Switch vs. Augment: Rewriting the Rules for Geriatric TRD - PsyQ Episode 33

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

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

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

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

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

In this episode of PsyQ, we review a large national inpatient study examining the association between cannabis use disorder (CUD) and suicide attempts/self-harm among hospitalized adolescents in the United States. Using data from more than 800,000 adolescent hospitalizations, the study demonstrates that CUD is independently associated with approximately 40% increased odds of suicide attempts and self-harm, even after controlling for psychiatric and substance use comorbidities. The data further highlight depression as a key moderator, with adolescents experiencing both CUD and depression showing markedly higher suicide risk compared to those with either condition alone. The findings reinforce the importance of routine substance use screening, suicide risk assessment across all inpatient settings (not just psychiatric units), and implementation of dual-diagnosis treatment approaches targeting both cannabis use and co-occurring psychiatric illness. These results are particularly relevant given rising cannabis use among adolescents and shifting risk perceptions related to legalization and accessibility. 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

In this episode of PsyQ, we review the landmark STEP-BD randomized controlled trial evaluating the effectiveness of adjunctive antidepressant treatment for bipolar depression. We analyze the study's methodology, specifically the use of equipoise-stratified randomization to mirror routine clinical care and the selection of "durable recovery"—defined as eight consecutive weeks of euthymia—as the primary outcome measure. The discussion focuses on the key data points demonstrating that the addition of standard antidepressants (bupropion or paroxetine) to mood stabilizers provided no statistically significant benefit over placebo in achieving durable recovery. Furthermore, we examine the safety findings, which indicated that adjunctive antidepressant use was not associated with an increased risk of treatment-emergent affective switch compared to mood stabilizers alone.ReferencesSachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression. N Engl J Med. 2007;356(17):1711-1722. 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

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

In this episode of PsyQ, we perform a forensic analysis of the landmark OPTIMUM trial, a study that fundamentally reshapes the treatment algorithm for resistant depression in older adults. We dissect the head-to-head battle between switching antidepressants versus augmentation, revealing why aripiprazole claims the crown for efficacy while exposing a counterintuitive and critical safety signal regarding bupropion-induced falls. Beyond the clinical pearls, we guide you through the statistical machinery under the hood—specifically how the Benjamini-Hochberg procedure saved the study's primary finding—and introduce the "Rule of Three," a data-driven threshold that suggests exactly when clinicians should stop cycling medications and pivot to interventional psychiatry. 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

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