Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

Part of paid clinical trials in Belmont, Massachusetts.

Sponsor
Mclean Hospital
Study ID
NCT07560878
Phase
EARLY_PHASE1
Status
Recruiting
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Conditions

  • Major Depression

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • D-Cycloserine (DCS) — DRUG
    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) — DEVICE
    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 — DEVICE
    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 — DRUG
    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) — 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 — DRUG
    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 — DRUG
    Sucrose packaged in identical cellulose capsules, administered orally.

Study Details

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.

Key Dates

Start date
Mar 11, 2026
Status verified
Apr 2026
Primary completion
Dec 31, 2030
Completion
Dec 31, 2030

Study Design

Enrollment
80 participants (estimated)
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE

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

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. ]

Central Contacts

Locations (1)

FacilityCityStateZIPSite coordinators
McLean HospitalBelmontMassachusetts02478
Dennis W Guevara
[email protected]
617-855-2340
Prem Ganesh, MS
[email protected]
617-855-2153

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