NCT07560878 · Mclean Hospital
Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression
(SyncT)
What this study is about
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.
View original scientific description
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.
Interventions
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.
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.
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.
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.
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.
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.
DRUG
Placebo
Sucrose packaged in identical cellulose capsules, administered orally.
Primary outcome measures
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.
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.
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.
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
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.
- Known allergic reaction to d-cycloserine, baclofen, memantine, or lorazepam
Where
- Belmont, Massachusetts
Collaborators
National Institute of Mental Health (NIMH)
Related conditions & keywords
Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
Is it safe to participate?
Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
Will I be compensated?
Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.
Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
Can I leave a trial if I change my mind?
Absolutely. Participation in clinical trials is completely voluntary. You have the right to withdraw from the study at any time, for any reason, without penalty or loss of benefits to which you are otherwise entitled.
How long does a clinical trial last?
Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.
Data: ClinicalTrials.gov · synced May 13, 2026 · Source of record for eligibility and locations