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.
Highlights
METHODThis is a narrative review examining the possible role of WM in treatment resistant schizophrenia and its putative utility as a therapeutic target
Decreased fractional anisotropy (FA) in the splenium correlated to illness duration (Holleran et al, 2014) and treatment resistance in this study was defined as failure to respond to two antipsychotic medications and prolonged period of moderate to severe symptoms as defined by the PANSS (Kay et al, 1987)
Six samples were from treatment resistant subjects and 6 samples were from treatment responsive individuals and these were compared to 9 normal controls. Though this is a small sample size study, tissue from the substantia nigra of treatment resistant patients showed aberrant myelination characterized by increased G ratio, axons without cytoplasm, and protrusions into the myelin sheath (Walker et al, 2018). The patients in both groups had an average duration of disease of 24 years so while treatment exposure is likely to have been different between groups, these results suggest cellular level changes that may be integral to treatment resistance
Summary
This is a narrative review examining the possible role of WM in treatment resistant schizophrenia and its putative utility as a therapeutic target. Examples that are relevant to treatment resistance but did not study it directly, include a recent DTI study that has shown cingulum bundle WM changes in chronic schizophrenia that may be associated with persistent delusions (Oestreich et al, 2016) Another recent study showed severity of psychotic symptoms in hospitalized patients was related to reductions in WM volume measured by T1 structural MRI imaging in the medial portion of the left superior frontal area (Banaj et al, 2018). 26 resistant with auditory verbal hallucinations 12 resistant with persistent negative symptoms but no hallucinations
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