Bipolar Affective Disorder (BD) is a common, severe, chronic and life-threatening illness. The discovery of lithium's efficacy revolutionized the treatment of patients with BD, and after more than two decades, lithium continues to be the mainstay of treatment. The effect on the broader community has been highlighted by one estimation that the use of lithium saved the United States US4 billion dollars in a recent year period, by reducing associated medical costs and restoring productivity. However, despite its role as one of psychiatry's most important treatments, lithium's mechanisms of action remain to be fully elucidated. Furthermore, increasing evidence suggests that a significant number of patients respond poorly to lithium therapy, with an estimated 20 percent to 40 percent failing to show an adequate therapeutic response to lithium. Studies such as these indicate two important and highly clinically relevant directions for future research: firstly, the need to better identify patients likely to respond to lithium treatment, and secondly, the necessity to develop more effective treatment regimens. The most widely accepted hypothesis underlying lithium's therapeutic efficacy is the inositol depletion hypothesis. This hypothesis posits that lithium produces a relative depletion of myo-inositol (mI) in critical areas of brain and it is this depletion of a major precursor of the phosphoinositide second messenger system which ultimately results in its therapeutic effects. Despite the attractiveness of the inositol depletion hypothesis, it has never been investigated in BD patients. Thus, there is a clear need to determine if lithium reduces the levels of mI critical brain regions of individuals with BD, and if individual differences in susceptibility to lithium-induced CNS mI reductions represent major factors determining resistance or sensitivity to lithium's therapeutic effects. The proposed research will utilize non-invasive proton magnetic resonance spectroscopy (MRS) technology to determine if lithium treatment alters regional mI concentrations in the human brain. In addition, the research will determine if alterations in brain mI levels are associated with responsiveness to lithium's antidepressants effects. This research offers the potential not only to facilitate in the identification of patients most likely to respond to lithium treatment, but may also facilitate the development of novel therapeutic agents.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Treatment Assessment Review Committee (TA)
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Rudorfer, Matthew V
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Wayne State University
Schools of Medicine
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Moore, Gregory J; Cortese, Bernadette M; Glitz, Debra A et al. (2009) A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry 70:699-705
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Manji, H K; Moore, G J; Chen, G (2000) Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness. J Clin Psychiatry 61 Suppl 9:82-96
Manji, H K; Moore, G J; Rajkowska, G et al. (2000) Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry 5:578-93
Manji, H K; Moore, G J; Chen, G (2000) Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry 48:740-54

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