, new research suggests.
In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.
After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.
“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.
“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
“Exciting early evidence”
“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.
“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.
Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.
“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”
However, she said in an interview that “a lack of safe human agents made translation tricky.”
As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.
The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”
Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.
In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m2, and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).
On day 6 of treatment administration, all participants underwent 3T MRI.
Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.
During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.