Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update

Abstract

Introduction: Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients’ genetics, paving the way toward individualized treatment.

Area covered: This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein.

Expert opinion: Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset.

Keywords:

• antipsychotics
• clinical response
• clozapine
• genetics
• pharmacogenetics
• schizophrenia
• side effects

Acknowledgments

V Sriretnakumar and E Huang are co-first authors. The authors would like to thank Dr. Arun K Tiwari and Dr. Vanessa F Goncalves for their advice in the writing of this article.

Declaration of interest

DJ Müler is supported by a NARSAD Independent Investigator grant and a Canadian Institutes of Health Research (CIHR) New Investigator Award. EH is supported by the Canada Graduate Scholarship (CGS). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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