Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder

Seth D. Friedman, Stephen R. Dager, Aimee Parow, Fuyuki Hirashima, Christina Demopulos, Andrew L. Stoll, In Kyoon Lyoo, David L. Dunner, Perry F. Renshaw

Research output: Contribution to journalArticlepeer-review

128 Scopus citations


Background: Prior work reported elevated gray matter (GM) lactate and Glx (glutamate + glutamine + GABA) concentrations in unmedicated patients with bipolar disorder (BP) compared with healthy controls (HC). This study examined whether lithium (Li) and valproic acid (VPA) treatment modulated these chemicals. Methods: A subset of previously reported BP patients were treated with Li (n = 12, 3.6 ± 1.9 months) or VPA (n = 9, 1.4 ± 1.7 months) and compared untreated HC subjects (n = 12, 2.9 ± 2.4 months) using proton echo-planar spectroscopic imaging. Regression analyses (voxel gray/white composition by chemistry) were performed at each time point, and change scores computed. Metabolite relaxation and regions of interest (ROI) were also examined. Results: Across treatment, Li-treated BP subjects demonstrated GM Glx decreases (Li-HC, p =. 08; Li-VPA p =. 04) and GM myo-inositol increases (Li-HC p =. 07; Li-VPA p =. 12). Other measures were not significant. Serum Li levels were positively correlated with Glx decreases at the trend level. Conclusions: Li treatment of BP was associated with specific GM Glx decreases and myo-inositol increases. Findings are discussed in the context of cellular mechanisms postulated to underlie Li and VPA therapeutic efficacy.

Original languageEnglish
Pages (from-to)340-348
Number of pages9
JournalBiological Psychiatry
Issue number5
StatePublished - 1 Sep 2004

Bibliographical note

Funding Information:
This study was supported in part by Grant No. RO1 MH58681 from the National Institute of Mental Health, Bethesda, Maryland, and the Poitras Foundation and the Stanley Foundation Bipolar Disorders Research Center at McLean Hospital, Boston, Massachusetts. Jeffrey Munson, Ph.D. provided helpful discussions on statistical handling for this manuscript.


  • Bipolar disorder
  • glutamate
  • glutamine
  • lithium
  • spectroscopy
  • valproic acid


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