Imipramine: Do Metabolite Plasma Levels Affect Treatment Response?

Although combined plasma levels of imipramine and its metabolite desipramine are routinely assessed during therapeutic drug monitoring (TDM) of imipramine treatment, individual plasma levels are often overlooked. Imipramine and desipramine differ in their pharmacokinetic properties. Previous research in patients with generalized anxiety disorder suggested that imipramine treatment efficacy might be negatively influenced by high desipramine levels. We thus explored the relationship between imipramine and desipramine levels and treatment response in depressed inpatients.

This exploratory retrospective study involved 70 inpatients with major depression disorder who had undergone 5-week imipramine treatment. Weekly combined levels were measured, and adjustments were made until adequate levels were reached. We assessed response rates on the 17-item Hamilton Rating Scale for Depression (HDRS17) and used Mann-Whitney U tests to compare imipramine and desipramine plasma levels between responders and nonresponders.

After 5 weeks of treatment, nonresponders had significantly higher desipramine levels (P = 0.015) and combined plasma levels (P = 0.020) than responders. Imipramine levels did not differ significantly between groups. Plasma levels did not differ significantly between patients with and without concomitant CYP2D6- or CYP2C19-inhibiting medication.

By showing that desipramine plasma levels were higher in nonresponders to imipramine treatment, our findings imply that desipramine negatively impacts imipramine's therapeutic effect. When performing TDM, it may be important to consider metabolite plasma levels as well as combined plasma levels.