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重大经济负担。许多抑郁症患者可以通过心理治疗和药物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恢复良好，并且可能长时间不适。工业界很难为顽固性抑郁症患者找到新的治疗方法，因此目前的提案旨在使用“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提供希望。实验医学方法包括在抑郁症患者中测试短期内潜在的抗抑郁治疗，以确定生物学和心理学测试是否表明相关治疗可能具有真正的临床抗抑郁潜力。如果获得了阳性结果，就可以进行正式的临床试验，并有很好的成功预期。我们将测试的第一种治疗方法是依布硒啉。在基础的实验室研究中，依布硒啉具有类似锂的特性，也影响一种被称为谷氨酸的神经递质，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。现在可以使用一种称为磁共振光谱（MRS）的技术来准确测量大脑中的谷氨酸盐。我们将在牛津使用最先进的MRS相机来测量抑郁症患者的谷氨酸盐，并检查一周的依布硒啉治疗对谷氨酸盐水平的影响。此外，为了进一步评估依布硒啉是否可能作为抗抑郁药，我们将研究它对大脑处理情绪信息的影响。我们以前的工作表明，这可能是一个很好的方法来发现一种药物是否可能对抑郁症患者临床有效。我们将测试的另一种药物是一种名为tofacitinib的抗炎药。目前人们对炎症在抑郁症病因中的作用非常感兴趣，血液中有炎症证据的患者通常对标准抗抑郁治疗反应不佳。托法替尼目前被用作类风湿性关节炎患者的治疗药物，并且已知其可抑制与抑郁症有关的一些炎症机制。因此，我们还将进行一项托法替尼的实验性医学研究，以观察一周的治疗是否会产生情绪处理的变化，这些变化表明有炎症证据的抑郁症患者具有潜在的抗抑郁作用。这些实验性医学研究的积极结果将促使我们与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硒啉和/或托法替尼的效果。这项提案中的研究也将为我们提供一个机会，以比以前更高的精度来检测抑郁症患者脑谷氨酸盐的异常。这些信息将在新的治疗开发中具有价值。

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.