Metabolic Psychiatry: Ketosis for TRD - PsyQ Episode 40

Dementia in Severe Schizophrenia - PsyQ Episode 41

In this episode of PsyQ, we critically examine the etiology of cognitive decline in severe, extremely treatment-resistant schizophrenia (SETRS) through the lens of a 2026 JAMA Psychiatry cohort study. By analyzing clinical and genetic data from 155 chronically institutionalized patients, the research demonstrates that the cognitive deficit profile in SETRS intensifies the patterns seen in community-dwelling schizophrenia rather than mimicking Alzheimer disease (AD) or frontotemporal dementia (FTD). Genomic sequencing revealed no pathogenic variants in Mendelian dementia genes and a significantly lower APOE4 allele frequency compared to AD and Lewy body dementia. Crucially, the profound cognitive impairment observed was not attributable to secondary factors such as antipsychotic exposure, anticholinergic burden, cardiometabolic risk factors, or premorbid intellectual disability. We discuss the clinical implication that severe cognitive decline is an intrinsic trajectory of the schizophrenia disease process itself, necessitating a paradigm shift away from frequent misdiagnoses of comorbid neurodegenerative conditions. Pathak US, Mehralizade A, Goldberg TE, Zoghbi AW. Dementia in Severe Schizophrenia. JAMA Psychiatry. Published online April 1, 2026. doi:10.1001/jamapsychiatry.2026.0171. 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 [https://upathak.substack.com?utm_medium=podcast&utm_campaign=CTA_1]

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 [https://upathak.substack.com?utm_medium=podcast&utm_campaign=CTA_1]

Brain and Blood Biomarkers in MDD - PsyQ Episode 39

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 [https://upathak.substack.com?utm_medium=podcast&utm_campaign=CTA_1]

In-Utero Antipsychotic Medication Exposure - PsyQ Episode 38

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 [https://upathak.substack.com?utm_medium=podcast&utm_campaign=CTA_1]

The Psychic Tourniquet: Ultra-Low-Dose Buprenorphine for Acute Suicidality - PsyQ Episode 37

In this episode of PsyQ, we confront the "zone of danger" in acute suicidality—the critical lag period where standard antidepressants often fail to address immediate "psychache". Anchored by the seminal Yovell et al. (2016) randomized controlled trial, we explore the neurobiological overlap between physical and social pain , testing the hypothesis that ultra-low-dose buprenorphine (starting at 0.1 mg) can modulate the endogenous opioid system to treat separation distress directly. We dissect the study's groundbreaking findings—including a significant reduction in suicidal ideation distinct from depression improvement and robust efficacy in patients with Borderline Personality Disorder —while rigorously outlining the safety parameters, zero-withdrawal protocols, and the critical clinical distinction between treating specific depressive symptoms and soothing the primal agony of the PANIC/GRIEF system. 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 [https://upathak.substack.com?utm_medium=podcast&utm_campaign=CTA_1]