Single-day accelerated TMS with D-cycloserine augmentation for depression: A placebo-controlled trial

TL;DR

This study tested if adding a drug called D-cycloserine could improve the effects of a fast TMS treatment for depression, but found limited additional benefit.

Contribution

The study is the first to investigate D-cycloserine's effect on single-day accelerated TMS for depression in a placebo-controlled trial.

Findings

DCS did not significantly enhance corticomotor plasticity compared to placebo during accelerated iTBS.

Clinical improvements were observed over time but were not significantly different between DCS and placebo groups.

High-intensity TMS protocols may reach a plasticity ceiling that limits further enhancement by NMDAR agonists.

Abstract

Accelerated transcranial magnetic stimulation (TMS) protocols have the potential to rapidly treat depression, yet the synaptic mechanisms underlying these intensive interventions remain poorly understood. d-cycloserine (DCS), a partial NMDAR agonist, enhances TMS-induced corticomotor plasticity and conventional daily TMS outcomes, but its effects on accelerated protocols are unknown. We conducted a double-blind placebo-controlled trial examining whether DCS could enhance single-day accelerated intermittent theta-burst stimulation (iTBS) in 30 participants with major depressive disorder. Participants received either 250 mg DCS or placebo the night before undergoing 10 iTBS treatments (1 800 pulses/treatment) delivered hourly to the left dorsolateral prefrontal cortex. Motor-evoked potentials (MEPs) were recorded before and after each treatment to assess corticomotor excitability, while depression severity was measured at baseline and one-week post-treatment using PHQ-9 and QIDS-SR16 scales. Normalized MEP amplitudes were analyzed using separate generalized linear mixed models for pre- and post-iTBS measurements, revealing a significant Group × Treatment interaction in only the pre-iTBS data (χ2 = 4.19, p = .041), with placebo showing increasing trajectories and d-cycloserine remaining stable. However, post-iTBS measurements showed no Group × Treatment interaction (χ2 = 0.92, p = .338), indicating no differential plasticity responses. Clinical outcomes showed improvement over time on QIDS-SR16 (p = .047) but not PHQ-9 (p = .206), with no between-group differences on either scale (PHQ-9: p = .112; QIDS: p = .286). These findings suggest that high-intensity accelerated protocols may reach a plasticity ceiling that occludes further synaptic enhancement with NMDAR agonism, highlighting the importance of parameter optimization for pharmacologically-augmented accelerated TMS.

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