Does Propranolol Attenuate Inflammatory Responses to a Psychological Stressor?

November 29, 2018 updated by: University of North Carolina, Chapel Hill

Beta-Blockers and Inflammatory Responses to Acute Psychosocial Stress

This randomized, double-blind, placebo-controlled study of propranolol will shed important light on how sympathetic nervous system (SNS) activation influences psychological and inflammatory responses to acute stress. Results from this study will inform both the basic science literature that is attempting to map the physiological mechanisms by which psychological stress may lead to poor mental and physical health, and may also ultimately have therapeutic relevance for individuals who are experiencing high levels of stress that is putting their health at risk. Utilizing a psychopharmacological approach allows for the circumvention of many of the challenges of conducting this research in human populations, and will allow for conclusions regarding causality, given that SNS activation will be experimentally manipulated, rather than relying on correlational measures of SNS activity that are difficult to assess and are not appropriate for asking if SNS activity causes changes in psychology and biology.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Psychological stress is implicated in the onset and progression of many common and costly chronic diseases, including cardiovascular disease, chronic pain conditions, and major depressive disorder (Cohen et al., 2007; Kendler et al., 1999; Steptoe and Kivimäki, 2012). An emerging body of evidence suggests that inflammation, indexed via levels of pro-inflammatory cytokines and reactive proteins, may be a key biological mechanism by which stress affects health (Baker et al., 2012; Miller et al., 2009; Slavich et al., 2010). Indeed, psychological stressors can induce increases in inflammation (Slavich and Irwin, 2014; Kiecolt-Glaser et al., 2003; Rohleder, 2014; Steptoe et al., 2007), and greater levels of inflammation may contribute to the development of disease (Capuron and Miller, 2004; Choy and Panayi, 2001; DellaGiola and Hannestad, 2010; Raison and Miller, 2013; The Emerging Risk Factors Collaboration, 2010). Despite this growing literature linking stress, inflammation, and poor health, little is known about the precise physiological mechanisms linking psychological stress and increases in inflammation.

One hypothesized mechanism that may translate psychological stress into increases in levels of inflammation is activation of the sympathetic nervous system (SNS). The SNS is part of the autonomic nervous system and is primarily indexed by release of the catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline). Prior research in non-human animal models has shown that stress-induced SNS activation leads to increases in levels of pro-inflammatory cytokines inflammation (Bierhaus et al., 2003; DeRijk et al., 1994; Kop et al., 2008; van Gool et al., 1990), while pharmacologically blocking sympathetic activation attenuates the inflammatory response to stress (Bierhaus et al., 2003). However, no known human studies to date have examined the relationship between psychological stress, SNS activation, and inflammation. The present study is designed to address this major gap in our knowledge of the physiological mechanisms that may link stress and disease.

A potential reason for the lack of human research linking stress, SNS activation, and inflammation is that SNS activity is difficult to measure. Indeed, adrenaline and noradrenaline are released into the bloodstream very rapidly during a stressor, making their kinetics difficult to capture during typical laboratory-based stress paradigms. Indirect measures of SNS activity may be acquired using psychophysiological approaches that involve peripheral measures of electrical activity and efficiency of the heart; however, these methods provide only indirect indicators of SNS activity, making them subject to criticism in the psychoneuroimmunology community.

To circumvent these issues with assessment of SNS activity, the present study will employ a psychopharmacological approach to experimentally block SNS activity using the drug propranolol. Propranolol is a beta-blocker medication that is very commonly prescribed by physicians in the United States for the treatment of hypertension, given that it blocked adrenergic receptors that lead to relaxation of the cardiac muscle and smooth muscle tissue. Interestingly, propranolol is also sometimes prescribed to individuals who have performance anxiety (i.e., public speaking anxiety), as reducing SNS activity (i.e., eliminating the increased heart rate, blood pressure, sweaty palms, etc., that typically accompany anxiety-provoking situations) has been anecdotally observed to decrease perceptions of stress during these situations. Psychological scientists have recently become more interested in the role SNS activity may play in the formation and reconsolidation of fear memories, and a number of studies have now used propranolol to investigate if blocking SNS activity may help treat individuals with Post-Traumatic Stress Disorder (PTSD; Pitman et al., 2002; Vaiva et al., 2003). However, only one known study to date has investigated if propranolol reduces stress-induced immune system activation (Benschop et al., 1994), and this (now dated) study did not specifically explore if propranolol reduces inflammatory responses to stress. Furthermore, no known studies have examined if blocking SNS activity with propranolol changes individuals' appraisals of the stressful situation, or their affective responses to stress. Results from this study will complement and extend the existing work on how SNS activity affects fear memories and stress by focusing on how propranolol affects inflammatory and psychological responses to a stressor.

In addition to these primary goals of the present study, the investigators will also explore the role of SNS activation in a number of additional exploratory tasks that are hypothesized to be affected by sympathetic arousal. More specifically, the investigators will examine if exposure to propranolol eliminates implicit biases toward out-group members (in this case, African Americans), given that a very large literature suggests that many White Americans hold implicit biases against African Americans (Wittenbrink et al., 1997; Nosek et al., 2002). While it has been hypothesized that sympathetic arousal based on cultural stereotypes associating African Americans with negativity may be leading to these implicit biases, no known studies have investigated this issue. The investigators will also explore of SNS activation is critical for empathy, or individual's ability to understand the emotional states of others, for avoiding risky decisions, and for moral judgments. Thus, this study will also answer a number of exploratory, unanswered questions in social psychology regarding the role that sympathetic arousal plays in some of our most fundamental psychological processes.

In sum, this randomized, double-blind, placebo-controlled study of propranolol will shed important light on how SNS activation influences our psychological and inflammatory responses to stress. Results from this study will inform both the basic science literature that is attempting to map the physiological mechanisms by which psychological stress may lead to poor mental and physical health, and may also ultimately have therapeutic relevance for individuals who are experiencing high levels of stress that is putting their health at risk. By utilizing psychopharmacological approaches, the investigators will circumvent many of the challenges of conducting this research in human populations. The investigators will also be in a place to draw strong conclusions regarding causality, given that they will have experimentally manipulated SNS activation, rather than relying on correlational measures of SNS activity that are difficult to assess and are not appropriate for asking if SNS activity causes changes in psychology and biology.

Study Type

Interventional

Enrollment (Actual)

92

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • Howell Hall

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 25 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusionary Criteria:

  1. Healthy volunteers
  2. Age 18-25
  3. Fluent in English

Exclusionary Criteria:

  1. presence or history of chronic physical illness (especially disorders with an inflammatory component, such as rheumatoid arthritis, asthma, allergies, or issues that can affect the heart, including low-blood pressure or other heart conditions)
  2. presence or history of psychiatric illness (depression, anxiety)
  3. any current prescription medication use
  4. currently pregnant or planning to become pregnant
  5. engagement in a number of health--compromising behaviors that may affect levels of pro-inflammatory cytokines, including cigarette smoking, excessive caffeine intake and sleep disturbance (e.g., working night shifts)
  6. body mass index (BMI) greater than 30, given that adiposity is known to relate to baseline levels of inflammation
  7. anxiety about or previous history of problems with blood draws (e.g., fainting)
  8. any reported heart conditions
  9. history of fainting spells
  10. low pulse, as measured at beginning of session I (below 60)
  11. low blood pressure, as measured at beginning of session I (below 80)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Propanolol Hydrochloride
This is the experimental group given the beta-blocker
Drug: Propanolol hydrochloride
One-time dose of 40mg of propranolol
Other Names:
  • Inderal
Placebo Comparator: Placebo
This is the control group given a placebo.
Other: Placebo
Outside casing matching that of active drug
Other Names:
  • Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Interleukin-6 (IL-6)
Time Frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 30-min post-stressor; 60-min post-stressor; 90-min post-stressor
Measured in blood plasma using enzyme-linked immunosorbent assay. Log-transformed prior to analysis to correct for skew in data. Four different change scores were calculated: first, change at post-drug from pre-drug baseline; second, the change at 30-min post-stressor from post-drug baseline; third, change at 60-min post-stressor from post-drug baseline; and fourth, change at 90-min post-stressor from post-drug baseline.
Pre-drug baseline; 60-min post-drug administration baseline before stressor; 30-min post-stressor; 60-min post-stressor; 90-min post-stressor

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Salivary Cortisol
Time Frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor; 30-min post-stressor
Concentration of cortisol in saliva quantified quantified by chemiluminescence immunoassay with high sensitivity. Three different change scores were calculated from pre-drug to post-drug baselines, 15-min post-stressor from post-drug baseline, and 30-min post-stressor from post-drug baseline.
Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor; 30-min post-stressor
Change in Salivary Alpha Amylase
Time Frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor
Concentration of alpha amylase in saliva quantified quantified by enzyme kinetic method. Two different change scores were calculated: first, the pre-drug to post-drug baseline change and, second, the 15-min post-stressor change from post-drug baseline.
Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor
Change in Pre-Ejection Period
Time Frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor
Mean level pre-ejection period (PEP; centered at zero) derived from impedance cardiography and electrocardiogram. Four different change scores were calculated: first, the change in average PEP from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average PEP that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average PEP that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average PEP that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.
Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor
Change in Respiratory Sinus Arrhythmia
Time Frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor
Mean level respiratory sinus arrhythmia (RSA) derived from electrocardiogram; measure of heart rate variability assessed as the ratio of low-to-high frequencies in the respiratory-cardiac power spectrum. Four different change scores were calculated: first, the change in average RSA from the 5-min pre-drug baseline to the 5-min post-drug baselines; second, the change in average RSA that occurred during the 2-min anticipatory stress speech preparation phase of the Trier Social Stress Test (TSST) from the post-drug baseline; third, the change in average RSA that occurred across the 15-min of the TSST (speech + math tasks) from the post-drug baseline; fourth and finally, the change in average RSA that occurred across 7-min in a post-stressor recovery period as compared to the post-drug baseline.
Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 15-min during stressor, 7-min recovery post-stressor
Change in Negative, High Arousal Emotion
Time Frame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 1-min post-stressor
Self-report measure of affect (emotion) state using the Positive & Negative Affect Schedule Negative Affect (PANAS). Answered on a Likert scale from 0 ("not at all") - 6 ("very much"). Mean score range is from 0-6. Higher numbers indicate more negative, high arousal emotions; low numbers indicate less negative, high arousal emotions. Three change scores were calculated from the four different rating measurement time points: a change in negative, high arousal emotions at the post-drug baseline from the pre-drug baseline; a change in emotions right before the Trier Social Stress Task (TSST) from the post-drug baseline; and a change in emotions during the TSST from the post-drug baseline.
Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 1-min post-stressor

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of North Carolina, Chapel Hill

Investigators

  • Principal Investigator: Keely A Muscatell, Ph.D, University of North Carolina at Chapel Hill, Psychology & Neuroscience

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 26, 2016

Primary Completion (Actual)

October 10, 2017

Study Completion (Actual)

October 10, 2017

Study Registration Dates

First Submitted

October 26, 2016

First Submitted That Met QC Criteria

November 20, 2016

First Posted (Estimate)

November 23, 2016

Study Record Updates

Last Update Posted (Actual)

December 19, 2018

Last Update Submitted That Met QC Criteria

November 29, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 16-2498

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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