Antidepressant activity of 2-hydroxydesipramine

We describe the relationship of 2-hydroxydesipramine (OH-DMI) plasma levels and response in a prospective DMI study in which dosage was rapidly adjusted to achieve a relatively uniform DMI plasma level. In prior studies, OH-DMI plasma levels were not related to response, but in these fixed-dose protocols the effects of OH-DMI are easily obscured by the higher concentrations of the parent drug. We hypothesized that in this study a contribution of OH-DMI to response might become apparent because DMI levels were relatively constant. Inpatients with nonpsychotic, unipolar DSM-III major depression who remained depressed (Hamilton score greater than 18) after 1 week of hospitalization without medication received a 4-week DMI trial. Twenty-four-hour drug plasma levels were used to adjust dose to reach a target DMI steady-state plasma level. Twenty-seven patients completed the trial. On every measure of response, total drug levels (DMI + OH-DMI) were more strongly correlated with outcome than were DMI levels alone. With multiple regression, both DMI and OH-DMI levels were independently and significantly associated with response. These findings suggest that OH-DMI has antidepressant activity.