Serum concentrations of hydroxybupropion for dose optimization of depressed patients treated with bupropion

Bupropion is a dopamine and norepinephrine reuptake inhibitor approved for the treatment of depression and smoking cessation. According to the recently published reviews, it is a candidate for therapeutic drug monitoring (TDM) to improve therapeutic outcomes and reduce risks of intolerability or intoxication. In practice, however, the use of TDM is limited due to the chemical instability of bupropion. This investigation sought to determine if the major, active, and chemically stable metabolite 4-hydroxybupropion is a suitable measure to guide antidepressant drug therapy with bupropion.

4-Hydroxybupropion serum levels were measured using a newly developed and validated high-performance liquid chromatography assay with ultraviolet detection. They correlated with therapeutic effects measured by the clinical global impression scale for improvement.

The study included 52 patients (50% women). Patients who were markedly improved according to the clinical global impression scale score had significantly (P = 0.042) higher 4-hydroxybupropion serum levels than those with moderate or minimal improvement (mean ± SD, 1113 ± 576, 825 ± 398, and 475 ± 331 ng/mL, respectively). Analysis of receiver operating characteristics revealed significant predictive properties of 4-hydroxybupropion serum levels (P = 0.002) for marked improvement with a lower threshold level of 858 ng/mL. Under similar mean doses (265 ± 107 versus 239 ± 100 mg, respectively), women attained significantly higher serum levels than men (1050 ± 524 versus 589 ± 352 ng/mL, respectively) and exhibited a better therapeutic effect (P = 0.018).

Despite multiple limitations of this naturalistic study, evidence could be given that the measurement of 4-hydroxybupropion in serum is suitable to perform TDM for bupropion. Blood levels should be above 860 ng/mL to attain therapeutic improvement. Potential sex differences in bupropion pharmacokinetics, probably due to differential activities of CYP2B6, should be taken into account when the drug is prescribed.