Background
Magnetic resonance imaging (MRI) studies suggest that antipsychotic -treated patients
with schizophrenia show a decrease in gray-matter volumes, whereas lithium-treated
patients with bipolar disorder show marginal increases in gray-matter volumes. Although
these clinical data are confounded by illness, chronicity, and other medications,
they do suggest that typical antipsychotic drugs and lithium have contrasting effects
on brain volume.
Methods
Rodent models offer a tractable system to test this hypothesis, and we therefore examined
the effect of chronic treatment (8 weeks) and subsequent withdrawal (8 weeks) with
clinically relevant dosing of an antipsychotic (haloperidol, HAL) or lithium (Li)
on brain volume using longitudinal in vivo structural MRI and confirmed the findings
postmortem using unbiased stereology.
Results
Chronic HAL treatment induced decreases in whole brain volume (−4%) and cortical gray
matter (−6%), accompanied by hypertrophy of the corpus striatum (+14%). In contrast,
chronic Li treatment induced increases in whole-brain volume (+5%) and cortical gray
matter (+3%) without a significant effect on striatal volume. Following 8 weeks of
drug withdrawal, HAL-induced changes in brain volumes normalized, whereas Li-treated
animals retained significantly greater total brain volumes, as confirmed postmortem.
However, the distribution of these contrasting changes was topographically distinct:
with the haloperidol decreases more prominent rostral, the lithium increases were
more prominent caudal.
Conclusions
The implications of these findings for the clinic, potential mitigation strategies,
and further drug development are discussed.
Key Words
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Article info
Publication history
Published online: January 16, 2012
Accepted:
December 1,
2011
Received in revised form:
November 22,
2011
Received:
September 28,
2011
Footnotes
Authors ACV and SN contributed equally to this work.
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
