Long acting injection versus oral risperidone in first-episode schizophrenia: differential impact on white matter myelination trajectory

Abstract

Context: Imaging and post-mortem studies provide converging evidence that subjects with schizophrenia (SZ) have a dysregulated trajectory of frontal lobe myelination. Prior MRI studies suggested that early in treatment of SZ, antipsychotic medications initially increase frontal lobe white matter (WM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of WM decline associated with chronic disease may be due to medication non-adherence, it may be modifiable by long acting injection (LAI) formulations.

Objectives: Examine the impact of antipsychotic formulation on the myelination trajectory during a randomized six-month trial of LAI risperidone (RLAI) versus oral risperidone (RisO) in first-episode SZ subjects.

Design: Two groups of SZ subjects (RLAI, N=11; and RisO, N=13) that were matched in pre-randomization oral medication exposure and 14 healthy controls (HCs) were prospectively examined. Frontal lobe WM volume was estimated using inversion recovery (IR) MRI images. A brief neuropsychological battery that focused on reaction times was performed at the end of the study.

Main outcome measure: WM volume change scores.

Results: WM volume remained stable in the RLAI and decreased significantly in the RisO groups resulting in a significant differential treatment effect, while the HC had a WM change intermediate and not significantly different from the two SZ groups. WM increase was associated with faster reaction times in tests involving frontal lobe function.

Conclusions: The results suggest that RLAI may improve the trajectory of myelination in first-episode patients and have a beneficial impact on cognitive performance. Better adherence provided by LAI may underlie the modified trajectory of myelin development. In vivo MRI biomarkers of myelination can help clarify mechanisms of action of treatment interventions.

Trial registration: ClinicalTrials.gov NCT00330551.

Figure 1. Quadratic (inverted U) trajectories of human brain myelination over the lifespan

Myelination (Y axis) versus age (X axis) in frontal lobes of normal individuals. Left panel is in vivo data from Bartzokis et al (2001). Right panel shows postmortem intracortical myelin (ICM) stain data from Kaes (1907) adapted and reproduced in Kemper (1994) depicting the heavy myelination of the lower cortical layers. Used with permission. The data were acquired 100 years apart yet the two samples of normal individuals show remarkably similar frontal lobe myelination trajectories, both reaching a peak in the middle of the fifth decade.

Figure 2

Coronal inversion recovery (IR) image of the frontal lobe used to measure myelinated volume. The outer border of the brain and “islands” of lighter material seen in the frontal gray matter are CSF areas that are eliminated from computation using a co-registered T₂ image (not shown here – see Bartzokis et al, 1993).

Figure 3. Covariate adjusted^† mean change scores (SD) of randomized long-acting injectable risperidone consta (RLAI) versus oral risperidone (RisO) treatment in subjects with first-episode schizophrenia

WM = White Matter; GM = Gray Matter Within-Group Test: ** p < .05 Between Group Tests (risperidone long-acting injection (RLAI) vs. oral risperidone (RisO)): * p < .05. ^†Results are based on covariance analyses adjusting for race.

Figure 4. Correlations between medication-related change in white matter (WM) volume and reaction time performance on higher-order executive tasks involving working memory

Figure 4A (left): the relationship between change in WM volume and reaction time on the Two-Back task (a working memory task), Figure 4B (right): the relationship between change in WM volume and reaction time on a Set-Shifting task (a measure of mental flexibility).