Antidepressant Pharmacogenetics of Bipolar Depression

以前在双相情感障碍中识别抗抑郁反应的生物学相关性的努力只取得了不大的成功。5-羟色胺能或其他神经递质异常在多大程度上导致抑郁症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的疗效可能不如单相抑郁，并对诱发躁狂或周期加速具有独特的风险。因此，迫切需要开发新的方法来更好地预测治疗结果。这一职业发展奖的重点是为私人投资者提供一种转化研究和培训经验，将精神遗传学应用于双相情感障碍的精神病理学和治疗结果的临床研究。作为这类研究的模型，抗抑郁反应的药物遗传学相关性，重点是5-羟色胺系统候选基因的多态，将在基于家庭的队列中进行检验。虽然初步研究已经确定了对精神病理学或精神药物作用具有重要意义的候选基因，但双相情感障碍的药物遗传学应用在很大程度上仍未被探索。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，STEP-BD是一项由NIMH赞助的多临床试验。DNA样本最初将从至少100名抑郁的先证者和家庭成员中获得；已经使用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的试验。在获奖期的后几年，基于家庭的基因和SSRI抗抑郁药物反应数据将从合作研究地点的数百名额外的双相先证者中增加。抗抑郁反应性将与4个已知功能意义的5-羟色胺相关多态候选基因的等位基因频率进行分析。将开发多变量模型来评估药物遗传多态对可能与治疗反应相关的临床因素的相对统计学贡献。职业发展计划的主要目标是让私人侦探获得人类遗传学和候选基因多态分析方面的专业知识，以便为未来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.