A selective serotonin 4 (5-HT4) receptor agonist approved for chronic constipation improved persistent cognitive symptoms in individuals with remitted major depressive disorder (MDD).

Results of the small, double-blind, placebo-controlled, proof-of-concept study showed that participants who received prucalopride performed significantly better than those who received placebo, with gains observed across multiple objective measures of nonemotional (cold) cognition.

“This is a very exciting development,” study investigator Angharad de Cates, MD, PhD, National Institute for Health and Care Research (NIHR) Clinical Lecturer and consultant psychiatrist, University of Birmingham in Birmingham and University of Oxford in Oxford, both in England, told Medscape Medical News.

However, she cautioned that more research is needed before clinicians can recommend the drug to improve cognition in this patient population.

The study was published online on June 15 in Psychological Medicine.

Why a Constipation Drug?

Cognitive impairment, often described as “brain fog,” is a common feature of depression, affecting about 80% of patients during a depressive episode. However, treatment options specifically targeting these cognitive symptoms remain limited.

Although prucalopride is approved at a 2-mg daily dose for chronic constipation, it has attracted interest beyond gastroenterology after preclinical and early human studies suggested that 5-HT4 receptor agonists may enhance learning and memory.

Several neurobiological mechanisms may explain these effects. Preclinical research suggests that 5-HT4 receptor agonists enhance synaptic plasticity in the hippocampus, increase acetylcholine release, and modulate glutamate signaling, mechanisms that may underlie the observed cognitive benefits, de Cates said.

To determine whether prucalopride could improve cognition in patients with remitted MDD, investigators randomly assigned participants to receive prucalopride, titrated from 1 mg to the licensed 2-mg daily dose, or placebo for 7-10 days.

The study included 50 adults aged 18-40 years who had experienced at least two previous depressive episodes but had been in remission for at least 6 months and were not taking antidepressants or other psychotropic medications. One participant was excluded before unblinding because of data quality concerns, leaving 49 participants in the final analysis.

Participants were randomly assigned to receive prucalopride, starting at 1 mg daily for 2 days and increasing to the licensed 2-mg daily dose, or an identical placebo. Treatment lasted a mean of just over 7 days in both groups.

The two study groups were well matched at baseline in terms of demographic characteristics, including age, sex, and ethnicity, as well as affect, as measured using the Positive and Negative Affect Schedule, and trait anxiety, using the State-Trait Anxiety Inventory, Trait Version.

Clearing ‘Brain Fog’

Participants completed a battery of nonemotional, or “cold,” cognitive tests before and after the intervention. These included the auditory verbal learning task (AVLT); the N-back working memory task; and tests of executive function, attention, and processing speed, including the trail-making task and digit-symbol substitution task.

As secondary outcomes, investigators evaluated emotional, or “hot,” cognition using the emotional test battery, which included the facial expression recognition task (FERT), emotional categorization task, emotional recall task, and emotional recognition memory task, as well as the emotional go/no-go task.

At the study conclusion, participants were asked to guess whether they had received prucalopride or placebo.

Compared with placebo, prucalopride improved immediate word recall on the AVLT and increased accuracy on the FERT. It also produced faster response times on the N-back task, with a trend toward improved accuracy.

Investigators also conducted a composite analysis of the “cold” cognitive tasks, which showed that participants who received prucalopride were more accurate (z = +0.59) and responded faster (z = -0.69) than those who received placebo.

The cognitive benefits were independent of baseline mood symptoms and self-reported cognitive difficulties. The drug’s effects also appeared to be independent of changes in emotional processing.

“I think these study results provide a really solid foundation in terms of thinking that these drugs appear to be improving cognition in this patient group,” said de Cates.

Prucalopride was well tolerated, although decreased appetite was reported slightly more often in the intervention group.

The study was underpowered for some cognitive tasks because of missing data. In addition, the study population was predominantly female, White, highly educated, and younger than 40 years, and the trial was not powered to determine whether sex or contraceptive use influenced the cognitive effects of prucalopride.

Another limitation was that cognitive deficits were not among the inclusion criteria, meaning some participants may have had little baseline impairment.

Participants assigned to placebo also were more likely than those receiving prucalopride to correctly guess their treatment assignment, raising the possibility of expectancy effects.

Beyond Depression

Looking ahead, de Cates and her colleagues plan to investigate how long the cognitive effects persist and better understand the mechanisms underlying them, research that could inform future drug development.

Beyond cognition, 5-HT4 receptor agonists also may have antidepressant effects. Previous research by de Cates’ group showed that a different 5-HT4 receptor agonist — not prucalopride — reduced depressive symptoms after just 1 week of treatment.

“Our working hypothesis at the moment is that the drug might be having an active kind of mood effect, but that needs further exploration,” she said.

“This really does open up a lot of doors in terms of thinking about how this [research] could be clinically applicable,” de Cates added, not only in depression but also in other disorders in which cognition is a key feature, such as psychosis.

A First Step

The study’s findings are consistent with previous research, said Nina Kraguljac, MD, executive vice chair, Department of Psychiatry and Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, Ohio, and chair of the American Psychiatric Association Council on Research.

She noted that similar studies have shown comparable cognitive effects of 5-HT4 receptor agonists in healthy volunteers, suggesting the benefits may not be specific to people with depression.

However, she said the cognitive gains observed in the current study were modest and that it remains unclear whether better performance on laboratory-based cognitive tests translates into meaningful improvements in everyday functioning. 

She also questioned whether differences in intelligence, or IQ, between the groups could have influenced the findings and noted that the study did not establish whether participants had clinically significant cognitive impairment at baseline.

“An improvement on a task of performance is nice to demonstrate, but it’s only the first step toward testing if these drugs are actually effective for cognition,” she said.

This research was supported by the NIHR Oxford Health Biomedical Research Centre. Disclosures for the investigators are available in the original study.Kraguljac reported no relevant disclosures.