Synaptic Mechanisms of Intermittent Theta Burst Stimulation for Major Depressive Disorder

Study Summary

Many people with depression do not get better with standard treatments like medications or talk therapy. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation treatment that uses magnetic pulses to stimulate areas of the brain involved in depression. One form of TMS called intermittent theta burst stimulation (iTBS) is FDA-cleared for depression and takes only 3 minutes to deliver. However, about one-third of patients do not respond to iTBS, and another one-third do not reach full remission. Improving iTBS requires a better understanding of how it works in the brain. iTBS is thought to work by strengthening connections between brain cells, a process called synaptic plasticity. This process depends on a type of brain receptor called the NMDA receptor. Most of what researchers know about how iTBS affects these connections comes from studies of healthy people. It is not known whether iTBS works the same way in the prefrontal cortex - the brain region targeted during depression treatment - or in people who actually have depression. This study has two phases. In Phase 1, both healthy volunteers and people with depression will complete 4 research visits to test how iTBS changes brain activity in the prefrontal cortex and whether medications that increase or decrease NMDA receptor activity change those effects. Each visit involves active or sham (inactive) iTBS combined with one of three study medications: a placebo (inactive pill), d-cycloserine (a medication that increases NMDA receptor activity), or dextromethorphan (a medication that decreases NMDA receptor activity). Brain activity is measured before and after each TMS session using electroencephalography (EEG), a painless test that records electrical signals from the scalp through a cap placed on the head. All participants also complete a brain MRI before beginning study visits for targeting purposes. In Phase 2, participants with depression will be offered a standard clinical course of 30 d

Primary Outcome

Change in P30 peak amplitude measured by TMS-EEG before and after a single iTBS session. The P30 is a positive deflection occurring approximately 30 milliseconds after a TMS pulse, reflecting glutamatergic excitatory synaptic transmission. Change in P30 amplitude serves as an index of iTBS-induced LTP-like plasticity in the left dorsolateral prefrontal cortex. Comparisons will be made across drug conditions (placebo, d-cycloserine, dextromethorphan), between TMS conditions (active vs. sham), and

Interventions

• DRUG Placebo
• DEVICE TMS
• DEVICE Sham iTBS
• DRUG D-cycloserine
• DRUG Dextromethophan