Clinical Psychopharmacology of 5-HT

Lead Research Organisation: University of Oxford
Department Name: Psychiatry

Abstract

Clinical depression is a common illness, often beginning during the teenage years, which can recur throughout a lifetime. The recurrent nature of clinical depression, together with the burden it places on sufferers and their families, makes this condition second only to heart disease in terms of suffering and disability. Understanding the biochemical changes in the brain in depression will help us to devise better treatments and also improve efforts at prevention. New advances in brain imaging now allow us to study the biochemistry of the brain directly in patients and healthy volunteers. Using a special radio-labelled marker with an imaging examination called positron emission tomography (PET) we have found a decrease in certain kinds of brain receptors for a chemical messenger called serotonin (also called 5-HT) in depressed patients, both when they are ill and after recovery. This suggests that abnormal function of 5-HT may play a role in making people vulnerable to developing depression. In the present research programme will use PET imaging to study other kinds of 5-HT receptors to better understand the range of brain 5-HT receptor abnormalities in depression. In addition we will use another kind of brain imaging called magnetic resonance spectroscopy (MRS) to see how 5-HT interacts with special neurons in the cerebral cortex that use a chemical messenger called GABA. We believe that the interactions between 5-HT and GABA may be very important in helping us understand the cause of depression and in developing more effective methods of treatment. Finally we will study young people who we know are at risk of depression to see if altered 5-HT activity predates the onset of depression and might therefore be useful as a means of predicting which people are most at risk. If changes in 5-HT do predate the onset of depression it is possible that a relatively simple means of modifying 5-HT (for example, a dietary intervention) could be used to prevent the onset of depression in young people at risk.

Technical Summary

Recurrent major depression is a common, often life-long condition, with a high morbidity. The neurobiology of the disorder is not well understood but abnormalities in brain 5-HT function appear to play an important role in the pathophysiology of both depression and the therapeutic effects of antidepressant treatment. The present proposal aims to build on our findings with both ligand PET imaging and 5-HT pharmacological challenge studies that depressed patients have abnormalities in aspects of brain 5-HT function that persist into clinical recovery. We will continue to use PET imaging to identify additional abnormalities in brain 5-HT receptors in depressed patients and examine their status as trait or state markers. Basic studies suggest that cortical GABA-ergic interneurones are a key target for ascending 5-HT pathways and that changes in GABA activity in mood-related circuitry could mediate the therapeutic effects of 5-HT promoting agents. We will therefore use proton magnetic resonance spectroscopy (MRS) to examine GABA-5-HT interactions in both healthy subjects and those at risk of depression. In addition we will use a 5-HT neuroendocrine challenge test and a 5-HT-sensitive emotional processing task to identify neurobiological abnormalities in young people at high risk of depression. Our long-term aim is to devise feasible preventative strategies to decrease the risk of early-onset, recurrent depression in this vulnerable group.

Publications

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Browning M (2007) A single dose of citalopram increases fear recognition in healthy subjects. in Journal of psychopharmacology (Oxford, England)

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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)

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Hinz R (2008) Effects of citalopram infusion on the serotonin transporter binding of [11C]DASB in healthy controls. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
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 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 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 MRC Research Grant
Amount £430,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2009 
End 11/2012
 
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 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
 
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 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 Press Conference Royal Society 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press Conference arranged by Royal Society to talk about burden of mental health problems

articles in media
Year(s) Of Engagement Activity 2009
 
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