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White Matter Deficits Increase Risk of Treatment Resistance in Schizophrenia

Susceptibility to white matter regional deficits in schizophrenia is associated with an increased likelihood of treatment resistance, a new study found. The study sample included 122 patients (mean age 38.2 years) with schizophrenia 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 controls (n=78; mean age 39.2 years). Researchers found:

  • Patients with treatment-resistant symptoms demonstrated the highest white matter regional vulnerability index (RVI), which was significantly higher than the RVI among patients with treatment-responsible symptoms.
  • Patients with schizophrenia showed higher RVI vs healthy control subjects at treatment onset.
  • RVIs were significantly correlated with performance on processing speed and negative symptoms.


Kochunov P, et al. White matter in schizophrenia treatment resistance. [Published online ahead of print July 29, 2019]. Am J Psychiatry. doi: 10.1176/appi.ajp.2019.18101212.


Schizophrenia is a heterogeneous disorder with highly variable outcomes. Unfortunately, some individuals with schizophrenia have a lack of responsivity to standard antipsychotic drugs. Earlier age of onset and more severe cognitive deficits in these individuals suggests both neurodevelopmental and cognitive contributions. Emerging research suggests that refractory illness may be identified by a specific set of biomarkers that could be used to help inform future research as well as clinical care. Findings of this study are consistent with results from some other research data sets and suggest that at least part of the cause of treatment resistance in schizophrenia may lie in white matter deficits. Patients showing a pattern of regional white matter impairment in the late-developing frontal associative fibers and no or limited impairment in the early-developing sensory and motor fibers were more likely to have symptoms that were resistant to standard antipsychotic drugs. Targeting white matter mechanisms could potentially be a fruitful avenue to explore in investigational approaches to treating refractory schizophrenia. —Martha Sajatovic, MD, Professor of Psychiatry and of Neurology; Willard Brown Chair in Neurological Outcomes Research; Director, Neurological and Behavioral Outcomes Center, University Hospitals Cleveland Medical Center; Case Western Reserve University School of Medicine.