Optimizing therapeutic drug monitoring of mirtazapine — applying therapeutic reference range, concentration–dose ratio/dose-related concentration, and metabolic ratio in a naturalistic setting

Purpose Mirtazapine is a common antidepressant, regularly monitored through therapeutic drug monitoring. The previously published Consensus Guidelines in Neuropsychopharmacology provide data on the therapeutic reference ranges (TRR), dose-related concentrations (DRC), and metabolic ratios (MR). We aimed to investigate these TDM ranges in a real-world naturalistic setting to offer more practical, evidence-based recommendations. Methods In a retrospective single-center cohort study, we screened 361 patients with major depressive disorder undergoing mirtazapine treatment. Following the Consensus Guidelines (Hiemke et al., 2017), we compared three TDM tools in combination: (I) the TRR, (II) the concentration-to-dose (C/D) ratio with DRC factors, and (III) the MR. Results We analyzed 328 patients (mean age 54 ± 16 years; 42% female). Serum levels of mirtazapine were below the TRR in 38% and above in 8%. Women exhibited an 18% higher C/D ratio compared to men, and elderly patients (> 65 years) demonstrated a 27% higher median C/D ratio than younger individuals. DRC values differed from the guideline-recommended ranges, likely due to higher dosing, unexpectedly lower serum values, interindividual pharmacokinetic variability, genetic polymorphisms, or polypharmacy. The median MR was 25% higher in women compared to men. Notably, 13 samples (4%) went beyond the designated MR range (either < 0.2 ng/mL or > 1.2 ng/mL). Conclusions This study provides real-world insights into established DRC values of mirtazapine. Observed age- and sex-related pharmacokinetic differences highlight the need for individualized dosing strategies, while further multicenter studies are needed to confirm their reproducibility.