A common constipation drug could have an unexpected benefit for people recovering from depression.
Depression is often thought of as a disorder of mood, but for many people, its most persistent symptoms are cognitive. Even after depressive episodes end, problems with memory, attention, and mental processing, often called “brain fog,” can linger for months or years, making it difficult to work, study, and carry out everyday tasks. Yet there are currently no approved treatments specifically designed to improve these cognitive deficits.
New research suggests an unexpected solution may already exist. In a study published in Psychological Medicine, researchers from the University of Birmingham and the University of Oxford found that prucalopride, a drug approved to treat chronic constipation, improved performance on tests of memory, attention, and executive function in people with a history of depression. The medication works by activating the serotonin 5-HT4 receptor, which is found in both the gut and the brain.
The trial included 50 people who had previously experienced depressive episodes. Participants were randomized to receive either 2mg Prucalopride, the dose currently licensed for chronic constipation, or a placebo for seven to 10 days.
Before and after taking either the active drug or placebo, each participant completed cognitive tests designed to measure executive function, short-term memory, long-term memory, and emotional cognition. The participants who received Prucalopride became faster and more accurate across the tests.
Dr. Angharad de Cates from the University of Birmingham and corresponding author of the study, said: “Cognitive problems, or brain fog, are an important and often overlooked feature of depression, and can persist even when mood improves. Our study suggests that a targeted serotonin 5-HT4 receptor medication, already used for chronic constipation, may improve cognitive functioning in people with a history of depression.
Repurposing drugs to treat depression
These findings support further research into whether 5-HT4-targeting medications can be repurposed for depression, or whether similar drugs could be developed to support people with depression and other mental disorders.”
The study enrolled adults ages 18 to 40 who had previously had two episodes of depression. Each person had recovered from a depressive episode at least six months before joining the trial, and none were taking current medication.
Participants assigned to Prucalopride received 2mg for five to eight days after titration, which is the dose licensed for chronic constipation. The trial did not find any significant side effects.
Dr. Angharad de Cates said: “Participants didn’t experience any serious gut complaints, because prucalopride works as a laxative, gently stimulating bowel movements.
The cognitive tests included:
- an auditory verbal learning and memory task testing declarative memory (AVLT),
- a working memory task (N-back),
- tests of executive functioning (including attention and processing speed: TMT, DSST))
The study also included three affective cognition tasks that tested emotional reasoning.
Across the “cold” cognitive tasks measuring memory and executive functioning, participants who took Prucalopride had higher accuracy scores (z=+0.59) and faster response times (z=-0.69) than those who received a placebo.
Professor Susannah Murphy, Associate Professor at the University of Oxford and senior author of the study said: “For many people, recovery from depression is incomplete because difficulties with memory and concentration persist. This study provides early evidence that 5-HT4 receptor agonists could help restore aspects of cognitive function, opening an exciting new direction for treatment development.”
The research group is continuing to study ways to treat cognitive problems, which are common in people with major depressive disorders and can affect short-term memory, long-term memory, attention, and focus. Earlier studies have also suggested that 5HT4 receptor agonists may reduce the risk of depression.
Reference: “Pro-cognitive effects of 5-HT4 receptor agonism in individuals with remitted depression” by Angharad N. de Cates, Sorcha Hamilton, Anutra Guru, Merethe Blandhol, Michael Colwell, Philip J. Cowen, Meghan Simmons, Bailey Jones, Catherine J. Harmer and Susannah E. Murphy, 15 June 2026, Psychological Medicine.
DOI: 10.1017/S0033291726104450
The work was supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Oxford Health.
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