White matter integrity as a predictor of response to treatment in first episode psychosis

Abstract

The integrity of brain white matter connections is central to a patient’s ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response.

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“…On the contrary, at follow-up FA values were generally numerically higher. In line with 2 recent longitudinal studies over 12 weeks that indicated clozapine treatment 51 and mixed antipsychotic treatment 52 improved white matter integrity, our findings support that second-generation antipsychotics may protect against myelin degradation 19,20 or even improve myelination. [53][54][55] Specifically, and consistent with previous observations of functional hyperfrontality in patients with first-episode schizophrenia, our findings could indicate that selective dopamine D2/3 blockade regulate the NMDA receptors, which in turn reduce the putatively elevated and neurotoxic levels of glutamate associated with psychosis.…”

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“…In a prospective design study, Reis Marques et al [61] found that non-responders showed lower FA than both responders and healthy control subjects mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. Interestingly, after 12 weeks of treatment, there was an increase in FA in both responders and non-responders that positively correlated with antipsychotic exposure, raising the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response.…”

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“…Conform the volumetric findings, neurodevelopmental decreased WM integrity in clinical high-risk populations 68,69 , as well as post-onset progression of widespread WM alterations in patients with late stage psychotic disorder 70 has been reported.…”

“…FA increase in mainly the uncinate, cingulum and corpus callosum in first-episode psychotic patients (n=42) after 12 weeks of antipsychotic treatment, whereas FA also positively correlated with AP exposure 68 and iv) widespread FA increase after 12…”

“…Although these environments are risk factors for schizophrenia 68 they have never been examined in relation to cerebral white matter in this patient population. The influence of cannabis on white matter volume in schizophrenia is weak 69,70 but DTI studies have shown both FA increases and decreases in cannabis-using patients with schizophrenia compared to non-using patients 28,71 .…”