Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia

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.