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.
People |
ORCID iD |
Phillip Cowen (Principal Investigator) |
Publications

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

Godlewska BR
(2014)
Short-term escitalopram treatment and hippocampal volume.
in Psychopharmacology

Godlewska BR
(2012)
Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients.
in Psychological medicine

Godlewska BR
(2015)
Neurochemistry of major depression: a study using magnetic resonance spectroscopy.
in Psychopharmacology

Harmer CJ
(2013)
'It's the way that you look at it'--a cognitive neuropsychological account of SSRI action in depression.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Mannie ZN
(2011)
Frontolimbic responses to emotional faces in young people at familial risk of depression.
in Journal of affective disorders

McCabe C
(2011)
SSRI administration reduces resting state functional connectivity in dorso-medial prefrontal cortex.
in Molecular psychiatry


Near J
(2011)
Efficient ?-aminobutyric acid editing at 3T without macromolecule contamination: MEGA-SPECIAL.
in NMR in biomedicine

Near J
(2013)
Unedited in vivo detection and quantification of ?-aminobutyric acid in the occipital cortex using short-TE MRS at 3 T.
in NMR in biomedicine
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 |