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Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

Molecular Psychiatry volume 14, pages 269–279 (2009)Cite this article

Abstract

Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and γ-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

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Acknowledgements

This research was supported by the Stanley Medical Research Institute and the donations of the Stanley brain collection courtesy of Drs Michael B Knable, E Fuller Torrey and Robert H Yolken. Special thanks to Dr Maree Webster for providing post-mortem brain samples. Thanks to all members of the Bahn Laboratory for discussions, help and encouragement. Most of all, thanks to all patients and healthy volunteers for their selfless donation of samples used in this study. MJL is the recipient of an NIH–Cambridge health scholarship and GAMcL is funded by the METAGRAD project (supported by AstraZeneca and Unilever). SB holds a NARSAD Essel Independent Investigator Fellowship.

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  1. M J Lan and G A McLoughlin: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biotechnology, University of Cambridge, Cambridge, UK

    M J Lan, J T J Huang & S Bahn

  2. Laboratory of Molecular Pathophysiology, National Institutes of Mental Health, Bethesda, MD, USA

    M J Lan, P Yuan & H Manji

  3. Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anesthetics, Faculty of Medicine, Imperial College, London, UK

    G A McLoughlin, T M Tsang & E Holmes

  4. Department of Biochemistry, University of Cambridge, Cambridge, UK

    J L Griffin

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  1. M J Lan
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Lan, M., McLoughlin, G., Griffin, J. et al. Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder. Mol Psychiatry 14, 269–279 (2009). https://doi.org/10.1038/sj.mp.4002130

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