A Genetic and Behavioral Model for the Human Response to Lithium

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DESCRIPTION (provided by applicant): The combined lifetime population incidence of mood disorders, including bipolar disorder and unipolar depression, is over 15%. Many of these individuals do not receive optimized pharmacological treatment, which is influenced by the fact that the ability to predict patients who will respond to a particular drug is limited. The therapeutic efficacy of lithium for the treatment of mood disorders is well characterized. It is commonly used as a mood stabilizer, and in some patients as an antidepressant or adjunct antidepressant. However, despite extensive clinical use, it remains unclear exactly by what mechanism lithium exerts its therapeutic effects, and which patients can be optimally treated with lithium. This lack of knowledge is related to two specific clinical problems: 1) a restricted capacity to apply pharmacogenetic approaches to study genes associated with lithium response as well as predict prior to treatment which patients will respond to lithium, and 2) an inability to use a hypothesis driven approach to improve upon lithium's side- effect profile and narrow dose range with second-generation compounds. This research proposal is designed to characterize an animal model that will allow future studies to experimentally address the above problems. Inbred and outbred mice are commonly utilized in the field of behavioral pharmacology to evaluate effects of biological and genetic variations in behavioral models of medication responses. These differential behavioral patterns that manifest in different mouse strains have assisted in the characterization of essential neural processes and response to medications that are influenced by strain-dependent inheritable traits. However, despite over 50 years of clinical use and an unidentified mechanism of action, the use of mouse strain differences has not yet been fully employed in the study of the mood stabilizer- and antidepressant-like effects of lithium. The objective in this R21 application is to identify, and characterize behaviorally and pharmacologically, strains of mice that manifest distinct responses to lithium treatment in behavioral models. The Specific Aims are to: 1) Identify strains of mice with differential antidepressant-like effects of lithium, 2) Identify lithium pharmacokinetic correlates to the differential behavioral effects of lithium, and 3) Assess the mood stabilizer-like actions of lithium in individual strains by contrasting strain variation in models of antimanic vs. antidepressant efficacy. The mouse strain variations in lithium response characterized through the proposed research will likely lead directly to studies that will help define the target, and the underlying genetics, of lithium response. This new knowledge would ultimately lead to further optimization of treatment for patients who suffer from mood disorders. PUBLIC HEALTH RELEVANCE: Despite extensive clinical use of lithium for the treatment of mood disorders it remains unclear which patients will respond best to lithium and by what mechanism lithium exerts its therapeutic effects. It has therefore not been possible to improve upon lithium's side- effect profile and narrow dose range by developing novel medications that share the therapeutic target of lithium. This research proposal is designed to characterize a model that will assist future studies in experimentally determining the clinically relevant targets and underlying genetics of human response to lithium.