Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania

Biol Psychiatry. 2008 Oct 15;64(8):718-726. doi: 10.1016/j.biopsych.2008.05.014. Epub 2008 Jul 7.


Background: At excitatory synapses, glutamate released from neurons is taken up by glial cells and converted to glutamine, which is cycled back to neurons. Alterations in this system are believed to play a role in the pathophysiology of bipolar disorder, but they have not been characterized in vivo. We examined the glutamine/glutamate ratio and levels of other metabolites in acute mania and schizophrenia in this exploratory study.

Methods: Data were obtained from 2 x 2 x 2 cm voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 Tesla and analyzed using LCModel. Fifteen bipolar disorder patients with acute mania and 17 schizophrenia patients with acute psychosis were recruited from an inpatient unit; 21 matched healthy control subjects were also studied. Glutamine/glutamate ratio and N-acetylaspartate, creatine, choline, and myo-inositol levels were evaluated in a repeated measures design. Medication effects and relationship to demographic and clinical variables were analyzed.

Results: Glutamine/glutamate ratio was significantly higher in ACC and POC in bipolar disorder, but not schizophrenia, compared with healthy control subjects. N-acetylaspartate was significantly lower in the ACC in schizophrenia. Patients on and off lithium, anticonvulsants, or benzodiazepines had similar glutamine/glutamate ratios.

Conclusions: The elevated glutamine/glutamate ratio is consistent with glutamatergic overactivity and/or defective neuronal-glial coupling in acute mania, although medication effects cannot be ruled out. Abnormalities in glutamatergic neurotransmission and glial cell function in bipolar disorder may represent targets for novel therapeutic interventions.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / metabolism
  • Bipolar Disorder / metabolism*
  • Case-Control Studies
  • Cerebral Cortex / metabolism*
  • Female
  • Glutamic Acid / metabolism*
  • Glutamine / metabolism*
  • Gyrus Cinguli / metabolism
  • Humans
  • Magnetic Resonance Imaging
  • Magnetic Resonance Spectroscopy
  • Male
  • Matched-Pair Analysis
  • Neuroglia / metabolism
  • Neurons / metabolism
  • Neurotransmitter Agents / metabolism
  • Occipital Lobe / metabolism
  • Parietal Lobe / metabolism
  • Pilot Projects
  • Reference Values
  • Schizophrenia / metabolism*
  • Synaptic Transmission / physiology
  • Young Adult


  • Neurotransmitter Agents
  • Glutamine
  • Aspartic Acid
  • Glutamic Acid
  • N-acetylaspartate