Imipramine dose in relation to therapeutic plasma level: are clinical trials using imipramine as a positive control flawed?

Abstract

Imipramine has often been used as positive control in studies investigating the efficacy of new antidepressants. Imipramine-controlled studies in general employ a fixed-dose design. It is unclear how many patients would achieve effective plasma levels with such a design. The objectives of this study were to assess the range of doses necessary to attain a therapeutic plasma level in the imipramine arms of two double-blind, fixed-plasma-level studies and to compare them with doses administered in efficacy studies with imipramine as a positive control. During two double-blind studies, imipramine doses were adjusted to a predefined fixed plasma level. Here we report an analysis of the range of doses necessary to attain that level in the imipramine arms of the studies. We also computed the cumulative percentage of patients with therapeutic plasma levels (> or = 200 ng/ml) at various imipramine doses in order to compare them with doses administered in efficacy studies with imipramine as a positive control. Target plasma levels were attained with a mean daily dose of 248 mg, with a dose range of 50-450 mg. We calculated a possible increase in efficacy of imipramine of about 20% if doses had been adjusted to therapeutic plasma levels in clinical trials using it as a positive control. The absence of significant differences in efficacy between selective serotonin re-uptake inhibitors (SSRIs) and imipramine in these trials is at least in part due to improper dosing of the latter; imipramine with therapeutic drug monitoring may be more effective than SSRIs.