Antipsychotic-Induced Metabolic and Cardiovascular Side Effects in Schizophrenia: A Novel Mechanistic Hypothesis
Open accessAbstract
The use of antipsychotics is hindered by the frequent occurrence of metabolic and cardiovascular side effects, resulting in worsened quality of life and greater mortality as a result of cardiovascular and cerebrovascular disorders in schizophrenia patients than the comparable general population. The various antipsychotics induce extrapyramidal symptoms, impaired glucose and lipid metabolism, weight gain, hypertension and arrhythmias, with variable frequency. Second-generation antipsychotics appear to have several advantages over first-generation antipsychotics, including a claimed better action on cognitive function and the negative symptoms of schizophrenia, and lower frequency of extrapyramidal side effects; however, their use is associated with a greater frequency of metabolic and cardiovascular disturbances. The mechanisms of these important side effects are not well understood, and generic approaches (psychoeducational programmes and symptomatic therapies) have been proposed to limit their severity. Extensive data from the literature indicate that autonomic nervous system dysfunction--intrinsic to schizophrenia and strongly exacerbated by antipsychotic treatment--is the cause of the pervasive metabolic and vascular dysfunctions associated with schizophrenia. In this article, we marshal further literature data to argue that the metabolic and cardiovascular side effects of antipsychotics are primarily mediated by their ability to block peripheral dopamine receptors, which physiologically modulate sympathetic activity. We also propose that these effects might be overcome by providing peripheral dopaminergic stimulation.
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D2 receptors modulate the release of epinephrine and norepinephrine from sympathetic terminals; abolishing peripheral dopaminergic modulation results in increased sympathetic tone through excessive stimulation of α-adrenergic receptors.
“D2 receptors modulate the release of epinephrine and norepinephrine from sympathetic terminals; abolishing peripheral dopaminergic modulation results in increased sympathetic tone through excessive stimulation of α-adrenergic receptors.”
From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [101]
In “The Peripheral Dopaminergic System,” the paper says D2 activation inhibits norepinephrine release from sympathetic nerve endings and epinephrine secretion from the adrenal medulla—not both from sympathetic terminals. In “Metabolic Effects of Peripheral Dopamine D2 Receptor Blockade,” it proposes that D2 blockade increases sympathetic tone, but makes the effect conditional on α-adrenergic receptors not being completely occupied by an antipsychotic; it does not attribute the increase solely to excessive α-receptor stimulation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPs influence autonomic functioning by binding and inhibiting dopamine D2, α-adrenergic and cholinergic M3 neurotransmitter receptors in the central and peripheral nervous system which, synergistically, may induce cardiometabolic side-effects.
“APs influence autonomic functioning by binding and inhibiting dopamine D2, α-adrenergic and cholinergic M3 neurotransmitter receptors in the central and peripheral nervous system which, synergistically, may induce these cardiometabolic side-effects100,101.”
From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [101]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredScigliano et al. have proposed a pathogenic hypothesis that centres around autonomic dysfunction due to chronic D2 receptor blockade by APs.
“Scigliano et al.101 have proposed a pathogenic hypothesis that centres around autonomic dysfunction due to chronic D2 receptor blockade by APs.”
From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [101]
Impaired glycemic control, dyslipidemia, hypertension, and increased risk of cardiac arrhythmias are some of the medical sequalae of chronic sympathetic activation.
“Impaired glycemic control, dyslipidemia, hypertension, and increased risk of cardiac arrhythmias are some of the medical sequalae of this chronic sympathetic activation.”
From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [101]
Simultaneous inhibition of muscarinic receptors prevents a reflexive parasympathetic response to maintain autonomic balance.
“Simultaneous inhibition of muscarinic receptors then prevents a reflexive parasympathetic response to maintain autonomic balance.”
From Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health (2021) · cites this paper as [101]
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Correll, C. U., Detraux, J., De Lepeleire, J., & De Hert, M. (2015) · World Psychiatry · doi:10.1002/wps.20204 · Cited by 820 · see citing works
Autonomic nervous system dysfunction in schizophrenia: impact on cognitive and metabolic health
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“Scigliano et al.(101) have proposed a pathogenic hypothesis that centres around autonomic dysfunction due to chronic D2 receptor blockade by APs.”
BackgroundHuang, W., Liu, W., Chen, T., Chen, W., & Huang, W. (2020) · Asia-Pacific Psychiatry · doi:10.1111/appy.12392 · Cited by 10 · see citing works
- Authors
- Scigliano, G., & Ronchetti, G.
- Affiliations
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Corresponding author
- Scigliano, Giulio
- Venue
- CNS Drugs
- Published
- 2013-03-27
- Volume
- 27
- Issue
- 4
- Pages
- 249-257
- ISSN
- 1172-7047 (ISSN-L)
- 1179-1934
- PMC
- PMC3657088
- OpenAlex
- W2091712663
- Cited by
- 92
- References
- 99
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 4 · 2023: 3 · 2022: 9 · 2021: 7 · 2020: 7 · 2019: 13 · 2018: 9 · 2017: 2 · 2016: 6 · 2015: 9 · 2014: 1 · 2013: 1
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- CNS Drugs (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- antipsychotic adverse effects, schizophrenia, metabolic side effects, cardiovascular side effects, atypical antipsychotics, typical antipsychotics, autonomic dysfunction, peripheral dopamine receptors, sympathetic activity, weight gain, hypertension, cardiac arrhythmias, glycolipid metabolism, extrapyramidal symptoms
- MeSH terms
- Animals, Cardiovascular Diseases, Dopamine, Humans, Metabolic Diseases, Quality of Life, Schizophrenia, Antipsychotic Agents
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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