The neural diathesis-stress model of schizophrenia revisited: an update on recent findings considering illness stage and neurobiological and methodological complexities
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Over the past decade, our understanding of the role of stress in serious mental illness has become more sophisticated. In this paper, we revisit the neural diathesis-stress model of schizophrenia that was initially proposed in 1997 and updated in 2008. In light of cumulative research findings, we must now encompass evidence on the premorbid periods of psychosis, and our more nuanced understanding of hypothalamic-pituitary-adrenal (HPA) axis function and its association with neurodevelopmental, epigenetic, neurotransmitter, and inflammatory processes, as well as brain structure and function. Giving consideration to the methodological complexities that have become more apparent as research in this area has burgeoned, the various indices of HPA axis function, and the different stages of illness, we review relevant research published since the 2008 update of the model. We conclude by proposing an extended neural diathesis-stress model that addresses the broader neurobiological context of stress psychobiology in psychosis progression. Implications of this model for best practice, with regards to both future research and treatment strategies, are discussed.
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Altered regulation and activity of the neuroendocrine stress response is a key vulnerability factor for the development, maintenance, and exacerbation of psychotic illness.
“Altered regulation and activity of the neuroendocrine stress response is a key vulnerability factor for the development, maintenance, and exacerbation of psychotic illness.”
From Towards an Integrative Account of Potential Mechanisms Mediating the Path From Sleep Dysfunction to Hallucinations (2025) · cites this paper as [65]
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OCT and OCT Angiography Offer New Insights and Opportunities in Schizophrenia Research and Treatment
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- Authors
- Pruessner, M., Cullen, A. E., Aas, M., & Walker, E. F.
- Affiliations
- Douglas Mental Health University Institute (CA)
- King's College London (GB)
- University of Oslo (NO)
- Emory University (US)
- Corresponding author
- Pruessner, Marita
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 73
- Pages
- 191-218
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W2562716042
- Cited by
- 315
- References
- 398
- Citations by year
- 2026: 17 · 2025: 37 · 2024: 33 · 2023: 53 · 2022: 34 · 2021: 32 · 2020: 35 · 2019: 35 · 2018: 26 · 2017: 13
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- National Institutes of Mental Health (UO1MH081988)
- Golden Family foundation, and Canadian Institutes of Health Research (CIHR125913)
- Sir Henry Wellcome Postdoctoral Fellowship (107395/Z/15/Z)
- Waterloo Foundation Child Development (164/1719)
- University of Oslo (#2013088)
- NARSAD Young Investigator (22388)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, hypothalamic-pituitary-adrenal axis, disease stage, brain development, epigenetics, neurotransmitters, neuroinflammation, brain structure and function
- MeSH terms
- Disease Susceptibility, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Psychotic Disorders, Schizophrenia
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