Nagamine T. Double-edged sword of antipsychotic therapy: Navigating the intersection of psychiatric recovery, endoplasmic reticulum stress, and cardiovascular survival. World J Psychiatry 2026; 16(6): 118149 [DOI: 10.5498/wjp.v16.i6.118149]
Corresponding Author of This Article
Takahiko Nagamine, MD, PhD, Professor, Psychiatric Internal Medicine, Sunlight Brain Research Center, 4-13-18 Jiyugaoka, Hofu 7470066, Yamaguchi, Japan. anagamine@yahoo.co.jp
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Psychiatry
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review-article
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Nagamine T. Double-edged sword of antipsychotic therapy: Navigating the intersection of psychiatric recovery, endoplasmic reticulum stress, and cardiovascular survival. World J Psychiatry 2026; 16(6): 118149 [DOI: 10.5498/wjp.v16.i6.118149]
World J Psychiatry. Jun 19, 2026; 16(6): 118149 Published online Jun 19, 2026. doi: 10.5498/wjp.v16.i6.118149
Double-edged sword of antipsychotic therapy: Navigating the intersection of psychiatric recovery, endoplasmic reticulum stress, and cardiovascular survival
Takahiko Nagamine
Takahiko Nagamine, Psychiatric Internal Medicine, Sunlight Brain Research Center, Hofu 7470066, Yamaguchi, Japan
Author contributions: Nagamine T conducted conceptualization, investigation, writing the manuscript.
AI contribution statement: The author denies using AI for proofreading or writing the manuscript. The only tool related to AI that was used was Google's English proofreading service.
Conflict-of-interest statement: The author reports no relevant conflicts of interest for this article.
Corresponding author: Takahiko Nagamine, MD, PhD, Professor, Psychiatric Internal Medicine, Sunlight Brain Research Center, 4-13-18 Jiyugaoka, Hofu 7470066, Yamaguchi, Japan. anagamine@yahoo.co.jp
Received: December 25, 2025 Revised: January 28, 2026 Accepted: February 26, 2026 Published online: June 19, 2026 Processing time: 155 Days and 1 Hours
Abstract
Individuals diagnosed with schizophrenia have been shown to have a significantly different lifespan, often dying 15 years to 20 years earlier than the general population. This excess mortality is primarily attributable to atherosclerotic cardiovascular disease, rather than the psychiatric symptoms themselves. Second-generation antipsychotics represent the prevailing standard of treatment in modern medicine; however, their efficacy is accompanied by significant drawbacks. While these medications are imperative in the prevention of suicide and relapse, they can concomitantly induce metabolic dysfunction. A rigorous examination of the molecular underpinnings of the endoplasmic reticulum stress response is imperative to elucidate its role as a mediator of antipsychotic-induced insulin dysregulation. Additionally, we examine the “clinical paradox” that the pursuit of psychiatric stabilization through pharmacotherapy may inadvertently expedite cardiovascular aging. Moving forward, clinical models must shift from an emphasis on individual variable analyses (e.g., body mass index or positive/negative symptom scale scores) to an integrated framework. This framework should consider the control of psychiatric symptoms as a prerequisite for metabolic health. In order to address the disparity in survival rates within this vulnerable population, there is a necessity to evolve research methodologies in order to facilitate clinical evaluation of a trinity of pharmacology, psychopathology, and lifestyle.
Core Tip: Cardiovascular mortality in schizophrenia is a systemic failure that cannot be solved by psychiatric or medical intervention in isolation. Effective care requires managing the molecular risks of medication alongside the functional necessity of psychiatric stability to enable life-saving lifestyle changes. Clinicians must recognize that antipsychotics like olanzapine pose dual risks: Chronic insulin resistance and acute, ketosis-prone diabetic emergencies.
