Pharmacogenetics of serious antipsychotic side effects

Abstract

First- and second-generation antipsychotics are common drugs for treatment of schizophrenia (SCZ). Both classes of drugs have different receptor-binding profiles and affinities that are likely involved in their propensity to cause adverse side effects such as tardive dyskinesia (TD), antipsychotic-induced weight gain (AIWG) and clozapine-induced agranulocytosis (CIA). Apart from clinical and demographic factors (e.g. age, drug exposure, etc.) associated with risk for specific antipsychotic-induced side effects, genetic factors have also been shown to modulate outcome to antispychotic drugs. Notably, some of the studied genetic variants have been shown to have relatively large effect sizes in the risk for specific side effects. Beyond genes involved in drug metabolism (in particular CYP2D6 and CYP1A2), SLC18A2, PIP5K2A, CNR1, DPP6 and HSPG2 gene variants have more recently been found to be associated with TD. Similarly, HTR2C, LEP, MC4R, NDUFS1 and CNR1 genes have been associated with AIWG in at least two independent samples. Finally, variants of the HLA and MPO genes have been associated with CIA. Notably, the first genetic test kits designed to reduce risk of antipsychotic-induced side effects have become available for use in clinical practice. However, the clinical relevance of these gene variants needs further evaluation, and future studies are required to better understand the molecular context of the variants in these side effects.