A repurposed med improves cognition in remitted depression
STUDY: de Cates AN et al, Psychological Medicine 2026
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: National Institute for Health and Care Research (NIHR), Wellcome Trust, NIHR Oxford Health Biomedical Research Centre
Background
Cognitive problems often persist after depression clears. Over 40% have trouble with memory, focus, and processing speed. Prucalopride (Motegrity) is a gut motility drug approved for chronic constipation that also stimulates serotonin-4 receptors in the brain.
Earlier studies in healthy volunteers showed it sharpens memory. This trial asked whether it does the same in people with a history of depression.
The Study
- 50 adults aged 18–40 with at least two prior episodes of major depressive disorder, currently in remission, off all psychotropic medications.
- Randomized to prucalopride 2 mg daily or placebo for 7–10 days, double-blind.
- Cognitive testing at baseline and post-intervention: word recall, working memory, executive function, and emotional processing tasks.
Results
Prucalopride improved immediate word recall across five learning trials (small effect size, 0.16). It also sped up responses on a working memory task (N-back) without sacrificing accuracy. A composite score across all non-emotional tasks showed faster responses (z = +0.69) and higher accuracy (z = +0.59) compared to placebo — both in the moderate effect range.
Prucalopride also improved accuracy in recognizing facial expressions, though this wasn’t specific to any particular emotion. It had no effect on emotional memory, attentional bias toward fearful or happy faces, or response inhibition.
Importantly, cognitive gains were independent of baseline mood or self-reported cognitive complaints, suggesting the drug acts on cognition directly rather than through mood improvement.
Side Effects
Prucalopride was well tolerated. The only difference from placebo was a small increase in decreased appetite (24% vs. 4% post-intervention).
Unlike first-generation 5-HT4 agonists (cisapride, tegaserod) that were withdrawn due to cardiovascular events, prucalopride has a favorable cardiovascular safety profile and no QTc prolongation.
Prucalopride is contraindicated in:
- Intestinal perforation or obstruction
- Crohn’s disease
- Ulcerative colitis
- Toxic megacolon/megarectum
Limitations
Small sample, mostly female, white, under age 40, and highly educated. Cognitive deficits weren’t required for enrollment, so some participants may have had limited room to improve. Short treatment duration (7–10 days).
Practice Implications
- We have close to zero medications for cognitive problems after depression clears, though exercise, sleep, and Mediterranean diet may help.
- Prucalopride is promising, with two trials supporting its cognitive benefits.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
