Bipolar disorder (BD) is a highly heritable neurobehavioral disorder that affects ~1 % of the global population and constitutes one of the most significant causes of death and disability in the world today. Lithium was first used to treat mania in 1949 and has remained the mainstay treatment of Bipolar disorder for the last 30 years, proving effective for as many as -50% of treated cases. However, despite lithium's demonstrated efficacy, at least half of cases do not respond positively to treatment, and toxicity is a critical concern requiring routine monitoring of several biological parameters in patients. The few alternative treatments that exist, such as Valproate, do not present improved success rates in clinical settings or comparative trials. Despite decades of concerted research, lithium's mode of efficacy remains unknown. Recent technological and conceptual developments in genomics and chemistry currently enable powerful approaches to drug discovery that have the potential to radically improve the processes of target identification, compound discovery, and drug development. In the present study, we propose the application of chemical genomics to the elucidation of lithium's therapeutic mode of action and the discovery of novel compounds for the treatment of BD. The effort will take advantage of emerging methodologies entailing the definition of expression signatures, high-throughput screening of chemical libraries in cell-based assays to recapitulate those signatures, followed by characterization of small molecule leads using morphological and other cellular assays. We hypothesize that in cellulo definition of targeted molecular pathways will identify the primary cellular processes that mediate lithium's efficacy and isolate compounds with high rational potential for drug development. Notably, any resolution of lithium's mode of action will likely indicate genetic pathways underlying the molecular etiology of the common disease state. While we intend to delineate the molecular pathways targeted by lithium and the resultant cellular effects, a driving focus of this proposal is the rapid identification of novel compounds with the potential for development of therapeutic drugs and highly specific reagents for experimental dissection of pathways relevant to psychiatric disorders.
