, we included patients diagnosed with schizophrenia from four independent cohorts for whom anti-NMDAR serostatus had been assessed (or could be assessed by us) with live cell-based assays. Included cohorts were from the EULAST study (a trial conducted across 15 European countries and Israel), the OPTiMiSE study (an interventional study in Europe), and the PPiP1 and PPiP2 studies (conducted in the UK). Patients from these cohorts were analysed if they had complete Positive and Negative Syndrome Scale (PANSS) data. No participant had been diagnosed with autoimmune encephalitis or received treatment for this condition. After calculating the prevalence of serum anti-NMDAR antibodies, we examined possible differences in PANSS scores (negative, positive, and general symptom subscales, and total score) between anti-NMDAR-seropositive and anti-NMDAR-seronegative patients. Psychosocial functioning as measured by Personal Social Performance (PSP) score was also compared. All analyses were exploratory and no adjustment was done for multiple testing. People with lived experience were not involved in the conduct of this study. FINDINGS: We collected individual patient data from 1114 patients with schizophrenia across the four cohorts. The study population had a mean age of 28·6 years (SD 7·6) and comprised 382 (34·3%) women and 732 (65·7%) men, including patients of White (929 [83·4%]), Asian (54 [4·8%]), Black (68 [6·1%]), and other (62 [5·6%]) ethnicities. Overall, 41 (3·7%) participants (range 3·1-4·0% across cohorts) tested positive for serum anti-NMDAR antibodies. Lower symptom severity on the negative symptoms PANSS subscale was observed for anti-NMDAR-seropositive patients (mean score 15·8 [SD 6·4]) than for anti-NMDAR-seronegative patients (18·2 [6·8]; Cohen's d=0·36; p=0·026), as well as on the general symptoms PANSS subscale (32·9 [8·9] vs 36·1 [10·1]; d=0·33; p=0·029) and total PANSS score (65·5 [18·5] vs 72·6 [19·3]; d=0·37; p=0·013). Mean PSP score was better in anti-NMDAR-positive patients (62·0 [17·0]) than in anti-NMDAR-negative patients (53·5 [16·3]; d=0·52; p=0·014). INTERPRETATION: Serum NMDAR antibodies are present in 3-4% of patients with schizophrenia and are associated with relatively low severity of negative symptoms and relatively good psychosocial functioning. Thus, although the findings await replication in cohorts from other geographical regions, serum anti-NMDAR antibodies might be associated with a different form of psychotic illness. These findings could inform future prognostic and interventional studies examining whether anti-NMDAR antibodies are associated with a specific course of illness or with treatment response. FUNDING: None.

Longitudinal changes in DNA methylation associated with clozapine use in treatment-resistant schizophrenia from two international cohorts.

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p < 5 × 10-5) in a linear model and 90 DMPs in a non-linear quadratic model. We compared these results to data from our previous epigenome-wide association study (EWAS) meta-analysis of psychosis, finding evidence that many previously identified DMPs associated with schizophrenia and treatment-resistant schizophrenia might reflect exposure to clozapine. In conclusion, our results indicate that clozapine exposure is associated with changes in DNA methylation and cellular composition. Our study shows that medication effects might confound many case-control studies of neuropsychiatric disorders performed in blood.

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 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 Participants: This 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. Exposures: Polygenic risk scores for SCZ. Main Outcomes and Measures: Multinomial 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. Results: Polygenic 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 Relevance: In 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.

An international research agenda for clozapine-resistant schizophrenia.

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life.

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.

Barriers to genetic testing in clinical psychiatry and ways to overcome them: from clinicians' attitudes to sociocultural differences between patients across the globe.

Genetic testing has evolved rapidly over recent years and new developments have the potential to provide insights that could improve the ability to diagnose, treat, and prevent diseases. Information obtained through genetic testing has proven useful in other specialties, such as cardiology and oncology. Nonetheless, a range of barriers impedes techniques, such as whole-exome or whole-genome sequencing, pharmacogenomics, and polygenic risk scoring, from being implemented in psychiatric practice. These barriers may be procedural (e.g., limitations in extrapolating results to the individual level), economic (e.g., perceived relatively elevated costs precluding insurance coverage), or related to clinicians' knowledge, attitudes, and practices (e.g., perceived unfavorable cost-effectiveness, insufficient understanding of probability statistics, and concerns regarding genetic counseling). Additionally, several ethical concerns may arise (e.g., increased stigma and discrimination through exclusion from health insurance). Here, we provide an overview of potential barriers for the implementation of genetic testing in psychiatry, as well as an in-depth discussion of strategies to address these challenges.

A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking.

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies, and clinical trials of aging interventions.

Impact of the first COVID-19 outbreak on mental health service utilisation at a Dutch mental health centre: retrospective observational study.

BACKGROUND: Previous studies into mental health service utilisation during the COVID-19 pandemic are limited to a few countries or specific type of service. In addition, data on changes in telepsychiatry are currently lacking. AIMS: We aimed to investigate whether the COVID-19 pandemic is associated with changes in mental health service utilisation, including telepsychiatry, and how these changes were distributed among patients with mental illness during the first COVID-19 outbreak. METHOD: This retrospective study obtained routinely assessed healthcare data from a large Dutch mental healthcare institute. Data from the second quarter of 2020 (the first COVID-19 outbreak period) were compared with the pre-pandemic period between January 2018 and March 2020. Time-series analyses were performed with the quasi-Poisson generalised linear model, to examine the effect of the COVID-19 lockdown and the overall trend of mental health service utilisation per communication modality and diagnostic category. RESULTS: We analysed 204 808 care contacts of 28 038 patients. The overall number of care contacts in the second quarter of 2020 remained the same as in the previous 2 years, because the number of video consultations significantly increased (B = 2.17, P = 0.488 × 10-3) as the number of face-to-face out-patient contacts significantly decreased (B = -0.98, P = 0.011). This was true for all different diagnostic categories, although this change was less pronounced in patients with psychotic disorders. CONCLUSIONS: Diminished face-to-face out-patient contacts were well-compensated by the substantial increase of video consultations during the first COVID-19 outbreak in The Netherlands. This increase was less pronounced for psychotic disorders. Further research should elucidate the need for disorder-specific digital mental healthcare delivery.