Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder

Abstract

ImportanceThe antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The theta-burst stimulation (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.ObjectiveTo test whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD.Design, Setting, and ParticipantsThis was a single-site 4-week, double-blind, placebo-controlled, randomized clinical trial conducted from November 6, 2019, to December 24, 2020, including 50 participants with MDD. Participants were recruited via advertisements and referral. Inclusion criteria were as follows: age 18 to 65 years with a primary diagnosis of MDD, a major depressive episode with score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work (including complete blood cell count, electrolytes, liver function tests, and creatinine level).InterventionsParticipants were randomly assigned 1:1 to either iTBS plus placebo or iTBS plus D-cycloserine (100 mg) for the first 2 weeks followed by iTBS without an adjunct for weeks 3 and 4.Main Outcomes and MeasuresThe primary outcome was change in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the conclusion of treatment. Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores.ResultsA total of 50 participants (mean [SD] age, 40.8 [13.4] years; 31 female [62%]) were randomly assigned to treatment groups: iTBS plus placebo (mean [SD] baseline score, 30.3 [4.2]) and iTBS plus D-cycloserine (mean [SD] baseline score, 30.4 [4.5]). The iTBS plus D-cycloserine group had greater improvements in MADRS scores compared with the iTBS plus placebo group (mean difference, −6.15; 95% CI, −2.43 to −9.88; Hedges g = 0.99; 95% CI, 0.34-1.62). Rates of clinical response were higher in the iTBS plus D-cycloserine group than in the iTBS plus placebo group (73.9% vs 29.3%), as were rates of clinical remission (39.1% vs 4.2%). This was reflected in lower CGI-severity ratings and greater CGI-improvement ratings. No serious adverse events occurred.Conclusions and RelevanceFindings 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.Trial RegistrationClinicalTrials.gov Identifier: NCT03937596

Practice makes plasticity: 10-Hz rTMS enhances LTP-like plasticity in musicians and athletes

“…Extensive motor practice in M&As incorporates the long-term effects of increased learning, which is known to be subserved by NMDA-receptor dependent LTP (Whitlock et al, 2006;Brown et al, 2021). The applicability of these results outside of the motor cortex and healthy subjects has been supported by Cole and colleagues who found that DCS was sufficient to enhance both motor physiology (Cole et al, 2021), and clinical outcomes in depressed patients (Cole et al, 2022).…”

Lysergic Acid Diethylamide Alters the Effects of Brain Stimulation in Rodents

“…A similar combinatorial approach using TMSpharmacologic augmentation of synaptic plasticity with D-cylcoserine (a partial N-methyl-D-aspartate agonist) recently demonstrated increased response rates in patients with depression. 62 Pairing plastogenic agents with brain stimulation may also help non-invasive stimulation overcome the high relapse rates currently limiting these interventions from making a larger clinical impact.…”

Brain Glutamate Dynamics Predict Positive Agency in Healthy Women

“…Heightened glutamatemediated learning of contextual cues, drug-cue associations, and glutamate-mediated reward processing in females would contribute to more rapid acquisition and severity of drug dependence in females compared to males. In the context of MDD, our ndings advance Glu as a novel treatment target for medication and adjunctive treatment for positive emotion recovery(Cole et al, 2022).…”