Synaptic Mechanisms of Intermittent Theta Burst Stimulation for Major Depressive Disorder

Conditions

• Healthy Participants
• Major Depression

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Accepted

Interventions

• Sham iTBS — DEVICE
  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.
• TMS — DEVICE
  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.
• D-cycloserine — DRUG
  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.
• Dextromethophan — DRUG
  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.
• Placebo — DRUG
  Microcrystalline cellulose capsule identical to the drug capsules, administered 2 hours prior to iTBS treatment.

Study Details

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.

Key Dates

Start date

Jul 1, 2026

Status verified

Apr 2026

Primary completion

Dec 1, 2030

Completion

Jun 30, 2031

Study Design

Enrollment

100 participants (estimated)

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Arms

• Sham Comparator: Sham iTBS + Placebo
  Placebo TMS and placebo drug
• Placebo Comparator: iTBS + Placebo
  Active TMS and placebo drug
• Experimental: iTBS + D-cycloserine
  Active TMS and active medication
• Experimental: iTBS + dextromethorphan
  Active TMS and active medication

Primary Outcome Measure

P30 TMS-Evoked Potential (TEP) Amplitude [ Time Frame: From baseline to approximately 10 minutes after cTBS administration, assessed at each of four study visits completed over a minimum of 3 to 6 weeks ]

Central Contacts

• Joshua C Brown, MD, PhD
  617-855-2944
  [email protected]
• Prem Ganesh, MS
  617-855-2153
  [email protected]

Locations (1)

Find similar trials in Belmont, MA

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