Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

Summary

Many people with depression do not get better with standard treatments like medication. One promising alternative is transcranial magnetic stimulation (TMS), a non-invasive procedure that uses magnetic pulses to stimulate specific brain regions. A particular pattern of TMS called continuous theta-burst stimulation (cTBS) is thought to reduce overactive brain activity in depression, but the investigators do not yet fully understand how it works at the level of brain cells and connections.

This study aims to determine the biological mechanism by which cTBS changes brain activity in people with depression. Specifically, the investigators are testing two competing ideas: (1) that cTBS works by weakening the connections between brain cells through a process called long-term depression (LTD), which is driven by a chemical messenger system called glutamate; or (2) that cTBS works by increasing the brain's natural "braking" system, driven by a different chemical messenger called GABA.

To test these ideas, participants with depression will receive cTBS along with one of four FDA-approved medications, or placebo, that either boost or block these chemical messenger systems. The investigators will measure changes in brain activity using electroencephalography (EEG) recorded simultaneously with TMS. Specific patterns in the EEG signal, called TMS-evoked potentials (TEPs), act as a window into how different brain cell types are responding to stimulation.

Each participant will complete four study visits, each testing a different drug-TMS combination in random order. One group of participants will test drugs targeting the glutamate system (d-cycloserine and memantine). A second group will test drugs targeting the GABA system (lorazepam and baclofen). All drugs are given as a single oral dose and are commonly used in clinical practice.

Understanding exactly how cTBS works at a biological level could open the door to more effective, personalized TMS treatments.

Conditions

• Major Depression

Interventions

DRUG

D-Cycloserine (DCS)

D-cycloserine 100 mg is administered as a single oral dose approximately two hours prior to cTBS, timed to peak plasma concentration. At this dose, DCS acts as a partial agonist at the glycine co-agonist site of the NMDA receptor, facilitating NMDAR-mediated synaptic transmission. It is used in Aim 1 to test whether NMDAR agonism enhances cTBS-induced LTD-like plasticity at the dlPFC.

DEVICE

Continuous theta-burst stimulation (cTBS)

Continuous theta-burst stimulation is delivered using the Nexstim NBS-6 system with integrated real-time neuronavigation. The cTBS protocol consists of 600 pulses delivered at 80% active motor threshold, targeting the left dorsolateral prefrontal cortex (dlPFC) localized to individual structural MRI.

DEVICE

Transcranial Magnetic Stimulation Sham

Sham TMS is delivered using an identical coil that produces the same auditory and somatosensory scalp sensation as active stimulation without inducing a significant cortical response. The stimulation protocol will be the same as the active cTBS protocol.

DRUG

Memantine

Memantine 10 mg is administered as a single oral dose approximately two hours prior to cTBS. Memantine is a non-competitive NMDA receptor antagonist acting at the phencyclidine site within the receptor channel. It is used in Aim 1 to test whether NMDAR antagonism blocks cTBS-induced LTD-like plasticity at the dlPFC.

DRUG

Lorazepam (drug)

Lorazepam 1 mg is administered as a single oral dose approximately two hours prior to cTBS, timed to peak plasma concentration. Lorazepam is a positive allosteric modulator at GABA-A receptors, increasing chloride influx and membrane hyperpolarization. It is used in Aim 2 to test whether GABA-A receptor potentiation enhances cTBS-induced inhibition at the dlPFC.

DRUG

Baclofen

Baclofen 50 mg is administered as a single oral dose approximately one hour prior to cTBS, timed to peak plasma concentration. Baclofen is a GABA-B receptor agonist that suppresses presynaptic neurotransmitter release from both GABAergic interneurons and glutamatergic neurons. It is used in Aim 2 to test whether GABA-B receptor agonism enhances cTBS-induced inhibition at the dlPFC.

DRUG

Placebo

Sucrose packaged in identical cellulose capsules, administered orally.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH)

  collaborator NIH

• Mclean Hospital

  lead OTHER

Principal Investigators

• Joshua C Brown, MD, PhD · Mclean Hospital

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-03-11

Primary Completion

2030-12-31

Completion

2030-12-31

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations