Treating Major Depressive Disorder With D-Cycloserine Plus Theta-Burst Stimulation

Major depression disorder (MDD), a common mental health disorder that affects up to three million people in the US each year, can be treated with transcranial magnetic stimulation (TMS). TMS is a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to relieve symptoms of depression. The effects of TMS protocols for MDD are thought to depend on synaptic plasticity. Synaptic plasticity, change that occurs at the junctions between neurons, controls how effectively two neurons communicate with each other. According to the Queensland Brain Institute, “The strength of the communication between two synapses can be likened to the volume of a conversation.” Theta-burst stimulation (TBS) protocol synaptic plasticity, a form of patterned TMS, is known to be N-methyl-D-aspartate (NMDA)–receptor dependent; however, research on whether enhancing NMDA-receptor signaling can improve outcomes in the treatment of MDD is lacking.

Published in JAMA Psychiatry, researchers from the Mathison Centre for Mental Health Research and Education and Hotchkiss Brain Institute at the University of Calgary conducted a double-blind, placebo-controlled, randomized clinical trial to investigate whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD. To meet the inclusion criteria, the MDD patients needed to have had a major depressive episode with a score of >18 on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of <8, and normal blood work. In total, 50 patients were enrolled in the study. The patients were assigned to either iTBS plus placebo or iTBS plus D-cycloserine for the first two weeks followed by just iTBS for the remaining two weeks. The primary outcomes for this study included change in depressive symptoms, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at the end of treatment. Researchers also investigated clinical response, clinical remission, and Clinical Global Impression (CGI) scores.

Patients in the iTBS plus D-cycloserine group had an improvement of -6.15 in MARDS scores, compared with an improvement of -2.43 in the iTBS plus placebo group. Additionally, patients in the iTBS plus D-cycloserine group had higher rates of clinical response to treatment than those in the placebo group (73.9 percent and 29.3 percent, respectively. iTBS plus D-cycloserine patients had a mean rate of clinical remission of 39.1 percent versus just 4.2 percent in patients who received iTBS plus placebo. Researchers reported that no serious adverse events occurred in either group. According to researchers, “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 iTBS requiring further investigation.”