Existing medicine used to treat constipation may increase people’s ability to think more clearly

The development of drugs to treat cognitive problems in patients with mental illness could be one more step after a team of researchers found that an existing drug – used to treat constipation – may be able to improve our ability to think more clearly.

Serious psychiatric disorders can have a devastating impact on a patient’s life. Cognitive impairment – ranging from decreased attention and working memory to impaired social cognition and language – is prevalent in psychiatric disorders such as major depression, schizophrenia, and bipolar disorder. These common problems are poorly treated with current medications and often have a big impact on people’s lives. Scientists are therefore looking for ways to improve or restore these functions.

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

44 healthy volunteers aged 18 to 36 participated in the trial. 23 received prucalopride and 21 received placebo. After 6 days, all volunteers underwent brain fMRI. Before entering the MRI scanner, volunteers were shown a series of images of animals and landscapes. They saw them and similar images again during the analysis. After the scan, the 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.

Presenting the work at the European College of Neuropsychopharmacology conference in Lisbon (with simultaneous publication, see below), Principal Investigator Dr Angharad de Cates of the University of Oxford said: “The participants who took prucalopride for 6 days performed much better than those who received 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 obvious cognitive improvement with the drug surprised us. “

The researchers found that, compared to those taking the placebo, the volunteers taking prucalopride were both significantly better on the memory test after the scan, and also had fMRIs indicating increased activity in areas of the brain related to cognition. The increased activity was in areas associated with memory, such as the hippocampus (in the center of the brain) and the right angular gyrus (towards the back of the brain).

Dr Susannah Murphy (Senior Research Fellow, University of Oxford and lead author of the study) said: “Even when the bad mood associated with depression is treated well with conventional antidepressants, many patients continue to experience memory problems. Our study provides exciting early evidence in humans of a new approach that may be a useful way to address these residual cognitive symptoms.

Angharad de Cates said: “This is a proof-of-concept study, and therefore a starting point for further investigation. We are currently planning and undertaking further studies with prucalopride and other 5HTs.₄ agonists in patients and clinically vulnerable populations, to see if our findings in healthy volunteers can be replicated and have clinical significance “.

Prucalopride is a 5-HT₄ agonist which is taken primarily for constipation. It does not have significant side effects if taken under medical supervision, although doctors warn of the possibility of headaches, gastrointestinal 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 this study.

This study highlights a very interesting and much needed potential for the reuse of drugs to help cognitive dysfunction, which is often associated with psychiatric disorders, even in states of remission. It is important to note that, as the authors also state, it will be critical to translate these findings from healthy populations into clinical populations. It will also be important to understand whether prucalopride adds to the effects of existing antidepressant treatments, or can be used as stand-alone therapy.“.

Dr Vibe Frokjaer, Assistant Professor, Department of Psychology, University of Copenhagen