Micro- and Macrostructural White Matter Integrity in Never-Treated and Currently Unmedicated Patients With Schizophrenia and Effects of Short-Term Antipsychotic Treatment

Abstract

Background: Schizophrenia is associated with progressive white matter changes, but it is unclear whether antipsychotic medications contribute to these. Our objective was to characterize effects of short-term treatment with risperidone on white matter diffusion indices.

Methods: We recruited 42 patients with schizophrenia (30 never treated and 12 currently untreated) and 42 matched healthy control subjects in this prospective case-control neuroimaging study. Patients received a 6-week trial of risperidone. Using diffusion tensor imaging, we assessed microstructural (fractional anisotropy, mean diffusivity, and radial diffusivity) and macrostructural (radial fiber trophy) white matter integrity deficits in unmedicated patients compared with control subjects and change in white matter integrity in patients before and after antipsychotic treatment (mean risperidone dose at end point was 3.73 ± 1.72 mg).

Results: At baseline, fractional anisotropy was decreased in the left medial temporal white matter (cluster extent: 123 voxels; Montreal Neurological Institute peak coordinates: x = -51, y = -44, z = -7; α < .05), and mean diffusivity was increased in the fusiform/lingual gyrus white matter extending to the hippocampal part of the cingulum (cluster extent: 185 voxels; peak coordinates: x = -27, y = -49, z = 2; α < .04) in patients compared with control subjects. Radial diffusivity and macrostructure were not abnormal. None of the diffusion indices showed a significant change after 6 weeks of treatment with both voxelwise and whole-brain white matter analyses.

Conclusions: We demonstrate microstructural white matter integrity abnormalities in the absence of macrostructural impairment in unmedicated patients with primarily early-stage schizophrenia. In our data, we found no significant white matter changes after short-term treatment with risperidone.

Trial registration: ClinicalTrials.gov NCT02034253.

Keywords: Diffusion tensor imaging; Fractional anisotropy; Longitudinal; Mean diffusivity; Radial diffusivity; Treatment response.

Conflict of interest statement

DISCLOSURES

ACL has received an investigator initiated grant from Janssen Pharmaceuticals. All other authors reported no biomedical financial interests or potential conflicts of interest.

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:

Schematic of the diffusion data processing pipeline. Major steps in preprocessing, image registration and statistical analyses are depicted here. The blue color signifies software programs used/ data processing steps applied, the green color signifies quality control steps. Abbreviations: DWI, diffusion weighted image; RMSabs and RMSrel, absolute and relative head motion; FA, fractional anisotropy; MD, mean diffusivity; RD, radial diffusivity

Figure 2:

White matter microstructural integrity abnormalities in never-treated and currently unmedicated patients with schizophrenia (SZ) compared to healthy controls (HC). Fractional anisotropy is decreased in the left medial temporal white matter (cluster extent: 123 voxels, peak: x= −51; y= −44; z= −7; α

Figure 3:

White matter scalar diffusion indices in healthy controls (HC; n= 41) and never treated and currently unmedicated patients with schizophrenia (SZ; n=38). We observed no significant group differences in fractional anisotropy, mean diffusivity, or radial diffusivity. Dots represent individual measurements, and the horizontal lines represent the group mean.

Figure 4:

Individual changes in whole brain white matter scalar diffusion indices in healthy controls (left column; n= 36) after six weeks and patients with schizophrenia (right column, n= 27) after six weeks of treatment with risperidone. We observed no significant changes in fractional anisotropy, mean diffusivity, or radial diffusivity.

Figure 5:

Relationship between Mean Diffusivity in the left fusiform/ lingual gyrus white matter extending to the hippocampal part of the cingulum bundle (cluster extent: 185 voxels, Montreal Neurological Institute (MNI) peak coordinates: x= −27; y= −49; z= 2) in never-treated and currently unmedicated patients with schizophrenia and Brief Psychiatric Rating Scale (BPRS) positive symptom severity.