The effects of SAMe on reward circuitry in depression

描述（由申请人提供）：重度抑郁症（MOD）是常见的，复发性和致残性的。尽管抗抑郁药物种类繁多，但MOD仍然难以治疗。因此，更好地了解治疗机制和确定治疗反应的可靠预测因素将成为对抗MOD的重大进展。最近，人们对研究替代药物治疗MOD的疗效产生了相当大的兴趣。在这方面，S-腺苷-L-甲硫氨酸（SAMe）已被广泛研究作为一种天然的治疗抑郁症。尽管临床前研究表明SAMe影响神经递质代谢（包括多巴胺，一种涉及奖励脑机制的神经递质），膜流动性和受体活性，但其抗抑郁作用的确切机制在人类中尚不清楚。作为对这些过程的机械理解的第一步，研究人员建议将SAMe的效果与标准的一线抑郁症治疗进行比较（选择性5-羟色胺再摄取抑制剂，艾司西酞普兰）对MOD中奖赏加工的神经活动的影响。通过使用功能磁共振成像（fMRI）结合奖赏任务，本研究将采用金钱强化的按钮按压任务和实验室的享乐能力行为测量方法，探讨：（1）SAMe和艾司西酞普兰对奖赏和惩罚相关线索加工的神经基质的影响;（2）对SAMe和艾司西酞普兰治疗反应的治疗前行为和神经预测因子;（3）SAMe和艾司西酞普兰作用的推定差异-由于其不同的药理学特征-对享乐能力的神经和行为标志物的影响。为此，将对45名MOD患者（和15名健康对照受试者）进行研究（SAMe与艾司西酞普兰12周双盲安慰剂对照给药前后）。基于表明SAMe增强中脑边缘多巴胺能奖赏系统中的传递的临床前证据，我们假设，与安慰剂相比，SAMe（和艾司西酞普兰）治疗将：（1）正常化（即，增加）辅助奖赏处理的区域（腹侧纹状体、眶额皮质、前扣带皮质）中的脑激活;（2）正常化（即，减少）服从惩罚处理的区域中的大脑激活（例如，杏仁核、杏仁核、海马、右背外侧前额叶皮质）;和（3）增加享乐能力，如通过信号检测任务所评估的。因为快感缺失（缺乏对愉快刺激的反应性）被认为是与抑郁症易感性相关的特征标记和复发的预测因子，利用最先进的神经成像技术和基于实验室的享乐能力测量的新实验方法有望揭示：（1）自然治疗抑郁症的抗抑郁功效的潜在机制;和（2）治疗反应的客观预测因子。更好地了解SAMe的作用机制，反过来，为未来的临床试验提供了基础。

DESCRIPTION (provided by applicant): Major depressive disorder (MOD) is common, recurrent, and disabling. Despite a wide range of antidepressant treatments available, MOD remains difficult to treat. Therefore, a better understanding of treatment mechanisms and identification of reliable predictors of treatment response would constitute major progress in the battle against MOD. Recently, there has been considerable interest in studying the efficacy of alternative medications in the treatment of MOD. In this regard, S-adenosyl-L-methionine (SAMe) has been widely investigated as a natural treatment of depression. Although preclinical studies have shown that SAMe influences neurotransmitter metabolism (including dopamine, a neurotransmitter implicated in reward brain mechanisms), membrane fluidity, and receptor activity, the precise mechanisms of its antidepressant actions are unknown in humans. As an initial step toward a mechanistic understanding of these processes, the investigators propose to compare the effects of SAMe to a standard, first-line treatment for depression (the selective serotonin reuptake inhibitor, escitalopram) on neural activity underlying reward processing in MOD. By using functional magnetic resonance imaging (fMRI) in conjunction with a reward task (a monetarily-reinforced button-press task) as well as a laboratory-based behavioral measure of hedonic capacity, this study will investigate: (1) the effects of SAMe and escitalopram on neural substrates underlying processing of reward- and punishment-related cues; (2) pre-treatment behavioral and neural predictors of treatment response to SAMe and escitalopram; and (3) putative differences in the effects of SAMe and escitalopram - due to their distinct pharmacological profiles - on neural and behavioral markers of hedonic capacity. To this end, 45 individuals with MOD (and 15 healthy control subjects) will be investigated (before and after a 12-week, double-blind, placebo-controlled administration of SAMe vs. escitalopram. Based on preclinical evidence suggesting that SAMe potentiates transmission in the mesolimbic dopaminergic reward system, we hypothesize that, compared to placebo, SAMe (and escitalopram) treatment will: (1) normalize (i.e., increase) brain activation in regions subserving reward processing (ventral striatum, orbitofrontal cortex, anterior cingulate cortex); (2) normalize (i.e., decrease) brain activation in regions subserving punishment processing (e.g., amygdala, insula, hippocampus, right dorsolateral prefrontal cortex); and (3) increase hedonic capacity, as assessed by a signal-detection task. Because anhedonia (lack of reactivity to pleasurable stimuli) has been considered a trait marker related to vulnerability to depression and a predictor of relapse, the use of a novel experimental approach capitalizing on state-of-the-art neuroimaging techniques and laboratory-based measures of hedonic capacity promises to shed important light on: (1) mechanisms underlying the antidepressant efficacy of a natural treatment for depression; and (2) objective predictors of treatment response. A better understanding of the mechanisms of actions of SAMe should, in turn, provide a foundation for future clinical trials.