Clinical Psychopharmacology of Depression

Lead Research Organisation: University of Oxford
Department Name: Psychiatry

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description BAP guideline on depression updated
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact The guideline helps clinicians using psychotropic drugs for the treatment of depression use the most effective evidence-based treatments in a logical and systematic way
 
Description NMHB
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Biomedical catalyst
Amount £1,113,147 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2014 
End 01/2019
 
Description Johnson and Johnson pre-competitive award
Amount $650,000 (USD)
Organisation Johnson & Johnson 
Sector Private
Country United States
Start 09/2013 
End 09/2015
 
Description Medical Research Council MICA award
Amount £1,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2017 
End 04/2020
 
Description Stanley Medical Research Insitute
Amount $800,000 (USD)
Organisation Stanley Medical Research Institute (SMRI) 
Sector Charity/Non Profit
Country Global
Start 07/2016 
End 06/2019
 
Description Biomedical Research Centre (BRC) 
Organisation Oxford Health NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution The University Department of Psychiatry and the Oxford Health NHS Foundation Trust were awarded an NIHR BRC. The work of my group on thus grant was included in the experimental medicine theme of the BRC.
Collaborator Contribution The partnership of the NHS Trust was essential in securing this award
Impact MRC Research Grant, Co-applicant (PI, Professor Catherine Harmer) "MICA: 5-HT4 receptor activation as a novel mechanism of antidepressant action". £1.0 million, 2017-2020
Start Year 2017
 
Description Bupropion study 
Organisation Johnson & Johnson
Department Neuroscience Johnson and Johnson
Country United States 
Sector Private 
PI Contribution Models for assessment of dopamine function in emotional processing and reward
Collaborator Contribution Financial contribution for the study
Impact Collaboration on planned study in depressed patients
Start Year 2013
 
Description Compton collaboration 
Organisation University of Oxford
Department Environmental Change Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration by providing clinical material to assess method for measuring salivary glutathione
Collaborator Contribution Provided methodology for simple non-invasive salivary measure of glutathione
Impact One paper on non-significant correlation between saliva and whole blood glutathione
Start Year 2016
 
Description IMANOVA serotonin collaboration 
Organisation Imanova
Country United Kingdom 
Sector Private 
PI Contribution The aim of the collaboration is to use a PET model of serotonin (5-HT) release to measure 5-HT activity on unmedicated depressed patients. We are providing the idea and rationale for the study and the drug-free depressed patients.
Collaborator Contribution IMANOVA are providing the PET ligand and imaging facilities
Impact Protocol, ethics application, PIC agreement and contract between University of Oxford and IMANOVA (still being negotiated)
Start Year 2017
 
Description McGill/Oxford/ZNZ collaboration- Inflammation workshop 
Organisation University of Zurich
Country Switzerland 
Sector Academic/University 
PI Contribution Together with a partner in Zurich we have funded a workshop on inflammation and depression. This will be an opportunity to exchange information and expertise and apply for further funding.
Collaborator Contribution (see above).
Impact Basic to clinical collaboration. Workshop is current output.
Start Year 2014
 
Description Pharmacology 
Organisation University of Oxford
Department Department of Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution MRC developmental pathway funding for ebselen in the treatment of impulsivity
Collaborator Contribution Studies in animals to act as a platform for human work
Impact Scientific knowledge and translational studies. Possible patent
Start Year 2015
 
Description Sound Pharmaceuticals 
Organisation Sound Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Study of lithium-mimetic in human models of emotional processing and brain neurochemistry
Collaborator Contribution Sourcing of ebselen suitable for human clinical trial use
Impact Press Release Submission to MHRA
Start Year 2016
 
Description Wellcome Trust Inflammation Collaboration 
Organisation University of Cambridge
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Part of a large collaboration with academe and Industry to identify the role of inflammation in depression. Our contribution is to identify the most suitable group of depressed patients and to provide patients and samples for the collaboration
Collaborator Contribution Expertise in immunophenotyping; access to novel therapeutic compounds
Impact Application for funding to Wellcome Trust- Funded approved in Sept 2014
Start Year 2013
 
Title Ebselen in impulsivity 
Description Ebselen is a lithium-mimetic which has potential anti-impulsivity effects. part of the work in this grant was used to justify the patient application. 
IP Reference WO2017187176A1 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact Other patents have been sought for ebselen and further funding sort to explore these indications.
 
Title Ebselen 
Description Antioxidant drug repurposed as lithium mimetic 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Principle of drug repurposing for psychiatry. basic to clinical collaboration. New drug development for area of great unmet clinical need. 
 
Title Ebselen in the treatment of acute mania 
Description Ebselen is a lithium mimetic which is likely to be better tolerated than lithium itself. We are currently carrying out a proof of concept of ebselen in mania. Funding is coming from the Stanley Medical Research Institute. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Collaboration between University and Sound Pharmaceuticals. Increased interest in drugs used to treat bipolar disorder. 
 
Description Interview for Radio in Cambridge 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Enquiries about future of antidepressant drug treatment

Positive feedback by email
Year(s) Of Engagement Activity 2014
 
Description Podcast for BAP 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Podcast stimulated discussion about future of psychopharmacology

request for further information
Year(s) Of Engagement Activity 2014
 
Description Podcast on psychiatry for University of Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Enquiries about academic psychiatry career

Interest in observer placements
Year(s) Of Engagement Activity 2014
 
Description Press Conference in London on treating depression 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press conference to discuss treatment of resistant depression in context of Lancet study on psilocybin
Year(s) Of Engagement Activity 2016