Synaptic Mechanisms of Intermittent Theta Burst Stimulation for Major Depressive Disorder
1 other identifier
interventional
100
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Jul 2026
Longer than P75 for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 19, 2026
CompletedFirst Posted
Study publicly available on registry
May 18, 2026
CompletedStudy Start
First participant enrolled
July 1, 2026
ExpectedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2030
Study Completion
Last participant's last visit for all outcomes
June 30, 2031
May 18, 2026
April 1, 2026
4.4 years
April 19, 2026
May 13, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
P30 TMS-Evoked Potential (TEP) Amplitude
Change in P30 peak amplitude measured by TMS-EEG before and after a single iTBS session. The P30 is a positive deflection occurring approximately 30 milliseconds after a TMS pulse, reflecting glutamatergic excitatory synaptic transmission. Change in P30 amplitude serves as an index of iTBS-induced LTP-like plasticity in the left dorsolateral prefrontal cortex. Comparisons will be made across drug conditions (placebo, d-cycloserine, dextromethorphan), between TMS conditions (active vs. sham), and between participant groups (MDD vs. healthy controls).
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
Secondary Outcomes (5)
Additional TEP Component Amplitudes
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
16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16)
From enrollment to the end of treatment at 6 weeks
Patient Health Questionnaire-9 (PHQ-9)
From enrollment to the end of treatment at 6 weeks
7-item Generalized Anxiety Disorder scale (GAD-7)
From enrollment to the end of treatment at 6 weeks
24-item Behavior and Symptom Identification Scale (BASIS-24)
From enrollment to the end of treatment at 6 weeks
Study Arms (4)
Sham iTBS + Placebo
SHAM COMPARATORPlacebo TMS and placebo drug
iTBS + Placebo
PLACEBO COMPARATORActive TMS and placebo drug
iTBS + D-cycloserine
EXPERIMENTALActive TMS and active medication
iTBS + dextromethorphan
EXPERIMENTALActive TMS and active medication
Interventions
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.
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 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.
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.
Microcrystalline cellulose capsule identical to the drug capsules, administered 2 hours prior to iTBS treatment.
Eligibility Criteria
You may qualify if:
- Can safely receive TMS and study drugs
- Stable medication regimen for one month prior to study participation, and for the duration of the study
- Not currently receiving TMS, ECT, or ketamine
- No active safety concerns related to suicidality
You may not qualify if:
- History of seizures or epilepsy
- History of intracranial pathology or lesions from any etiology
- History of traumatic brain injury including prolonged loss of consciousness more than 15 min
- Signs of increased intracranial pressure
- Any major neurological conditions (ex: recent stroke, tumor, neurodegenerative disorders, etc.)
- Major medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
- Severe migraines that may result in treatment intolerance.
- Inability to tolerate MRI.
- Pregnancy
- Known allergic reaction to d-cycloserine or dextromenthorphan
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Mclean Hospitallead
- National Institute of Mental Health (NIMH)collaborator
Study Sites (1)
McLean Hospital
Belmont, Massachusetts, 02478, United States
Related Publications (3)
Ganesh P, Kweon J, Siddiqi SH, Carpenter LL, Brown JC. Comparing synaptic mechanisms of iTBS and 10-Hz rTMS corticomotor plasticity. Transcranial Magn Stimul. 2025 Dec;5:100191. doi: 10.1016/j.transm.2025.100191. Epub 2025 Aug 26.
PMID: 41341503BACKGROUNDGanesh P, Kweon J, Tom J, Kim H, Varone G, McGirr A, Brown J. Single-day accelerated TMS with D-cycloserine augmentation for depression: A placebo-controlled trial. Res Sq [Preprint]. 2025 Dec 11:rs.3.rs-7980692. doi: 10.21203/rs.3.rs-7980692/v1.
PMID: 41510278BACKGROUNDRossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24.
PMID: 33243615BACKGROUND
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Joshua C Brown, MD, PhD
Mclean Hospital
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- CROSSOVER
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Director, TMS Research
Study Record Dates
First Submitted
April 19, 2026
First Posted
May 18, 2026
Study Start (Estimated)
July 1, 2026
Primary Completion (Estimated)
December 1, 2030
Study Completion (Estimated)
June 30, 2031
Last Updated
May 18, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
- Time Frame
- Data will be submitted to the NDA within 1 year of primary study completion or upon publication of primary results, whichever comes first.
- Access Criteria
- Data will be accessible to qualified researchers through the NIMH Data Archive data access request process.
De-identified individual participant data will be shared through the National Institute of Mental Health Data Archive (NDA) in accordance with NIMH data sharing expectations. Data to be shared will include demographic information, clinical scale scores, and TMS-EEG outcome data. Data will be submitted to the NDA following standard de-identification procedures and will be made available to qualified researchers through the NDA data access request process.