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.
Highlights
Response to treatment in first episode of psychosis is heterogeneous, with approximately 55% of patients responding to antipsychotics in the first 12 months (Boter et al, 2009)
The first study, in a small sample, showed that patients with chronic schizophrenia who responded to antipsychotics (n = 8), as assessed 28 days after the brain imaging, had reduced white matter microstructural integrity compared with nonresponders (n = 5), who were in turn no different from control subjects (Garver et al, 2008)
We examined differences in white matter microstructural integrity at baseline between responders and non-responders, and found that non-responders had significantly lower fractional anisotropy across multiple brain regions when compared to responders (P 5 0.05; FWE-corrected) (Fig. 2A)
Summary
Response to treatment in first episode of psychosis is heterogeneous, with approximately 55% of patients responding to antipsychotics in the first 12 months (Boter et al, 2009). Two cross-sectional studies, suggested an association between less extensive fractional anisotropy reductions and subsequent good clinical outcome, in the wholebrain and along tracts such as the uncinate and the superior longitudinal fasciculus (Mitelman et al, 2006; Luck et al, 2011). These studies did not perform a second evaluation of white matter at follow-up. These questions can be best addressed by investigating patients with first episode psychosis, where treatment has occurred for only a short time, and the additional effect of illness duration on brain white matter is less likely to be present
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