Serotonin-receptor Agonism in Reward Processing (SARP)

There is growing animal and human evidence for role of 5HT1A receptor agonism in treating depression and reward deficits. The next step is to translate this evidence directly into humans by characterising the effects of buspirone, as a 5HT1A agonist, on cognitive models of reward and emotional processing.

There is a paucity of behavioural evidence for the effect of 5HT1A receptor agonism, using buspirone as a probe, on primary reward processing (e.g. food), effort-based decision making or reward learning. Furthermore, the effects of 5HT1A agonism on non-emotive cognition, such as working memory, has yet to be investigated at a behavioural level in humans.

This study will characterise the effects of buspirone, as a probe for 5HT1A receptor agonism, on reward processing in human cognitive models. Furthermore it will examine its role in emotional processing and working memory. This will add to the evidence base of the neurocognitive effects of 5HT1A receptor agonism in humans, which is of relevance to the development of this as a target for future treatment development.

The study will be a double blinded, placebo controlled study involving healthy volunteers. Participants will receive a single dose of buspirone and then undergo a battery of psychometric testing to examine reward processing, emotional processing and a memory. Frequent monitoring of temperature and salivary cortisol shall be taken as surrogate markers of pre- and postsynaptic 5HT1A receptor activation.

Study Overview

• Status: Completed
• Conditions: Anhedonia
• Intervention / Treatment: Drug: Buspirone 20mg; Drug: Placebo comparator

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7JX
      • Neurosciences building, Department of Psychiatry, Warneford hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 30
• Not currently taking any medications (except for contraception)

Exclusion Criteria:

• • Any current Axis 1 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) psychiatric disorder
• Any previous episode of a severe mental illness,
• A first degree relative diagnosed with Bipolar Affective Disorder Type 1 or Schizophrenia
• Body Mass Index outside the range of 18 to 30 inclusive
• Any significant current medical condition likely to interfere with conduct of the study or analysis of data (epilepsy, renal disease, hepatic disease, myasthenia gravis, acute closed-angle glaucoma)
• 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)
• 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
• Known lactase deficiency or any other problem absorbing lactose, galactose, or glucose
• Participation in a study using the same tasks in the last year
• Any physical (including visual and auditory) or language impairment that would make complying with the study protocol challenging. This includes any taste/olfactory disturbance e.g. secondary to Covid-19 infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control	Drug: Placebo comparator; Lactose-sucrose tablets in opaque capsule
Experimental: Buspirone	Drug: Buspirone 20mg; Buspirone tablets in opaque capsule. Used as probe for 5HT1A agonism

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary reward perception	Visual Analogue Scale of anticipation of pleasure, intensity of taste and pleasure experienced when tasting one of four 4 tastes representing a primary reward stimulus processing.	On day of intervention (30 minutes pre-intervention and post-intervention (60 - 180 minutes))
Effort based reward task:	offer acceptance based upon effort required (grip force on hand held dynamometer) to obtain outcome and success rate in expending correct amount of effort required for reward	On day of intervention ( 90 - 180 minutes post intervention)
Changes in reward sensitivity	Sensitivity to reward as measured by the Probabilistic Instrumental Learning Task (Amount won, amount lost, total monetary amount earned , proportion of participants choosing the correct symbol in win and loss trials)	On day of intervention (90 - 180 minutes post intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in recognition of emotional facial expressions	Accuracy of emotion labels (e.g. disgusted face) assigned by participants to expressive faces which have appeared on a computer screen for a period of 500ms.	On day of intervention (90 - 180 minutes post intervention)
Changes in categorisation of emotional words	Accuracy to categorise positive and negative descriptor words	On day of intervention (90 - 180 minutes post intervention)
Changes in recall of emotional words	Number of words accurately recalled	On day of intervention (90 - 180 minutes post intervention)
Change in N-back task performance	Accuracy on the N-back task	On day of intervention (90 - 180 minutes post intervention)
Change in Auditory Verbal Learning Task	Accuracy on AVLT (number of items recalled across blocks)	On day of intervention (90 - 180 minutes post intervention)
Cortisol measurement	Salivary cortisol measurement at 30 minute intervals as surrogate of 5HT1A receptor activation	On day of intervention (30 minutes pre-intervention, at time of intervention, at 30 minute intervals thereafter)
Temperature measurement	Temperature measurement at 30 minute intervals as surrogate of 5HT1A receptor activation	On day of intervention (30 minutes pre-intervention, at time of intervention, at 30 minute intervals thereafter)
Temporal Experience of Pleasure scale (TEPS)	Measure of anticipatory and consummatory aspects of reward (state measure). 18 item questionnaire (10 items for anticipatory; 8 items for consummatory). Each item scored on 6 point Likert scale (1 = very false for me to 6 = very true for me). Lower score indicates greater anhedonia.	On screening day and testing day

Collaborators and Investigators

• Sponsor: University of Oxford
• Investigators: Principal Investigator: Catherine Harmer, DPhil, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2022
• Primary Completion (Actual): April 18, 2023
• Study Completion (Actual): April 18, 2023

Study Registration Dates

• First Submitted: March 24, 2022
• First Submitted That Met QC Criteria: April 26, 2022
• First Posted (Actual): May 3, 2022

Study Record Updates

• Last Update Posted (Actual): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Emotion; Memory; Reward; Buspirone; 5HT1A receptor
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Anhedonia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Receptor Agonists; Anti-Anxiety Agents; Buspirone
• Other Study ID Numbers: SARP01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: An anonymised dataset will be published as open access data on a secure repository (e.g. Open Science Framework https://osf/io/).
• IPD Sharing Time Frame: Indefinitely
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No