Lithium and the Expanding Brain

CORRESPONDENCE Lithium and the Expanding Brain To the Editor: read with great interest the article by Vernon et al. (1) entitled, “Contrasting Effects of Haloperidol and Lithium on Rodent Brain Structure: A Magnetic Resonance Imaging Study with Postmortem Confirmation,” describing their elegant imaging and postmortem study that showed lithium-related increases and haloperidolrelated decreases in whole brain and cortical gray matter volume in rats. Their inclusion of postmortem histological confirmation of in vivo brain volume imaging data is a significant advancement over previous human studies limited to imaging (2– 4). Interestingly, both their imaging and postmortem studies performed 8 weeks following withdrawal of lithium showed that although the 5% increase in whole brain volume attributable to 8 weeks of lithium chloride (LiCl) feeding persisted, the 3% increase in cortical gray matter volume did not. The authors did not have a ready explanation for this discrepancy and acknowledged that the transient increase in cortical gray matter volume could have explanations other than a lithium induced neurotrophic effect, which would be unlikely to vanish after only 8 weeks of lithium withdrawal. One explanation they considered is that the increase in cortical gray matter volume resulted from an increase in tissue water as has been reported in rats following 5 weeks of LiCl feeding (5). They quickly dismissed this possibility because the previous report of a lithium-related 3.1% increase in cortex (CTX) tissue water was in frontal CTX (the only cortical region studied), and their CTX volume increase was a function of statistically significant increases in middle and caudal cortical slices. However, the authors do state that “Li treatment resulted in a significant increase in CTX volume when compared with vehicle (⫹3.3%; p ⬍ .01; Table 2; Figure 2B” and that “closer examination of the cortical slice profile in LiCltreated animals suggests a small, persisting increase across the whole cortical profile.” Therefore, they are clearly making the case that lithium feeding resulted in a transitory increase in cortical gray matter volume generally. The authors mentioned that they intend to follow up on their puzzling finding that cortical volume alterations induced by lithium

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were reversed following drug withdrawal with “further image analysis and corroborative histological work.” I suggest that it would be worthwhile to definitively rule in or out lithium-related increased tissue hydration as an explanation for the cortical gray matter volume expansion by reserving a brain hemisphere to perform some very simple dehydration experiments as previously described (5). Although lithium clearly has neuroprotective and neurotrophic effects, which may be clinically relevant, to date imaging and postmortem studies assessing its effects on cortical gray matter volume or density have been driven by the neurotrophic hypothesis and have not adequately controlled for lithium-associated increases in tissue water. William T. Regenold* Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland. *Corresponding author E-mail: [email protected]. Dr. Regenold reports no biomedical financial interests or potential conflicts of interest. Please also see associated correspondence, http://dx.doi:10.1016/j.biopsych.2012. 04.007.

1. Vernon AC, Natesan S, Crum WR, Cooper JD, Modo M, Williams SC, et al. (2012): Contrasting effects of haloperidol and lithium on rodent brain structure: a magnetic resonance imaging study with postmortem confirmation. Biol Psychiatry 71:855– 863. 2. Bearden CE, Thompson PM, Dalwani M, Hayashi KM, Lee AD, Nicoletti M, et al. (2007): Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry 62:7–16. 3. Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK (2000): Lithium-induced increase in human brain grey matter. Lancet 356:1241–1242. 4. Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, et al. (2002): Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett 329:243–245. 5. Phatak P, Shaldivin A, King LS, Shapiro P, Regenold WT (2006): Lithium and inositol: effects on brain water homeostasis in the rat. Psychopharmacology (Berl)186:41– 47. http://dx.doi.org/10.1016/j.biopsych.2012.03.036

BIOL PSYCHIATRY 2012;72:e17 © 2012 Society of Biological Psychiatry