MICA: An experimental medicine model for fast acting antidepressant drug treatment in treatment resistant depression

MICA：快速作用抗抑郁药物治疗难治性抑郁症的实验医学模型

• 批准号: MR/S035591/1
• 负责人: Catherine Harmer
• 金额: $ 101.03万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS035591%2F1
• 关键词: MICA; experimental; medicine; model; fast

Depression is common and disabling. There are effective treatments for depression but around 30% of patients are not helped by existing treatments. Recent evidence suggests that these patients respond well to a new class of medication acting on the brain's glutamate system. For example, a low dose of the anaesthetic agent ketamine, which acts on the glutamate system, led to improvements in depression very quickly which lasted for up to a week. Ketamine itself is not an ideal treatment for depression since it is also a drug of abuse and has many side effects. There is therefore a huge need to develop similar drugs to ketamine, which work well in this subgroup of patients but without these unwanted effects. Potential new drugs exist but it is very time consuming and expensive to test all these drugs, at different doses, in full clinical trials. Experimental medicine models can help as they allow these drugs to be tested in smaller groups in the lab, exploring effects on key mechanisms of illness rather than less sensitive clinical ratings of mood. This is thought to provide more accurate information and help select the most promising treatments to take forward to full clinical trial testing. Data from rodent models suggests that drugs like ketamine may have distinct effects on the brain and behaviour. These involve effects on how rewarding information is handled and how emotional memories are retrieved and experienced. However, these mechanisms have not been tested in humans. We therefore plan to test the effects of ketamine on reward learning and emotional memory retrieval in humans. We will first characterise these effects in healthy people as this will allow us to identify core processes affected by ketamine and ascertain whether these actions are dose specific. We will then validate these mechanisms in depressed patients who have not responded to conventional treatments. We will assess learning about reward and punishment and the recall of established memories as well as the brain networks which underpin these effects. We think that ketamine will have effects on a network in the brain involving the lateral habenula, medial prefrontal cortex and hippocampus, which have been implicated in the ketamine studies using animals and which play a key role in learning, memory and emotion. These two studies will help develop a set of measures which can be used in future studies to select the most promising drug treatments for treatment resistant depression.

抑郁症很常见，而且会导致残疾。抑郁症有有效的治疗方法，但大约30%的患者没有得到现有治疗的帮助。最近的证据表明，这些患者对一类作用于大脑谷氨酸系统的新型药物反应良好。例如，低剂量的麻醉剂氯胺酮，作用于谷氨酸系统，导致抑郁症的改善非常迅速，持续长达一周。氯胺酮本身并不是抑郁症的理想治疗方法，因为它也是一种滥用药物，并且有许多副作用。因此，非常需要开发与氯胺酮类似的药物，这些药物在这一亚组患者中效果良好，但没有这些不良反应。潜在的新药是存在的，但在全面的临床试验中以不同的剂量测试所有这些药物是非常耗时和昂贵的。实验医学模型可以提供帮助，因为它们允许这些药物在实验室中以较小的群体进行测试，探索对疾病关键机制的影响，而不是对情绪的不太敏感的临床评级。这被认为提供了更准确的信息，并有助于选择最有希望的治疗方法进行全面的临床试验测试。来自啮齿动物模型的数据表明，氯胺酮等药物可能对大脑和行为有明显的影响。这些影响涉及如何处理奖励信息以及如何检索和体验情感记忆。然而，这些机制尚未在人类中进行过测试。因此，我们计划测试氯胺酮对人类奖励学习和情感记忆提取的影响。我们将首先在健康人群中验证这些影响，因为这将使我们能够确定氯胺酮影响的核心过程，并确定这些作用是否具有剂量特异性。然后，我们将在对常规治疗无反应的抑郁症患者中验证这些机制。我们将评估关于奖励和惩罚的学习，以及对已建立记忆的回忆，以及支持这些效应的大脑网络。我们认为氯胺酮会对大脑中涉及外侧缰核、内侧前额叶皮层和海马体的网络产生影响，这些网络在使用动物的氯胺酮研究中有牵连，并在学习、记忆和情绪中发挥关键作用。这两项研究将有助于制定一套措施，可用于未来的研究，以选择最有前途的药物治疗难治性抑郁症。

项目成果

A translational perspective on the anti-anhedonic effect of ketamine and its neural underpinnings.

• DOI: 10.1038/s41380-021-01183-1
• 发表时间: 2022-01
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Pulcu E;Guinea C;Cowen PJ;Murphy SE;Harmer CJ
• 通讯作者: Harmer CJ

Dynamic modulation of inequality aversion in human interpersonal negotiations.

• DOI: 10.1038/s42003-022-03318-8
• 发表时间: 2022-04-14
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Murphy, Daniel A. J.;Xie, Jiaxin;Harmer, Catherine J.;Browning, Michael;Pulcu, Erdem
• 通讯作者: Pulcu, Erdem