Introduction: In clinical practice, therapeutic drug monitoring (TDM) for bupropion is limited by bupropion's instability at room temperature and by the absence of a well-defined therapeutic reference range. Further it is unclear to date to what extent bupropion and its metabolites contribute to therapeutic effects even though hydroxybupropion, the active metabolite of bupropion, seems to account for the major antidepressant effects. The aim of this examination was to check if measurement of only hydroxybupropion is useful to guide the antidepressant therapy with bupropion. Methods: Hydroxybupropion plasma levels were measured according to a newly developed and validated high performance liquid chromatography (HPLC) assay with ultra violet (UV) detection and related to therapeutic effects measured by the Clinical Global Impression Scale (CGI) for improvement. Results: The study included 52 patients (50% female). Patients under bupropion who were very much improved according to CGI had significantly (p=0.042) higher hydroxybupropion serum levels than patients with moderate or minimal improvement (mean±SD, 1113±576ng/ml, 825±398ng/ml and 475±331ng/ml, respectively). Receiver operating characteristics (ROC) analysis revealed significant predictive properties of hydroxybupropion serum levels (p=0.002) for improvement with a lower threshold level of 858ng/ml. Women attained significantly higher serum levels than men (1050±524 vs. 589±352ng/ml, respectively) and also exhibited a better therapeutic effect (p=0.018), though they did not receive higher doses (265±107 vs. 239±100mg, respectively). Conclusions: Measurement of hydroxybupropion plasma levels can be used to optimize the therapeutic outcome of patients treated with bupropion. Plasma levels between 850 and 1500ng/ml can be regarded as optimal. Potential sex differences in bupropion pharmacokinetics, probably due to differential activities of CYP2B6, should be taken into account when performing TDM for bupropion.
