Association Between Placebo-Activated Neural Systems and Antidepressant Responses Neurochemistry of Placebo Effects in Major Depression
Association Between Placebo-Activated Neural Systems and Antidepressant Responses Neurochemistry of Placebo Effects in Major Depression
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DOI：
10.1001/jamapsychiatry.2015.1335
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发表时间：
2015-11-01
期刊：
影响因子：
25.8
通讯作者：
Zubieta, Jon-Kar
中科院分区：
文献类型：
--
作者：
Pecina, Marta;Bohnert, Amy S. B.;Zubieta, Jon-Kar
重要性高安慰剂反应已被观察到在广泛的病理，严重影响药物development.OBJECTIVE检查神经化学机制的基础上形成的安慰剂效应的患者与重性抑郁症（MDD）。设计，设置，和参与者在这项研究中，涉及2安慰剂导入阶段，随后是一个开放的抗抑郁药管理，我们对2种相同的口服安慰剂进行了为期2周的单盲交叉随机临床试验（被描述为具有活性或非活性的速效抗抑郁剂样作用），随后用选择性5-羟色胺再摄取抑制剂进行10周的开放标签治疗，或者在某些情况下，根据临床指征使用另一种药物。志愿者（35名大学卫生系统的无药物MDD患者）在每1周非活性和活性口服安慰剂治疗后，用正电子发射断层扫描和μ阿片受体选择性放射性示踪剂[C-11]卡芬太尼进行研究。此外，仅在1周活性安慰剂治疗后，在正电子发射断层扫描期间，在志愿者的视线内静脉内给予1 mL等渗盐水，每4分钟一次，持续20分钟，说明该化合物可能与参与情绪改善的脑系统激活相关。这种挑战刺激被用来测试个人的能力，急性激活内源性阿片类神经transmision下的预期antidepressant effects.Main结果和措施的变化，抑郁症状的积极安慰剂和抗抑郁药。μ-阿片受体结合的基线和激活措施。结果：更高的基线μ-阿片受体结合在脑桥核与抗抑郁治疗的反应更好（r = 0.48; P = 0.02）。与非活动组相比，在接受活性安慰剂治疗1周后，抑郁症状的减轻与安慰剂诱导的μ-阿片类神经传递增加有关，这些神经传递涉及情感、应激调节和MDD的病理生理学，即膝下前扣带回皮质、丘脑核、中线丘脑和杏仁核（丘脑核：r = 0.6; P <0.001）。安慰剂诱导的内源性阿片样物质释放在这些地区与更好的抗抑郁治疗反应，预测43%的方差在症状改善的抗抑郁试验结束时。结论和相关性这些数据表明，安慰剂诱导的μ-阿片系统的激活是牵连在形成安慰剂抗抑郁作用的MDD患者，也参与抗抑郁反应，在开放管理期间赋予疾病弹性。
IMPORTANCE High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.OBJECTIVE To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).DESIGN, SETTING, AND PARTICIPANTS In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the mu-opioid receptor-selective radiotracer [C-11]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.MAIN OUTCOMES AND MEASURES Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of mu-opioid receptor binding.RESULTS Higher baseline mu-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced mu-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.CONCLUSIONS AND RELEVANCE These data demonstrate that placebo-induced activation of the mu-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.