Recruiting
Early Phase 1

cTBS with Medication

Sponsor:

Mclean Hospital

Code:

NCT07560878

Conditions

Major Depression

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

D-Cycloserine (DCS)

Continuous theta-burst stimulation (cTBS)

Transcranial Magnetic Stimulation Sham

Memantine

Lorazepam (drug)

Study Details

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 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.

Conditions

Major Depression

Study ID

NCT07560878

Start date

Mar 11, 2026

Status verified date

Apr, 2026

Completion date

Dec, 2030

Anticipated

Primary completion date

Dec, 2030

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

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 Design

Enrollment

80 participants

Anticipated

Allocation

Randomized

Intervention Model

Crossover

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

sham comparator: Sham + Placebo

Sham TMS and placebo drug

placebo comparator: TMS + Placebo

Active TMS and placebo drug

experimental: NMDAR Antagonism

Active TMS and memantine

experimental: NMDAR Agonism

Active TMS and d-cycloserine

experimental: GABA-A Agonsim

Active TMS and lorazepam

experimental: GABA-B Agonism

Active TMS and baclofen

Interventions

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.

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.

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.

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.

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.

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.

Placebo

Sucrose packaged in identical cellulose capsules, administered orally.

Primary outcome measure

  • 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 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 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. ]

Central Contacts and Locations

Central contacts

Prem Ganesh, MS

617-855-2153pganesh@mgb.org

Dennis W Guevara

617-855-2340dguevara@mclean.harvard.edu

Locations

McLean Hospital

Recruiting

Belmont, Massachusetts, United States, 02478

Contacts

Dennis W Guevara

617-855-2340dguevara@mclean.harvard.edu

Prem Ganesh, MS

617-855-2153pganesh@mgb.org

More Information

Sponsor

Mclean Hospital

Last update posted

May 13, 2026

Last verified

Apr, 2026

Keywords

  • TMS
  • EEG
  • TMS-EEG
  • Depression
  • Pharmacologic Augmentation

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Mclean Hospital on 2026-05-13.