Synaptic Mechanisms of Intermittent Theta Burst Stimulation for Major Depressive Disorder

Summary

Many people with depression do not get better with standard treatments like medications or talk therapy. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation treatment that uses magnetic pulses to stimulate areas of the brain involved in depression. One form of TMS called intermittent theta burst stimulation (iTBS) is FDA-cleared for depression and takes only 3 minutes to deliver. However, about one-third of patients do not respond to iTBS, and another one-third do not reach full remission. Improving iTBS requires a better understanding of how it works in the brain.

iTBS is thought to work by strengthening connections between brain cells, a process called synaptic plasticity. This process depends on a type of brain receptor called the NMDA receptor. Most of what researchers know about how iTBS affects these connections comes from studies of healthy people. It is not known whether iTBS works the same way in the prefrontal cortex - the brain region targeted during depression treatment - or in people who actually have depression.

This study has two phases.

In Phase 1, both healthy volunteers and people with depression will complete 4 research visits to test how iTBS changes brain activity in the prefrontal cortex and whether medications that increase or decrease NMDA receptor activity change those effects. Each visit involves active or sham (inactive) iTBS combined with one of three study medications: a placebo (inactive pill), d-cycloserine (a medication that increases NMDA receptor activity), or dextromethorphan (a medication that decreases NMDA receptor activity). Brain activity is measured before and after each TMS session using electroencephalography (EEG), a painless test that records electrical signals from the scalp through a cap placed on the head. All participants also complete a brain MRI before beginning study visits for targeting purposes.

In Phase 2, participants with depression will be offered a standard clinical course of 30 daily iTBS sessions (Monday through Friday over 6 weeks). Each session is combined with one blinded study medication (placebo, d-cycloserine, or dextromethorphan) taken daily. Brain activity measurements and standard depression and anxiety questionnaires are collected weekly throughout this phase to track how the brain changes over the course of treatment and whether those changes relate to improvements in symptoms.

Together, the two phases of this study aim to identify the brain mechanism by which iTBS works in people with depression. This knowledge could lead to more effective TMS treatments for people who have not responded to medications or other therapies.

Conditions

• Major Depression
• Healthy Participants

Interventions

DEVICE

Sham iTBS

ham intermittent theta burst stimulation delivered to the left dorsolateral prefrontal cortex using a sham coil identical in appearance to the active coil. No active magnetic stimulation is delivered. Used to control for the sensory experience of TMS.

DEVICE

TMS

Active intermittent theta burst stimulation (iTBS) delivered to the left dorsolateral prefrontal cortex combined with oral placebo. iTBS consists of 50 Hz triplets delivered in 2-second bursts at 5 Hz, totaling 600 pulses per session over approximately 3 minutes, delivered using a figure-of-8 coil with real-time neuronavigation at an intensity set relative to each participant's resting motor threshold.

DRUG

D-cycloserine

D-cycloserine at 100 mg acts as a partial agonist at the glycine co-agonist site of the NMDA receptor, facilitating NMDAR-mediated synaptic transmission. It is administered orally approximately 2 hours before iTBS to coincide with near-peak plasma concentration. Compounded as 100 mg capsules.

DRUG

Dextromethophan

Dextromethorphan at 150 mg acts as an NMDA receptor antagonist, blocking NMDAR-mediated synaptic transmission at brain concentrations consistent with in vitro receptor blockade. Administered orally approximately 2 hours before iTBS.

DRUG

Placebo

Microcrystalline cellulose capsule identical to the drug capsules, administered 2 hours prior to iTBS treatment.

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

TREATMENT

Masking

QUADRUPLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2026-07-01

Primary Completion

2030-12-01

Completion

2031-06-30

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations