The current study has two aims:

1. To test the effect of 5-HT4 receptor agonism on cognition (including memory, attention and cognitive control) in individuals with previous history of depression.
2. To explore if prucalopride has an effect on emotional processing biases consistent with its effects on serotonin.

Cognitive impairment within depression is common and appears to be at least partly separate from the mood component. It is not well targeted by current treatments and it may persist even after remission of mood symptoms. Therefore, it may be clinically beneficial to search for new therapies that are able to improve cognition in those who have, or are recovering from, depression.

Agonists of the serotonin receptor subtype 4 (5-HT4) have shown two profiles of effect in animal models: (i) a pro-cognitive profile, improving in learning and memory on a range of rodent paradigms; and (ii) an antidepressant-like profile, reducing depression and anxiety-related behaviours in rodent models of depression and anxiety.

A previous study in our group examining acute prucalopride administration (1mg) in 40 healthy human volunteers found improvements in learning and memory but little effect on emotional processing. This pro-cognitive effect was supported by a subsequent study where healthy volunteers received 7 days of prucalopride. In this study, prucalopride led to both better performance on a visual memory task, and increased activation in the hippocampus and an associated memory processing region in response to a memory stimulus. As short-term treatment with clinically-effective antidepressants such as SSRIs is known to produce positive biases in the processing of emotional information in healthy volunteers, this lack of effect on emotional processing was not consistent with prucalopride having antidepressant potential, and is surprising considering the strength of the animal data. One factor that has not yet been explored is whether the translation was limited due to the low dose of prucalopride used in our previous study.

Therefore, we wish to see if we (i) can translate this pro-cognitive effect of prucalopride into participants with a previous history of depression and current mild cognitive issues; and (ii) can use a full treatment dose of prucalopride to evaluate its effect on emotional processing.

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the research
• Male or female
• Body mass index in the range of 18 to 33
• Not currently taking any medications (except for contraception), including being antidepressant free for at least three months
• Have at least two previous episodes of depression, and have been recovered from the most recent episode of depression for six months
• Current PHQ-9 score < 10 (the cut off for DSM major depression)

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

• Any current Axis 1 DSM-5 psychiatric disorder
• Any previous episode of a severe mental illness, other than Depressive Disorder. Comorbid Anxiety disorders will be allowed, but not OCD (Obsessive Compulsive Disorder) or PTSD.
• A first degree relative diagnosed with Bipolar Affective Disorder Type 1 or Schizophrenia
• Body Mass Index outside the range of 18 to 33 inclusive
• Any significant current medical condition likely to interfere with conduct of the study or analysis of data
• Current use of psychoactive and / or medically significant medication as judged by a study medic, whether prescribed or bought over the counter (the contraceptive pill, the Depo-Provera injection or the progesterone implant will not result in exclusion)
• Ongoing psychopharmacological treatment for depression, including hypnotics (psychotherapy will be allowed as long as not newly-started in the last 6 weeks)
• High consumption of licit substances to an extent that would make complying with study protocol challenging (including alcohol, caffeine, nicotine)
• Past history of dependence to illicit substances, and any consumption of illicit substances in the three months prior to the study
• Currently pregnant or breast feeding
• Current, or a significant history of, gastro-intestinal disorder or irritable bowel syndrome
• Known lactase deficiency or any other problem absorbing lactose, galactose, or glucose
• Participation in a study that involves the use of a medication or novel vaccine within the last three months
• Participation in a study using the same tasks in the last two years
• Any physical (including visual and auditory) or language impairment that would make complying with the study protocol challenging