Therapeutic Drug Monitoring of the Antidepressant Mirtazapine and Its N-Demethylated Metabolite in Human Serum

Abstract

Mirtazapine is a novel antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. Because very little is known about serum concentrations in relation to clinical effects, the use of therapeutic drug monitoring is so far unclear. A rapid automated HPLC method with fluorescence detection was developed for routine quantification of mirtazapine and its demethylated metabolite N-desmethylmirtazapine in human serum. The precision of the method was suitable because the day-to-day (n = 7) coefficient of variation (CV) of mirtazapine was 9.8, 4.2, and 5.1% for concentrations of 10, 40, and 80 ng/mL, respectively, and the CV for N-desmethylmirtazapine were 11.6, 10.3, and 9.5% for 5, 20, and 40 ng/mL, respectively. The bias ranged between 0.7 and 4.2 ng/mL and between 0.9 and 2.0 ng/mL for mirtazapine and N-desmethylmirtazapine, respectively. Serum samples of 100 patients, aged between 18 and 93 years, were analyzed. There was wide interindividual variability of serum concentrations on each dose level, and the median (25th to 75th percentiles) of the mirtazapine and N-desmethylmirtazapine concentrations was 19.5 (11.0-28.7) and 9.0 (6.0-17.0) ng/mL, respectively. Women had higher dose-corrected concentrations (C/Ds, ng/mL/mg) of mirtazapine [median (25th-75th percentiles) 0.6 (0.4-0.9) vs 0.4 (0.3-0.6) and N-desmethylmirtazapine [0.4 (0.2-0.6) vs 0.2 (0.1-0.4)] than men. Patients over 60 years of age (mean age +/- SD was 72.2 +/- 7.1) had higher C/Ds of mirtazapine and N-desmethylmirtazapine [0.7 (0.4-1.2) vs 0.53 (0.4-0.8) and 0.5 (0.2-0.9) vs 0.3 (0.2-0.9), respectively] than younger patients (mean age +/- SD was 43.3. +/- 10.6). Patients with N-desmethylmirtazapine/mirtazapine ratios less than 0.4 had significantly more side effects (P < 0.05) than those having higher ratios. Comedications were assessed for drug-drug interaction, and significantly (P < 0.05) lower N-desmethylmirtazapine/mirtazapine ratios were found under concomitant medications of the antidepressant sertraline and the antipsychotic amisulpride.