Persistence of Antipsychotic Use After Clozapine Discontinuation:A Real-World Study Across Antipsychotics

Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for >= 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P <0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients

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

Towards personalized treatment of clozapine

The aim of this thesis was to find potential factors associated with side effects and efficacy that could be used in clinical practice to personalize clozapine treatment. In this chapter, the main findings from the performed research are presented. Then, a general discussion, methodological considerations and implications for the future are provided. The conclusions following from the data in each chapter are: - Clozapine is more effective as a first or second-line treatment compared to other antipsychotics, especially when compared to risperidone. This suggests that clozapine might be useful for some patients in earlier disease stages than currently practiced (Chapter 2). - Patient-related reasons to delay clozapine initiation are regular blood tests, side effects concerns, and unwillingness to switch medication. Practitioner-related reasons to delay clozapine initiation are regular blood tests, side effects concerns, and fear for treatment-emergent complications. Most patients (according to practitioners) and practitioners worry about the side effects. However, practitioners worry more about severe, rare side effects, while they indicate that their patients worry about the more prevalent, less severe side effects (Chapter 3). - From the four single nucleotide polymorphisms (SNPs) most associated with agranulocytosis and/or neutropenia in previous genome-wide association studies (GWASs), we found rs113332494 being significantly associated in all ethnical groups (Turkish, Caucasian, Total). In meta-analysis of our results and the previously reported genome-wide results, rs113332494 (HLA-DQB1), rs41549217 (HLA-B), and rs149104283 (SCLO1B3/SCLO1B7) were significantly associated with agranulocytosis/neutropenia in participants with Caucasian ancestry. Our results hint at ethnicity-dependent and clinically relevant effects of genetic polymorphisms on the risk to develop agranulocytosis/neutropenia (Chapter 4). - Meta-analyses suggest that three baseline demographic and clinical features are associated with better clozapine response; younger age, few negative symptoms and paranoid schizophrenia subtype. These variables may be considered by clinicians who consider treating a specific patient with clozapine (Chapter 5). - When performing a genome wide association study (GWAS) on higher vs. lower symptom severity in clozapine users, no locus surpassed the genome-wide significance threshold. However, rs1923778 within the NFIB gene showed a suggestive association with symptom severity. Higher cross-disorder and schizophrenia polygenic risk scores (PRS) and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine (Chapter 6). - When performing meta-analyses on GWASs investigating clozapine concentrations with and without smoking status as a covariate, no locus surpassed the genome-wide threshold. When performing a GWAS on a subset of participants with data available on smoking status and caffeine use, a genome-wide significant locus was identified: rs62225273. Factors such as smoking status and caffeine use influence clozapine metabolism. In addition, the clozapine concentrations phenotype can be determined in multiple ways, i.e. with/without using dose-adjusted concentrations. Therefore, it would be good to perform additional research to find out what the “right” phenotype is, as well as what covariates are applicable before conclusions can be drawn (Chapter 7)

Differences between physicians' and nurse practitioners' viewpoints on reasons for clozapine underprescription

INTRODUCTION: Clozapine (CLZ) is the only proven effective therapy for treatment-resistant schizophrenia, but it is underutilized across the globe. Previous findings suggest a lack of experience with CLZ prescription and concerns about CLZ's pharmacological characteristics are the prime reasons for CLZ underutilization. To our knowledge, it is currently unknown whether the reasons for underutilization and suggested solutions differ between physicians and nurse practitioners. Such differences are important as nurse practitioners are becoming increasingly involved in prescribing CLZ. METHODS: To examine to what degree physicians and nurse practitioners differ with regard to their take on reasons for CLZ underutilization and suggested solutions, an online questionnaire was distributed to physicians and nurse practitioners. The primary outcome was to compare the patient-related and prescriber-related reasons for CLZ underprescription between physicians and nurse practitioners, while secondary outcome measures included the potential solutions to prevent this underprescription. RESULTS: Physicians (N = 112) and nurse practitioners (N = 41) agreed that the two most common reasons for underprescription (patient-related and prescriber-related) were refusal to undergo regular blood tests and side-effect concerns. They also agreed that the third most common prescriber-related reason was medical complications. Physicians rated patients' unwillingness to switch medication as the third most common reason for CLZ underprescription, whereas nurse practitioners rated refusal to undergo baseline bloodtests as the third most common reason. The solutions to reduce underprescription largely corresponded between both groups. CONCLUSIONS: We conclude that slight differences exist between physicians' and nurse practitioners' viewpoints on patient-related and prescriber-related reasons for CLZ underprescription. Future research projects should involve patients to elucidate whether the patient-related factors put forward by prescribers align with the patients' opinions

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&nbsp;=&nbsp;698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4&nbsp;% of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6&nbsp;%), weight gain (69.3&nbsp;%), and increased sleep necessity (65.9&nbsp;%), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (&gt;10&nbsp;%). 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

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 that 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 (PCs) from CpG-level data as input for biological age prediction. Our retrained PC 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 previous knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of PC-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies and clinical trials of aging interventions