Methylphenidate Use to Improve Outcomes in Geriatric Depression

描述（由申请人提供）：只有不到50%的老年抑郁症患者通过一线抗抑郁药物治疗获得缓解和功能恢复。大多数患者留下了明显的残余症状，使他们面临慢性、复发性疾病、虚弱和自杀的风险。提高对老年抑郁症的神经生物学和治疗反应机制的理解可能会改善这种普遍和致残性疾病的临床管理。虽然5 -羟色胺系统一直是单极重性抑郁症药物治疗的重点，但研究其他单胺系统也有令人信服的理由。即使在抑郁症状改善后，执行功能的损害仍然存在，并且这些症状对单独的血清素能治疗反应较差。我们假设，在血清素能药物西酞普兰中加入哌醋甲酯（MPH）可能会对晚期抑郁症的情感和认知症状产生更好的临床结果。这些考虑为我们的初步研究提供了动力，以评估西酞普兰和哌醋甲酯（MPH）联合治疗与西酞普兰和安慰剂相比的治疗反应。我们观察到西酞普兰和哌醋甲酯（MPH）联合使用增强了抗抑郁反应和执行认知功能测试的改善。多巴胺转运蛋白基因型（DAT VNTR10/10）纯合的患者执行功能的改善更大。目前的提案将评估辅助MPH治疗的作用，以确定多巴胺药理学增加对选择性5 -羟色胺再摄取（SSRI）治疗的临床和认知反应的影响。我们还将探讨参与多巴胺能神经传递（即COMT， DAT1, DRD4）和血清能神经传递（即HTR2A）调控的候选基因在哌醋酯和西酞普兰治疗的临床和认知反应中的作用。我们将招募168名患有重度抑郁症的老年非痴呆受试者参加一项双盲随机安慰剂对照试验。参与者将被随机分配到三组：一组将接受西酞普兰和MPH的联合治疗，第二组将接受MPH和安慰剂，第三组将接受西酞普兰和安慰剂。所有受试者将在基线和16周的治疗期间接受全面的医学、神经精神和认知评估，以及基因检测。我们的研究将提供关于使用哌甲酯改善认知和临床结果的独特信息，并将阐明老年抑郁症治疗反应的潜在机制。从情绪和认知症状以及治疗反应方面评估老年抑郁症中选择的多巴胺相关基因可能会导致老年抑郁症的针对性个体化治疗的发展。

DESCRIPTION (provided by applicant): Fewer than 50% of elderly depressed patients achieve remission and functional recovery in response to first-line antidepressant pharmacotherapy. The majority of patients are left with significant residual symptoms, putting them at risk of chronic, relapsing illness, frailty, and suicide. Improved understanding of neurobiology of geriatric depression and mechanisms of treatment response may lead to the improved clinical management of this pervasive and disabling disorder. While the serotonin system has been the focus of pharmacotherapy in unipolar major depression, there is a compelling rationale for the study of other monoamine systems. Impairment of executive functions persists even after amelioration of depressive symptoms and that these symptoms are poorly responsive to serotonergic treatment alone. We hypothesized that the addition of methylphenidate (MPH) to the serotonergic drug, citalopram, may result in better clinical outcomes of the affective and cognitive symptoms of late life depression. These considerations provided the impetus for our pilot study to evaluate the treatment response of the combination of citalopram and methylphenidate (MPH) compared to citalopram and placebo. We observed enhanced antidepressant response and improvement in executive cognitive function tests to a combination of citalopram and methylphenidate (MPH). The improvement in executive function was greater in patients who were homozygous for the dopamine transporter genotype (DAT VNTR10/10). The current proposal will evaluate the role of adjunctive MPH treatment to determine the effects of pharmacologic increase of dopamine on the clinical and cognitive response to selective serotonin reuptake (SSRI) treatment. We will also explore the role of the candidate genes involved in the regulation of dopaminergic neurotransmission (i.e., COMT, DAT1, DRD4) and sertonergic neurotransmission (i.e., HTR2A) in the clinical and cognitive response to treatment with methylphenidate and citalopram. We will recruit 168 elderly non-demented subjects with major depression to participate in a double-blind randomized placebo- controlled trial. Participants will be randomly assigned to three groups: one group will receive combination of citalopram and MPH, the second group will receive MPH and placebo, and the third group will receive citalopram and placebo. All subjects will undergo comprehensive medical, neuropsychiatric and cognitive assessments, and genetic testing at baseline and over the 16 weeks of treatment. Our study will provide the unique information regarding the use of methylphenidate to improve cognitive and clinical outcomes, and will shed light on the underlying mechanism of treatment response in geriatric depression. Evaluating selected dopamine-related genes in late-life depression with respect to mood and cognitive symptoms, and treatment response may lead to the development of the targeted individualized treatments in geriatric depression.