Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder

Background: Compounds that reduce N-methyl-D-aspartate receptor (NMDAR) function, including NMDAR antagonists and partial agonists at the NMDAR-associated glycine (GLY) site, may act as antidepressants. The antibiotic drug D-cycloserine (DCS) acts as a partial agonist at the NMDAR-GLY site. Preclinical and clinical data suggest that at dosages >= 100 mg/day DCS acts as a functional NMDAR antagonist and may have antidepressant effects. Methods: Twenty-two treatment resistant major depression patients participated in a double-blind, placebo-controlled 6-week crossover trial with 250 mg/day DCS added to their ongoing antidepressant medications. Results: DCS treatment was well tolerated and resulted in symptom reductions. However, biweekly-performed clinical assessments, including the Hamilton Depression Rating Scale, Hamilton Rating Scale for Anxiety and Zung Self-Rating Depression Scale did not reveal statistically significant therapeutic advantages of DCS vs. placebo adjuvant treatment. Limitations: Small sample, uneven treatment resistance criteria across subjects. The exposure to DCS (dose/length of treatment) may not have been sufficient. Conclusions: This exploratory study represents the first attempt to assess the effects of a NMDAR-GLY site partial agonist in depression treatment. The findings and limitations of this study should be taken into account in the planning of future clinical trials with NMDAR modulators in depression. (c) 2006 Elsevier B.V. All rights reserved.