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

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Abstract

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 states.

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Acknowledgements

We would like to thank the members of the Mood Disorders Unit (GRUDA) for their work, as well as the volunteers for their collaboration.

Funding

The Sao Paulo Research Foundation (FAPESP) financed this study (2012/23796-2 and 2010/12286-8).

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Authors and Affiliations

  1. Mood Disorders Unit (GRUDA), School of Medicine (FMUSP), University of São Paulo, São Paulo, Brazil

    Estêvão Scotti-Muzzi, Ricardo Moreno & Márcio Gerhardt Soeiro-de-Souza

  2. Genetics and Pharmacogenetics Unit (PROGENE), School of Medicine (FMUSP), University of São Paulo, São Paulo, Brazil

    Thais Chile, Homero Vallada & Márcio Gerhardt Soeiro-de-Souza

  3. Institute of Radiology (InRad), School of Medicine FMUSP, University of Sao Paulo, São Paulo, Brazil

    Bruno Fraccini Pastorello, Cláudia da Costa Leite & Maria Concepcion Garcia Otaduy

  4. Institute for Biomedical Engineering University and ETH Zurich, Zurich, Switzerland

    Anke Henning

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  1. Estêvão Scotti-Muzzi
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Scotti-Muzzi, E., Chile, T., Moreno, R. et al. 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 271, 537–547 (2021). https://doi.org/10.1007/s00406-020-01096-0

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