Intestinal drug found to boost memory and cognition

The development of drugs to treat cognitive problems in patients with mental illness may be a step closer, with UK researchers discovering that an existing drug — used to treat constipation — may be able to boost our ability to think more clearly.

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 often have a large impact on people’s lives, so scientists are searching for ways of improving or restoring these functions.

Previous animal studies have shown that the drugs which target one of the serotonin receptors (the 5-HT₄ receptor) have shown promise in improving cognitive function, serotonin being the neurotransmitter which is targeted by SSRI antidepressants. However, it has been difficult to translate these animal findings into humans because of worries about side effects. Now researchers at the University of Oxford have tested an existing approved drug, prucalopride, which targets the 5-HT₄ receptor, and found that it may improve cognition. Prucalopride is primarily prescribed for constipation, and has an acceptable level of side effects if taken under medical supervision.

Out of 44 healthy trial participants aged 18–36, 23 were given prucalopride and 21 were given a placebo. After six days all the volunteers were given an fMRI brain scan. Before entering the MRI scanner, volunteers were 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.

“Participants who had taken prucalopride for six days performed much better than those receiving the placebo on the memory test; the prucalopride group identified 81% of previously viewed images versus 76% in the placebo group,” said lead researcher Dr Angharad de Cates. “Statistical tests indicate that this was a fairly large effect — such an obvious cognitive improvement with the drug was a surprise to us.”

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. The increased activity was in areas associated with memory, such as the hippocampus and the right angular gyrus. The team’s results were presented at the 34th ECNP Congress and published in the journal Translational Psychiatry.

“This is a proof-of-concept study, and so a starting point for further investigation,” de Cates said. “We are currently planning and undertaking further studies looking at prucalopride and other 5HT₄ agonists in patient and clinically vulnerable populations, to see if our findings in healthy volunteers can be replicated and have clinical importance.”

Explaining the significance of the study, senior author Dr Susannah Murphy said, “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.”

Image caption: fMRI brain scans, showing the increased brain activity in the right angular gyrus in the prucalopride group versus the placebo group. Image courtesy of Angharad de Cates under CC BY 4.0.

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