Clinical Psychopharmacology of Depression

Clinical depression is common and sometimes difficult to treat successfully. We need to develop better pharmacological treatments for depressed patients but this goal is hindered by a lack of knowledge of the brain chemistry involved in the illness. Two important chemical messengers, serotonin and glutamate, are thought to be involved in depression and in the present investigation we will use two advanced imaging techniques, positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) to increase our knowledge of how these chemicals are involved in depression and its treatment. We will also link our findings to measures of inflammation because some depressed patents appear to have inflammatory changes in their blood and inflammation can affect serotonin and glutamate.

It will greatly increase our understanding of the role of serotonin in depression if we could measure its release in the living human brain and in one project we will try to achieve this using PET imaging of a specific label of serotonin receptors in healthy volunteers whose brain serotonin levels have been temporarily lowered by a dietary manipulation. We will use MRS to investigate levels of brain glutamate. We will first study patients with hepatitis who are receiving the anti-viral agent, interferon, for the treatment of their viral disorder. Interferon is known to cause depression when it is used to treat hepatitis and we will make ratings of depression and look at changes in brain glutamate during interferon treatment. We will then use the same MRS examination to look at glutamate levels in patients with clinical depression. We will use a blood test called CRP to divide the patients up into those with significant inflammation and those without. We will then see whether the changes in glutamate in patients with inflammation resemble those seen in patients treated with interferon.

The response of depressed patients to conventional antidepressant treatment with SSRIs is quite variable. We will therefore see whether the presence of inflammation affects the response to the SSRI drug, escitalopram. We predict that patients with high levels of CRP before treatment will do less well with antidepressant therapy. If this is the case CRP could become a useful clinical marker to decide who will do well with standard antidepressant treatment.

The aim of the proposal is to study the role of the neurotransmitters, serotonin (5-HT) and glutamate in the pathophysiology of depression using state-of-the-art imaging in the form of positron emission tomography (PET) and magnetic resonance imaging at 7 Tesla (7T). A key objective is to establish a model of endogenous 5-HT release in healthy volunteers using [11C]CUMI-101 in conjunction with PET. Our MRS investigations will focus on the link between glutamate, inflammation and depression by studying the effect of treatment with the cytokine, interferon-alpha, on MRS glutamate and mood in patients with hepatitis C and comparing these data to MRS glutamate changes seen in a large group of depressed patients stratified according to peripheral inflammatory markers such as C-reactive protein (CRP). Finally we will assess in depressed patients how stratification for inflammatory status affects clinical response to serotonin potentiating treatment with the selective serotonin re-uptake inhibitor (SSRI), escitalopram. The overall objective in these latter studies is to use stratification by inflammatory markers to improve our understanding of the pathophysiology of depression and help predict response to first line SSRI treatment.

The aim of the research is to provide a better understanding of the link between inflammation and depression, how inflammation may modify glutamate and serotonin function to produce depression and whether stratification for inflammation in depressed patients can help understanding of pathophysiology and treatment. Finally we plan to devise a reliable PET model to measure serotonin release in vivo.

In addition to academic beneficiaries, the research will be of value to clinicians particularly those treating depressed patients and selecting appropriate treatments for them. The ability to use a relatively simple biochemical predictor to identify likely responders to conventional treatment would greatly improve practice and services for depressed patients. This will also, of course, benefit patients and families and wider society in terms of less time spent depressed while the correct treatment is found on the current 'trial and error' basis.

The work will also be of value to clinicians and patients involved in interferon treatment in terms of understanding the origin of psychological symptoms and exploring possible means of prevention and treatment. This might include glutamatergic treatments (for example, lamotrigine) or new agents that are being developed to target the tryptophan/kynurenine pathway. A better understanding of the fatigue caused by interferon could have important consequences for patients with chronic fatigue and the various health and support services that have developed to help them.

Other beneficiaries are likely to be the Pharmaceutical Industry who will benefit from the ability to conduct more cost-effective clinical trials in responsive groups of patients as well as clues to the development of different kinds of treatment for example glutamatergic agents and anti-inflammatory drugs for depressed patients with relevant pathophysiological changes. The ability to measure serotonin release in vivo will also benefit the Industry in the development of new drugs designed to modify 5-HT neurotransmission. Finally the training provided by the project to the staff involved, particularly psychiatrists in training will be valuable in developing the next generation of clinical psychiatry researchers.