PF-04995274 and emotional processing in treatment-resistant depression
Research type
Research Study
Full title
The effects of PF-04995274 on emotional processing in treatment-resistant, medicated depressed patients
IRAS ID
236125
Contact name
Catherine Harmer
Contact email
Sponsor organisation
Clinical Trials and Governance, University of Oxford
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
The aim of this study is to test the short-term effects of a novel drug candidate PF-04995274, which may be better tolerated and faster acting than currently available antidepressants. The primary aim is to administer the drug to treatment-resistant, currently medicated patients with Major Depressive Disorder (MDD) for a week (15mg daily) and then test for early changes in emotional processing, which have been previously found to predict treatment response. A secondary aim will be to test the effects of the drug on non-emotional information processing to better understand antidepressant effects on cognition. The study will recruit 50 patients with treatment-resistant depression who are currently medicated and randomise them into two groups (PF-04995274 or placebo). The participants will undergo an initial medical screening session and after a week of drug administration they will be tested on a battery of information processing tasks. The work will take place at the Department of Psychiatry in Warneford hospital at University of Oxford.
Summary of Results:
STUDY BACKGROUND The antidepressants doctors prescribe now, while useful for many, don’t work for everybody. Their side effects can also be a problem.
Doctors sometimes prescribe an extra drug when an antidepressant isn’t working on its own. This called “combination therapy” or “augmentation therapy”. Our study looked at a new drug which might be helpful to take in combination with a regular antidepressant.
In our brain, we have chemical messengers – one of these is called serotonin. We also have receptors, which receive signals from these chemical messengers. There are multiple types of serotonin receptors.
Antidepressants often work by making lots of serotonin receptors respond differently. A new approach could be to make specific serotonin receptors more “active”. One type of drug which does this is called a 5-HT4 agonist.
Research on animals has suggested that 5-HT4 agonists could help treat depression. In particular, this research suggested that combining a 5-HT4 agonist with a common antidepressant could be helpful. Therefore, we chose to look at how a 5-HT4 agonist works in our study.
Current antidepressants reduce the negative ways that people think about themselves, others, and the world. This is called “emotional bias”. One way to study emotional bias is by asking people to interpret facial expressions.
One of the most commonly prescribed antidepressants is citalopram. We have found in previous studies that citalopram can reduce negative biases. Citalopram seems to make people less sensitive to negative faces. It also leads people to see faces more positively.STUDY QUESTION
We wanted to study people who were taking an antidepressant but were still depressed. We wanted to find out if taking a 5-HT4 agonist plus an antidepressant would change emotional bias. We also wanted to find out if a 5-HT4 agonist plus an antidepressant could help with other problems in depression, such as memory.STUDY METHODS
Between 2018 and 2022, we asked for volunteers to take part in a study based at the University of Oxford. Fifty four volunteers with clinical depression helped our research study. All of them were already taking a regular antidepressant, but were still depressed.
All volunteers were first seen by a psychiatrist. Then they were randomly put into one of two groups. For seven days, volunteers either took:
• a 5-HT4 agonist, called PF-04995274 (new drug)
• a dummy pill containing no medicine (placebo).
All volunteers continued taking their regular antidepressant as normal throughout the study. The study tablets looked identical for all volunteers. Neither the researchers nor the volunteers knew which sort of pill they were taking (this is known as a ‘double blind’ trial).
Seven days after starting the pills, the volunteers completed computer tasks. These tasks mostly looked at emotional bias and memory.
Separate to the computer tasks, we also rated volunteers for their symptoms of depression before and after the study. We did this without knowing which of the two groups they were in.
Patients with experience of depression helped motivate the study, and gave advice on the running of the study. They also helped review the information given to volunteers and helped write this summary.STUDY FINDINGS
Volunteers in the two groups did not show any differences in emotional bias or memory. There was also no difference in depression scores.
We also recorded experience of side effects. There were no serious side effects reported in the study.FUTURE RESEARCH
For people taking an existing antidepressant and still feeling depressed, a 5-HT4 agonist does not seem to provide extra benefits. However, we have also ran a very similar study in people who were not taking an antidepressant. This study did find potential benefits and we are exploring that further.
We are also currently researching the effects of a 5-HT4 agonist in people recovering from depression. We are using a bigger range of computer tasks and looking at memory in more detail.ACKNOWLEDGEMENTS
We would like to thank all the volunteers who gave their time to make this research possible. We would also like to thank all the many staff involved over the four years.
The Medical Research Council gave us money to look at this. Pfizer, a pharmaceutical company, gave us a new 5-HT4 agonist to use. Pfizer did not give us any money or talk to us about our results. None of the research staff have any financial investment in the 5-HT4 agonist. The Wellcome Trust provided money to support one of the doctors working on the study. The NIHR Oxford Health Biomedical Research Centre also supported the study.
For more information about this study, you can email amy.gillespie@psych.ox.ac.uk.REC name
South Central - Oxford C Research Ethics Committee
REC reference
18/SC/0074
Date of REC Opinion
27 Feb 2018
REC opinion
Favourable Opinion