MICA: 5-HT4 receptor activation as a novel mechanism of antidepressant action
Lead Research Organisation:
University of Oxford
Department Name: Psychiatry
Abstract
People with depression often receive treatment with antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). SSRIs produce activation of all types of serotonin receptors and some of these receptors are thought to mediate side-effects rather than the therapeutic effect of SSRIs. Also activation of certain other serotonin receptors may delay the onset of therapeutic action of the SSRI treatment.
Animal experimental studies have suggested that the 5-HT4 serotonin receptor may be important in mediating the antidepressant effects of SSRIs and targeting this receptor directly may work more quickly than conventional SSRI treatment. Carrying out large-scale clinical trials of new agents in depressed patients is costly and time consuming and therefore one would only want to pursue this approach when there was supporting evidence from experimental medicine studies in humans that 5-HT4 receptor drugs may well be useful in depression.
We have developed models of emotional processing (psychological tests that measure how people respond to emotional stimuli) that can detect potential antidepressant effects of novel compounds after only a few days of treatment. We therefore plan to use these models to see whether a new drug that selectively activates 5-HT4 receptors can produce antidepressant-like changes in emotional processing after just one week of treatment.
We will carry out these studies in two separate groups of depressed patients: first, those who are not taking any antidepressant medication and second, people who have not experienced a good response to their current treatment. Both these clinical situations are where advances in drug treatment are badly needed.
Positive results from one or both of these studies will lead on to formal clinical trials of a 5-HT4 receptor agonist drug in depressed patients.
Animal experimental studies have suggested that the 5-HT4 serotonin receptor may be important in mediating the antidepressant effects of SSRIs and targeting this receptor directly may work more quickly than conventional SSRI treatment. Carrying out large-scale clinical trials of new agents in depressed patients is costly and time consuming and therefore one would only want to pursue this approach when there was supporting evidence from experimental medicine studies in humans that 5-HT4 receptor drugs may well be useful in depression.
We have developed models of emotional processing (psychological tests that measure how people respond to emotional stimuli) that can detect potential antidepressant effects of novel compounds after only a few days of treatment. We therefore plan to use these models to see whether a new drug that selectively activates 5-HT4 receptors can produce antidepressant-like changes in emotional processing after just one week of treatment.
We will carry out these studies in two separate groups of depressed patients: first, those who are not taking any antidepressant medication and second, people who have not experienced a good response to their current treatment. Both these clinical situations are where advances in drug treatment are badly needed.
Positive results from one or both of these studies will lead on to formal clinical trials of a 5-HT4 receptor agonist drug in depressed patients.
Technical Summary
The study will explore the potential antidepressant effect of PF-04995274, a novel 5-HT4 receptor partial agonist originally developed by Pfizer for dementia and cognitive impairment. We will use an experimental medicine model, sensitive to the early effects of antidepessant drug treatment, in depressed patients. This battery of tasks measures different aspects of emotional processing (perception, memory, attention and physiological reactivity) and is affected early in treatment by a range of antidepressant drug treatments. The study will recruit two groups of depressed patients, those currently unmedicated and those who have failed to respond to current SSRI treatment. In study one, unmedicated patients will be randomised to PF-04995274, citalopram (as a positive control) or placebo. In study two, patients not responding to current therapy will be randomised to either the addition of PF-04995274 or placebo while they continue their current treatment. The treatment period in both studies will be seven days. Study design will be parallel group, double-blind, placebo-controlled and with emotional processing measured before and after the seven day treatment period. It is hypothesised that PF-04995274 will show antidepressant-like effects in these models, expressed as an increase in perception and memory for positive vs negative stimuli. A positive screen in these models would provide support for assessment of 5HT4 agonists in the treatment of depression.
Planned Impact
Depression is the leading cause of disability worldwide, and is a major contributor to the overall global burden of disease. Current treatments are limited in terms of efficacy, time to onset and unwanted side effects.
The aim of the current research project is to assess a role for a specific serotonin receptor (the 5-HT4 receptor) in antidepressant drug action based on exciting evidence from preclinical approaches. If this research is successful it could lead to the first use of a selective 5-HT receptor subtype ligand to treat clinical depression both as a first line treatment and in treatment resistant depression. Patients with depression (particularly that which does not respond to current approaches) and their families will therefore benefit by a new form of drug treatment becoming available.
In addition to patients, the research will be of value to clinicians, particularly those treating depression, because it will increase awareness of the availability of new approaches.
The work will also be of importance to the field of psychiatry in general, emphasising the link that it is possible to continue to improve antidepressant drug treatments and that basic research and 'drug repurposing' are important in this effort.
Other beneficiaries could be the Pharmaceutical Industry who will benefit from the ability to have new targets to treat depression and associated disorders.
The aim of the current research project is to assess a role for a specific serotonin receptor (the 5-HT4 receptor) in antidepressant drug action based on exciting evidence from preclinical approaches. If this research is successful it could lead to the first use of a selective 5-HT receptor subtype ligand to treat clinical depression both as a first line treatment and in treatment resistant depression. Patients with depression (particularly that which does not respond to current approaches) and their families will therefore benefit by a new form of drug treatment becoming available.
In addition to patients, the research will be of value to clinicians, particularly those treating depression, because it will increase awareness of the availability of new approaches.
The work will also be of importance to the field of psychiatry in general, emphasising the link that it is possible to continue to improve antidepressant drug treatments and that basic research and 'drug repurposing' are important in this effort.
Other beneficiaries could be the Pharmaceutical Industry who will benefit from the ability to have new targets to treat depression and associated disorders.
Publications
De Cates A
(2022)
The Effect of the 5-HT4 Agonist, Prucalopride, on a Functional Magnetic Resonance Imaging Faces Task in the Healthy Human Brain
in Frontiers in Psychiatry
De Cates AN
(2021)
Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task.
in Translational psychiatry
De Cates AN
(2023)
5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action.
in Biological psychiatry. Cognitive neuroscience and neuroimaging
Murphy SE
(2021)
Translating the promise of 5HT4 receptor agonists for the treatment of depression.
in Psychological medicine
Murphy SE
(2020)
A role for 5-HT4 receptors in human learning and memory.
in Psychological medicine
Description | Biomedical Research Centre: Theme on Depression Therapeutics |
Amount | £35,000,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 11/2022 |
End | 11/2027 |
Description | Characterising the direct effects of fenfluramine on cognition: an experimental medicine study |
Amount | £265,000 (GBP) |
Organisation | Zogenix Inc |
Sector | Private |
Country | United States |
Start | 11/2020 |
End | 04/2023 |
Description | Pfizer asset sharing |
Organisation | Pfizer Inc |
Country | United States |
Sector | Private |
PI Contribution | We set up the research studies outlined in the application and are collecting/analysing the data. |
Collaborator Contribution | Pfizer contributed their asset (5HT4 partial agonist) and are involved in stability testing |
Impact | A dataset testing the role of 5HT4 receptors in antidepressant drug action |
Start Year | 2016 |
Description | Banbury Museum & Gallery 'Your amazing brain exhibition' (talk) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | As part of the Banbury Museum 'Your amazing brain exhibition', a talk was given by one of the DPhil/clinical psychiatrist's (Dr de Cates) on this grant, illustrating the research we are carrying out and the first hand experience of being a clinical research psychiatrist. The students were very engaged and asked a lot of questions. Students came away from the event with better knowledge and understanding of what it is like to work in this area and thus better informed to make a choice as to whether they would like to pursue this career themselves. |
Year(s) Of Engagement Activity | 2022 |
Description | Café Scientifique |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | An evening event with a talk and discussion. The aim of the Café Scientifique is to provide a public forum in which scientific ideas can be discussed informally. We presented our work on novel approaches to depression treatment, including our work on the 5-HT4 receptor. There were around 50-60 attendees in total and the talk was followed by a lively discussion with many questions. |
Year(s) Of Engagement Activity | 2023 |
URL | https://users.ox.ac.uk/~quarrell/cafescientifique/oxford/ |
Description | Festival activities |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | We initiated a programme of activities including holding stands at local festivals (restore, headington festival) and talks at schools (surprising science) around this project and its background |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.restandstudy.co.uk/restandstudyupdates.html |
Description | Library Lates |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | We ran an interactive session at the Western Library (organised by the Bodleian Library: library lates) including presenting as a living book and public engagement games focused on how we find new antidepressants |
Year(s) Of Engagement Activity | 2021 |
Description | NIHR Oxford & Oxford Health BRCs Joint Open Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | NIHR Oxford & Oxford Health BRCs Joint Open Day showcased research being conducted through the Biomedical Research centres (BRC). This grants work is supported by the Oxford Health BRC. We had a stall at this Open Day with information about our research and how people could participate. |
Year(s) Of Engagement Activity | 2022 |
Description | NIHR Oxford & Oxford health BRC Open Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | We ran a stall at the open day at the, Westgate shopping centre Oxford, 10th May 2023. This reached a large number of people and attracted signficant inerest |
Year(s) Of Engagement Activity | 2023 |
Description | Oxford Neuroscience Experience |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | We hosted a workshop during the Oxford Neuroscience Experience with 12 A'level students interested in neuroscience as a career. Our event focused on designing an experimental medicine study inspired by work carried out in this grant award |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.neuroscience.ox.ac.uk/oxford-neuroscience-experience |
Description | Restore Fayre |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | We held a public engagement stall at a local mental health charity fayre (RESTORE Fayre) in August 2022. We had lots of interactive games for the general public and their families, that facilitated conversations about our experimental medicine research. We spoke to lots of people with wide ranging views and levels of prior knowledge, which lead to very informative and interesting discussion. People came away from the stall with further knowledge about what we do as researchers and why and how we conduct our studies. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.psych.ox.ac.uk/research/psychopharmacology-and-emotion-research-laboratory/volunteer-for... |
Description | School neuroscience experience |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | We hosted a workshop during the Oxford Neuroscience Experience with 24 year 12 students interested in neuroscience as a career. Our event focused on designing an experimental medicine study inspired by work carried out in this grant award |
Year(s) Of Engagement Activity | 2021,2022 |
URL | https://www.psych.ox.ac.uk/research/psychopharmacology-and-emotion-research-laboratory |