Antidepressant Pharmacogenetics of Bipolar Depression

以前的努力，以确定生物学相关的抗抑郁反应在双相情感障碍只取得了一定的成功。抑郁症在多大程度上是由肾上腺素能或其他神经递质异常引起的仍然是一个悬而未决的问题。此外，标准抗抑郁药对双相抑郁症的疗效可能不如单相抑郁症，并对诱发躁狂或周期加速造成独特的风险。因此，迫切需要开发新的方法来更好地预测治疗结果。该职业发展奖的重点是为P.I.提供转化研究和培训经验。精神遗传学在双相情感障碍的精神病理学和治疗结果的临床研究中的应用。作为这类研究的一个模型，将在一个以家庭为基础的队列中研究抗-β-羟色胺反应的药物遗传学相关性，重点是5-羟色胺系统候选基因多态性。虽然初步研究已经确定了具有对精神病理学或精神药物作用具有重要意义的多态性的候选基因，但药物遗传学在双相情感障碍中的应用在很大程度上尚未探索。拟议的核心研究项目将是双相情感障碍系统治疗增强计划（STEP-BD）的辅助研究，这是一项NIMH申办的多临床试验。最初将从至少100名抑郁先证者和家庭成员中获得DNA样本;已经对丙戊酸盐或锂进行优化的先证者将接受为期6周的5-羟色胺再摄取抑制剂试验。在奖励期的后几年，将从合作研究中心的数百名双相先证者中添加基于家族的基因型和SSRI抗抑郁药反应数据。将相对于已知功能意义的4个阿托宁相关多态性候选基因的等位基因频率分析抗抑郁反应性。将开发多变量模型，以评估药物遗传学多态性添加到可能与治疗应答相关的临床因素中的相对统计学贡献。职业发展计划的主要目标是为PI。获得人类遗传学和候选基因多态性分析的专业知识，以便为未来的精神药物反应和可能代表双相情感障碍表型的精神病理学其他方面的临床研究提供信息。

Previous efforts to identify biological correlates of anti-depressant response in bipolar disorder have yielded only modest success. The degree to which depression arises from serotonergic or other neurotransmitter abnormalities remains an unsolved question. Moreover, standard anti-depressants may be less effective for bipolar than unipolar depression and pose unique risks for inducing mania or cycle acceleration. Therefore, a compelling need exists to develop new methodologies to better anticipate treatment outcomes. The focus of this Career Development Award is to provide a translational research and training experience for the P.I. in applications of psychiatric genetics to clinically-based studies of psychopathology and treatment outcome in bipolar illness. As a model for this type of research, pharmacogenetic correlates of anti-depressant response, focusing on serotonin system candidate gene polymorphisms, will be examined in a family-based cohort. While preliminary studies have identified candidate genes with polymorphisms of significance to psychopathology, or psychotropic drug action, pharmacogenetic applications ti bipolar disorder remain largely unexplored. The proposed core research project will be an ancillary study to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), an NIMH-sponsored multi-clinical trial. DNA samples will initially be obtained from a minimum of 100 depressed probands and family members; probands already optimized on valproate or lithium will undergo a 6-week trial of a serotonin reuptake inhibitor. In later years of the Award period, family-based genotype and SSRI antidepressant response data will be added from several hundred additional bipolar probands at collaborative research sites. Antidepressant responsivity will be analyzed relative to allele frequencies of 4 serotonin-related polymorphic candidate genes of known functional significance. Multivariate models will be developed to assess the relative statistical contribution of pharmacogenetic polymorphisms added to clinical factors potentially associated with treatment response. The primary aim of the career development plan is for the P.I. to acquire expertise in human genetics and candidate gene polymorphism analyses in order to inform future clinical studies of psychotropic drug response and other aspects of psychopathology that may represent phenotypes of bipolar disorder.