A Genetic and Behavioral Model for the Human Response to Lithium

描述（由申请人提供）：包括双相情感障碍和单相抑郁症在内的情绪障碍的综合终生人群发病率超过15%。这些人中的许多人没有接受最佳的药物治疗，这是由于预测患者对特定药物的反应能力有限的事实所影响。锂治疗情绪障碍的疗效已被很好地表征。它通常用作情绪稳定剂，在一些患者中用作抗抑郁药或辅助抗抑郁药。然而，尽管广泛的临床应用，锂发挥其治疗作用的确切机制仍然不清楚，哪些患者可以用锂进行最佳治疗。这种知识的缺乏与两个特定的临床问题有关：1)应用药物遗传学方法研究与锂反应相关的基因的能力有限，以及在治疗前预测哪些患者会对锂有反应；2)无法使用假设驱动的方法来改善锂的副作用概况和第二代化合物的窄剂量范围。本研究计划旨在确定动物模型的特征，使未来的研究能够通过实验解决上述问题。近交和远交小鼠通常用于行为药理学领域，以评估生物和遗传变异对药物反应行为模型的影响。这些在不同小鼠品系中表现出的不同行为模式有助于描述受品系依赖的遗传性状影响的基本神经过程和对药物的反应。然而，尽管有超过50年的临床应用和尚未确定的作用机制，使用小鼠品系差异尚未完全用于研究锂的情绪稳定剂和抗抑郁样作用。本R21应用程序的目的是在行为模型中识别并表征对锂治疗表现出不同反应的小鼠品系的行为和药理学特征。具体目的是：1)鉴定具有不同抗抑郁样作用的锂小鼠品系；2)鉴定与锂的不同行为效应相关的锂药代动力学；3)通过对比抗躁狂和抗抑郁疗效模型中的品系差异，评估锂在单个品系中的情绪稳定样作用。通过所提出的研究表征的锂反应的小鼠品系变化可能会直接导致有助于确定锂反应的目标和潜在遗传学的研究。这一新知识最终将导致对患有情绪障碍的患者的治疗进一步优化。公共卫生相关性：尽管临床广泛使用锂治疗情绪障碍，但仍不清楚哪些患者对锂反应最好，以及锂通过何种机制发挥其治疗效果。因此，不可能通过开发共享锂治疗靶点的新型药物来改善锂的副作用和狭窄的剂量范围。本研究计划旨在描述一个模型，该模型将有助于未来的实验研究，确定临床相关靶点和人类对锂反应的潜在遗传学。

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.