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)