Clozapine pharmacogenomics: A review of efficacy, pharmacokinetics, and agranulocytosis

Abstract

Purpose of review To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis. Recent findings Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5-rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse – 2.11x risk [95% confidence interval (CI) 1.22–3.64], 1.7x risk (95% CI 1.13–2.59), and 2.15x risk (95% CI 1.3–3.55), respectively. BDNF and NR3C1 had no significant associations with CLZ response. Candidate genes within neurotransmitter pathways continue to be explored including dopaminergic (DRD1–4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, SLC6A9, GRIA1, GAD1). Despite promising trending data, no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic effect of catecholamine O-methyltransferase (COMT) Met and dopamine receptor-4 (DRD4) single 120bp duplicate associated with improved CLZ response odds ratio (OR) 0.15 (95% CI 0.03–0.62) while COMT Val/Val confer a risk of CLZ nonresponse OR 4.34 (95% CI 0.98–23.9). Diagnostic performance testing continues through human leukocyte antigen (HLA) and other genetic loci but have yet to find statistically or clinically meaningful results. Summary Current landscape of pharmacogenomic research in CLZ continues to be limited by small sample sizes and low power. However, many promising candidate genes have been discovered and should be further investigated with larger cohorts.