Adjunctive d-serine treatment for major depressive disorder: A randomized clinical trial

BACKGROUND: The antidepressant effects of N-methyl-d-aspartate receptor (NMDAR) antagonists highlight glutamatergic neurotransmission as a promising therapeutic target for major depressive disorder (MDD). The NMDAR co-agonist d-serine, binding on the glycine site, may enhance standard treatments' efficacy while showing fewer side effects. AIM: To evaluate the efficacy of d-serine as an adjunctive treatment for alleviating depressive symptoms, anxiety, and anhedonia in patients with moderate-to-severe MDD. METHODS: A six-week, randomized, double-blind, placebo-controlled clinical trial was conducted with 44 adult inpatients with moderate-to-severe MDD. Participants were randomly assigned to receive either d-serine (2 g/day) or placebo alongside treatment as usual (TAU). The primary outcome was the change in clinician-rated depressive symptoms (HDRS-17) from baseline to post-intervention. Secondary outcomes included self-reported depressive symptoms (BDI-II), anxiety (STAI-1), and anhedonia (SHAPS). RESULTS: Both groups exhibited significant symptom reductions across all measures by post-intervention, with no significant differences between d-serine and placebo in the overall sample. Subgroup analyses indicated that d-serine significantly improved depressive symptoms in participants with severe MDD, with a trend towards improvement in anhedonia. In the d-serine group, greater clinical improvements in depressive symptoms and anhedonia were correlated with higher baseline depression severity and higher TAU medication doses. CONCLUSION: While d-serine did not show superior efficacy over placebo in the overall sample, it demonstrated potential as an adjunctive treatment in patients with severe MDD, particularly those receiving higher medication doses. These findings suggest that d-serine may provide synergistic benefits when combined with standard treatments in specific subgroups of patients with MDD. Trial Registration at ClinicalTrials.gov Identifier: NCT04721249.