Treatment with prucalopride for seven to 10 days improved performance on several objective cognitive measures in patients with remitted recurrent depression. Researchers reported improvements in verbal learning, working-memory performance, and facial-expression recognition compared with placebo, sup­porting further investigation of serotonin 4 receptor agonism as a potential approach to cognitive symp­toms associated with depression.

The strongest effect was observed on a verbal learning and memory task. Patients receiving prucalopride recalled more words across five learning trials than patients receiving placebo, with a moderate effect size. On a working-memory task, patients in the prucalopride group responded more quickly across in­creasing levels of cognitive load without a significant difference in overall accuracy. Researchers also reported greater overall accuracy and faster response times in a prespecified composite analysis of non­-emotional cognitive tasks.

Additional findings suggested a more limited effect on emotional processing. Patients receiving prucalo­pride were more accurate at identifying facial expressions and made fewer misclassifications of emo­tional faces as neutral, although they were significantly slower in their responses. However, the treatment was not associated with emotion-specific effects and did not significantly affect performance on other measures of emotional cognition, including emotional memory, attentional vigilance, and emotional go/no-go tasks.

Researchers conducted the randomized, double-blind, placebo-controlled trial in 50 patients aged 18 to 40 years with a history of at least two episodes of major depressive disorder who had been free of de­pression for at least six months. Participants were assigned to receive prucalopride or placebo for seven to 10 days. Patients in the active-treatment group received 1 mg daily for two days followed by 2 mg daily for five to eight days. One participant was excluded prior to unblinding because of data-quality con­cerns, leaving 49 patients for analysis.

The study focused primarily on non-emotional cognitive function, including verbal learning and memory, working memory, attention, processing speed, and executive function. Secondary analyses examined emotional processing. Baseline depressive symptoms were low in both groups, consistent with remitted depression, and groups were generally well matched for demographic and clinical characteristics.

Not all cognitive outcomes favored prucalopride. Researchers found no statistically significant differences on measures of executive function, including the Digit Symbol Substitution Task and Trail Making Test. Short- and long-delay verbal recall also did not differ between treatment groups, suggesting that the observed bene­fits were concentrated in learning, processing speed, and selected aspects of cognitive performance rather than across all domains tested.

Prucalopride was generally well tolerated. Rates of commonly reported adverse effects, including headache, nausea, abdominal pain, diarrhea, dizziness, and vomiting, were similar between groups. De­creased appetite was reported more frequently among patients receiving prucalopride.

Researchers reported that the cognitive findings were unchanged after adjustment for baseline mood symptoms and subjective cognitive difficulties, suggesting that the observed effects were not explained by differences in mood. Although positive affect scores were higher in the prucalopride group at follow-up, with a borderline significant between-group difference, state anxiety and negative affect were similar between groups, and subjective mood did not significantly differ over time across groups.

Several limitations should be considered when interpreting the findings. The study was designed as an experimental medicine trial and was powered to examine cognitive mechanisms rather than clinical effi­cacy. The sample was relatively small, treatment duration was limited to seven to 10 days, and partici­pants were predominantly female, White, and highly educated and were limited to adults younger than 40 years. In addition, patients were not selected based on objective cognitive impairment, which may limit the generalizability of the findings to broader clinical populations.

“Short-term 5-HT₄R agonism improved performance on multiple objective cognitive measures in individ­uals with remitted depression,” wrote lead study author Angharad N. de Cates, MBChB, of the University of Birmingham and the University of Oxford, and colleagues. The researchers added that the findings support further investigation of serotonin 4 receptors as a target for cognitive enhancement in mood disorders.

Disclosures: Several investigators reported consulting fees or research funding from pharmaceutical companies, including Janssen Pharmaceuticals, UCB, Lundbeck, Johnson & Johnson Pharmaceuticals, and Pfizer. Other researchers reported no competing interests.

Source: Psychological Medicine