White Matter Changes in Schizophrenia: Evidence for Myelin-Related Dysfunction

Davis, Kenneth L.; Stewart, Daniel G.; Friedman, Joseph I.; Buchsbaum, Monte; Harvey, Philip D.; Hof, Patrick R.; Buxbaum, Joseph; Haroutunian, Vahram

doi:10.1001/archpsyc.60.5.443

Cited by 793Schizophrenia research and treatmentMental Health and PsychiatryMultiple Sclerosis Research Studies

White Matter Changes in Schizophrenia: Evidence for Myelin-Related Dysfunction

Davis, Kenneth L., Stewart, Daniel G., Friedman, Joseph I., Buchsbaum, Monte, Harvey, Philip D., Hof, Patrick R., Buxbaum, Joseph, Haroutunian, Vahram·2003·Archives of General Psychiatry

DOI 10.1001/archpsyc.60.5.443

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Abstract

Numerous lines of inquiry implicate connectivity as a central abnormality in schizophrenia. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphologic abnormalities in the oligodendroglia demonstrated in schizophrenic brains are all examined in light of the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome.

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In schizophrenia, axon disruption with concurrent reduced myelin levels and oligodendrocyte abnormalities has been postulated as a key pathology based on imaging and postmortem studies.
“In schizophrenia, a severe mental illness characterized by positive (e.g., hallucinations and delusions) and negative (e.g., anhedonia and flat affect) symptoms, axon disruption with concurrent reduced myelin levels and oligodendrocyte abnormalities has been postulated as a key pathology based on both imaging and postmortem studies (Davis et al., 2003;Vikhreva et al., 2016).”
From NODDI in clinical research (2020) · cites this paper as Davis et al., 2003
Oligodendrocytes and myelination are clearly impaired in schizophrenia.
“Oligodendrocytes and myelination are clearly impaired in schizophrenia (Chew et al., 2013; Davis et al., 2003; Takahashi et al., 2011).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Davis et al., 2003

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Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence
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Neural synchrony indexes disordered perception and cognition in schizophrenia
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Automated probabilistic reconstruction of white-matter pathways in health and disease using an atlas of the underlying anatomy
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Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors
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Cerebral White Matter
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Disrupted Modularity and Local Connectivity of Brain Functional Networks in Childhood-Onset Schizophrenia
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Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia
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Neuregulin 1 and Schizophrenia: Genetics, Gene Expression, and Neurobiology
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The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys
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Neuroanatomical abnormalities in schizophrenia: A multimodal voxelwise meta-analysis and meta-regression analysis
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Neuregulin-1/ErbB Signaling Serves Distinct Functions in Myelination of the Peripheral and Central Nervous System
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Schizophrenia, “Just the Facts”: What we know in 2008
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Polarized Domains of Myelinated Axons
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Support for the involvement of large copy number variants in the pathogenesis of schizophrenia.
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Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia
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Association of Genetic Risks for Schizophrenia and Bipolar DisorderWith Specific and Generic Brain Structural Endophenotypes
McDonald, C., Bullmore, E. T., Sham, P. C., Chitnis, X., Wickham, H., Bramon, E., & Murray, R. M. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.10.974 · Cited by 379 · see citing works
Progressive Brain Change in Schizophrenia: A Prospective Longitudinal Study of First-Episode Schizophrenia
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Altered Functional and Anatomical Connectivity in Schizophrenia
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What Happens After the First Episode? A Review of Progressive Brain Changes in Chronically Ill Patients With Schizophrenia
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Evolution of increased glia–neuron ratios in the human frontal cortex
Sherwood, C. C., Stimpson, C. D., Raghanti, M. A., Wildman, D. E., Uddin, M., Grossman, L. I., Goodman, M., Redmond, J. C., Bonar, C. J., Erwin, J. M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605843103 · Cited by 342 · see citing works
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Functional Anatomy of the Inferior Longitudinal Fasciculus: From Historical Reports to Current Hypotheses
Herbet, G., Zemmoura, I., & Duffau, H. (2018) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2018.00077 · Cited by 296 · see citing works
Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia
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The molecular genetics of schizophrenia: new findings promise new insights
Owen, M. J., Williams, N. M., & O’Donovan, M. C. (2003) · Molecular Psychiatry · doi:10.1038/sj.mp.4001444 · Cited by 322 · see citing works
Deficient Hippocampal Neuron Expression of Proteasome, Ubiquitin, and Mitochondrial Genes in Multiple Schizophrenia Cohorts
Altar, C. A., Jurata, L. W., Charles, V., Lemire, A., Liu, P., Bukhman, Y., Young, T. A., Bullard, J., Yokoe, H., Webster, M. J., et al. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.03.031 · Cited by 318 · see citing works
Neuroinflammation and white matter pathology in schizophrenia: systematic review
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The association between autism and schizophrenia spectrum disorders: A review of eight alternate models of co-occurrence
Chisholm, K., Lin, A. P., Abu-Akel, A. M., & Wood, S. J. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.04.012 · Cited by 325 · see citing works
Neuroinflammation in schizophrenia especially focused on the role of microglia
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Critical period revisited: impact on vision
Morishita, H., & Hensch, T. K. (2008) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2008.05.009 · Cited by 311 · see citing works
Excessive Extracellular Volume Reveals a Neurodegenerative Pattern in Schizophrenia Onset
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CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy
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Prenatal Nutritional Deficiency and Risk of Adult Schizophrenia
Brown, A. S., & Susser, E. (2008) · Schizophrenia Bulletin · doi:10.1093/schbul/sbn096 · Cited by 290 · see citing works
NODDI in clinical research
Kamiya, K., Hori, M., & Aoki, S. (2020) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2020.108908 · Cited by 283 · see citing works
“pathology based on both imaging and postmortem studies (Davis et al., 2003; Vikhreva et al., 2016).”
The involvement of Reelin in neurodevelopmental disorders
Folsom, T. D., & Fatemi, S. H. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.08.015 · Cited by 275 · see citing works
Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?
Steullet, P., Cabungcal, J. H., Monin, A., Dwir, D., O'Donnell, P., Cuenod, M., & Do, K. Q. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2014.06.021 · Cited by 262 · see citing works
Excitotoxic damage to white matter
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Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia
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Wrapped to Adapt: Experience-Dependent Myelination
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The thalamus and schizophrenia: current status of research
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DNA Methylation Status ofSOX10Correlates with Its Downregulation and Oligodendrocyte Dysfunction in Schizophrenia
Iwamoto, K., Bundo, M., Yamada, K., Takao, H., Iwayama‐Shigeno, Y., Yoshikawa, T., & Kato, T. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0766-05.2005 · Cited by 243 · see citing works
Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia
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White matter alterations in early stages of schizophrenia: a systematic review of diffusion tensor imaging studies
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Neurodevelopmental and neurodegenerative models of schizophrenia: white matter at the center stage
Kochunov, P., & Hong, L. E. (2014) · Schizophrenia Bulletin · doi:10.1093/schbul/sbu070 · Cited by 236 · see citing works
Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood–CSF barrier dysfunction
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White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis
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Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: A gene ontology study
Katsel, P., Davis, K. L., & HAROUTUNIAN, V. (2005) · Schizophrenia Research · doi:10.1016/j.schres.2005.06.007 · Cited by 223 · see citing works
Self-citation
Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection
Lieberman, J. A., Bymaster, F. P., Meltzer, H. Y., Deutch, A. Y., Duncan, G. E., Marx, C. E., Aprille, J. R., Dwyer, D. S., Li, X., Mahadik, S. P., et al. (2008) · Pharmacological Reviews · doi:10.1124/pr.107.00107 · Cited by 223 · see citing works
Regional thinning of the cerebral cortex in schizophrenia: Effects of diagnosis, age and antipsychotic medication
Nesvåg, R., Lawyer, G., Varnäs, K., Fjell, A. M., Walhovd, K. B., Frigessi, A., Jönsson, E. G., & Agartz, I. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2007.09.015 · Cited by 219 · see citing works
Schizophrenia and the inferior parietal lobule
Torrey, E. F. (2007) · Schizophrenia Research · doi:10.1016/j.schres.2007.08.023 · Cited by 215 · see citing works
Identifying blood biomarkers for mood disorders using convergent functional genomics
Le-Niculescu, H., Kurian, S. M., Yehyawi, N., Dike, C., Patel, S. D., Edenberg, H. J., Tsuang, M. T., Salomon, D. R., Nürnberger, J. I., & Niculescu, A. B. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.11 · Cited by 211 · see citing works
Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy
Bernstein, H., Steiner, J. H., Guest, P. C., Dobrowolny, H., & Bogerts, B. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.03.035 · Cited by 203 · see citing works
Maternal Iron Deficiency and the Risk of Schizophrenia in Offspring
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The Neuropathology of White Matter in Schizophrenia
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Authors: Davis, K. L., Stewart, D. G., Friedman, J. I., Buchsbaum, M., Harvey, P. D., Hof, P. R., Buxbaum, J., & Haroutunian, V.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
ORCID: Davis, Kenneth L.
Friedman, Joseph I.
Buchsbaum, Monte
Harvey, Philip D.
Hof, Patrick R.
Buxbaum, Joseph
Haroutunian, Vahram
Venue: Archives of General Psychiatry
Publisher: American Medical Association (AMA)
Published: 2003-05-01
Volume: 60
Issue: 5
Pages: 443
ISSN: 0003-990X (ISSN-L)
DOI: 10.1001/archpsyc.60.5.443
OpenAlex: W2049973822
Cited by: 793
References: 258
Citations by year: 2026: 9 · 2025: 12 · 2024: 20 · 2023: 11 · 2022: 17 · 2021: 14 · 2020: 25 · 2019: 35 · 2018: 28 · 2017: 27 · 2016: 36 · 2015: 41 · 2014: 34 · 2013: 32 · 2012: 50
FWCI: 24.15
Type: journal article
Language: en
Open access: closed
Locations: Archives of General Psychiatry (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords: schizophrenia, white matter, myelination, oligodendrocytes, myelin, neuronal connectivity, demyelinating disease, oligodendrocyte dysfunction, age-related white matter changes, neuroimaging
MeSH terms: Age Factors, Brain, Demyelinating Diseases, Humans, Myelin Sheath, Nerve Fibers, Myelinated, Oligodendroglia, Schizophrenia, Anisotropy, Cell Death, Protein Array Analysis

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White Matter Changes in Schizophrenia: Evidence for Myelin-Related Dysfunction

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