CYP1A2 genotype-dependent effects of smoking on mirtazapine serum concentrations

Introduction: Psychopharmacotherapy with mirtazapine is commonplace. Lower serum concentrations of mirtazapine were reported in smokers due to CYP1A2 induction. However, no previous study that investigated CYP1A2 genetics and mirtazapine treatment considered CYP1A2-inducing parameters. Aim: We aimed to investigate the association of CYP1A2 variants, mirtazapine serum concentration, and treatment outcome, considering the smoking status of the patients. Methods: Two depression cohorts were investigated for the association between serum concentration and treatment response of mirtazapine and CYP1A2-163C>A (rs762551) and -3860G>A (rs2069514) genotype groups, also considering smoking status, sex, and age of the patients. In total, 124 patients (82 non-smokers and 42 smokers) were eligible for the analyses. Results: Dose-corrected serum concentration (CD) of mirtazapine was associated with smoking status, sex, and age, with lower CD in smokers, females, and older patients. Considering non-smokers and genotype-grouped smokers, CD of mirtazapine in CYP1A2 normal metabolizer smokers (N = 6) did not differ from CD of non-smokers. By contrast, smokers carrying the CYP1A2*1A/*1F and *1F/*1F genotype groups showed 34.4% and 33.4% lower mirtazapine CD compared to non-smokers. Discussion: As yet, for clinical practice, it may be more relevant to focus on smoking status than on the CYP1A2 gene variants. Considering the relevant impact of smoking on the mirtazapine CD, physicians should monitor an increase in side effects due to the expected increase in mirtazapine serum concentrations. In these cases, measurement of mirtazapine CD and/or subsequent dosage reduction is recommended. The clinical relevance of CYP1A2 genotyping prior to treatment with drugs metabolized by CYP1A2 needs further investigation.