The goal of this clinical trial is to test whether combining a ketogenic diet (KD) with personalized, accelerated intermittent theta burst stimulation (iTBS) produces greater reductions in depressive symptoms than iTBS combined with a standard healthy diet in adults with treatment-resistant depression. The trial also aims to determine whether participants can feasibly follow a ketogenic diet during an accelerated iTBS treatment course and whether the diet produces measurable changes in ketone levels. Specifically, the study aims to determine whether the combined intervention: 1. Reduces depressive symptoms 2. Increases circulating ketone levels 3. Is feasible and tolerable during accelerated iTBS treatment Participants will begin either a KD or a Canadian Food Guide-aligned diet (CFGD) with a 3-week dietary lead-in period, after which they will undergo a course of personalized, accelerated iTBS while continuing their assigned diet. Before and after the iTBS treatment course, participants will complete clinical assessments, provide blood samples for metabolic testing, and undergo MRI scans to assess brain connectivity. Ketone levels will be measured daily throughout the 12-week dietary intervention. Within-group and between-group differences will be compared to characterize changes in clinical outcomes, metabolism, and brain functioning.
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Change in Depression Score on the Montgomery-Asberg Depression Rating Scale (MADRS)
Timeframe: Baseline, Day 5 (post-iTBS), Week 4 (post-iTBS), Week 8 (post-iTBS)
Changes in Ketone Levels
Timeframe: Baseline through week 12
Safety and Tolerability
Timeframe: Baseline through week 12
Sean M Nestor, M.D., PhD