An interventional study of Prucalopride and Placebo Comparator in Low Mood and Depression - Major Depressive Disorder, sponsored by University of Oxford. Not yet recruiting at 1 site in United Kingdom. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-09-30.
Sponsored by University of Oxford · Not applicable, Interventional, and Basic science
Serotonin is a chemical in the brain that plays an important role in mood, sleep, and other functions. It works by attaching to different types of serotonin receptors on brain cells. These receptors act like "locks", with serotonin acting like a "key". Different types of serotonin receptors have different effects in the brain.
Prucalopride is a licensed medication used to treat constipation. It acts on a particular serotonin receptor, called the serotonin 4 receptor. Researchers are interested in this receptor because understanding how it works in the brain may help us learn more about depression and could contribute to the development of new treatments in the future.
The purpose of this study is to investigate the effects of prucalopride in people experiencing low mood. We will compare prucalopride with a placebo (a treatment with no active medication) to find out whether activating the serotonin 4 receptor affects sleep and aspects of thinking, including memory, attention and decision making.
Cognitive symptoms are common in depression and can persist even when other symptoms of depression have improved (1). These difficulties can include impairments in memory, attention and executive function, and there remains a need for treatments that specifically target cognitive dysfunction associated with depression.
Evidence from preclinical and human experimental studies suggests that activation of the serotonin 4 receptor (5-HT4R) may represent a potential therapeutic approach for targeting cognitive symptoms in depression (2). The 5-HT4R is expressed in brain regions involved in learning and memory, and experimental studies have investigated whether selective activation of this receptor can influence cognitive processes relevant to depression.
Prucalopride is a selective 5-HT4R agonist. In previous human experimental studies, we have found evidence that prucalopride can influence cognitive processes, including learning and memory, in healthy volunteers and people who have recovered from depression (3,4). The present study extends this work by investigating the cognitive effects of prucalopride in people who are currently experiencing low mood.
The study will use an experimental medicine approach to examine the effects of 5-HT4R activation on cognitive processes relevant to depression. In addition, the study will investigate the effect of prucalopride on sleep architecture. Sleep will be assessed in the home environment using wearable chest patches capable of sleep staging.
The study will provide proof-of-concept evidence regarding the effects of 5-HT4R activation on cognition and sleep in people experiencing low mood. These data will inform the design and feasibility of a future randomised controlled trial evaluating prucalopride in people with depression and cognitive impairment.
1) Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 Jun;41(6):1165-74. doi: 10.1017/S0033291710001911. Epub 2010 Oct 8. PMID: 20932356.
(2) Murphy SE, de Cates AN, Gillespie AL, Godlewska BR, Scaife JC, Wright LC, Cowen PJ, Harmer CJ. Translating the promise of 5HT4 receptor agonists for the treatment of depression. Psychol Med. 2021 May;51(7):1111-1120. doi: 10.1017/S0033291720000604. Epub 2020 Apr 3. PMID: 32241310; PMCID: PMC8188527.
(3) Murphy SE, Wright LC, Browning M, Cowen PJ, Harmer CJ. A role for 5-HT4 receptors in human learning and memory. Psychol Med. 2020 Dec;50(16):2722-2730. doi: 10.1017/S0033291719002836. Epub 2019 Oct 16. PMID: 31615585.
(4) de Cates AN, Wright LC, Martens MAG, Gibson D, Türkmen C, Filippini N, Cowen PJ, Harmer CJ, Murphy SE. Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task. Transl Psychiatry. 2021 Oct 4;11(1):497. doi: 10.1038/s41398-021-01568-4. PMID: 34602607; PMCID: PMC8488034
Exclusion Criteria:
Additional Exclusion Criteria for Participants in the Sleep Study Cohort:
Participants will receive daily oral prucalopride for 14 days.
Drug: Prucalopride
Participants will receive daily oral placebo for 14 days.
Drug: Placebo Comparator
Prucalopride will be administered orally once daily for 14 days. Participants will receive 1 mg once daily on Days 1-2 and 2 mg once daily on Days 3-14.
A matching placebo (lactose) will be administered orally once daily for 14 days. Participants will take one placebo capsule on Days 1-2 and two placebo capsules on Days 3-14, matching the dosing schedule of the prucalopride intervention.
Auditory Verbal Learning Test (AVLT)
Verbal learning and memory will be assessed using the Auditory Verbal Learning Test, including measures of immediate recall, delayed recall, and recognition memory. AVLT performance will be compared between prucalopride and placebo groups following the intervention.
Time frame: Day 14 (post-intervention)
Sleep outcomes measured using wearable sleep monitoring
Sleep will be assessed using a wearable chest patch in a subset of participants (n=20 total, 10 per intervention group). Measures will include sleep duration, sleep quality and sleep staging. Sleep outcomes will be compared between the prucalopride and placebo groups.
Time frame: Baseline (Day 0) and Days 1-4 of the intervention
Digit Span Task
Maximum digit span will be assessed as a measure of working memory and compared between the prucalopride and placebo groups
Time frame: Baseline and Day 14 (post-intervention)
Emotional Go/No-Go (EGNG)
Inhibitory control will be assessed using the EGNG task, including measures of commission errors, omission errors, and reaction time. Performance will be compared between prucalopride and placebo groups follwing the intervention.
Time frame: Day 14 (post-intervention)
Probabilistic Reversal Learning Task (PRL)
Cognitive flexibility and reward-based learning will be assessed using the PRL task, including measures such as response accuracy, reversal errors, and sensitivity to reward and punishment. Performance will be compared between prucalopride and placebo groups following the intervention.
Time frame: Day 14 (post-intervention)
Mnemonic Similarity Task (MST)
Pattern separation and recognition memory will be assessed using the MST. Performance will be compared between the prucalopride and placebo groups following the intervention.
Time frame: Day 14 (post-intervention)
Serial Addition Task (SAT)
Working memory will be assessed using the SAT. Performance will be compared between the prucalopride and placebo groups following the intervention
Time frame: Day 14 (post-intervention)
Matrix Span Task
Visual working memory assessed using the Matrix Span Task, administered remotely via the NeuroUX app. Performance (accuracy/reaction time) will be compared between prucalopride and placebo groups.
Time frame: Baseline and Days 2, 3, 5, 6, 8, 10, 11 and 13 of the 14-day intervention.
Variable Difficulty List Memory Test (VDLMT)
Verbal learning and recognition memory will be assessed using the VDLMT, administered remotely via the NeuroUX app. Performance will be compared between the prucalopride and placebo groups.
Time frame: Baseline and Days 1, 2, 4, 6, 7, 9, 11, 12 and 14 of the 14-day intervention.
N-Back Test
Working memory will be assessed using the 2-back version of the N-back task, administered remotely via the NeuroUX app. Performance will be compared between the prucalopride and placebo groups.
Time frame: Baseline and Days 1, 3, 4, 6, 8, 9, 11, 13 and 14 of the 14-day intervention.
Digit Symbol Substitution Task (DSST)
Processing speed will be assessed using the DSST, administered remotely via the NeuroUX app. Performance will be compared between the prucalopride and placebo groups.
Time frame: Baseline and Days 1, 3, 5, 7, 8, 10, 12 and 13 of the 14-day intervention.
Quick Tap 2 Test
Response inhibition will be assessed using the Quick Tap 2 test, a go/no-go task administered remotely via the NeuroUX app. Performance will be compared between the prucalopride and placebo groups.
Time frame: Baseline and Days 2, 4, 5, 7, 9, 10, 12 and 14 of the 14-day intervention.
Paired Associates Learning (PAL)
Verbal associative and episodic memory will be assessed using the PAL task. Performance will be compared between the prucalopride and placebo groups.
Time frame: Day 14 (post-intervention)
State Subjective Cognition Scale (SSCS)
Subjective cognitive functioning will be assessed using the State Subjective Cognition Scale (SSCS). Responses will be compared between the prucalopride and placebo groups.
Time frame: Baseline and daily during the 14-day intervention.
Positive and Negative Affect Schedule (PANAS)
Positive and negative affect will be assessed using the PANAS. Scores will be compared between the prucalopride and placebo groups.
Time frame: Baseline and daily during the 14-day intervention.
Patient Health Questionnaire-9 (PHQ-9)
Depressive symptoms will be assessed using the PHQ-9. Scores will be compared between the prucalopride and placebo groups.
Time frame: Baseline, Day 7 and Day 14 of the intervention
Perceived Deficits Questionnaire (PDQ)
Subjective cognitive difficulties will be assessed using the PDQ. Scores will be compared between the prucalopride and placebo groups.
Time frame: Baseline, Day 7 and Day 14 of the intervention
Generalized Anxiety Disorder-7 (GAD-7)
Anxiety symptoms will be assessed using the GAD-7. Scores will be compared between the prucalopride and placebo groups.
Time frame: Baseline, Day 7 and Day 14 of the intervention.
Temporal Experience of Pleasure Scale (TEPS)
Anticipatory and consummatory pleasure will be assessed using the TEPS. Scores will be compared between the prucalopride and placebo groups.
Time frame: Baseline, Day 7 and Day 14 of the intervention.
Plan to share: Yes — Anonymised individual participant data (IPD) that underlie the results reported in publications arising from this study will be available to researchers upon request, subject to appropriate ethical, data protection and institutional requirements
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