Doxepin plasma concentrations: is there really a therapeutic range?

Despite the introduction of numerous new agents, tricyclic antidepressants remain an important option for the treatment of depression. Doxepin is still in wide use, and determining its concentration is a standard procedure in many psychiatric clinics. Some widely cited reviews indicate a therapeutic range from 150 to 250 ng/mL (parent plus desmethyl metabolite). The vast majority of the authors' patients fell short of these concentrations under customary doses. To resolve this issue, the authors' serum-level databank was analyzed, a questionnaire was sent to U.S. and German psychiatric university departments and laboratories, and the literature was reviewed. The main results were the following: (1) Only 9% of all samples analyzed (N = 217) displayed plasma levels (high-performance liquid chromatography) between 150 and 250 ng/mL; 88% were subtherapeutic. The mean doxepin + desmethyldoxepin steady-state serum concentration was 89+/-75 ng/mL (N = 32, doxepin >3 weeks). The mean daily dose was 143+/-30 mg. There was no correlation between concentrations and improvement. (2) A wide variety of recommendations is given by the different university departments (10-1,000 ng/mL). (3) According to the studies published to date, there is not enough evidence for recommending a therapeutic range. The preliminary suggestions given in some influential reviews have been widely adopted without critical re-evaluation. Compared with the concentrations found in the original studies, the therapeutic ranges suggested are too high. A methodologically sound study to determine a therapeutic range is required for the rational monitoring of this drug. Meanwhile, a preliminary working range of 50 to 250 ng/mL is proposed on the basis of critical reassessment of published data.