Clinical Psychopharmacology of 5-HT

Lead Research Organisation: University of Oxford

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

10 25 50
 
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 NMHB
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
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 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 P1vital 
Organisation P1vital Consortium
Country United Kingdom 
Sector Private 
PI Contribution A MICA grant submitted to the MRC. The contribution is from J&J and has been brokered by P1vital
Collaborator Contribution Intellectual and financial contribution to studies of chocolate mediated reward
Impact Application to MRC
Start Year 2010
 
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