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.

The main aim of the study is to use experimental medicine methods to assess two novel pharmacological approaches to the management of treatment resistant depression (TRD), using change in emotional processing as a key biomarker for potential antidepressant efficacy. Ebselen is a putative lithium-mimetic which also inhibits the glutamate synthesising enzyme, glutaminase. We will use a placebo-controlled design to assess the effect of one week of ebselen treatment in TRD patients where we will use magnetic resonance spectroscopy (MRS), as well as neuropsychological and clinical measures, to determine changes in brain levels of inositol and glutamate, emotional processing and depressive symptomatology during ebselen treatment. We will use a similar design to test the effect of the JAK inhibitor, tofacitinib, a novel anti-inflammatory agent, in TRD patients with evidence of peripheral inflammation determined by elevated levels of C-reactive protein. Here we will use functional magnetic resonance imaging to measure the effect of tofacitinib on the neural response to emotional and rewarding stimuli in addition to neuropsychological and clinical measures. The recruitment of patients for the above studies will provide us with an opportunity to characterise glutamate and glutamine abnormalities in TRD in cortical-striatal regions with the outstanding precision permitted by MRS imaging at 7T using a case-control design. We will also use this 7T methodology to test the hypothesis that the decrease in glutamate level produced by ebselen is associated with diminished glutamate release in the living human brain in a functional MRS paradigm employing visual stimulation.

Depression is a leading cause of disability worldwide, and a major contributor to the overall global burden of disease. Current treatments are limited in terms of efficacy, particularly in patients who fail to respond to first line approaches, so called 'treatment resistant depression' (TRD). The present study aims to develop two novel pharmacological approaches specifically for this group of patients. It will also clarify abnormalities in the neurotransmitter, glutamate in treatment resistant depression.

Therefore the main beneficiaries of this research, should it prove successful, are patients with depression and their families. In addition, because people with TRD are often unable to work, treatments which facilitate recovery will produce a substantial economic benefit to the UK as a whole.

Because of the lack of effective treatments, clinicians often find the management of TRD difficult; accordingly the availability of new treatments will be of great value to professionals striving to help their TRD patients.

The work will also be of importance to the field of psychiatry in general, emphasising that it is possible to continue to improve antidepressant drug treatments and that basic research and 'drug repurposing' are important in this effort. It will also provide a better understanding of the neurobiological basis of TRD.

Other beneficiaries could include the Pharmaceutical Industry who will benefit from the ability to have new targets to treat depression and associated disorders, as well as the demonstration that experimental medicine approaches can play a facilitatory role in psychotropic drug discovery.