Clinical Psychopharmacology of 5-HT

Lead Research Organisation: University of Oxford
Department Name: Psychiatry

Abstract

Clinical depression is a common illness, often beginning in early adulthood, which can recur throughout a lifetime. The recurrent nature of clinical depression, together with the burden it places on patients and their families, makes this condition one of leading medical causes of suffering and disability. Understanding the biochemical changes in the brain in depression will help us devise better treatments and also improve efforts at prevention. A neurotransmitter called serotonin (5-HT) plays an important role in both the causation of depression and in current drug treatments. In this study we will use advances in brain imaging to study how 5-HT acts in the brain to alter mood. For example we will use magnetic resonance spectroscopy (MRS) to see how 5-HT interacts with special neurons in the brain that use a chemical messenger called glutamate. We believe that the interactions between 5 HT and glutamate may be very important in helping us understand the cause of depression and in developing more effective methods of treatment. A major problem in the treatment of depression is the unpredictability of response to current drug treatments; some patients do well, others are not helped very much. We believe that antidepressants which work through 5-HT such as the selective serotonin re-uptake inhibitors (SSRIs) may produce their therapeutic effects by acting on the way the brain analyses emotional information. The use of functional magnetic resonance imaging (fMRI) allows us to examine the brain networks involved in emotional experience. We will use therefore use fMRI to study how these brain networks are influenced by SSRIs in depressed patients and whether the changes we see enable us to predict those patients who will do well with treatment.

Technical Summary

Abnormalities in brain serotonin (5-HT) function appear to play an important role in the pathophysiology of depression and the therapeutic effects of antidepressant treatment. The present proposal builds on our previous work with ligand positron emission tomography (PET) showing that people at high risk of depression have abnormal expression of 5-HT receptors on cortical and limbic neurones. We believe that the abnormal expression of 5-HT receptors on prefrontal glutamatergic neurones leads to excessive glutamatergic feedback on 5-HT cells in the dorsal raphe, an idea we shall test using ligand PET to measure 5-HT release in this brain region. Animal experimental studies suggest that the effects of ascending 5-HT pathways on mood in depressed patients are mediated via critical interactions with glutamatergic neurones, an idea we shall translate to human studies using developments in proton magnetic resonance spectroscopy (MRS) to measure glutamate concentrations in medial prefrontal cortex in response to 5-HT manipulation. We will also assess whether effects of the NMDA receptor antagonist, ketamine, on cortical glutamate are linked to its reported antidepressant action in patients unresponsive to conventional treatments. At a neuropsychological level we believe that the effects of 5-HT on mood are exerted via modulatory actions on the neural circuitry supporting emotional experience and regulation. We will therefore use functional magnetic resonance imaging (fMRI) to test the hypothesis that the therapeutic effects of selective serotonin re-uptake inhibitors (SSRIs) in depressed patients are mediated by early positive changes in the neural processing of emotional information.

Publications

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Arnone D (2009) Early effects of mirtazapine on emotional processing. in Psychopharmacology

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Chandra P (2010) NK1 receptor antagonism and emotional processing in healthy volunteers. in Journal of psychopharmacology (Oxford, England)

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Cooper CM (2015) Tianeptine in an experimental medicine model of antidepressant action. in Journal of psychopharmacology (Oxford, England)

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Cowen PJ (2011) Has psychopharmacology got a future? in The British journal of psychiatry : the journal of mental science

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Cowen PJ (2015) What has serotonin to do with depression? in World psychiatry : official journal of the World Psychiatric Association (WPA)

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Cowen PJ (2013) Classification of depressive disorders. in Current topics in behavioral neurosciences

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Di Simplicio M (2009) Oxytocin enhances processing of positive versus negative emotional information in healthy male volunteers. in Journal of psychopharmacology (Oxford, England)

 
Description BAP guideline on depression
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact Improvement in the pharmacological management of depression
 
Description MRC strategic review on Mental Health Research
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description NICE Panel on GAD
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact An evidence-based guideline on the treatment of generalised anxiety disorder. Improvements in clinical practice and management.
 
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 MRC Research Grant
Amount £1,500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2013
 
Description Programme Grant
Amount £1,700,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 09/2018
 
Title MRS development 
Description New developments in MRS analysis 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Papers in high impact journals. Further research funding 
 
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 Oxford Biomedical Research Centre 
Organisation University of Oxford
Department Nuffield Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Study of the effect of interferon alpha on brain neurochemistry using MRS
Collaborator Contribution provision of patients and immunological expertise
Impact papers submitted fro publication
Start Year 2009
 
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 Pharmacology 
Organisation University of Oxford
Department Department of Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on clinical translation of a lithium-mimetic
Collaborator Contribution basic animal studies which act as platform for human work.
Impact Grant from BBSRC
Start Year 2010
 
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 Emotional Test Battery 
Description A psychological test battery for the detection of psychotropically active drugs 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2010
Licensed Yes
Impact Industrial support including funding
 
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. 
 
Company Name P1Vital 
Description Interface between Oxford University Dept of Psychiatry and Pharmaceutical Industry. Applying novel methods of drug discovery to screen for new antidperessants at phase 1-2; http://www.p1vital.com/ 
Year Established 2006 
Impact Income generation from Industry through take up of screening studies
Website http://www.p1vital.com
 
Description Autumn psychiatry school 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact 40 medical students and junior doctors attended a series of lectures and visits to our department

Increased interest in a career in psychiatry in students and junior doctors which will hopefully lead to better recruitment rates to the speciality.
Year(s) Of Engagement Activity 2013
URL http://www.psych.ox.ac.uk
 
Description Cheltenham Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 200 people attended talk on antidepressants by Catherine Harmer. Led to intense audience discussion and newspaper articles.

Newspaper articles and journalists contacting the lab
Year(s) Of Engagement Activity 2012
 
Description Newspaper interviews and reports 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Catherine Harmer gave interviews to newspapers about her work on emotional processing and antidepressants

Further articles in the press
Year(s) Of Engagement Activity 2006,2008
 
Description School visit Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Attending schools to talk about biological research in mental health

Requests for work placements
Year(s) Of Engagement Activity 2006,2007