Trazodone serum levels are not significantly affected by factors such as age, gender, body mass index or smoking: pilot results

Introduction: Trazodone is a frequently used antidepressant and recently published results in two Chinese populations [1, 2] have shown that its serum concentration can be significantly influenced by other factors (e.g. age, gender, body mass index - BMI, smoking, trazodone formulation).

Aim: The primary aim of our research was to clarify whether similar significant effects also occur in an ethnically homogeneous population of patients treated under controlled conditions of hospitalization. Secondary aims were to evaluate the linearity of pharmacokinetics and to test whether the standard dosing regimen corresponds to the therapeutic concentration range (700–1000 ng/ml) recommended by AGNP [3].

Methods: A retrospective study of patients hospitalized between 2019 and 2024 at the University Hospital in Hradec Králové was conducted. Therapeutic drug monitoring (TDM) is routinely performed in hospitalized patients and the electronic medical record database contained 126 trazodone TDM during the mentioned period. Inclusion criteria were: participants identifying as White Europeans, TDM collection at steady state, standardized sampling time (~ 11 hours after the last dose). Exclusion criteria were: use of known CYP3A4 inhibitors/inducers, known liver lesions or elevated liver enzymes, consumption of fatty foods. The Mann–Whitney U and Kruskal–Wallis H tests were used for group comparisons of non-normally distributed variables. The Spearman rank coefficient was applied for correlation analysis. The concentration-to-dose (C/D) value was preferred in statistical evaluation as it acts as a useful quantifier of how efficiently the body removes a drug.

Results: Data from 28 patients were used. The relationship between dose and serum trazodone concentration was linear. Daily dose accounted for 48% of the variability in concentration (p < 0.001). The median C/D value was 6.31 ng/mL/mg and the interquartile range of C/D was 4.81–8.61 ng/mL/mg. At a daily dose of ~ 200 mg and higher, the concentration tended to exceeded 1000 ng/ml. The correlation between BMI and C/D was not significant (ρ = −0.05, p = 0.802). The effect size of BMI on C/D value (r = −0.05) was negligible. The distribution of C/D ratio values did not differ significantly between smokers (n = 9) and non-smokers (n = 18) (p = 0.487). The effect size of smoking status was small (r = −0.14). The correlation between age and C/D was not significant (ρ = −0.21, p = 0.282) and the effect size was minimal (r = −0.18). Gender (women and men, n = 19 and 9) did not significantly affect C/D and its effect size was negligible (p = 0.731, r = 0.07). Neither the dosage form of trazodone (controlled release vs. OAD tablets) had an effect on C/D (p = 0.417) and the effect size of the formulation was minimal (r = −0.16).

Conclusion: The results of our pilot study in hospitalized patients do not indicate a significant effect of age, gender, BMI, smoking and trazodone formulation on trazodone clearance. The pharmacokinetic of trazodone was linear. The serum concentration was significantly influenced by the daily dose of trazodone. However, the results must be interpreted with caution, as only a relatively small group of patients was evaluated.

References

Ding, J., Chen, Y., Zhang, Y., Zhang, S., Li, L., Xing, H., & Zhai, Y., 2025. Analysis of factors affecting laboratory alert level of trazodone based on therapeutic drug monitoring data. Clin Chim Acta 577, 120487.
Song, Y., Chang, L., Lun, Y., Chen, C., Fu, R., Wang, D., & Zhou, C., 2024. Analysis of Factors Affecting Concentrations and Concentration-To-Dose Ratios of Trazodone. Ther Drug Monit 46(2), 252-258.
Hiemke, C., Bergemann, N., Clement, H. W., Conca, A., Deckert, J., Domschke, K., . . . Baumann, P., 2018. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry 51(1-02), 9-62.