Antipsychotics and glucose metabolism: how brain and body collide
Abstract
Since the serendipitous discovery of the first antipsychotic (AP) drug in the 1950s, APs remain the cornerstone of treatment for schizophrenia. A shift over the past two decades away from first-generation, conventional APs to so-called “atypical” (or 2nd/3rd generation) APs parallels acknowledgment of serious metabolic side-effects associated in particular with these newer agents. As will be reviewed, AP drugs and type 2 diabetes are now inextricably linked, contributing to the three- to fivefold increased risk of type 2 diabetes observed in schizophrenia. However, this association is not straightforward. Biological and lifestyle-related illness factors contribute to the association between type 2 diabetes and metabolic disease independently of AP treatment. In addition, APs have a well-established weight gain propensity which could also account for elevated risk of insulin resistance and type 2 diabetes. However, compelling preclinical and clinical evidence now suggests that these drugs can rapidly and directly influence pathways of glucose metabolism independently of weight gain and even in absence of psychiatric illness. Mechanisms of these direct effects remain poorly elucidated but may involve central and peripheral antagonism of neurotransmitters implicated not only in the therapeutic effects of APs but also in glucose homeostasis, possibly via effects on the autonomic nervous system. The clinical relevance of studying “direct” effects of these drugs on glucose metabolism is underscored by the widespread use of these medications, both on and off label, for a growing number of mental illnesses, extending safety concerns well beyond schizophrenia.
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Increased sympathetic outflow leads to suppressed insulin release and high levels of circulating epinephrine, norepinephrine, glucagon and cortisol, all of which promote glycogenolysis and endogenous glucose production, thereby inducing hyperglycaemia.
“Increased sympathetic outflow leads to suppressed insulin release and high levels of circulating epinephrine, norepinephrine, glucagon and cortisol, all of which promote glycogenolysis and endogenous glucose production, thereby inducing hyperglycaemia95.”
From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [95]
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Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences
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Self-citationImmunoendocrine Peripheral Effects Induced by Atypical Antipsychotics
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Self-citationEffects of Antipsychotic Drugs: Cross Talk Between the Nervous and Innate Immune System
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Adiposity in schizophrenia: A systematic review and meta‐analysis
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Self-citationPeripheral and central regulation of insulin by the intestine and microbiome
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Brain insulin action: Implications for the treatment of schizophrenia
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Antipsychotics impair regulation of glucose metabolism by central glucose
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Self-citationFemale mice are protected against acute olanzapine-induced hyperglycemia
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Self-citationAntipsychotic-Induced Alterations in Lipid Turnover
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Self-citationDifferential Effects of Acute Treatment With Antipsychotic Drugs on Peripheral Catecholamines
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The Candidate Schizophrenia Risk Gene Tmem108 Regulates Glucose Metabolism Homeostasis
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Self-citationAtypical Antipsychotic Medications Disrupt the Cardio-Metabolic and Cardio-Immune Axes
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Self-citationGLP-2 attenuates antipsychotics’ adverse metabolic effects
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- Authors
- Kowalchuk, C., Castellani, L. N., Chintoh, A., Remington, G., Giacca, A., & Hahn, M. K.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- University of Toronto (CA)
- Corresponding author
- Giacca, Adria
- Hahn, Margaret K.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2019-01-01
- Volume
- 316
- Issue
- 1
- Pages
- E1-E15
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2810590812
- Cited by
- 85
- References
- 107
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 12 · 2023: 15 · 2022: 9 · 2021: 11 · 2020: 12 · 2019: 7 · 2018: 3
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institute for Health Research
- Banting and Best Diabetes Centre, University of Toronto (BBDC)
- Canadian Diabetes Association (Association Canadienne du Diabète)
- University of Toronto Psychiatry Excellence Fund
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- antipsychotic drugs, glucose metabolism, type 2 diabetes, schizophrenia, atypical antipsychotics, metabolic side effects, weight gain, insulin resistance, glucose homeostasis, autonomic nervous system, off-label drug use
- MeSH terms
- Animals, Autonomic Nervous System, Clozapine, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin Resistance, Schizophrenia, Antipsychotic Agents, Glucose Clamp Technique, Weight Gain, Receptors, Dopamine D2, Receptors, Serotonin, 5-HT2
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