Preliminary randomized double-blind placebo-controlled trial of tryptophancombined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects

Because the initial phase of treatment of depression with a selective serot onin reuptake inhibitor is often complicated by a delayed onset of action o f the antidepressant or severe insomnia or both, we investigated whether tr yptophan, an amino acid with both antidepressant-augmenting and hypnotic ef fects, would benefit patients with depression at the beginning of treatment with fluoxetine. Design: I Randomized, double-blind, placebo-controlled tr ial. Patients: Thirty individuals with major depressive disorder. intervent ions: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tr yptophan (2 to 4 g per day) or placebo. Outcome measures: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. Results: Du ring the first week of treatment, there was a significantly greater decreas e in HDRS-29 depression scores, and a similar trend in BDI scores, in the t ryptophan/fluoxetine group than in the placebo/fluoxetine group. No signifi cant differences were noted at later time points. With respect to sleep mea sures, there was a significant group-by-time interaction for slow-wave slee p at week 4. Further analysis revealed a significant deep-ease-in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred , and the combination was well tolerated, although the 4 g per day dosage o f tryptophan produced daytime drowsiness. Conclusions: Combining 20 mg of f luoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rap id antidepressant effect and a protective effect on slow-wave sleep. Furthe r large-scale studies are needed to confirm these initial findings.