1. ¹Laboratory of Molecular Pathophysiology, Department of Health and Human services, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
2. ²College of Physicians and Surgeons, Columbia University, New York, NY, USA
3. ³Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan

Correspondence: Dr HK Manji, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institute of Health, Department of Health and Human Services, Building 35, 1C-912, 35 Convent Drive, Bethesda, MD 20892, USA. Tel: +1 301 496 9802; Fax: +1 301 480 0123; E-mail: manji@nih.gov

⁴These authors contributed equally to this work

Received 18 September 2007; Revised 15 December 2007; Accepted 15 December 2007; Published online 30 January 2008.

Abstract

Bipolar disorder (BPD) has traditionally been conceptualized as a neurochemical disorder, but there is mounting evidence for impairments of cellular plasticity and resilience. Here, we review and synthesize the evidence that critical aspects of mitochondrial function may play an integral role in the pathophysiology and treatment of BPD. Retrospective database searches were performed, including MEDLINE, abstract booklets, and conference proceedings. Articles were also obtained from references therein and personal communications, including original scientific work, reviews, and meta-analyses of the literature. Material regarding the potential role of mitochondrial function included genetic studies, microarray studies, studies of intracellular calcium regulation, neuroimaging studies, postmortem brain studies, and preclinical and clinical studies of cellular plasticity and resilience. We review these data and discuss their implications not only in the context of changing existing conceptualizations regarding the pathophysiology of BPD, but also for the strategic development of improved therapeutics. We have focused on specific aspects of mitochondrial dysfunction that may have major relevance for the pathophysiology and treatment of BPD. Notably, we discuss calcium dysregulation, oxidative phosphorylation abnormalities, and abnormalities in cellular resilience and synaptic plasticity. Accumulating evidence from microarray studies, biochemical studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of BPD. We propose that although BPD is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role in various facets of BPD, and that enhancing mitochondrial function may represent a critical component for the optimal long-term treatment of the disorder.