Methylphenidate Use to Improve Outcomes in Geriatric Depression

描述（由申请人提供）：不到50%的老年抑郁症患者在一线抗抑郁药物治疗后获得缓解和功能恢复。大多数患者留下了显著的残留症状，使他们处于慢性复发性疾病、虚弱和自杀的风险中。提高对老年抑郁症的神经生物学和治疗反应机制的理解，可能会导致这种普遍性和致残性疾病的临床管理的改善。虽然5-羟色胺系统一直是单相抑郁症药物治疗的重点，但对其他单胺系统的研究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，并且这些症状对单用多巴胺能治疗的反应很差。我们假设，哌醋甲酯（MPH）添加到多巴胺能药物西酞普兰，可能会导致更好的临床结果的情感和认知症状的晚年抑郁症。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）联合用药后抗抑郁反应增强，执行认知功能测试改善。多巴胺转运蛋白基因型（DAT VNTR 10/10）纯合子患者的执行功能改善更大。目前的建议将评估连续性MPH治疗的作用，以确定多巴胺的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。我们还将探索参与多巴胺能神经传递调节的候选基因的作用（即，COMT、DAT 1、DRD 4）和血清素能神经传递（即，HTR 2A）在哌甲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的组合，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。评估选择多巴胺相关基因在晚年抑郁症的情绪和认知症状，治疗反应可能会导致老年抑郁症有针对性的个性化治疗的发展。

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.