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Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

ConditionMajor Depression
Trial statusRecruiting
Trial phaseEarly Phase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorMclean Hospital

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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

Trial design

Design model

Crossover

Treatments tested in this trial

  • 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.

Treatment groups

80 Participants
are divided into 6 treatment groups

6

Treatment groups

See each treatment group below.

Group A: Sham + PlaceboSham comparator 2 interventions
Group B: TMS + PlaceboPlacebo comparator 2 interventions
Group C: NMDAR AntagonismExperimental treatment 2 interventions
Group D: NMDAR AgonismExperimental treatment 2 interventions
Group E: GABA-A AgonsimExperimental treatment 2 interventions
Group F: GABA-B AgonismExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

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.

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.
2

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.

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.
3

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.

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.

Secondary outcomes

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Mclean Hospital

Lead sponsor

National Institute of Mental Health (NIMH)

Collaborator

Source ClinicalTrials.gov
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