Losartan and Emotional Learning

The Effects of Single-dose Losartan on Cognitive Flexibility and Learning in Healthy Adults: a Randomised Controlled Study

This study explores the effects of single-dose losartan (50mg) versus placebo on emotional processing in healthy volunteers.

Study Overview

• Status: Recruiting
• Conditions: Emotional Processing
• Intervention / Treatment: Drug: Losartan potassium 50mg; Other: Placebo

Detailed Description

The renin-angiotensin system is a major hormone system involved in blood pressure regulation. However, its major receptors are also found in the brain, particularly in areas implicated in anxiety and depression. In line with this topography, drugs blocking angiotensin-II receptors have been shown to have effects on cognition that are opposite to those seen in emotional disorders. For instance, angiotensin receptor blockade improves fear extinction, and it dampens stress responsivity to highly aversive images. In line with such cognitive effects, population-based studies suggest that angiotensin receptor blockers - compared to other antihypertensive drugs - prevent the development of post-traumatic stress disorder following trauma exposition and improve outcomes in patients taking SSRI.

This study aims to shed further light on how the renin-angiotensin system affects different aspects of cognitive processing in humans relevant to emotional disorders. In a double-blind, randomized between-group design, we will investigate the effects of a single dose of losartan (50mg) versus placebo on emotional processing in N=60 healthy volunteers aged 18-50 years. Results from this study will help us understand how the renin-angiotensin system affects emotional processing in humans, and they will help us identify potential synergistic overlaps with the cognitive mechanisms of action of effective treatment of emotional disorders.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Andrea Reinecke, PhD; Phone Number: +44 01865 618320; Email: andrea.reinecke@psych.ox.ac.uk
• Study Contact Backup: Name: Sanika Kulkarni, MSc; Email: sanika.kulkarni@psych.ox.ac.uk

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX37JX
      • Recruiting
      • Warneford Hospital, University of Oxford
      • Contact: Andrea Reinecke, PhD; Phone Number: 01865 618320; Email: andrea.reinecke@psych.ox.ac.uk
      • Principal Investigator: Andrea Reinecke, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Willing and able to provide informed consent
• Aged 18-50 years
• Score of or below 45 on the Dimensional Anhedonia Rating Scale (DARS; Rizvi et al., 2015)
• Sufficient written and spoken English skills to understand what the study involves, and to complete the questionnaires
• Non- or light-smoker (5 cigarettes a day)

Exclusion Criteria:

• Past or present DSM-5 axis-I diagnosis (based on SCID results at screening) other than anxiety disorder, dysthymia or unipolar depression
• First-degree family member with severe psychiatric illness
• CNS-medication last 6 weeks (including as part of another study)
• Current blood pressure or other heart medication (especially aliskiren or beta blockers)
• Diagnosis of intravascular fluid depletion or dehydration
• History of angioedema
• Impaired kidney function (based on self-report)
• Very low blood pressure (defined as repeated (at least three consecutive measurements) measures of blood pressure under standardised conditions where either the systolic or the diastolic blood pressure or both are below 90/50 mmHg (in accordance with established standard definitions: DOI 10.1186/s12887-016-0633-7))
• Lifetime history of epilepsy or other neurological disease (e.g. autism, ADHD)
• Lifetime history of systemic infection, or clinically significant hepatic, cardiac, obstructive respiratory, renal, cerebrovascular, metabolic, endocrine or pulmonary disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study
• Significant loss of hearing that is not corrected with a hearing device
• Women: pregnancy, breast-feeding

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
Experimental: losartan; oral single-dose losartan potassium (Cozaar; 50mg)	Drug: Losartan potassium 50mg; Single dose losartan (50 mg, weight-adjusted), encapsulated identically to placebo
Placebo Comparator: placebo; Microcellulose placebo in identical capsule	Other: Placebo; Single tablet encapsulated identically to losartan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reinforcement Learning	reinforcement learning, calculated as the learning rate from aversive and appetitive decision outcomes. Larger scores indicate better learning from an outcome.	1 hour after capsule intake

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Flexibility	switch cost, calculated by rank-ordering the differences between each switch trial RT and each participants average RT for all non-switch trials from 1 - 10 (with better and worse bins having values closer to 1 and 10, respectively), and then summing the bin values to compute a total bin score for each participant. Inaccurate responses are penalized by being assigned a score of 20. Smaller bin scores indicate greater accuracy and lower RT.	1 hour after capsule intake
AAT effect score	mean reaction time of the pull trials of a valence category subtracted from the push trials of the same category, yielding a single indicator of approach/avoidance, with positive scores indicating relatively stronger approach and negative scores indicating relatively stronger avoidance	1hour after capsule intake
Motivational effort in the Apples Task	effort valuation, calculated as the willingness to engage in physical effort to obtain rewards of certain values using the Apples Task (and computational approaches)	1hour after capsule intake

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Oxford Health Biomedical Research Centre (OH BRC) support scheme
• Investigators: Principal Investigator: Andrea Reinecke, PhD, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): August 14, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: September 30, 2024
• First Submitted That Met QC Criteria: October 2, 2024
• First Posted (Actual): October 4, 2024

Study Record Updates

• Last Update Posted (Actual): October 4, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: depression; anxiety; reward; emotional processing
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: R80447

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No