A drug approved to treat constipation appears to improve cognitive impairment and boost brain activity for patients with mental illness, 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,” 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,” 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 told Medscape Medical News 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 US 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.
In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.
However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.
Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).
Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.
There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).
“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.
“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.
De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.
“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET [positron-emission tomography] data to tell us what the optimal dose for binding at the receptor should be,” said de Cates.
“In safety studies, the dose was trialled in healthy volunteers at 4mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, Department of Psychology, Copenhagen University, Copenhagen, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”
He noted that cognitive dysfunction is often associated with psychiatric disorders ― even in states of remission.
“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Frøkjær, who was not involved in the research.
“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.
The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.
34th European College of Neuropsychopharmacology (ECNP) Congress: Abstract IN.08.03. Presented October 4, 2021.
Transl Psychiatry. Published online October 4, 2021. Full text
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