The results of a small trial in healthy human volunteers suggest that a drug currently used to treat constipation might potentially also help to improve cognitive problems in patients with mental illness. The trial, headed by researchers at the University of Oxford, demonstrated that prucalopride, a drug that activates the 5-HT4 receptor, may also boost our ability to think more clearly. Prucalopride has an acceptable level of side effects, if taken under medical supervision.

“This is a proof-of-concept study, and so a starting point for further investigation,” said Angharad de Cates, PhD, first author of the team’s published study in Translational Psychiatry.  “We are currently planning and undertaking further studies looking at prucalopride and other 5HT4 agonists in patients and clinically vulnerable populations, to see if our findings in healthy volunteers can be replicated and have clinical importance.” The authors, including researchers at Maastricht University, and the IRCCS San Camillo Hospital in Venice, reported on their findings in a paper titled, “Déjà-vu? Neural and behavioral effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task.”

Severe psychiatric disorders can have a devastating impact on patients’ lives. Cognitive impairments—ranging from decreased attention and working memory to disrupted social cognition and language—are widespread in psychiatric disorders such as major depression, schizophrenia, and bipolar disorder. These common problems are poorly treated with current medications, and so scientists are searching for ways of improving or restoring these functions. “ … cognitive deficits may appear alongside but seem separate from other coexisting psychopathology, and often are not well treated by interventions that relieve other symptoms of the disorder,” the team stated. “Given the significant impact such impairments can have on quality of life, there is a critical need for the development of treatments that can ameliorate the cognitive deficits associated with psychiatric disorder.”

Serotonin is the neurotransmitter that is targeted by SSRI antidepressants, and in animals studies, drugs targeting the 5-HT4  serotonin receptor have shown promise in improving cognitive function. However, it has been difficult to translate animal findings into humans, because of concerns about potential side effects. More recently, prucalopride, a selective high-affinity 5HT4 partial agonist, was licensed as a treatment for constipation, and this has opened up an avenue for study, the authors noted. “This has allowed us to investigate 5-HT4-receptor agonism in humans using an experimental medicine model to assess potential enhancement of cognition in healthy humans. We hypothesized that prucalopride would improve episodic memory and increase the activation of the hippocampus and related neural circuitry during memory retrieval.”

Their reported randomized, double-blind trial involved 44 healthy volunteers, aged 18–36 years. Twenty-three participants were given 1 mg prucalopride per day, for seven days, and the remaining 21 individuals were given a placebo, also for seven days. After six days all the volunteers underwent a functional MRI brain scan. Before entering the MRI scanner, each individual was shown a series of images of animals and landscapes. They viewed these again plus similar images during the scan. After the scan, volunteers performed a memory test: they were asked to distinguish the images they had seen before and during the scan from a set of completely new images.

Illustration: fMRI brain scans, showing the increased brain activity in the right angular gyrus in the prucalopride group versus the placebo group. [Angharad De Cates. This illustration is licensed under Creative Commons Attribution 4.0 International License. See Creative Commons license for more information.]
The researchers found that, compared with those taking the placebo, the volunteers taking prucalopride were both significantly better at the memory test after the scan, and also had fMRI scans indicating enhanced activity in brain areas related to cognition. “Specifically, in the post-scan recall task, participants on prucalopride were better able to distinguish each type of image, as well as demarcate those seen before and/or during the scan from the new distractor images,” the team noted. The increased activity was in areas associated with memory, such as the hippocampus, which is in the center of the brain, and the right angular gyrus, located towards the rear of the brain.

“At a neural level, prucalopride bilaterally increased hippocampal activity and activity in the right angular gyrus compared with placebo,” the authors stated. “Our study confirms that 5-HT4-receptor agonism with prucalopride appears to lead to hippocampal activation in response to a memory stimulus, which is likely associated with behavioral effects related to cognitive performance … Prucalopride also significantly increased activation in a region associated with memory retrieval (the right angular gyrus) during a task where participants had to recall recently encoded information.”

Presenting the work at the European College of Neuropsychopharmacology conference in Lisbon, to coincide with publication, de Cates reported, “Participants who had taken prucalopride for six days performed much better than those receiving placebo on the memory test; the prucalopride group identified 81% of previously viewed images versus 76% in the placebo group. Statistical tests indicate that this was a fairly large effect—such an obvious cognitive improvement with the drug was a surprise to us.”

Prucalopride doesn’t have significant side effects if taken under medical supervision, although doctors caution of the possibility of headache, gastro-intestinal symptoms such as abdominal pain, nausea, and diarrhea, and fatigue or dizziness. There were no significant side effects shown by any of the volunteers taking prucalopride in the reported study.

Senior study author Susannah Murphy PhD, a University of Oxford senior research fellow, further commented, “Even when the low mood associated with depression is well treated with conventional antidepressants, many patients continue to experience problems with their memory. Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms.”

The authors acknowledged that further research will be required to investigate the use of the drug further, including optimizing dose, and determining which specific areas of the brain may benefit from 5-HT4 receptor agonism, which would “… enable precise targeting of deficits as part of a personalized approach to treatment.” The team concluded, Our study holds promise for the future use of 5-HT4-receptor agonists in terms of ameliorating some of the cognitive impairments associated with psychiatric disorders.”