Clinical Psychopharmacology of Depression

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.