1. ¹Institute of Biotechnology, University of Cambridge, Cambridge, UK
2. ²Laboratory of Molecular Pathophysiology, National Institutes of Mental Health, Bethesda, MD, USA
3. ³Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anesthetics, Faculty of Medicine, Imperial College, London, UK
4. ⁴Department of Biochemistry, University of Cambridge, Cambridge, UK

Correspondence: Dr S Bahn, Institute of Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, Cambridgeshire CB2 1QT, UK. E-mail: sb209@cam.ac.uk

⁵These authors contributed equally to this work.

Received 11 December 2006; Revised 1 October 2007; Accepted 2 October 2007; Published online 5 February 2008.

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 -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.