A drug called prucalopride appears to enhance functional connectivity between major cognitive networks in the brain, according to new research published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. The new findings provide a possible explanation for why previous studies have shown that drugs that activate a specific type of serotonin receptor called the 5-HT4 receptor can improve cognitive function.
Based on these findings, there is hope that drugs targeting the 5-HT4 receptor, like prucalopride, could be used as potential treatments for people with psychiatric conditions that involve cognitive problems.
The motivation behind this study was rooted in the significant impact of depression on cognitive function and the limitations of current treatments in addressing these cognitive deficits. Major depressive disorder is a prevalent mental health condition affecting approximately 1 in 5 individuals during their lifetime.
It not only leads to emotional distress but also causes cognitive impairments, such as memory problems, difficulties with attention and concentration, reduced processing speed, and impaired executive functioning. These cognitive deficits can be severe and disabling, often persist even after the mood symptoms have improved, and are rated by patients as their most significant concern after low mood.
Despite the widespread occurrence of cognitive deficits in depression and their profound effect on individuals’ quality of life and functioning, existing antidepressant medications, which primarily target serotonin receptors, do not consistently address these cognitive symptoms effectively. While they may improve mood and reduce emotional symptoms, they often fall short in enhancing cognitive function. This unmet need for treatments that specifically target cognitive impairment in depression has spurred researchers to explore new avenues for intervention.
In this context, the authors of this study turned their attention to serotonin receptors, particularly the 5-HT4-type receptors, which are found in brain regions responsible for cognitive function and mood regulation. Preclinical data in animals had already suggested that stimulating 5-HT4 receptors could rapidly improve learning and memory, and these effects persisted for extended periods. Moreover, early human studies with prucalopride, a drug that acts as a highly selective agonist of the 5-HT4 receptor, showed promise in enhancing cognitive function in healthy individuals.
“Drugs that stimulate the fourth serotonin receptor (5-HT4) are fascinating,” said study author Angharad de Cates, a Guarantors of Brain Clinical Postdoctoral Fellow at the at the University of Oxford.
“Pre-clinical work has identified that these agents may have a beneficial impact on learning and memory in animals. What’s really interesting is that they seem to have these effects very quickly – within a few doses. However, we’ve only just started to look at whether they can have the same impact in humans. If they can, then they may have clinical benefit for those with mental illnesses like depression, where cognitive problems are common but not successfully treated with current antidepressants.”
The study involved 50 healthy volunteers, half of whom received prucalopride for six days, while the other half received a placebo. The researchers used functional magnetic resonance imaging (fMRI) to scan the participants’ brains at rest, allowing them to examine the resting-state functional connectivity (rsFC) between different brain regions involved in cognitive processing.
The findings revealed that participants who received prucalopride showed more functional connectivity in their resting-state between major cognitive networks in the brain. Specifically, they had increased connectivity between the central executive network (used for processing thoughts) and the posterior and anterior cingulate cortex (regions that regulate information processing and attention). There was also increased connectivity between the anterior cingulate cortex and a region associated with visual attention and between the caudal anterior cingulate cortex and a sensorimotor region responsible for visuospatial attention.
In addition to increased connectivity between cognitive networks, participants who received prucalopride also showed reduced connectivity within the default mode network (DMN), which is a network activated during mind-wandering and implicated in attentional deficits.
These results suggest that prucalopride may enhance cognitive function by improving connectivity within cognitive networks and reducing connectivity within the DMN. The drug appears to modulate brain regions important for learning and memory. The researchers believe that these findings offer promise for using drugs that target the 5-HT4 receptor as potential treatments for depression and cognitive impairment.
“This study adds significantly to the evidence base that the common laxative treatment, prucalopride, which affects a subtype of serotonin receptors (5-HT4), can have important effects in the brain,” de Cates told PsyPost. “In particular, it affects brain circuits which are important for learning and memory. Together with our lab’s previous data, this suggests that this drug might be useful as a pro-cognitive treatment in disorders such as depression.”
The researchers propose that these changes in resting-state connectivity may serve as a “signature” of a drug that improves cognition and suggest that prucalopride could be a pro-cognitive treatment for conditions like depression where cognitive deficits are prominent.
But it’s important to note that this study was conducted in healthy individuals, and further research is needed to determine the effectiveness of prucalopride in people with depression and cognitive deficits.
“At the moment, we’re not completely sure of the best dose of prucalopride to stimulate brain 5-HT4 receptors, although data from our previous reports indicate that the dose of 1mg we used in this study is sufficient to demonstrate procognitive potential,” de Cates said. “We also don’t know if these findings are specific to prucalopride or whether they would be the same with any 5-HT4 agonist drug.”
Nonetheless, the study provides valuable insights into potential new treatment approaches for cognitive symptoms associated with mood disorders.
“The consistency of some of our findings – for example, the left and right rostral part of the anterior cingulate cortex showed greater connectivity with prucalopride for the exact same attentional region: the left lateral occipital cortex,” de Cates told PsyPost. “This makes us pretty sure that what we’re finding is replicable.”
“We are currently undertaking further studies looking at prucalopride and other drugs that work in a similar way in both patient and clinically vulnerable populations, to see if they improve cognition in those experiencing or at risk of mood disorders, and therefore have the potential to be an effective clinical treatment option,” the researcher added.
The study, “5-HT4 Receptor Agonist Effects on Functional Connectivity in the Human Brain: Implications for Procognitive Action“, was authored by Angharad N. de Cates, Marieke A.G. Martens, Lucy C. Wright, Daisy Gibson, Gershon Spitz, Cassandra D. Gould van Praag, Sana Suri, Philip J. Cowen, Susannah E. Murphy, and Catherine J. Harmer.
