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Genetic variation in CYP3A43 is associated with response to antipsychotic medication

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Genetic variation in cytochrome enzymes is known to affect drug metabolism and influence treatment response. Recently, the rs472660 variant in CYP3A43 has been associated with olanzapine response and clearance. In this study, we investigated the impact of rs472660 and the putatively functional marker rs680055 on antipsychotic response. We genotyped the rs472660 and rs680055 single nucleotide polymorphisms (SNPs) in N = 152 schizophrenia patients of European descent collected at two sample sites who were predominately treated with second generation antipsychotics for up to 6 months. Treatment response was assessed prospectively using Brief Psychiatric Rating Scale (BPRS) scores. Statistical analysis was performed using Chi square and analysis of covariance. The rs680055 SNP was significantly associated with treatment response. Carriers of the minor allele had significantly lower BPRS scores at study end (p = 5.9 × 10–4) with 8 % of the variance being explained by rs680055 genotype. Post hoc analyses revealed that this effect was present in both samples and in both genders. The rs472660 SNP was also associated with response (p = 0.027); however, this finding was not significant after multiple test correction. This is the first evidence that the rs680055 missense mutation influences antipsychotic response. Although our finding for rs472660 was only a non-significant trend after correction, our results still support the notion that this SNP may play a role in antipsychotic response. Despite the fact that the functional role of CYP3A43 in antipsychotic metabolism is not fully understood yet, our study provides an important contribution to understanding genetic factors of antipsychotic response.

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EJB/AKT/TAL/NIC/DJM: no competing interests. HYM has received grants or is or was a consultant to: Abbott Labs, ACADIA, Alkemes, Bristol Myers Squibb, DaiNippon Sumitomo, Eli Lilly, EnVivo, Janssen, Otsuka, Pfizer, Roche, Sunovion, and BiolineRx. HYM is a shareholder of ACADIA and Glaxo Smith Kline. In the past 3 years JAL reports having received research funding or is a member of the advisory board of Allon, Alkermes Bioline, GlaxoSmithKline Intracellular Therapies, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Psychogenics, F. Hoffmann-La Roche LTD, Sepracor (Sunovion) and Targacept. JAL received no direct financial compensation or salary support for participation in these researches, consulting, or advisory board activities. JLK has been a consultant to GSK, Sanofi-Aventis, and Dainippon-Sumitomo. AKT: recipient of NARSAD 2010 young investigator award. NIC: OMHF research studentship. DJM: CIHR operating grant (Genetics of antipsychotics induced metabolic syndrome, MOP: 89853); NARSAD independent investigator award, early researcher award by the Ministry of Research and Innovation of Ontario, CIHR Michael Smith new investigator salary prize for research in Schizophrenia. JLK: recipient of a CIHR operating grant (MOP: 115097).

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Correspondence to Daniel J. Müller.

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Brandl, E.J., Chowdhury, N.I., Tiwari, A.K. et al. Genetic variation in CYP3A43 is associated with response to antipsychotic medication. J Neural Transm 122, 29–34 (2015).

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