Treatment Prediction in Adolescent and Adult Depression

描述(由申请人提供)：尽管有越来越多的证据表明青春期和成人期抑郁症持续存在，临床表现和自然病史相似，但成熟期的差异也得到了强调。具体地说，几项研究报告称，与成年人相比，抑郁症青少年的脑电(EEG)睡眠变化、下丘脑-垂体-肾上腺(HPA)活动和抗抑郁(AD)反应的差异更大。这项建议旨在了解这些发育差异背后的机制(S)，并制定一种策略，用于识别那些可能从一般AD治疗和特别是安非他酮治疗中受益的患者，包括青少年和成年人。基于我们实验室进行的初步研究结果，这项研究建议通过在开始治疗前评估单剂量安非他酮对快速眼动(REM)睡眠和HPA活动的反应来预测抑郁症青少年和成年人对安非他酮缓释剂的AD反应。在完成睡眠和神经内分泌评估后，受试者将接受为期8周的安非他酮缓释临床治疗。除了研究REM睡眠(和HPA)对安非他酮挑战的反应和临床对药物的反应之间的关联强度外，还将获得心理社会措施(特别是应激生活经历和社会支持)，以评估它们对AD反应的贡献，包括单独的和与神经生物学措施相结合的。之所以选择安非他酮，是因为与其他AD化合物(特别是三环类药物和选择性5-羟色胺再摄取抑制剂)相比，安非他酮对REM睡眠的影响相对较小。由其他AD化合物诱导的强大的REM睡眠抑制可能掩盖了个体间的差异；与治疗反应相关的内在敏感性差异可能会由于“天花板效应”而丢失。青少年抑郁症是一个重大的公共卫生问题，不仅关系到年轻人，而且关系到成年人的长期心理健康和社会功能。由于青少年的抑郁症与严重的发病率和死亡率有关，而且由于它标志着相当大比例的成年人进入复发性情绪障碍的大门，因此，青少年抑郁症的早期识别和有效治疗是至关重要的。由于AD药物对发育中的人脑的长期影响尚不清楚，而且最初的治疗会影响随后的治疗依从性和临床病程，因此确定谁将(或将不会)从AD药物治疗中受益是至关重要的。这项研究的结果不仅有助于为青少年开发新的、更有效的AD药物和治疗策略，而且还将加深我们对一些成年抑郁症患者AD反应不足的神经生物学的理解。

DESCRIPTION (provided by applicant): Although there is growing evidence for continuities in adolescent and adult depression, with similarities in clinical presentation and natural history, maturational differences also have been highlighted. Specifically, several studies reported greater variations in electroencephalographic (EEG) sleep changes, hypothalamicpituitary-adrenal (HPA) activity and antidepressant (AD) response in depressed adolescents compared with the findings in adults. This proposal aims to understand the mechanism(s) underlying these developmental differences and to develop a strategy for use in identifying those patients, both youngsters and adults, who might benefit from AD treatment in general, and from bupropion treatment in particular. Based on the results of preliminary studies conducted in our laboratory, this investigation proposes to predict AD response to sustained-release bupropion in depressed adolescents and adults by assessing rapid eye movement (REM) sleep and HPA activity responses to single-dose bupropion administration prior to initiating treatment. Following completion of the sleep and neuroendrocrine assessments, subjects will receive clinical treatment with sustained-release bupropion for 8 weeks. In addition to examining the strength of association between REM sleep (and HPA) response to the bupropion challenge and clinical response to the drug, psychosocial measures (specifically stressful life experiences and social support) will be obtained in order to assess their contribution to AD response, both singly and in combination with the neurobiological measures. Bupropion was selected specifically because of its relatively subtle effects on REM sleep compared with the other AD compounds (tricyclic agents and selective serotonin reuptake inhibitors, in particular). The robust REM sleep suppression induced by the other AD compounds might mask inter-individual variability; inherent differences in sensitivity that relate to treatment response could be lost due to a "ceiling effect". Adolescent depression is a major public health problem that not only relates to the younger population, but also for the long-term mental health and social functioning of adults. Because depression in youngsters is associated with serious morbidity and mortality, and since it marks the gateway into recurrent mood disorders in a large proportion of adults, the early identification and effective treatment of depression in youngsters is of utmost importance. Because the long-term effects of AD agents on the developing human brain are not known, and because initial treatment can influence subsequent treatment compliance and clinical course, the identification of depressed youth who would (or would not) benefit from treatment with AD drugs is crucial. Results of the proposed study should not only be helpful in developing novel and more effective AD drugs and treatment strategies for youngsters, but also will enhance our understanding of the neurobiology of inadequate AD response in some adult patients with depression.