Clinical Psychopharmacology of Depression

临床抑郁症导致许多个人痛苦和残疾，并通过失业对英国造成巨大的经济负担。许多抑郁症患者可以通过心理治疗和药物治疗在初级保健中得到有效治疗。然而，那些没有得到这些标准治疗帮助的人可能很难很好地恢复，并且可能长时间不舒服。业界很难为难治性抑郁症患者找到新的治疗方法，因此目前的提议旨在使用一种“实验医学”方法，看看两种新的药物治疗方法是否可能为抑郁症患者带来希望。实验医学方法包括在短期内对抑郁症患者进行潜在的抗抑郁疗法测试，以了解生物学和心理测试是否表明相关治疗可能具有真正的临床抗抑郁药物潜力。如果获得积极的结果，那么就可以在正式的临床试验中研究这种治疗，并有良好的成功预期。我们要测试的第一种治疗方法是艾布selen。在基本的实验室研究中，艾布林具有类似锂的特性，也会影响一种叫做谷氨酸的神经递质，这种神经递质被认为在抑郁症的病因和治疗中起着重要作用。现在有可能使用一种叫做磁共振波谱（MRS）的技术来精确测量大脑中的谷氨酸。我们将在牛津使用最先进的磁共振成像相机来测量抑郁症患者体内的谷氨酸，并检查一周的依布selen治疗对谷氨酸水平的影响。此外，为了进一步评估埃布selen是否有潜力作为抗抑郁药，我们将研究它对大脑处理情绪信息的方式的影响。我们之前的工作表明，这可能是一种很好的方法，可以找出一种药物是否可能对抑郁症患者临床有效。我们要测试的另一种药物是一种叫做托法替尼的抗炎剂。目前，人们对炎症在抑郁症病因中的作用很感兴趣，有证据表明血液中有炎症的患者往往对标准抗抑郁药物治疗反应不佳。托法替尼目前用于治疗类风湿性关节炎患者，并且已知可以抑制与抑郁症有关的一些炎症机制。因此，我们还将开展一项托法替尼的实验医学研究，以观察一周的治疗是否会对情绪处理产生变化，从而表明对有炎症迹象的抑郁症患者有潜在的抗抑郁作用。这些实验医学研究的积极结果将促使我们与NHS和工业界进行合作研究，以便在抑郁症患者的正式临床试验中评估埃布selen和/或托法替尼的效果。本提案中的研究也将为我们提供一个机会，使我们能够比以前更精确地描述抑郁症患者的大脑谷氨酸异常。这一信息将对开发新的治疗方法有价值。

Clinical depression causes much personal suffering and disability and is a substantial economic burden to the UK through loss of employment. Many patients with depression can be effectively treated in primary care with psychological therapies and medication. However, those who are not helped by these standard treatments may have difficulties in making a good recovery and can be unwell for long periods of time. It has been hard for Industry to find new treatments for patients with resistant depression so the current proposal aims to use an 'experimental medicine' approach to see whether two novel pharmacological treatments might offer promise for depressed patients. The experimental medicine approach involves testing potential antidepressant therapies in depressed patients for a short period of time to see whether biological and psychological tests indicate that the treatment concerned may have true potential as a clinical antidepressant. If a positive result is obtained the treatment can then be studied in a formal clinical trial with a good expectation of success.The first treatment we will test is called ebselen. In basic laboratory studies, ebselen has lithium-like properties, and also influences a neurotransmitter called glutamate which is thought to play an important role in the causation and treatment of depression. It is now possible to measure glutamate accurately in the brain using a technique called magnetic resonance spectroscopy (MRS). We will use a state-of-the-art MRS camera in Oxford to measure glutamate in depressed patients and examine the effect of one week of ebselen treatment on glutamate levels. In addition, to assess further whether ebselen may have potential as an antidepressant we will study its effects on the way the brain processes emotional information. Our previous work indicates that this can be a good way of finding out whether a drug is likely to be clinically effective in depressed patients. The other drug we will test is an anti-inflammatory agent called tofacitinib. There is currently much interest in the role of inflammation in the causation of depression and patients with evidence of inflammation in the blood are often among those who do not respond well to standard antidepressant treatments. Tofacitinib is currently used as a treatment for patients with rheumatoid arthritis and is known to inhibit some of the inflammatory mechanisms that have been implicated in depression. We will therefore also carry out an experimental medicine study of tofacitinib to see whether one week of treatment produces changes in emotional processing that indicate a potential antidepressant effect in depressed patients with evidence of inflammation. Positive results in either of these experimental medicine studies would prompt us to undertake collaborative studies with the NHS and Industry so that the effect of ebselen and/or tofacitinib can be assessed in formal clinical trials in depressed patients. The studies in this proposal will also provide an opportunity for us to characterise abnormalities in brain glutamate in patients with depression with greater precision than has been possible previously. This information will be of value in new treatment development.