Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression (SyncT)

May 8, 2026 updated by: Joshua C. Brown, MD, PhD, Mclean Hospital

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Major depressive disorder (MDD) affects an estimated 280 million people worldwide, and a substantial proportion do not respond adequately to first-line pharmacological treatments. Continuous theta-burst stimulation (cTBS) is a widely used form of repetitive transcranial magnetic stimulation (rTMS) that quiets targeted brain networks, and holds particular promise for patients who are not well-served by conventional excitatory TMS protocols due to safety or tolerability concerns. Despite its common clinical use, the synaptic mechanisms by which cTBS works remain poorly characterized, limiting systematic efforts to improve its efficacy.

Two mechanistic hypotheses have been proposed. The first is that cTBS induces LTD-like synaptic depression through NMDA receptor (NMDAR)-dependent mechanisms, analogous to the low-frequency stimulation protocols that produce AMPA receptor internalization and synapse weakening in animal models. Evidence for this comes from studies in the healthy motor cortex demonstrating that cTBS-induced corticomotor inhibition is blocked by NMDAR antagonists. The second hypothesis is that cTBS works through GABA receptor-mediated inhibition, either via GABA-A receptors reducing signal propagation through membrane hyperpolarization, or GABA-B receptors suppressing presynaptic neurotransmitter release. Whether GABAergic mechanisms contribute to cTBS effects has not been directly tested, and these hypotheses are not mutually exclusive.

Critically, all prior mechanistic evidence comes from the motor cortex in healthy volunteers. The dorsolateral prefrontal cortex (dlPFC), the clinical target for depression, differs substantially from motor cortex in anatomy, interindividual variability, and plasticity. Depression itself is associated with reduced synaptic plasticity, including reduced expression of NMDAR subunits and synapse-related genes in postmortem prefrontal tissue. Whether cTBS mechanism established in healthy motor cortex translates to the depressed dlPFC cannot be assumed, and has not been tested. Furthermore, whether cTBS-induced inhibition can be pharmacologically enhanced remains entirely unexplored.

This study uses a randomized, double-blind, placebo-controlled crossover design to directly test NMDAR- and GABA receptor-mediated contributions to cTBS-induced plasticity in the dlPFC of individuals with MDD. Participants are assigned to one of two parallel aims. Aim 1 tests glutamatergic mechanisms: participants complete four visits receiving cTBS paired with placebo, d-cycloserine (DCS), or memantine (MEM), with two placebo visits. Aim 2 tests GABAergic mechanisms: participants complete four visits receiving cTBS paired with placebo, lorazepam (LZP), or baclofen (BAC). All drugs are FDA-approved and administered as single oral doses timed to peak plasma concentration approximately two hours prior to cTBS.

TMS-EEG provides the primary measurement approach. TMS-evoked potentials (TEPs) are scalp-recorded electrical responses to individual TMS pulses that reflect summated excitatory and inhibitory postsynaptic activity from stimulated neuronal populations. Characteristic peaks are named by polarity and latency: P30 and P60 reflect glutamatergic excitatory transmission, N45 reflects GABA-A-mediated inhibitory tone, and N100 reflects GABA-B-mediated inhibitory tone. Up to 200 single TMS pulses are delivered per TEP session at the individualized dlPFC target. TEPs are acquired at several timepoints each visit. cTBS consists of 600 pulses delivered at 80% of resting motor threshold.

TMS is delivered using the Nexstim NBS-6 system with integrated real-time neuronavigation, with targeting based on individual structural MRI acquired prior to experimental visits.

The central hypothesis is that cTBS reduces P30 amplitude through LTD-like synaptic depression driven by NMDAR activation and consequent AMPA receptor internalization. Under this hypothesis, DCS will enhance and memantine will block the post-cTBS reduction in P30, without corresponding changes in N45 or N100. If instead GABAergic mechanisms contribute, cTBS will increase N45 and/or N100 amplitude, with additive effects from lorazepam and baclofen respectively. The design allows estimation of relative contributions from each receptor system.

A functional measure of dlPFC network integration, the N-back working memory task, is administered before and after cTBS at each visit. Resting-state fMRI acquired at baseline is used for exploratory post-hoc correlations with TEP outcomes and EEG source localization. Peripheral blood is collected for drug plasma quantification, and saliva samples are collected for BDNF Val66Met genotyping.

Statistical analysis uses a linear mixed model with Drug Type, TMS Type (active vs. sham), and Time (pre-drug, post-drug/pre-cTBS, post-cTBS) as within-subject factors, including all two- and three-way interactions, with relevant demographic and clinical covariates. The study is powered to detect a moderate effect size (Hedges' g = 0.5) with 80% power at α = 0.05, requiring 31 completers per aim. Enrollment targets 35 completers per aim, with up to 80 participants enrolled to account for attrition.

Study Type

Interventional

Enrollment (Estimated)

80

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Sham Comparator: Sham + Placebo
Sham TMS and placebo drug
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.
Other Names:
  • Sham TMS
Drug: Placebo
Sucrose packaged in identical cellulose capsules, administered orally.
Placebo Comparator: TMS + Placebo
Active TMS and placebo drug
Drug: Placebo
Sucrose packaged in identical cellulose capsules, administered orally.
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.
Other Names:
  • TMS
  • cTBS
  • Transcranial magnetic stimulation
Experimental: NMDAR Antagonism
Active TMS and memantine
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.
Other Names:
  • TMS
  • cTBS
  • Transcranial magnetic stimulation
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.
Experimental: NMDAR Agonism
Active TMS and d-cycloserine
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.
Other Names:
  • TMS
  • cTBS
  • Transcranial magnetic stimulation
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.
Experimental: GABA-A Agonsim
Active TMS and lorazepam
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.
Other Names:
  • TMS
  • cTBS
  • Transcranial magnetic stimulation
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.
Experimental: GABA-B Agonism
Active TMS and baclofen
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.
Other Names:
  • TMS
  • cTBS
  • Transcranial magnetic stimulation
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in N100 TEP Peak Amplitude
Time Frame: 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.
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.
Change in P30 TEP Peak Amplitude
Time Frame: 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. Visits separated by at least 1 week.
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 2 hours post-drug administration (immediately prior to cTBS), and approximately 5 and 20 minutes post-cTBS. Visits separated by at least 1 week.
Change in N45 TEP Peak Amplitude
Time Frame: 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.
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 hours post-drug administration (immediately prior to cTBS), and approximately 5 and 20 minutes post-cTBS.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mclean Hospital

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Joshua C Brown, MD, PhD, McLean Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 11, 2026

Primary Completion (Estimated)

December 1, 2030

Study Completion (Estimated)

December 1, 2030

Study Registration Dates

First Submitted

April 24, 2026

First Submitted That Met QC Criteria

April 24, 2026

First Posted (Actual)

May 1, 2026

Study Record Updates

Last Update Posted (Actual)

May 13, 2026

Last Update Submitted That Met QC Criteria

May 8, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2025P000736
  • R01MH139697 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing 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.

IPD Sharing Access Criteria

Data will be accessible to qualified researchers through the NIMH Data Archive data access request process.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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