Metabolic Psychiatry: Ketosis for TRD - PsyQ Episode 40

In this episode of PsyQ, we critically evaluate the recent randomized clinical trial by Gao et al. published in JAMA Psychiatry investigating the ketogenic diet (KD) as an adjunctive treatment for treatment-resistant depression (TRD). The study randomized 88 adults with TRD to either a 6-week, highly supported KD or an active phytochemical control diet, specifically isolating the dietary variable by strictly controlling for weight loss. While both cohorts demonstrated rapid symptom reduction, the KD group showed a modest, statistically significant advantage in PHQ-9 scores at 6 weeks compared to the control (-2.18 points). We break down the clinical utility of these findings by examining critical caveats: the loss of the therapeutic advantage by week 12, the failure to improve secondary domains like anhedonia and cognition, and the paradoxical lack of correlation between blood ketone concentrations and depressive symptom improvement. Join us as we discuss the profound logistical challenges of maintaining strict ketosis and debate whether the structural scaffolding of the intervention—rather than the metabolic shift itself—drove the observed psychiatric benefits. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit upathak.substack.com