<p>The CYP2C19*2 and CYP2C19*17 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>

Abstract

Introduction: Clozapine (CLZ) is the gold standard drug for treatment-refractory schizophrenia (TRS). However, approximately 30% of patients partially respond to CLZ, defining this subset with super refractory schizophrenia (SRS). Alterations in enzyme activity may affect CLZ responses; the CYP3A4, CYP1A2 and CYP2C19 genes are primarily responsible for CLZ metabolism. Objective: The aim of this study was to assess if CYP2C19 variants were associated with TRS or SRS. Methods: CYP2C19*2 loss-of-function and CYP2C19*17 gain-of-function polymorphism genotype testing were performed in 108 individuals undergoing pharmacological treatment for TRS or SRS. DNA was extracted and polymorphisms were analyzed by polymerase chain reaction (PCR) and sequencing. Results: CYP2C19*17 had positive correlations with SRS and lower Brief Psychiatric Rating Scale (BPRS) scores for TRS. In addition, CYP2C19*2 was associated with lower CLZ dosages for TRS. Conclusion: These results show that CYP2C19*2 and CYP2C19*17 polymorphisms influence CLZ responses during schizophrenia treatment.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorder

“…Furthermore, we found a positive association between genotype-predicted CYP2C19 enzyme activity and symptom severity. This finding aligns with a previous study of 137 clozapine-treated patients that reported CYP2C19 ultrarapid metabolizers ( *17/*17 ) were five times more likely to show clinical improvements, 74 although smaller studies have shown no association 31, 75 or an inverse association 76 between CYP2C19*17 carriers and clozapine-related symptomatic outcomes. Although CYP2C19 is involved in the demethylation of clozapine to N-desmethylclozapine, a pharmacologically active metabolite that binds to an array of receptors including dopamine D2 and D3 receptors, muscarinic receptors and serotonergic receptors 25 , current evidence suggests CYP2C19 genetic variation has limited effect on clozapine metabolism.…”

Possible pharmacogenetic factors in clozapine treatment failure: a case report

“…Further, recent research suggests that polymorphisms at CYP 450 2C19 influence clozapine treatment response. 50 Several case reports and clinical studies where fluvoxamine has been used to increase clozapine levels have been published. These have been systematically reviewed.…”

“…Further, recent research suggests that polymorphisms at CYP 450 2C19 influence clozapine treatment response. 50 …”

Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis

“…Genetic factors also contribute to this variability; thus, considering that CYP1A2, CYP2D6, CYP3A4 and CYP2C19 are involved in biotransformation of CLZ (Thorn et al, 2012; Lesche et al, 2020; Rodrigues‐Silva et al, 2020), variants in the genes coding for these enzymes affect their activity which, in turn, might modulate CLZ metabolism and ADRs, but the evidence is not consistent (Caetano & Piatkov, 2016; Lesche et al, 2020). Based on the literature, herein, we chose CYP genetic variants that: increase, decrease or abolish the corresponding enzymatic activity, those that modify enzyme inducibility or common concomitant drug treatment in these patients (e.g.…”

“…The analysis of CYP genetic variants and their relationship with CLZ pharmacokinetics only showed an association between the GA genotype of rs4244285 variant of CYP2C19 (also known as CYP2C19*2 variant, which is associated with a decreased enzyme activity) and higher CLZ adjusted dose‐corrected concentrations compared to the other genotypes ( p ‐corrected = .011) (Table 2). This allelic variant has been associated with lower CLZ concentrations in treatment of refractory SZ, and with lower BPRS scores in a super‐refractory SZ group (Rodrigues‐Silva et al, 2020). Even though our results agree with this report; its correlation was lost in the regression model.…”