PsyQ: Journal Club

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

In this episode, we break down a major longitudinal synthesis of seven North American cohort studies following children with ADHD into adulthood over 10–30 years. The data are striking: while full diagnostic persistence varies, the majority of individuals continue to experience clinically meaningful symptoms and impairment well into adult life. Persistent ADHD is associated with lower educational attainment, unemployment, financial instability, higher rates of mood and substance use disorders, antisocial behavior, driving risk, emergency medical utilization, and even reduced life expectancy. Comorbid disruptive behavior disorders emerge as the strongest predictors of adverse adult outcomes, while internalizing symptoms in females drive elevated suicide risk. Although stimulant treatment remains effective for short-term symptom control, long-term functional normalization is inconsistent, underscoring that medication alone is insufficient. This episode reframes childhood ADHD as a chronic, life-course disorder with major implications for early intervention, comorbidity management, and long-term care planning. 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, we dissect a landmark 2022 randomized controlled trial published in the American Journal of Psychiatrythat challenges the traditional "daily dose" paradigm for treating Alcohol Use Disorder (AUD). We review the efficacy of targeted, event-driven oral naltrexone—taken only in anticipation of heavy drinking or cravings—specifically for sexual and gender minority (SGM) men with mild-to-moderate AUD.We analyze how this "chemical shield" approach yielded a Number Needed to Treat (NNT) of just 2 to prevent a binge-drinking day , significantly reduced overall consumption volume , and demonstrated sustained therapeutic effects six months post-treatment through likely pharmacological extinction. Join us as we explore how decoupling alcohol from its neurobiological reward can bridge the massive treatment gap for binge drinkers who are resistant to total abstinence. 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, we unpack the psychiatric relevance of the ketogenic diet through the lens of a recent and compelling systematic review and meta-analysis from JAMA Psychiatry. Join us as we explore how ketogenic diets may modulate mood, inflammation, neurotransmission, and energy metabolism—domains increasingly central to the practice of modern psychiatry. We’ll break down what the evidence says (and doesn’t say) about its utility in depression and anxiety, clinical pearls for implementation, safety considerations, and which patients may benefit most. Perfect for psychiatry residents, faculty, and anyone curious about nutritional psychiatry with a rigorous, translational focus. 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

Antidepressant discontinuation is one of the most contentious topics in psychiatry, fueling both patient fear and clinical uncertainty. But what does the highest quality, placebo-controlled evidence actually say? In this episode, we dive deep into the 2025 JAMA Psychiatry systematic review and meta-analysis by Kalfas et al. that re-examines the incidence and nature of discontinuation symptoms. We break down the study's striking headline finding—that stopping an antidepressant, on average, results in just one additional symptom compared to stopping placebo, a number below the threshold for clinically significant discontinuation syndrome. We discuss which symptoms, like dizziness , are pharmacologically real versus those that are not, and explore the paper's most critical clinical implication: its finding that early mood worsening is not associated with discontinuation, providing a data-driven framework for distinguishing withdrawal from true depressive relapse 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, our psych journal club dives deep into the Bush–Francis Catatonia Rating Scale (BFCRS), guided by the 2022 BFCRS Training Manual and its original 1996 validation study. We walk through each of the 23 items in the scale, clarifying their definitions, how to observe and score them, and the key differentiations between overlapping signs such as mutism, withdrawal, and negativism. From subtle signs like mitgehen and ambitendency to high-risk indicators of malignant catatonia, this conversation aims to strengthen clinical fluency and improve bedside assessment. Whether you’re a trainee learning to recognize catatonia or a seasoned clinician refining your exam technique, this episode provides a practical, evidence-based approach to mastering the BFCRS. 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 week’s episode of PsyQ, we break down the American Journal of Psychiatry review “Ketamine for Depression, but at What Cost?” by Li and colleagues. Here we explore the balance between ketamine’s rapid antidepressant benefits and its potential neurotoxic risks. We’ll discuss what animal and human studies reveal about dose, frequency, and safety, why FDA-regulated esketamine appears cognitively safe while off-label ketamine use raises concern, and how clinicians can responsibly navigate this evolving treatment landscape. Reference: Li SW, Kumpf KT, Urrutia J, Krystal JH, Sanacora G, Wilkinson ST. Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies. Am J Psychiatry. 2025;182:903–912. 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, we take a clinical look at psychedelic-assisted therapy — what it is, how it works, and where it’s headed. We cover MDMA for PTSD and psilocybin for depression, break down the science behind how these drugs work with therapy, and review key trial data, safety concerns, and how psychiatrists may soon integrate these treatments into practice. This episode delivers clear takeaways, clinical pearls, and a balanced view on this rapidly evolving field. 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 take a critical look at the evolution of major depression treatment over the past two decades. We start with the foundational Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, a study that has shaped clinical practice for years with its widely cited ~70% cumulative remission rate. However, we then dive deep into a startling 2023 re-analysis that challenges this cornerstone of psychopharmacology, revealing a cumulative remission rate closer to 35% when the original study's protocol is strictly followed. This critical re-evaluation serves as a springboard to explore the future, as we discuss a 2024 review on the novel and emerging treatments moving beyond monoamines, including glutamatergic agents like ketamine and the promising field of psychedelic-assisted therapy. Join us as we journey from the bedrock of modern depression treatment to the cutting edge of psychiatric research.Articles Discussed:Rush AJ, Fava M, Wisniewski SR, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials. 2004.Pigott HE, Kim T, Xu C, et al. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study’s patient-level data with fidelity to the original research protocol. BMJ Open. 2023.Ghasemi M, Rezaei F, Falahati F, et al. Trends in research on novel antidepressant treatments. Frontiers in Pharmacology. 2024. 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, we break down BrainsWay’s 6-day accelerated Deep TMS for major depression—how its iTBS, 5-sessions-per-day schedule compresses a month of treatment into 6 days with non-inferior outcomes to standard daily TMS—then stack it up against conventional 4–6 week TMS and Stanford’s SAINT (the 5-day, 50-session, MRI-guided protocol boasting rapid, high remission rates). We’ll walk through patient flow (session length, spacing, acute + maintenance phases), efficacy (response/remission and time-to-relief), safety (mostly transient scalp discomfort/headache; no new safety signals), practicalities (staffing and workflow for multi-session days), and the real-world stuff clinicians care about—FDA status (BrainsWay’s accelerated clearance for MDD in 2025; SAINT cleared for TRD), coverage gaps (daily caps vs 5x/day), and how to counsel patients on choosing between speed, access, and cost. 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, we dissect the alarming 75.6% rise in private equity (PE) ownership of US psychiatric hospitals and unpack the central paradox from a landmark 2025 JAMA Psychiatry study: how do these facilities operate with significantly fewer nurses and social workers, yet report better outcomes on official quality metrics like restraint use and readmissions? We deconstruct this quality illusion, revealing how self-reported data, administrative gaming, and the strategic "cream-skimming" of less-ill patients can mask the erosion of care. Drawing stark warnings from the devastating impact of PE in other sectors—where the model is linked to increased patient mortality—we provide a critical guide for clinicians to navigate a healthcare landscape where the pursuit of profit often conflicts with the mission of healing. 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 week’s episode of PsyQ, we explore psychiatry’s role in decreasing violence in America. While mental illness is often blamed for violent acts, research shows it accounts for only a small fraction of overall violence. Instead, substance use, social stressors, and access to firearms are far more influential. We discuss how psychiatrists can assess and mitigate risk, the limits of violence prediction, and how tools like red flag laws, crisis intervention teams, and public policy reforms can save lives. The episode highlights practical pearls for clinicians and trainees: focus on modifiable risks, document and act decisively when threats emerge, and embrace psychiatry’s dual role as healer and advocate for safer communities. 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 we’ll orient listeners to catatonia’s core features and standard pathways (lorazepam → ECT), then pivot to emerging third-line options when Ativan is ineffective and ECT isn’t feasible. Using a recent systematic review and a bipolar-catatonia case report as anchors, we’ll cover why NMDA antagonism makes mechanistic sense, dosing patterns (most reports used 0.5 mg/kg IV over ~40 min, often as a short series), and what the aggregate signals show: ~80% response and ~44% remission across published cases, with no reported worsening of catatonia or psychosis and only one discontinuation for dissociation. We’ll also highlight real-world scenarios where ketamine helped patients who were medically unfit for ECT (e.g., cardiomyopathy, advanced lung disease) and improved within hours to days—illustrating ketamine’s potential role as a bridge or alternative in treatment-resistant catatonia, especially in mood-disorder presentations. 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

How should psychiatrists respond when patients use racist language or refuse care based on a clinician’s identity? In this episode, we translate the NEJM five-factor framework into psychiatry’s day-to-day reality—balancing EMTALA obligations and patient autonomy with Title VII protections and clinician well-being—and turn it into practical playbooks for the ED, inpatient units, and clinic. We cover rapid triage in emergencies, capacity and intent assessment (illness-driven vs. bigotry), boundary-setting scripts, when (and when not) to accommodate, safe transfer options, documentation, debriefing, and institution-level policies (codes of conduct, bystander support, reporting pathways). Pearls focus on protecting staff while ensuring care, distinguishing culturally appropriate concordance from prejudice, and leading post-incident team recovery—so trainees can respond clearly, ethically, and confidently. 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, we explore the role of olanzapine/samidorphan (OLZ/SAM) in the treatment of schizophrenia and bipolar I disorder. While olanzapine is one of the most effective second-generation antipsychotics, its use has long been limited by substantial weight gain and metabolic side effects. The addition of samidorphan, an opioid receptor antagonist, represents an innovative approach to mitigate these concerns. We’ll dive into the pathophysiology of schizophrenia and bipolar I disorder, review current treatment strategies, and then unpack the evidence behind OLZ/SAM—including its mechanism of action, clinical trial results, metabolic profile, and potential role in treatment-resistant cases. Along the way, we’ll highlight clinical pearls, prescribing considerations, and real-world implications for psychiatry trainees navigating the complexities of antipsychotic treatment. 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

Combining aripiprazole and haloperidol presents a clinical and pharmacological puzzle. On one hand, you have haloperidol, a potent D₂ antagonist that fully blocks dopamine; on the other, aripiprazole, a partial agonist with high affinity that displaces the antagonist only to provide a weaker signal. This interplay can be dangerous, potentially triggering a "dopamine supersensitivity psychosis" in a brain already adapted to chronic blockade, leading to a sudden worsening of symptoms. Yet, this same mechanism can be harnessed to treat stubborn side effects like hyperprolactinemia, making it a tempting strategy. In this episode of PsyQ, we dissect the competing pharmacology, review the conflicting case literature—from successful augmentation to severe relapse—and provide evidence-based, practical guidance on how to navigate this combination. Join us for a deep dive into this double-edged sword of psychopharmacology, equipping you with the knowledge to proceed with caution and confidence. 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 journey from the historical notion of "gut feelings" to the cutting edge of psychiatric research: the microbiota-gut-brain axis. This episode unravels the paradigm shift that recast the gut's microbial inhabitants as a dynamic metabolic organ, actively shaping our mental health. We dissect the core communication network, exploring how neural (vagus nerve), endocrine (HPA stress axis), and immune (cytokine) pathways form a three-way dialogue between our microbes and our mind. Delving into the 'chemical language' of the gut, we discuss how microbial metabolites like short-chain fatty acids and bile acids modulate brain function by influencing key cells like microglia and the integrity of the blood-brain barrier. Finally, we critically examine the clinical implications for disorders like autism and depression, evaluating the current evidence, promises, and pitfalls of therapeutic strategies such as psychobiotics and fecal microbiota transplantation, and look toward the future of this revolutionary field.References:Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Reviews Neuroscience, 13(10), 701–712.Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024). Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduction and Targeted Therapy, 9(1), 37.Morais, L. H., Schreiber, H. L., & Mazmanian, S. K. (2021). The gut microbiota–brain axis in behaviour and brain disorders. Nature Reviews Microbiology, 19(4), 241–255. 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 episode of PsyQ delves into the rare and puzzling condition of non-catatonic mutism in individuals with schizophrenia, a profound silence that is not attributable to the physical inability to speak or the classic signs of catatonia. We explore the case of "Mr. X," a man who was mute for three years, to understand the complexities of diagnosis and the surprising cultural patterns that see this condition reported more frequently in specific regions like the Indian subcontinent. The discussion covers the crucial distinctions from catatonic mutism, potential neurological underpinnings, and the profound psychological impact on patients. Furthermore, we reveal a surprising "game-changer" in treatment, highlighting how ECT, particularly when combined with other medications in a "triple therapy" approach, has shown remarkable success in restoring speech, offering significant hope where conventional treatments have often failed. 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

The field of psychiatry is at a technological crossroads, with Artificial Intelligence promising to revolutionize care delivery amidst a global mental health crisis. But does this new frontier offer a solution or a source of new, profound harm? This episode of PsyQ: Journal Club takes a critical, evidence-based look at the role of Large Language Models (LLMs) in mental health, moving beyond the hype to provide clinicians with a guide to responsible innovation. We explore a comprehensive framework for safely augmenting clinical practice, examine a case study in using digital phenotyping to forecast mental states in schizophrenia, and confront the chilling evidence of how current "therapy bots" fail in moments of crisis by expressing stigma, colluding with delusions, and dangerously mishandling suicidal ideation. We argue that the future is not the autonomous AI therapist, but a human clinician empowered by validated tools, and we provide a playbook for how psychiatrists can become the essential "ethical guardians" and "digital augurs" in this new era. 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

Public perception often creates a direct and frightening link between mental illness and violence, but what does the evidence actually show? In this episode of PsyQ, we challenge common assumptions by exploring the complex reality of violence risk assessment. Using a case study of a patient making homicidal threats, we break down the crucial difference between static risk factors (like history and personality) and dynamic risk factors (like substance use and situational stressors) that clinicians can actually influence. We'll walk through the structured, evidence-based frameworks, including the "Five D's" of management, that guide professionals in high-stakes situations where the threat of violence may not stem from a treatable acute psychiatric illness. This is a deep dive into moving beyond intuition to a defensible, nuanced approach for every clinician facing this profound challenge.Source:Saxton, A., Resnick, P., & Noffsinger, S. (2018). Chief complaint: Homicidal. Assessing violence risk. Current Psychiatry, 17(5), 26–28, 30–32, 34, 55. 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, we tackle one of psychiatry's most complex challenges: Obsessive-Compulsive Disorder. We begin with a deep dive into the landmark 2005 Foa et al. trial, a methodologically rigorous study that definitively established the superior efficacy of intensive Exposure and Ritual Prevention (ERP) over potent pharmacotherapy with clomipramine. Using this foundational evidence, we build a practical, stepped-care algorithm for managing treatment-resistant OCD (TR-OCD). The discussion navigates the nuances of maximizing first-line SRIs, evidence-based augmentation with antipsychotics and glutamatergic agents, and the role of advanced neuromodulation techniques like TMS and Deep Brain Stimulation. We'll synthesize these disparate treatments through the unifying neurobiological lens of the Cortico-Striato-Thalamo-Cortical (CSTC) circuit, providing trainees with a cohesive framework for treating their most challenging OCD patients.Article:Foa, E. B., Liebowitz, M. R., Kozak, M. J., Davies, S., Campeas, R., Franklin, M. E., ... & Tu, X. (2005). Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder. American Journal of Psychiatry, 162(1), 151-161. 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

We dive into two landmark studies that have dramatically expanded the genetic map of bipolar disorder, identifying nearly 300 risk loci from over 150,000 patients. We explore the game-changing discovery of the AKAP11 gene, which provides a direct molecular link to lithium's mechanism, and unpack the complex genetic architecture that both unites and separates bipolar disorder from schizophrenia and its own subtypes. Finally, we translate these complex findings into clinical practice, discussing the current role of pharmacogenetic testing, how to counsel families about genetic risk, and what the future of precision psychiatry for bipolar disorder might look like.Sources:Mullins, N. et al. (2021). Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nature Genetics, 53, 817-829.O'Connell, K.S. et al. (2025). Genomics yields biological and phenotypic insights into bipolar disorder. Nature, 639, 968-975. 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

Treating adolescent depression is one of the most significant challenges in mental health, a landscape complicated by the FDA's black box warning about antidepressant-associated suicide risk. This episode dives deep into the landmark Treatment for Adolescents With Depression Study (TADS), the large-scale, NIMH-funded trial designed to bring clarity to this complex issue. We explore the study's crucial findings, from the "horse race" between fluoxetine, CBT, and their combination, to the critical data on safety and suicidality. Join us as we unpack why combination therapy emerged as a superior strategy, how CBT acts as a protective shield, and what these results mean for clinicians, families, and teens making real-world treatment decisions today.Reference: The TADS Team. (2007). The Treatment for Adolescents With Depression Study (TADS): Long-term Effectiveness and Safety Outcomes. Archives of General Psychiatry, 64(10), 1132–1144. 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 we explore the landmark MTA study, unraveling its insights into ADHD treatment from childhood to adulthood. We'll cover the initial trial's findings on medication and combined therapy, then trace how these effects evolved, highlighting the surprising persistence of impairment compared to peers and the nuanced impact of long-term stimulant use on height versus symptoms. This episode offers essential clinical pearls, emphasizing individualized, quality care, the chronic nature of ADHD, and the importance of addressing comorbidities.Studies Referenced in this Episode:The MTA at 8 Years: Prospective Follow-Up of Children Treated for Combined Type ADHD in a Multisite StudyMultimodal Interventions Are More Effective in Improving Core Symptoms in Children With ADHDA 14-Month Randomized Clinical Trial of Treatment Strategies for Attention-Deficit/Hyperactivity DisorderYoung adult outcomes in the follow-up of the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder: symptom persistence, source discrepancy and height Suppression 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 episode, we delve into the rapidly evolving landscape of GLP-1 receptor agonists in psychiatry. We'll critically appraise Hendershot et al.'s (2025) JAMA Psychiatry study on once-weekly semaglutide for Alcohol Use Disorder, examining its efficacy in reducing alcohol consumption and craving in a randomized clinical trial. We then broaden our scope with Pierret et al.'s (2025) systematic review and meta-analysis in JAMA Psychiatry, which assesses the psychiatric safety profile and quality of life outcomes associated with GLP-1 RA treatment. Finally, we integrate insights from the Carlat Psychiatry Report (Aiken & Liebers, 2025) on "New Weight Loss Drugs in Psychiatry," exploring mechanisms, potential applications for antipsychotic-induced weight gain, binge eating disorder, mood, and cognition, alongside crucial risk considerations. Join us as we synthesize these findings and discuss their clinical implications for psychiatric practice.Sources:Hendershot CS, et al. (2025). Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry.Pierret ACS, et al. (2025). Glucagon-Like Peptide 1 Receptor Agonists and Mental Health: A Systematic Review and Meta-Analysis. JAMA Psychiatry.Aiken C & Liebers D. (2025). New Weight Loss Drugs in Psychiatry. The Carlat Psychiatry Report. 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 two-part episode takes a comprehensive look at clozapine, one of psychiatry's most impactful and complex medications. The two parts are (1) context, and (2) clinical pearls. We explore its challenging history, landmark clinical trials, unique pharmacology, practical prescribing guidelines, and the recent evolution of its regulatory oversight. Essential listening for psychiatry trainees and practicing clinicians.Sources used:1. Kane (1988). Clozapine for the Treatment-Resistant Schizophrenic: A Double-blind Comparison With Chlorpromazine. Arch Gen Psychiatry2. Hippius (1999). A Historical Perspective of Clozapine. J Clin Psychiatry3. Clozapine—serious adverse effects and clinical management. Chapter 12 in Antidotes to Toxins and Drugs.4. FDA. Feb 2025 Information on Clozapine. FDA.gov.5. Schneider-Thoma (2025). Efficacy of clozapine versus second-generation antipsychotics in people with treatment-resistant schizophrenia: a systematic review and individual patient data meta-analysis. Lancet 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 week on PsyQ, we dive into the controversial practice of co-administering parenteral olanzapine and benzodiazepines for agitation. We revisit the 2005 FDA warning prompted by post-marketing reports (Marder et al., 2010) and critically examine the causality behind the reported fatalities. Contrasting this, we explore subsequent research, including observational studies (Williams, 2018; Wilson et al., 2012), an RCT using IV formulations (Chan et al., 2013), and a large recent retrospective study (Cole et al., 2024), which suggest the combination may be safer than the initial warning implied, finding no significant increase in severe cardiorespiratory events like intubation compared to olanzapine alone, even within 60 minutes and in patients with alcohol intoxication. We discuss the differing regulatory stances (FDA vs. EMA), practical implications, patient selection (caution with respiratory compromise/alcohol), and how this evolving evidence landscape might impact clinical decision-making in managing acute agitation.Key Studies Discussed:Marder SR et al. (2010): Original post-marketing case reports leading to the warning. J Clin Psychiatry.Williams AM (2018): MUE finding no SAEs with IM olanzapine + lorazepam. Ment Health Clin.Wilson MP et al. (2012): Compared olanzapine+benzo vs haloperidol+benzo; highlighted alcohol risk. J Emerg Med.Chan EW et al. (2013): RCT showing safety of IV olanzapine + midazolam. Ann Emerg Med.Cole JB et al. (2024): Large retrospective study finding no difference in intubation/hypoxia/hypotension rates between olanzapine+benzo vs olanzapine x2. Ann Emerg Med.Carlat Psychiatry Report Summary: Overview and clinical take on the evidence.This podcast is AI generated with human input and review, however there may be errors, so for the most accurate and up to date information, please consult the primary sources. 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 an AI generated podcast with human review. This episode provides guidance on the prophylactic management of bipolar disorder during pregnancy and postpartum, referencing the Uguz et al. (2023) review. We cover the high relapse risks (particularly postpartum), the core dilemma of balancing maternal health with infant safety, and evidence-based medication choices. Key takeaways include the importance of individualized planning, avoiding high-risk drugs like valproate, adjusting doses dynamically, and integrating medication with crucial psychosocial supports and sleep strategies.Notes: pronunciation issues with medication names and "Bipolar 1" is said as "Bipolar i", content has been reviewed for accuracy.Article: https://pubmed.ncbi.nlm.nih.gov/37683233/ 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

Timestamps(0:00) Context & Rationale(11:25) Methods & Findings(27:06) Critical Appraisal(43:26) Impact & Clinical TakeawayThis is a journal club discussion on the CATIE trial. We cover the study's background and methodology to its critical appraisal and clinical impact. Keep in mind this merely a summary of a journal article and with the use of AI we are susceptible to some hallucination. Please refer to the source material linked below for the most accurate information about the CATIE Trial.https://www.nejm.org/doi/full/10.1056/NEJMoa051688 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