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

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.