Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

Abstract

Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs’ ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk–benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine.

Antipsychotic Abuse, Dependence, and Withdrawal in the Pediatric Population: A Real-World Disproportionality Analysis

“…In child psychiatry, despite limited evidence regarding their efficacy and safety profiles, APs are increasingly subject to off-label use [ 4 , 5 , 6 ]. This phenomenon stems from a global increase in the prescribing of APs [ 7 , 8 ], a restricted pattern of marketing authorizations, as well as the lack of guidelines for their use in this population [ 9 , 10 ].…”