Researchers at the University of Birmingham and the University of Oxford report that prucalopride, a drug licensed for chronic constipation, improved cognitive test performance in people with a history of depression.
The randomized, placebo-controlled trial enrolled 50 adults aged 18–40 who had experienced at least two depressive episodes and who were in remission for six months or more. Participants were randomized to 2 mg daily prucalopride (the licensed dose) or placebo for about a week, and completed tests of short- and long-term memory, working memory, attention and executive function, plus three emotional cognition tasks, before and after treatment.
Across the ‘cold’ cognitive tasks (memory and executive function), people who received prucalopride were both more accurate and faster than those on placebo (accuracy z = +0.59; response time z = −0.69). The report says there were no significant side effects in the short treatment window.
“Cognitive problems, or brain fog, are an important and often overlooked feature of depression, and can persist even when mood improves,” said Dr. Angharad de Cates (University of Birmingham), corresponding author. “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.”
Prucalopride is a 5‑HT4 receptor agonist; those receptors are present in gut tissue and in brain regions involved in learning and memory. The trial used standard neuropsychological tasks including an auditory verbal learning task (AVLT), an N‑back working memory task, the Trail Making Test (TMT) and the Digit Symbol Substitution Test (DSST).
“For many people, recovery from depression is incomplete because difficulties with memory and concentration persist,” said Professor Susannah Murphy (University of Oxford), senior author. “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 paper, “Pro‑cognitive effects of 5‑HT4 receptor agonism in individuals with remitted depression,” was published 15 June 2026 in Psychological Medicine (DOI: 10.1017/S0033291726104450). The authors say further and longer trials are needed to test durability, dosing and effects in people currently depressed or on medication.
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Tags: prucalopride, 5-HT4 receptor, depression, cognitive deficits, drug repurposing
Topics: Stress, focus & mental clarity, Neuroscience & neuroplasticity