Adjunctive D-Cycloserine Improves Efficacy of Brain Stimulation in Patients With MDD


Adding D-cycloserine to intermittent theta-burst stimulation (TBS) significantly improved outcomes in patients with major depressive disorder (MDD), according to study findings published online ahead of print in JAMA Psychiatry. 

“The antidepressant effects of transcranial magnetic stimulation protocols for MDD are thought to depend on synaptic plasticity,” explained a research team from the University of Calgary in Alberta, Canada, in the study background. “The TBS protocol synaptic plasticity is known to be N-methyl-D-aspartate (NMDA)–receptor-dependent, yet it is unknown whether enhancing NMDA-receptor signaling improves treatment outcomes in MDD.”

To investigate whether the NMDA-receptor partial-agonist D-cycloserine would enhance intermittent TBS treatment, researchers conducted a double-blind, placebo-controlled, randomized clinical trial of 50 adults diagnosed with MDD. All participants had a major depressive episode with score of 18 or higher on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or lower, and normal blood work.

The 4-week, single-site trial randomly assigned patients to intermittent TBS plus either 100-mg of D-cycloserine or placebo for the first 2 weeks of the intervention. Weeks 3 and 4 consisted of intermittent TBS without an adjunct for all patients.

Related: Novel 4-Minute Bilateral TBS Noninferior to rTMS for Depression in Older Adults

Montgomery-Åsberg Depression Rating Scale (MADRS) scores improved more in the added D-cycloserine group than in the placebo group, the study showed. The mean difference in MADRS improvement between the treatment groups was 6.15.

Secondary outcomes, too, favored intermittent TBS plus D-cycloserine, according to the study. Rates of clinical response were 73.9% in added-D-cycloserine group compared with 29.3% in the intermittent TBS plus placebo group, and rates of clinical remission were 39.1% with added-D-cycloserine compared with 4.2% with added placebo. Clinical Global Impression (CGI) severity and improvement scores were also better with added D-cycloserine.

No serious adverse events were reported.

“Findings from this clinical trial indicate that adjunctive D-cycloserine may be a promising strategy for enhancing transcranial magnetic stimulation treatment outcomes in MDD using intermittent TBS,” researchers wrote, “requiring further investigation.”

—Jolynn Tumolo


Cole J, Sohn MN, Harris AD, Bray SL, Patten SB, McGirr A. Efficacy of adjunctive D-cycloserine to intermittent theta-burst stimulation for major depressive disorder: a randomized clinical trial. JAMA Psychiatry. Published online October 12, 2022. doi: 10.1001/jamapsychiatry.2022.3255