Clinical Psychopharmacology of Depression

临床抑郁症会导致许多个人痛苦和残疾，并因失业而给英国带来巨大的经济负担。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难以实现良好的康复，并可能长时间感到不适。对于工业公司来说，很难为顽固性抑郁症患者找到新的治疗方法，所以目前的提案旨在使用一种“实验医学”的方法，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。实验医学的方法是在短期内测试抑郁症患者的潜在抗抑郁药物治疗方法，看看生物和心理测试是否表明有关治疗方法可能真正具有临床抗抑郁药物的潜力。如果获得阳性结果，则该疗法可以在正式的临床试验中进行研究，并有望获得成功。我们将测试的第一种疗法称为依贝赛伦。在基础实验室研究中，ebselen具有类似锂的特性，还影响一种名为谷氨酸的神经递质，谷氨酸被认为在抑郁症的病因和治疗中发挥重要作用。现在，使用一种名为磁共振波谱(MRS)的技术可以准确地测量大脑中的谷氨酸。我们将使用牛津大学最先进的MRS相机来测量抑郁症患者的谷氨酸，并检查一周的易卜赛林治疗对谷氨酸水平的影响。此外，为了进一步评估ebselen是否具有作为抗抑郁剂的潜力，我们将研究其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，可以发现一种药物是否可能对抑郁症患者有效。我们将测试的另一种药物是一种名为tofacitinib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，血液中有炎症证据的患者往往是那些对标准抗抑郁药物治疗反应不佳的人。托法替尼目前用于治疗类风湿性关节炎患者，已知可以抑制与抑郁症有关的一些炎症机制。因此，我们还将进行托法替尼的实验医学研究，看看一周的治疗是否会在情绪处理方面产生变化，这表明有炎症证据的抑郁症患者具有潜在的抗抑郁效果。这两项实验医学研究中的任何一项的积极结果都将促使我们与NHS和行业进行合作研究，以便在抑郁症患者的正式临床试验中评估依布塞伦和/或tofacitinib的效果。这项提案中的研究还将为我们提供一个机会，比以前更精确地描述抑郁症患者大脑谷氨酸的异常。这些信息将对新的治疗方法的开发有价值。

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.