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Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia.

ABSTRACT: Despite development of comprehensive approaches to treat schizophrenia and other psychotic disorders and improve outcomes, there remains a proportion (approximately one-third) of patients who are treatment resistant and will not have remission of psychotic symptoms despite adequate trials of pharmacotherapy. This level of treatment response is stable across all stages of the spectrum of psychotic disorders, including early phase psychosis and chronic schizophrenia. Our current pharmacotherapies are beneficial in decreasing positive symptomology in most cases, however, with little to no impact on negative or cognitive symptoms. Not all individuals with treatment resistant psychosis unfortunately, even benefit from the potential pharmacological reductions in positive symptoms. The existing pharmacotherapy for psychosis is targeted at neurotransmitter receptors. The current first and second generation antipsychotic medications all act on dopamine type 2 receptors with the second generation drugs also interacting significantly with serotonin type 1 and 2 receptors, and with varying pharmacodynamic profiles overall. This focus on developing dopaminergic/serotonergic antipsychotics, while beneficial, has not reduced the proportion of patients experiencing treatment resistance to date. Another pharmacological approach is imperative to address treatment resistance both for response overall and for negative symptoms in particular. There is research suggesting that changes in white matter integrity occur in schizophrenia and these may be more associated with cognition and even negative symptomology. Here we review the evidence that white matter abnormalities in the brain may be contributing to the symptomology of psychotic disorders. Additionally, we propose that white matter may be a viable pharmacological target for pharmacoresistant schizophrenia and discuss current treatments in development for schizophrenia that target white matter.

SUBMITTER: Crocker CE

PROVIDER: S-EPMC6201564 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia.

Crocker Candice E CE Tibbo Philip G PG

Frontiers in pharmacology 20181018

Despite development of comprehensive approaches to treat schizophrenia and other psychotic disorders and improve outcomes, there remains a proportion (approximately one-third) of patients who are treatment resistant and will not have remission of psychotic symptoms despite adequate trials of pharmacotherapy. This level of treatment response is stable across all stages of the spectrum of psychotic disorders, including early phase psychosis and chronic schizophrenia. Our current pharmacotherapies ...[more]

PMID: 30405407

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Project description:ObjectiveFailure of antipsychotic medications to resolve symptoms in patients with schizophrenia creates a clinical challenge that is known as treatment resistance. The causes of treatment resistance are unknown, but it is associated with earlier age at onset and more severe cognitive deficits. The authors tested the hypothesis that white matter deficits that are involved in both neurodevelopment and severity of cognitive deficits in schizophrenia are associated with a higher risk of treatment resistance.MethodsThe study sample (N=122; mean age, 38.2 years) included schizophrenia patients at treatment initiation (N=45), patients whose symptoms were treatment responsive (N=40), and patients whose symptoms were treatment resistant (N=37), as well as healthy control subjects (N=78; mean age, 39.2 years). White matter regional vulnerability index (RVI) was tested as a predictor of treatment resistance and cognitive deficits. Higher RVI is indicative of better agreement between diffusion tensor imaging fractional anisotropy across the brain in an individual and the pattern identified by the largest-to-date meta-analysis of white matter deficits in schizophrenia.ResultsPatients with treatment-resistant symptoms showed the highest white matter RVI (mean=0.38 [SD=0.2]), which was significantly higher than the RVI among patients with treatment-responsive symptoms (mean=0.30 [SD=0.02]). At the onset of treatment, schizophrenia patients showed significantly higher RVI than healthy control subjects (mean=0.18 [SD=0.03] and mean=0.13 [SD=0.02], respectively). RVIs were significantly correlated with performance on processing speed and negative symptoms.ConclusionsSchizophrenia affects white matter microstructure in specific regional patterns. Susceptibility to white matter regional deficits is associated with an increased likelihood of treatment resistance. Developments to overcome schizophrenia treatment resistance should consider white matter as an important target.

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Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia.

Publications

Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia.

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