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

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.