Laxative drug could ease depression-related brain fog, early trial suggests

People with depression who find that it affects their memory or attention span could benefit from an existing licensed drug currently used to treat chronic constipation.

In a paper published in Psychological Medicine today, a team of researchers, led by Dr. Angharad de Cates from the University of Birmingham along with colleagues from the University of Oxford, conducted an experimental study investigating whether a type of laxative could address cognitive issues. Problems with cognition, including difficulties with thinking, planning tasks and memory (sometimes known as brain fog), are very common in depression and other mental disorders.

The team, who are supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Oxford Health, used a licensed medicine called prucalopride, which stimulates a specific serotonin receptor (the fourth serotonin receptor, or 5-HT₄ R) in the gut and brain.

The trial recruited 50 patients who had previously had depressive episodes, and participants were randomized to receive either 2 mg of prucalopride, which is a dose currently licensed for chronic constipation, or a placebo for between seven and 10 days.

Each participant underwent a series of cognitive tests to measure executive function, short- and long-term memory, as well as emotional cognition tasks, before and after taking either the active drug or placebo. The research team found that patients in the experimental group were more accurate and faster across the tests after taking the laxative.

Researchers report early benefits

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.

“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 recruited 18- to 40-year-olds who had previously had two episodes of depression, with recovery from an episode at least six months before recruitment, and who were not on any current medication.

Participants who received prucalopride took 2 mg for five to eight days after titration, which is the licensed dose for use in chronic constipation. No significant side effects were observed during the trial.

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 team also included three affective cognition tasks testing emotional reasoning.

What the tests showed

Across the “cold” cognitive tasks assessing memory and executive functioning, the composite scores across the group taking prucalopride were more accurate (z=+0.59) and had faster response times (z=-0.69) compared with the placebo group.

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 team is continuing to research ways to address problems with cognition, which are prevalent among people with major depressive disorders and can affect short- and long-term memory, attention and focus. Previous studies have also shown that 5HT4 receptor agonists may reduce the risk of depression.

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Gaby Clark

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Robert Egan

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