Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression
SyncT
2 other identifiers
interventional
80
1 country
1
Brief 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 we 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, we 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. We 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for early_phase_1
Started Mar 2026
Longer than P75 for early_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
Study Start
First participant enrolled
March 11, 2026
CompletedFirst Submitted
Initial submission to the registry
April 24, 2026
CompletedFirst Posted
Study publicly available on registry
May 1, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2030
ExpectedStudy Completion
Last participant's last visit for all outcomes
December 1, 2030
May 1, 2026
April 1, 2026
4.7 years
April 24, 2026
April 24, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
Change in P30 TEP Peak Amplitude
Change in P30 TMS-evoked potential peak amplitude measured via simultaneous 64-channel EEG in response to single-pulse TMS delivered at the left dlPFC. P30 amplitude reflects AMPA receptor-mediated glutamatergic excitatory transmission and is the primary index of LTD-like synaptic depression induced by cTBS. Change is assessed between post-drug/pre-cTBS and post-cTBS timepoints, and relative to the sham+placebo condition.
Measured at 4 timepoints within each study visit: pre-drug baseline, approximately 2hrs post-drug administration (immediately prior to cTBS), and approximately 5 and 20 mins post-cTBS. Visits separated by at least 1 week.
Change in N45 TEP Peak Amplitude
Change in N45 TMS-evoked potential peak amplitude measured via simultaneous 64-channel EEG. N45 amplitude reflects GABA-A receptor-mediated inhibitory transmission. In Aim 1, N45 serves as a specificity control - changes are not expected with NMDAR-targeting drugs. In Aim 2, N45 is a primary index of whether cTBS engages GABA-A-mediated inhibition, and whether lorazepam produces additive inhibition post-cTBS.
Measured at 4 timepoints within each study visit: pre-drug baseline, approximately 2 hrs post-drug administration (immediately prior to cTBS), and approximately 5 and 20 mins post-cTBS.
Change in N100 TEP Peak Amplitude
Change in N100 TMS-evoked potential peak amplitude measured via simultaneous 64-channel EEG. N100 amplitude reflects GABA-B receptor-mediated inhibitory transmission. In Aim 1, N100 serves as a specificity control alongside N45. In Aim 2, N100 is a primary index of whether cTBS engages GABA-B-mediated inhibition, and whether baclofen produces additive inhibition post-cTBS.
Measured at 4 timepoints within each study visit: pre-drug baseline, approximately 2 hours post-drug administration (immediately prior to cTBS), and approximately 5 and 20 minutes post-cTBS.
Study Arms (6)
Sham + Placebo
SHAM COMPARATORSham TMS and placebo drug
TMS + Placebo
PLACEBO COMPARATORActive TMS and placebo drug
NMDAR Antagonism
EXPERIMENTALActive TMS and memantine
NMDAR Agonism
EXPERIMENTALActive TMS and d-cycloserine
GABA-A Agonsim
EXPERIMENTALActive TMS and lorazepam
GABA-B Agonism
EXPERIMENTALActive TMS and baclofen
Interventions
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.
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.
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.
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.
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.
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.
Sucrose packaged in identical cellulose capsules, administered orally.
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
- Moderate to severe Major Depressive Disorder as indicated by the Patient Health Questionnaire or Quick Inventory of Depressive Symptomatology
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, baclofen, memantine, or lorazepam
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 (2)
Rossi 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: 33243615BACKGROUNDGanesh 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: 41341503BACKGROUND
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
- early phase 1
- Allocation
- RANDOMIZED
- Masking
- TRIPLE
- Who Masked
- PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
- Masking Details
- Participants will be aware of which Aim they are participating in, where they will receive all of the different arms in random order. They will not know which drug they are receiving or if the TMS is active or sham.
- Purpose
- BASIC SCIENCE
- Intervention Model
- CROSSOVER
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Director, TMS Research
Study Record Dates
First Submitted
April 24, 2026
First Posted
May 1, 2026
Study Start
March 11, 2026
Primary Completion (Estimated)
December 1, 2030
Study Completion (Estimated)
December 1, 2030
Last Updated
May 1, 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.