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Cited by 1,677Schizophrenia research and treatmentMental Health and PsychiatryNeurotransmitter Receptor Influence on Behavior

The neuropathology of schizophrenia

Harrison, Paul J.·1999·Brain
DOI 10.1093/brain/122.4.593
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Abstract

Despite a hundred years' research, the neuropathology of schizophrenia remains obscure. However, neither can the null hypothesis be sustained--that it is a 'functional' psychosis, a disorder with no structural basis. A number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. These are characteristic of schizophrenia as a whole, rather than being restricted to a subtype, and are present in first-episode, unmedicated patients. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries. There are several candidates for the histological and molecular correlates of the macroscopic features. The probable proximal explanation for decreased cortical volume is reduced neuropil and neuronal size, rather than a loss of neurons. These morphometric changes are in turn suggestive of alterations in synaptic, dendritic and axonal organization, a view supported by immunocytochemical and ultrastructural findings. Pathology in subcortical structures is not well established, apart from dorsal thalamic nuclei, which are smaller and contain fewer neurons. Other cytoarchitectural features of schizophrenia which are often discussed, notably entorhinal cortex heterotopias and hippocampal neuronal disarray, remain to be confirmed. The phenotype of the affected neuronal and synaptic populations is uncertain. A case can be made for impairment of hippocampal and corticocortical excitatory pathways, but in general the relationship between neurochemical findings (which centre upon dopamine, 5-hydroxytryptamine, glutamate and GABA systems) and the neuropathology of schizophrenia is unclear. Gliosis is not an intrinsic feature; its absence supports, but does not prove, the prevailing hypothesis that schizophrenia is a disorder of prenatal neurodevelopment. The cognitive impairment which frequently accompanies schizophrenia is not due to Alzheimer's disease or any other recognized neurodegenerative disorder. Its basis is unknown. Functional imaging data indicate that the pathophysiology of schizophrenia reflects aberrant activity in, and integration of, the components of distributed circuits involving the prefrontal cortex, hippocampus and certain subcortical structures. It is hypothesized that the neuropathological features represent the anatomical substrate of these functional abnormalities in neural connectivity. Investigation of this proposal is a goal of current neuropathological studies, which must also seek (i) to establish which of the recent histological findings are robust and cardinal, and (ii) to define the relationship of the pathological phenotype with the clinical syndrome, its neurochemistry and its pathogenesis.

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Authors
Harrison, P. J.
Affiliations
Warneford Hospital (GB)
Corresponding author
Harrison, Paul J.
ORCID
Harrison, Paul J.
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
1999-04
Volume
122
Issue
4
Pages
593-624
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/122.4.593
OpenAlex
W2284323937
Cited by
1,677
References
398
Citations by year
2026: 11 · 2025: 14 · 2024: 13 · 2023: 22 · 2022: 18 · 2021: 27 · 2020: 24 · 2019: 24 · 2018: 28 · 2017: 41 · 2016: 47 · 2015: 56 · 2014: 55 · 2013: 59 · 2012: 59
FWCI
12.99
Type
journal article
Language
en
Open access
closed
Locations
  • Brain (publishedVersion)
  • PubMed (publishedVersion)
Funders
Wellcome Trust
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
schizophrenia, neuropathology, ventriculomegaly, cortical volume, hippocampal volume, temporal lobe, brain asymmetry, neuropil, neuron size, synaptic organization, cognitive impairment, prefrontal cortex, hippocampus, neuronal connectivity, brain development, dopamine, serotonin, glutamate, GABA, gliosis
MeSH terms
Brain, Humans, Schizophrenia, Synapses

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