Genetic

Mirtazapine is given as a racemic mixture of S + and R − mirtazapine [32]. It is absorbed from the gut with a rate constant of 0.2/minute (half-life 3.5 minutes) for the S + isomer and 0.08/minute (half-life 9 minutes) for the R − isomer. The kinetics of R − mirtazapine are not related to CYP2D6 genotype, but the total clearance of the S + enantiomer is 1.3, 2.3, and 3.4 l/minute in poor, extensive, and ultrarapid metabolizers of CYP2D6 respectively; there was substantial first-pass metabolism in rapid and ultrarapid metabolizers. The effects of mirtazapine on heart rate and blood pressure correlated better with R − than S + concentrations, but sedation correlated equally with the two enantiomers.

A polymorphism in the 5HT transporter gene 5HTTLPR may affect the risk of adverse reactions to mirtazapine. In a ouble-blind, randomized, 8-week study of 246 cognitively intact patients aged 65 years or older with major depression, who took mirtazapine 15–45 mg/day (n = 124) or paroxetine 20–40 mg/day (n = 122), S allele carriers treated with paroxetine showed a small impairment in antidepressant response, but there was no effect on the antidepressant efficacy of mirtazapine [33]. Among paroxetine-treated subjects, S allele carriers had more severe adverse events during the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Among mirtazapine-treated subjects, the S allele carriers had fewer discontinuations because of adverse events, had less severe adverse events, and achieved higher final daily doses.