Synaptic mechanisms of intermittent theta burst stimulation for major depressive disorder

The National Institute of Mental Health awarded The McLean Hospital Corporation $771,937 on September 1, 2026, under the Mental Health Research Grants program (CFDA 93.242) to investigate the synaptic mechanisms underlying intermittent theta burst stimulation (ITBS) as a treatment for major depressive disorder.

The research examines whether ITBS, an FDA-cleared patterned form of transcranial magnetic stimulation delivered clinically to the dorsolateral prefrontal cortex, works by enhancing synaptic plasticity through N-methyl-D-aspartate receptor (NMDAR) activation. The project proposes two aims: blocking NMDAR function during ITBS in depressed patients (Aim 1) and activating it (Aim 2) to assess long-term potentiation-associated changes using EEG-based TMS-evoked potentials. The study will compare 40 depressed patients to 40 healthy controls. This work validates a theory that pharmacologic augmentation with D-cycloserine combined with ITBS enhances clinical outcomes through synaptic plasticity mechanisms, with results intended to guide optimization of plasticity-promoting treatments for depression and other disorders.

The project period runs through July 31, 2031, with performance at McLean Hospital in Belmont, Massachusetts. McLean Hospital, a nonprofit psychiatric teaching hospital affiliated with Harvard Medical School, serves as the recipient organization.

Abstract

Major depressive disorder is associated with deficits in neuroplasticity. Rescue of this plasticity is the putative mechanism of action of an FDA-cleared treatment for depression called intermittent theta burst stimulation (ITBS), a patterned form of transcranial magnetic stimulation (TMS). We have previously found that agonism of the N-methyl-D-aspartate receptor (NMDAR), which acts as a gatekeeper for synaptic plasticity, is sufficient to enhance the facilitation produced by TMS to the motor cortex of healthy subjects. This suggesting that long- term potentiation (LTP) is the underlying cause of TMS-induced facilitation. We further found a partial rescue of MDD plasticity deficits in the motor cortex, and in a clinical trial for depression, have observed an unprece- dented improvement in clinical symptoms with NMDAR agonist, D-cycloserine (DCS) combined with ITBS. IT is essential now that this promising new treatment approach which is based on the premise of promoting synaptic plasticity be directly tested to validate the theoretical underpinnings enabling optimization and guidance of PO- tent plasticity inducers for the treatment of depression and other disorders. We propose to determine whether ITBS, as delivered clinically, works through enhancing synaptic plasticity, and to validate our theory that DCS pharmacologic augmentation of ITBS indeed works through this mechanism of action. We propose to examine synaptic plasticity induced by ITBS using concurrent pharmacology to block (aim 1) and activate (aim 2) the NMDAR during ITBS in 40 depressed patients compared to 40 healthy controls. For the first time, this pharmacologic augmentation strategy will be used to assess LTP-associated changes in the dorsolateral prefrontal cortex (DLPFC), where clinical ITBS treatments are delivered, using electroencephalog- raphy (EEG)-based TMS-evoked potentials (TEPS). In a double-blind, randomized, crossover design, each subject will receive a single session of 1) ITBS + NMDAR antagonist, dextromethorphan, 2) ITBS + NMDAR agonist, DCS, 3) ITBS + placebo, 4) sham ITBS + placebo. In an exploratory and independent aim 3, we will test each drug, including placebo, over 30 daily (ACTIVE) ITBS sessions in a parallel design with only MDD sub- jects. Together, these aims will test the LTP-like mechanisms of a session of ITBS as well as a course of ITBS, which can, and likely does, involve homeostatic changes whereby neurons globally scale receptor levels to maintain the ability to receive additional inputs. We will then understand how plasticity changes over the course of ITBS, as well as pharmacologically augmented ITBS. Within each session, TEP assessments will be given at baseline, after drug, and then after ITBS + drug. This design will control for the effects of ITBS and drug, and will demonstrate the necessity and sufficiency of NMDAR activity for ITBS-induced plasticity, both essential evidences for LTP, and will directly test the hypothesis that our promising clinical trial results were due to EN- hanced plasticity, validating and paving the way to transformative treatment approaches in the brain that may triple current efficacy rates.