Diseases of White Matter and Schizophrenia-Like Psychosis

Walterfang, Mark; Wood, Stephen J.; Velakoulis, Dennis; Copolov, David L.; Pantelis, Christos

doi:10.1080/j.1440-1614.2005.01678.x

Cited by 78 publications

(37 citation statements)

References 140 publications

(209 reference statements)

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“…5 This novel finding advanced our current knowledge revealed by multiple lines of evidence implicating abnormal Oligs and myelin in schizophrenia. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Also, it is consistent with the clinical observation that QUE has direct effects on negative symptoms and cognitive deficits of patients with schizophrenia. 46,47 Indeed, the alterations in white matter have been considered to be associated with the negative symptoms of schizophrenia.…”

Section: Discussionsupporting

confidence: 77%

“…Moreover, a number of white matter disorders are associated with schizophrenia-like psychosis at a rate greater than chance. 15 Given that oligodendrocytes (Oligs) are myelinforming cells in the brain, it is unlikely that Oligs are spared in schizophrenia. In fact, as early as 1938, swollen Oligs were observed in schizophrenia brains postmortem.…”

Section: Introductionmentioning

confidence: 99%

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Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes

et al. 2007

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Recent neuroimaging and postmortem studies have reported abnormalities in white matter of schizophrenic brains, suggesting the involvement of oligodendrocytes in the etiopathology of schizophrenia. This view is being supported by gene microarray studies showing the downregulation of genes related to oligodendrocyte function and myelination in schizophrenic brain compared to control subjects. However, there is currently little information available on the response of oligodendrocytes to antipsychotic drugs (APDs), which could be invaluable for corroborating the oligodendrocyte hypothesis. In this study we found: (1) quetiapine (QUE, an atypical APD) treatment in conjunction with addition of growth factors increased the proliferation of neural progenitors isolated from the cerebral cortex of embryonic rats; (2) QUE directed the differentiation of neural progenitors to oligodendrocyte lineage through extracellular signal-related kinases; (3) addition of QUE increased the synthesis of myelin basic protein and facilitated myelination in rat embryonic cortical aggregate cultures; (4) chronic administration of QUE to C57BL/6 mice prevented cortical demyelination and concomitant spatial working memory impairment induced by cuprizone, a neurotoxin. These findings suggest a new neural mechanism of antipsychotic action of QUE, and help to establish a role for oligodendrocytes in the etiopathology and treatment of schizophrenia.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes

et al. 2007

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“…Recent studies have shown that myelination is essential for social experience-based cognition and motor skill learning [31][32][33] [34][35][36] , abnormalities of the myelin sheath may contribute to defects of neuronal function. Increasing evidence has shown that the impairment of white matter integrity is prominent in schizophrenic brains [10,11,14,15] and further underscores the importance of the myelin sheath in schizophrenia, pointing to myelin repair as a potential therapeutic strategy for schizophrenia. In support of this notion, quetiapine, an atypical anti-schizophrenic drug, has been found to be potent in promoting the differentiation of OLs in vitro and enhancing remyelination in mouse models of demyelination [17][18][19][20] .…”

Section: Resultsmentioning

confidence: 99%

“…More importantly, properly myelinated nerve fibers allow precise and accurate information to fl ow within and between neuronal circuits [3,8,9] . A number of imaging studies have shown that the white matter volume of schizophrenic brains is lower than in healthy controls, suggesting that myelin sheath damage or demyelination is involved in the schizophrenic brain [10][11][12][13][14][15] . In line with this hypothesis, microarray analyses have shown that genes down-regulated in schizophrenic brains are related to OL development and myelination, arguing that myelin repair may be an unmet need that has been overlooked in therapies for schizophrenia [16] .…”

Section: Introductionmentioning

confidence: 99%

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

et al. 2015

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Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open fi eld test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our fi ndings indicate that enhancing remyelination may be a potential therapy for schizophrenia.

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“…The importance of human brain myelination has been generally underappreciated, but recently a conceptual "myelin model" has served to correct this gap in our knowledge and provide novel and testable approaches to treatment and prevention efforts (Bartzokis, 2002;Bartzokis, 2004b;Bartzokis, 2005;Walterfang et al, 2005;Woo and Crowell, 2005). The advent of in vivo neuroimaging methods that can assess myelination on a regional basis may have direct applications in medication development (Bartzokis, 2004a;Bartzokis et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia

Bartzokis

Nuechterlein

et al. 2007

Schizophrenia Research

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Context-Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination even in adulthood. Atypical antipsychotics have been shown to have a wide spectrum of efficacy across multiple psychiatric diseases and to be particularly efficacious in treatment resistant cases of disorders such as schizophrenia.Objective-To test the a priori hypothesis that antipsychotic medications may differentially impact frontal lobe myelination in patients with schizophrenia.Design, setting, and participants-Participants ranged in age from 18-35 years, were all male, and were recruited by a single group of investigators using the same criteria. Two cohorts of subjects with schizophrenia early in their disease who were treated either with oral risperidone (Ris) or fluphenazine decanoate (Fd) were imaged in conjunction with cohorts of healthy controls. Each cohort was imaged using a different MRI instrument using identical imaging sequences. Main outcome measure-MRI measures of frontal lobe white matter volume.Results-We estimated differences due to differences in the MRI instruments used in the two studies in the two healthy control groups matched to the patient samples, adjusting for age and other covariates. We then statistically removed those differences (which we assumed were instrument artifacts) from the data in the schizophrenia samples by subtraction. Relative to the differences seen in controls, the two groups of schizophrenic patients differed in their pattern of frontal lobe structure with the Ris-treated group having significantly larger white matter volume than the Fd group.

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Diseases of White Matter and Schizophrenia-Like Psychosis

Cited by 78 publications

References 140 publications

Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes

Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia

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