Constipation drug may improve cognition, memory in patients with psychiatry disorder: Study

UK: A recent study in the journal Translational Psychiatry has underlined the potential of 5-HT4 receptor agonists for the treatment of cognitive impairment in patients with psychiatric disorders.

The study found that short-term administration of the 5-HT4-receptor agonist, prucalopride improved recall and increased neural activation in the hippocampus and functionally related areas relative to placebo. The findings put together, show the potential of 5-HT4-receptor activation in humans and support its potential as a treatment target for cognitive impairment. 

psychiatric disorders are often accompanied by cognitive deficits but are often under recognized and difficult to treat. Previous studies have shown the 5-HT4 receptor to be a potential treatment target for cognitive impairment. In animal studies, 5-HT4 receptor agonists enhance hippocampal-dependent memory processes. To date, not much research has been done to translate these effects to humans. 

Against the above background, Angharad N. de Cates, Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK, and colleagues tested IF short-term administration of the 5-HT4 partial agonist, prucalopride, modified behavioral and neural (fMRI) memory processing in 44 healthy human volunteers using an experimental medicine model.

44 healthy volunteers aged 18-36 participated in the trial. 23 were given prucalopride, and 21 were given a placebo. After 6 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.

Presenting the work at the European College of Neuropsychopharmacology conference in Lisbon (with simultaneous publication, see below), lead researcher, Dr Angharad de Cates of the University of Oxford said, "Participants who had taken prucalopride for 6 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".

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 (in the center of the brain) and the right angular gyrus (towards the rear of the brain).

Dr Susannah Murphy (Senior Research Fellow, University of Oxford and a senior author of the study) 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".

Angharad de Cates said "This is a proof-of-concept study, and so a starting point for further investigation. 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".

Prucalopride is a 5-HT4 agonist which is taken primarily for constipation. It doesn't have significant side effects if taken under medical supervision, although doctors caution of the possibility of headache, 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.

Commenting, Dr Vibe Frokjaer (Adjunct Professor, Dept. Psychology, Copenhagen University) said:

"This study highlights a very interesting and much-needed potential for repurposing drugs to help cognitive dysfunction, which is often associated with psychiatric disorders even in remitted states. Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations. 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".

Reference:

1) de Cates, A.N., Wright, L.C., Martens, M.A.G. et al. Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task. Transl Psychiatry 11, 497 (2021). https://doi.org/10.1038/s41398-021-01568-4

2) This work is presented at the 34th ECNP Annual conference, which takes place in Lisbon and online from 2-5 October, see https://www.ecnp.eu/Congress2021/ECNPcongress .