Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia

Abstract

Context: Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination even in adulthood. Atypical antipsychotics have been shown to have a wide spectrum of efficacy across multiple psychiatric diseases and to be particularly efficacious in treatment resistant cases of disorders such as schizophrenia.

Objective: To test the a priori hypothesis that antipsychotic medications may differentially impact frontal lobe myelination in patients with schizophrenia.

Design, setting, and participants: Participants ranged in age from 18-35 years, were all male, and were recruited by a single group of investigators using the same criteria. Two cohorts of subjects with schizophrenia early in their disease who were treated either with oral risperidone (Ris) or fluphenazine decanoate (Fd) were imaged in conjunction with cohorts of healthy controls. Each cohort was imaged using a different MRI instrument using identical imaging sequences.

Main outcome measure: MRI measures of frontal lobe white matter volume.

Results: We estimated differences due to differences in the MRI instruments used in the two studies in the two healthy control groups matched to the patient samples, adjusting for age and other covariates. We then statistically removed those differences (which we assumed were due to instrument effects) from the data in the schizophrenia samples by subtraction. Relative to the differences seen in controls, the two groups of schizophrenic patients differed in their pattern of frontal lobe structure with the Ris-treated group having significantly larger white matter volume than the Fd group.

Conclusions: The results suggest that the choice of antipsychotic treatment may differentially impact brain myelination in adults with schizophrenia. Prospective studies are needed to confirm this finding. MRI can be used to dissect subtle differences in brain tissue characteristics and thus could help clarify the effect of pharmacologic treatments on neurodevelopmental and pathologic processes in vivo.

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 figure is in vivo data from Bartzokis et al (2001) where an inversion recovery sequence was used to assess white matter volume. Right figure shows post-mortem intracortical myelin stain data from Kaes (1907), [adapted and reproduced in Kemper (1994)]. 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 at age 45.

Figure 2

Inversion recovery (IR) image used to measure myelinated volume in the frontal lobe. 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. Frontal Lobe Volume Residual z-scores in Male Subjects with Schizophrenia Receiving a Typical or Atypical Antipsychotic Medication

WM = Frontal lobe white matter; GM = Frontal lobe gray matter. Between Group Tests (risperidone vs. fluphenazine): † P < 0.05. Within Group Tests (schizophrenic vs. healthy controls, standardized to mean = 0 and SD = 1): *P < 0.05, **P < .05, ***P < .001.