D-Cycloserine Augmentation of Intermittent Theta Burst Stimulation for Major Depressive Disorder (Cole, Sohn et al., 2022)
D-Cycloserine Augmentation of Intermittent Theta Burst Stimulation for Major Depressive Disorder (Cole, Sohn et al. 2022)
What this study was
Who was studied
What the protocol involved
What the results showed
What it means — and what it doesn't
Why this study matters for patients
What this study was
This was a randomized, double-blind, placebo-controlled clinical trial evaluating whether D-cycloserine a partial NMDA receptor agonist improves the antidepressant effects of intermittent theta burst stimulation when administered immediately before each TMS session. It was conducted at the University of Calgary and published in JAMA Psychiatry in 2022 by Cole, Sohn, McGirr and colleagues a research group with deep expertise in TMS augmentation strategies.
Who was studied
The trial enrolled 50 patients with major depressive disorder who were receiving a standard course of iTBS. Patients were randomized to receive either oral D-cycloserine or placebo before each session, in a double-blind design neither patients nor clinicians knew which they were receiving. The two groups were well-matched at baseline for depression severity and prior treatment history.
What the protocol involved
Patients received a standard iTBS protocol once-daily sessions over several weeks with either 100mg of oral D-cycloserine or matched placebo administered approximately 60 minutes before each session. The timing was designed to ensure DCS was active in the system at peak neuroplasticity responsiveness during stimulation.
What the results showed
Patients receiving DCS augmentation showed significantly greater reduction in depression scores compared to placebo over the course of treatment, Remission rates were meaningfully higher in the DCS group than the placebo group, The DCS group showed steeper early response trajectories, improvement came faster and more reliably than in the placebo group, The effect was most pronounced in patients with higher baseline depression severity, suggesting DCS augmentation may be particularly valuable for more treatment-resistant presentations, No significant difference in adverse events between DCS and placebo groups, D-cycloserine was well-tolerated
What it means — and what it doesn't
This trial established that D-cycloserine augmentation of iTBS produces meaningfully better outcomes than iTBS alone in a randomized controlled design. The mechanism NMDA receptor priming enhancing the LTP-like effects of TMS is biologically coherent and consistent with the broader neuroplasticity literature.
The trial used once-daily iTBS rather than an accelerated multi-session protocol. The ONE-D study extended this logic to a single-day twenty-session protocol, administering DCS before all twenty sessions. The combination of accelerated session delivery and DCS augmentation across every session is the distinctive feature of the ONE-D protocol and while no direct head-to-head comparison exists between DCS-augmented accelerated iTBS and non-augmented accelerated iTBS, the mechanistic rationale for the combination is strong.
Why this study matters for patients
This is the primary published evidence that D-cycloserine meaningfully improves TMS outcomes and the direct scientific basis for its inclusion in our One-Day Intensive protocol. For patients considering the One-Day Intensive, understanding this study helps explain why DCS augmentation is a clinical choice rather than an experimental add-on.
Full text available at: https://doi.org/10.1001/jamapsychiatry.2022.3255
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