ACC Glu/GABA ratio is decreased in euthymic bipolar disorder I patients: possible in vivo neurometabolite explanation for mood stabilization

Eur Arch Psychiatry Clin Neurosci. 2021 Apr;271(3):537-547. doi: 10.1007/s00406-020-01096-0. Epub 2020 Jan 28.


Bipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (1H-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T 1H-MRS in the dACC (2 × 2 × 4.5 cm3) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood registration: NCT01237158.

Keywords: Anticonvulsants; Bipolar; GABA; GAD1; Glutamate.

MeSH terms

  • Adolescent
  • Adult
  • Anticonvulsants / pharmacology*
  • Antipsychotic Agents / pharmacology*
  • Bipolar Disorder / diagnostic imaging
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / genetics
  • Bipolar Disorder / metabolism*
  • Female
  • Glutamate Decarboxylase / genetics
  • Glutamic Acid / metabolism*
  • Gyrus Cinguli / diagnostic imaging
  • Gyrus Cinguli / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Proton Magnetic Resonance Spectroscopy
  • Young Adult
  • gamma-Aminobutyric Acid / metabolism*


  • Anticonvulsants
  • Antipsychotic Agents
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1

Associated data