Evaluation of the central effects of a delta opioid agonist on biomarkers of efficacy in anxiety and depression

大多数治疗精神疾病的药物在实验室里看起来很有前途和新奇，但却无法到达床边。这通常是因为当它们在大型且非常昂贵的临床研究中对药物预期的患者进行测试时，它们不起作用。越来越多的人认为，失败的金融风险通常太大，无法维持发展所需的主要基础设施。几家公司已经关闭了他们的开发计划，尽管他们拥有前景看好的新药。这些药物通常对特定的神经递质系统具有高度选择性的作用。因此，它们作为了解神经递质在精神疾病中的作用的工具，引起了科学界的极大兴趣。此外，社区拥有承担一些临床开发的专业知识和能力，特别是当针对疾病中可识别的亚群时。降低开发风险的一种方法是试图在临床开发的早期检测有效性，即使是在健康的志愿者中，使用探索药物相关行为的大脑功能(生物标记物)测试。这些申请者为工业界和学术界所熟知，因为他们开发了支持焦虑和抑郁的中枢神经系统过程的生物标记物。生物标记物是基于测量人们对面部或场景的温和情绪图像的自动且通常是无意识的反应，这些图像很少或根本没有引起观众的情绪。这些指标通常包括反应时间、准确度或自动记忆。重要的是，大脑系统的反应也可以使用功能磁共振成像(FMRI)进行可视化和量化。使用这些测量方法的研究表明，抑郁症的风险与一种无意识的倾向有关，即自动注意和处理世界上和关于自己的负面信息。值得注意的是，即使在没有抑郁风险和不影响情绪的人中，抗抑郁药物也可以将偏见转向积极的方向。在检测药物效应方面，一些最有效的方法已经被整理成情绪测试组合(ETB)。这项提议是为了从关闭的阿斯利康精神病学计划中拯救一种药物(AZD7268)，该药物对增量阿片受体(DOR)有明确的作用。DOR检测并传递大脑中被称为脑啡肽的内啡肽的影响。AZD7268模拟脑啡肽刺激DOR的作用。临床前和临床数据表明，AZD7268将对与高度焦虑相关的抑郁症有效。DOR位于大脑的特定区域，如杏仁核和海马体，这些区域调节动物的行为影响及其对人类的主观影响。缺乏DOR或缺乏脑啡肽的转基因小鼠表现出恐惧和抑郁(获得性无助)的行为特征，而DOR药物，如AZD7268，则具有相反的效果。在一项对247名患者的临床试验中，与安慰剂相比，AZD7268仅在预测的焦虑抑郁组有效，在没有明显焦虑的抑郁症中无效。我们的目的是通过使用ETB来描述AZD72688对非临床志愿者样本中评估奖励、惩罚和情绪处理的心理任务的表现和脑成像测量的影响，以建立对这一发现的信心。一半的志愿者将被选为高度焦虑和抑郁的人，使用标准的自我评级问卷。AZD7268对ETB的强劲影响表明，DORS至少在焦虑和抑郁的原因中具有调节作用，这值得在MRC和阿斯利康的联合开发计划中进行治疗。

Most drugs for mental illness which look promising and novel in the laboratory, fail to reach the bedside. This is generally because they do not work when they are tested in large and very expensive clinical studies in patients for which the drug is intended. Increasingly, the financial risk of failure is seen as generally too great to maintain the major infrastructure necessary for development. Several companies have closed down their development programs even though they have novel drugs which show promise. These drugs are often very well characterised with highly selective actions on specific neurotransmitter systems. They are therefore of great interest to the scientific community as tools to understand the role of neurotransmitters in mental illnesses. Furthermore, the community has the expertise and capacity to take on some of the clinical development, especially when targeted at identifiable subgroups within a disorder.One approach to de-risking development is to attempt to detect efficacy early in clinical development, even in healthy volunteers, using tests of brain functioning (biomarkers) that probe relevant actions of drugs. The applicants are known to Industry and Academia for their development of biomarkers for CNS processes that underpin anxiety and depression. The biomarkers are based on measuring people's automatic and usually unconscious responses to mildly emotional images of faces or scenes that evoke little or no emotion in the viewer. The measures typically involve reaction times, accuracy or automatic memorising. Importantly, the responses of brain systems can also be visualised and quantified using functional magnetic resonance imaging (fMRI). Studies using these measures suggest that the risk of depression is associated with an unconscious tendency to automatically attend to, and process negative information in the world and about themselves. Remarkably, antidepressant drugs can shift biases in a positive direction even in people with no risk of depression and without affecting mood. Some of the most efficient measures at detecting drug effects have been collated into the Emotional Test Battery (ETB). This proposal is to rescue a drug (AZD7268), which has well-defined actions at the delta opioid receptor (DOR), from the closed AstraZeneca psychiatry program. The DOR detects and transmits the effects of endorphins in the brain called enkephalins. AZD7268 mimics the effects of enkephalins in stimulating the DOR. Preclinical and clinical data suggested that AZD7268 would be effective in depressive illnesses associated with high levels of anxiety. The DOR is located specifically in regions of the brain such as the amygdala and hippocampus that mediate behavioural effects of stress in animals and its subjective effects in humans. Genetically modified mice made to lack the DOR or to lack enkephalin show behavioural characteristics of fearfulness and depression (learned helplessness) and DOR drugs such as AZD7268 have the opposite effect. In a clinical trial in 247 patients, AZD7268 was effective in reducing depression compared to placebo only in the predicted anxious-depressed group and not in depression without marked anxiety. We aim to build confidence in this finding by using the ETB to profile the effects of AZD72688 on performance and brain imaging measures of psychological tasks that assess reward, punishment and emotion processing in a non-clinical sample of volunteers. Half the volunteers will be selected for high levels of anxiety and depression using standard self-rating questionnaires. Robust effects of AZD7268 on the ETB would suggest that DORs have at least a modulatory role in the causation of anxiety and depression that is worth pursuing therapeutically in a joint development programme between the MRC and AstraZeneca.