Elsevier

Biological Psychiatry

Volume 69, Issue 10, 15 May 2011, Pages 936-944
Biological Psychiatry

Archival Report
Effect of Chronic Antipsychotic Treatment on Brain Structure: A Serial Magnetic Resonance Imaging Study with Ex Vivo and Postmortem Confirmation

https://doi.org/10.1016/j.biopsych.2010.11.010Get rights and content

Background

There is increasing evidence that antipsychotic (APD) may affect brain structure directly. To examine this, we developed a rodent model that uses clinically relevant doses and serial magnetic resonance imaging (MRI), followed by postmortem histopathological analysis to study the effects of APD on brain structures.

Methods

Antipsychotic , haloperidol, and olanzapine were continuously administered to rats via osmotic minipumps to maintain clinic-like steady state levels for 8 weeks. Longitudinal in vivo MRI scanning (T2-weighted) was carried out at baseline, 4 weeks, and 8 weeks, after which animals were perfused and their brains preserved for ex vivo MRI scanning. Region of interest analyses were performed on magnetic resonance images (both in vivo as well as ex vivo) along with postmortem stereology using the Cavalieri estimator probe.

Results

Chronic (8 weeks) exposure to both haloperidol and olanzapine resulted in significant decreases in whole-brain volume (6% to 8%) compared with vehicle-treated control subjects, driven mainly by a decrease in frontal cerebral cortex volume (8% to 12%). Hippocampal, corpus striatum, lateral ventricles, and corpus callosum volumes were not significantly different from control subjects, suggesting a differential effect of APD on the cortex. These results were corroborated by ex vivo MRI scans and decreased cortical volume was confirmed postmortem by stereology.

Conclusions

This is the first systematic whole-brain MRI study of the effects of APD, which highlights significant effects on the cortex. Although caution needs to be exerted when extrapolating results from animals to patients, the approach provides a tractable method for linking in vivo MRI findings to their histopathological origins.

Section snippets

Animals

Male Sprague-Dawley rats (Charles River UK, Ltd., Kent, United Kingdom), initial body weight 240 g to 250 g (9 weeks of age) were housed four per cage under a 12-hour light/dark cycle (7:00 am lights on) with food and water available ad libitum. Room temperature was maintained at 21 ± 2°C and relative humidity at 55 ± 10%. Animals were habituated for 7 days before experimental procedures. Animal experiments were carried out with local ethical approval and in accordance with the Home Office

Plasma Levels and Behavior

Administration of APD by osmotic pump achieved plasma levels (mean ± SD) of 20.58 ± 1.99 ng/mL for HAL and 60.13 ± 20.75 ng/mL for OLZ, respectively. The emergence of VCMs in both HAL and OLZ treated animals by 2 weeks confirmed animals were responding to the APD (Figure 2). However, there was poor correlation (Spearman's ρ = .112; ns) between drug plasma levels and VCM behavior at 8 weeks. The dosing regimen used in this study was tailored to capture clinical practice, i.e., OLZ with a median

Discussion

This is the first in vivo longitudinal study in rodents demonstrating that chronic (8 weeks) APD treatment results in altered brain morphology. We observed a decrease in WBV and CTX volume in rats chronically treated with therapeutically relevant doses of either HAL or OLZ (40, 41). Exposure to either drug resulted in similar reductions in brain volumes, compared with vehicle-treated animals, the magnitude of these effects being 6% to 8% on WBV and 8% to 12% on CTX volume, respectively. The

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    Authors ACV and SN contributed equally to this work.

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