Constipation Drug Could Help Clear Depression Brain Fog

Traditional depression treatments can help heal emotional wounds, but they often leave patients stranded with frustrating memory lapses and poor concentration.

To solve this, researchers at the University of Birmingham and the University of Oxford tested a gut-targeting drug, typically used to treat constipation, on recovered individuals. They found that the medication acted as a cognitive booster, enhancing verbal memory and processing speeds.

Traditional depression treatments leave patients stranded in brain fog

Recovering from a depressive episode involves more than just a change in mood. For many people, symptoms such as brain fog linger long after other symptoms vanish. This cognitive impairment, which includes struggles with memory and attention, affects ~80% of individuals during an active episode, and over 40% of patients continue to face these deficits after they have recovered. These persistent issues prevent people from returning to their normal lives and increase the risk of the condition returning.

Current depression treatments are often successful at lifting a person's mood but fail to clear the mental fog.

“Cognitive problems, or brain fog, are an important and often overlooked feature of depression, and can persist even when mood improves,” said lead author Dr. Angharad de Cates, a NIHR clinical lecturer at the University of Birmingham, and an honorary member of the Department of Psychiatry at the University of Oxford.

This gap in treatment has led researchers to look for new ways to boost brain function.

Previous research suggested that a specific serotonin receptor in the brain, known as 5-HT4, could improve memory. In earlier tests, a drug called prucalopride—typically used to treat chronic constipation—showed signs of improving memory in healthy volunteers. Prucalopride works by stimulating specific serotonin receptors located in the gut and the brain to promote mental clarity.

However, scientists did not know if the results could be generalized to patients who had a history of depression.

The new study aimed to find out if a higher standard dose of 2mg could help these individuals regain their mental sharpness.

Common gut drug sharpens memory after depression

The team conducted a trial involving 50 young adults aged 18–40. Every participant had a history of at least two bouts of depression but had recovered and been off medication for a minimum of six months to allow the researchers to see how the drug affected the brain without the influence of current mood symptoms.

Participants were split into two groups: one received a 2mg daily dose of prucalopride, and the other received a placebo for between 7–10 days. After the treatment period, participants took several mental tests:

• An auditory verbal learning and memory task testing declarative memory
• A working memory task
• Tests of executive functioning
• Affective cognition tasks testing emotional reasoning

Participants taking the drug were significantly better at remembering words in a memory task and responded faster on a complex working memory test without losing accuracy. When the researchers looked at all the non-emotional tests together, also termed the “cold” cognitive tests, the prucalopride group was faster and more accurate than the placebo group.

The drug also changed how people processed emotions. Participants were better at identifying facial expressions, although they seemed to take more time to be sure of their answers.

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The treatment was also safe and easy for the participants to handle.

“Participants didn’t experience any serious gut complaints, because prucalopride works as a laxative, gently stimulating bowel movements,” explained de Cates.

Future directions and clinical limitations for the novel depression drug

Since prucalopride works differently compared to standard antidepressants, it could offer a new way to help people who still feel the mental cloudiness that accompanies depression.

“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,” said corresponding author Prof. Susannah Murphy, an associate professor in the Department of Psychiatry at the University of Oxford.

However, the study had some limitations. The group tested was relatively small and mostly consisted of highly educated, young, white women. It is also unknown how long the benefits last after someone stops taking the drug. The participants were not explicitly screened for baseline cognitive deficits before entry, meaning the findings reflect enhancement rather than strict deficit reversal.

Despite these hurdles, de Cates believes that the potential is clear: “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”.

Reference: De Cates AN, Hamilton S, Guru A, et al. Pro-cognitive effects of 5-HT4 receptor agonism in individuals with remitted depression. Psychol Med. 2026;56:e178. doi: 10.1017/S0033291726104450

This article is a rework of a press release issued by the University of Birmingham. Material has been edited for length and content.