Brain Metabolic Alterations in Medication-Free Patients With Bipolar Disorder

Arch Gen Psychiatry. 2004 May;61(5):450-8. doi: 10.1001/archpsyc.61.5.450.


Background: Bipolar disorder (BD) has substantial morbidity and incompletely understood neurobiological underpinnings.

Objective: To investigate brain chemistry in medication-free individuals with BD.

Design: Two-dimensional proton echo-planar spectroscopic imaging (PEPSI) (32 x 32, 1-cm(3) voxel matrix) acquired axially through the cingulate gyrus was used to quantify regional brain chemistry.

Setting: The Center for Anxiety and Depression at the University of Washington in Seattle and the Bipolar Research Programs at McLean Hospital and the Massachusetts General Hospital in Boston.

Participants: Thirty-two medication-free outpatients with a diagnosis of BD type I (BDI) or BD type II (BDII), predominantly in a depressed or mixed-mood state, were compared with 26 age- and sex-matched healthy controls.

Main outcome measures: Tissue type (white and gray) and regional analyses were performed to evaluate distribution of lactate; glutamate, glutamine, and gamma-aminobutyric acid (Glx); creatine and phosphocreatine (Cre); choline-containing compounds (Cho); N-acetyl aspartate; and myo-inositol. Chemical relationships for diagnosis and mood state were evaluated.

Results: Patients with BD exhibited elevated gray matter lactate (P =.005) and Glx (P =.007) levels; other gray and white matter chemical measures were not significantly different between diagnostic groups. Isolated regional chemical alterations were found. An inverse correlation between 17-item Hamilton Depression Rating Scale scores and white matter Cre levels was observed for BD patients.

Conclusions: Gray matter lactate and Glx elevations in medication-free BD patients suggest a shift in energy redox state from oxidative phosphorylation toward glycolysis. The possibility of mitochondrial alterations underlying these findings is discussed and may provide a theoretical framework for future targeted treatment interventions.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Ambulatory Care
  • Bipolar Disorder / diagnosis
  • Bipolar Disorder / metabolism*
  • Brain / metabolism*
  • Brain Chemistry*
  • Creatine / metabolism
  • Echo-Planar Imaging
  • Female
  • Glycolysis
  • Gyrus Cinguli / metabolism
  • Humans
  • Lactates / metabolism
  • Lactates / pharmacology
  • Magnetic Resonance Spectroscopy
  • Male
  • Mitochondrial Encephalomyopathies / diagnosis
  • Mitochondrial Encephalomyopathies / metabolism
  • Oxidative Phosphorylation
  • Psychiatric Status Rating Scales
  • gamma-Aminobutyric Acid / metabolism


  • Lactates
  • gamma-Aminobutyric Acid
  • Creatine