Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: A double-blind, randomized study

Abstract

Background: Although several antidepressants are now available, all have limited efficacy and a delayed onset of action. The current study was undertaken as a proof of the concept that combining norepinephrine and serotonin reuptake inhibition would be more effective and act more rapidly than either drug alone. Methods: Inpatients with nonpsychotic unipolar major depression and a Hamilton Depression Rating Scale (HAMD) score of at least 18 after 1 week of hospitalization without antidepressant medication were randomized to 6 weeks of treatment with fluoxetine (FLX) 20 mg/day, desipramine (DMI) adjusted to an adequate plasma level, or the combination of FLX 20 mg/day and DMI, given under double-blind conditions. Twenty-four-hour DMI levels were used to rapidly adjust DMI dose to achieve a therapeutic level and to anticipate the enzyme-inhibiting effects of FLX. Treatment-resistant patients were stratified. Patients were rated with the HAMD and the Montgomery-Asberg Depression Rating Scale (MADRS). Results: Thirty-nine patients began treatment. One patient withdrew consent. The DMI-FLX combination was significantly more likely to result in remission on the MADRS than either FLX or DMI alone [53.8% vs. 7.1% and 0%, respectively; χ2(2) = 13.49, p = .001]. The advantage for combined treatment was not explained by history of treatment resistance or by drug plasma concentrations. Rapid response, at 1 or 2 weeks, was neither statistically nor meaningfully greater with combined treatment. Conclusions: This study supports the hypothesis that the combination of a noradrenergic and serotonergic agent is more likely to result in remission than either selective agent alone during a 6-week treatment period.