PF-04995274 and emotional processing in un-medicated depression
Research type
Research Study
Full title
The effects of PF-04995274 on emotional processing in un-medicated depressed patients
IRAS ID
237793
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
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 un-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 and a tertiary aim is to examine its effects in brain activity using functional Magnetic Resonance Imaging (fMRI). The study will recruit 75 patients with depression who are currently unmedicated and randomise them into three groups (PF-04995274, citalopram or placebo). Citalopram will act as a positive control. The participants will undergo an initial medical screening session and after a week of drug administration they will undergo the fMRI scan and 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. Our study looked at a new drug which might be an improvement.
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. Therefore, we chose to look at a 5-HT4 agonist in our study. We wanted to understand how this treatment might work in depression.
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 find out if a 5-HT4 agonist changes emotional bias, in the same way as citalopram. We also wanted to find out if a 5-HT4 agonist 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. Ninety volunteers with clinical depression helped our research study. None were receiving any specific treatment for depression.
All volunteers were first seen by a psychiatrist. Then they were randomly put into one of three groups. For seven days, volunteers either took:
* a 5-HT4 agonist, called PF-04995274 (new drug)
* citalopram (common antidepressant)
* a dummy pill containing no medicine (placebo).
The tablets looked identical for all volunteers. Neither the researchers nor the volunteers knew which sort of pill they were taking (known as a ‘double blind’ trial).
We gave each volunteer an MRI scan six days after starting the pills. The scan looked at their brain activity while they completed some computer tasks. One looked at emotional bias and one looked at memory. Then a day later they completed more computer tasks, but not in the scanner. These tasks also 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 three groups they were in.
Patients helped motivate the study, and give advice on the running of the study. They also helped review the information given to volunteers and helped write this summary.
STUDY FINDINGS
We had three main findings:
One, volunteers given citalopram had less negative bias when looking at faces. Their brain activity also showed related changes when they looked at emotional faces. These results were expected and similar to previous research.
Two, volunteers given the 5-HT4 agonist didn’t show the same changes as the citalopram group. However, their MRI did show changes in brain activity during the memory task. The citalopram group didn’t show these changes. The 5-HT4 agonist seems to change how we remember new information rather than how we interpret emotional information.
Three, volunteers in both the citalopram and 5-HT4 agonist groups reported bigger decreases in their depression symptoms compared with the group taking the dummy pill. This early finding suggests that 5-HT4 agonists may have clinical benefits as an antidepressant. However, a one-week study is not enough time to clearly say whether a drug has the potential to treat clinical depression.
We also recorded experience of side effects. There were no serious side effects reported in the study. Volunteers given the 5-HT4 agonist had similar (or lower) levels of side effects than those given citalopram.
FUTURE RESEARCH
We recommend that there is a formal clinical trial into whether 5-HT4 agonists work as an antidepressant. It should also look into whether the benefits of 5-HT4 agonists in depression come from changes in memory.
We are 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 Oxford Health Biomedical Research Centre also supported the study.
REC name
South Central - Oxford B Research Ethics Committee
REC reference
18/SC/0076
Date of REC Opinion
7 Mar 2018
REC opinion
Further Information Favourable Opinion