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.
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.
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.
Organisations
- University of Oxford (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- Sound Pharmaceuticals (Collaboration)
- University of Zurich (Collaboration)
- Johnson & Johnson (Collaboration)
- Oxford Health NHS Foundation Trust (Collaboration)
- Imanova (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
Publications
Arnone D
(2018)
The effects of serotonin modulation on medial prefrontal connectivity strength and stability: A pharmacological fMRI study with citalopram.
in Progress in neuro-psychopharmacology & biological psychiatry
Barkus C
(2018)
The putative lithium-mimetic ebselen reduces impulsivity in rodent models.
in Journal of psychopharmacology (Oxford, England)
Bukala BR
(2019)
Overnight transdermal scopolamine patch administration has no clear effect on cognition and emotional processing in healthy volunteers.
in Journal of psychopharmacology (Oxford, England)
Capitão LP
(2023)
Acute neural effects of fluoxetine on emotional regulation in depressed adolescents.
in Psychological medicine
Capitão LP
(2019)
A single dose of fluoxetine reduces neural limbic responses to anger in depressed adolescents.
in Translational psychiatry
Chamberlain S
(2017)
Treatment-resistant depression and peripheral C-reactive protein
Chamberlain SR
(2019)
Treatment-resistant depression and peripheral C-reactive protein.
in The British journal of psychiatry : the journal of mental science
Cipriani A
(2018)
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in service personnel.
in The lancet. Psychiatry
Clarke WT
(2021)
FSL-MRS: An end-to-end spectroscopy analysis package.
in Magnetic resonance in medicine
Cooper CM
(2018)
Interferon-a induces negative biases in emotional processing in patients with hepatitis C virus infection: a preliminary study.
in Psychological medicine
Cowen PJ
(2017)
Backing into the future: pharmacological approaches to the management of resistant depression.
in Psychological medicine
Cowen PJ
(2015)
What has serotonin to do with depression?
in World psychiatry : official journal of the World Psychiatric Association (WPA)
De Kovel C
(2019)
No Alterations of Brain Structural Asymmetry in Major Depressive Disorder: An ENIGMA Consortium Analysis
in American Journal of Psychiatry
DeMaster D
(2022)
Effective connectivity between resting-state networks in depression.
in Journal of affective disorders
Erritzoe D
(2023)
Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge.
in Biological psychiatry
Fang F
(2022)
Effects of escitalopram therapy on functional brain controllability in major depressive disorder.
in Journal of affective disorders
Fang F
(2023)
Predicting Antidepressant Treatment Response Using Functional Brain Controllability Analysis
in Brain Connectivity
Godlewska B
(2019)
Changes in brain Glx in depressed bipolar patients treated with lamotrigine: A proton MRS study
in Journal of Affective Disorders
Godlewska B
(2021)
Brain glutamate concentration in men with early psychosis: a magnetic resonance spectroscopy case-control study at 7 T
in Translational Psychiatry
Godlewska BR
(2016)
Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression.
in Translational psychiatry
Godlewska BR
(2017)
Brain glutamate in anorexia nervosa: a magnetic resonance spectroscopy case control study at 7 Tesla.
in Psychopharmacology
Godlewska BR
(2018)
Brain glutamate in medication-free depressed patients: a proton MRS study at 7 Tesla.
in Psychological medicine
Godlewska BR
(2017)
Ultra-High-Field Magnetic Resonance Spectroscopy in Psychiatry.
in Frontiers in psychiatry
Godlewska BR
(2022)
Neurochemical abnormalities in chronic fatigue syndrome: a pilot magnetic resonance spectroscopy study at 7 Tesla.
in Psychopharmacology
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 a guidance/advisory committee |
Description | Biomedical catalyst |
Amount | £1,113,147 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
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 | 08/2013 |
End | 09/2015 |
Description | Medical Research Council MICA award |
Amount | £1,000,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2017 |
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 | 06/2016 |
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 in study of treatment resistant depression |
Impact | Ethics submission of experiemntal medicine study |
Start Year | 2020 |
Description | Wellcome Trust Inflammation Collaboration |
Organisation | University of Cambridge |
Department | Department of Psychology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Extension of collaboration into clinical trial of a P2X receptor blocker in patients with resistant depression |
Collaborator Contribution | Access to novel therapeutic compound, contribution to multiicentre study in patients with depression. |
Impact | Application for funding to Wellcome Trust- Funded approved in Sept 2014 |
Start Year | 2013 |
Title | TREATMENT OF IMPULSIVITY-RELATED DISORDERS |
Description | The invention relates to the treatment of impulsivity-related disorders, such as a substance-related addiction, a behavioural addiction, relapse to a substance-related or behavioural addiction, a habit or impulsive disorder, an emotional unstable personality disorder, intentional self harm, an eating disorder, a dopamine agonist-induced impulse control disorder, or attention deficit hyperactivity disorder (ADHD) by administering a compound of Formula I or a salt thereof to a subject; Formula (I) wherein: E is S or Se; R1 and R2 are optional substituents, and are at each occurrence independently selected from: (1) a halogen, which is preferably selected from F, CI and Br; (2) C1-C4 alkyl, such as C1-C2 alkyl or C1 alkyl, optionally substituted with one or more halogen atoms, each of which is preferably selected from F, CI and Br; and (3) C1-C4 alkoxy, such as C1-C2 alkoxy or C1 alkoxy; optionally substituted with one or more halogen atoms, each of which is preferably selected from F, CI and Br; m is an integer in the range of from 0 to 5; and n is an integer in the range of from 0 to 4. The compound can also be used to treat or control impulsivity control disorders in patients undergoing dopamine agonist treatment, for example in patients suffering from Parkinson's disease or ADFID. |
IP Reference | WO2017187176 |
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 depression |
Description | Ebselen is an anti-oxidant which produces lithium-like effects on the enzyme, IMPase. Ebselen also produces positive shifts in emotional processing suggesting an antidepressant action. Lithium is effective an as 'add-on' treatment in patients with resistant depression. We are therefore developing ebselen for this purpose via and experimental medicine model in depressed patients. Funding has been received from the MRC for an experimental medicine study examining ebselen in patients with treatment resistant depression. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2018 |
Development Status | Under active development/distribution |
Impact | Patent applied for the use of ebselen in patients with depression. |
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. |
URL | https://clinicaltrials.gov/show/NCT03013400 |
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 |