Does Propranolol Attenuate Inflammatory Responses to a Psychological Stressor?

• ClinicalTrials.gov Identifier: NCT02972554
• Recruitment Status: Completed
• First Posted: November 23, 2016
• Results First Posted: December 19, 2018
• Last Update Posted: December 19, 2018
• Sponsor: University of North Carolina, Chapel Hill
• Information provided by (Responsible Party): University of North Carolina, Chapel Hill

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Stress, Psychological; Inflammation; Cortisol; Sympathetic Nervous System	Drug: Propanolol hydrochloride; Other: Placebo	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Beta-Blockers and Inflammatory Responses to Acute Psychosocial Stress
• Actual Study Start Date: January 26, 2016
• Actual Primary Completion Date: October 10, 2017
• Actual Study Completion Date: October 10, 2017

Arms and Interventions

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 Name: Inderal
Placebo Comparator: Placebo; This is the control group given a placebo.	Other: Placebo; Outside casing matching that of active drug; Other Name: Sugar pill

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 25 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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)

Contacts and Locations

Locations

United States, North Carolina

Howell Hall

Chapel Hill, North Carolina, United States, 27599

Sponsors and Collaborators

University of North Carolina, Chapel Hill

Investigators

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

  Study Documents (Full-Text)

Documents provided by University of North Carolina, Chapel Hill:

Study Protocol and Statistical Analysis Plan  [PDF] October 12, 2016

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

MacCormack JK, Armstrong-Carter EL, Gaudier-Diaz MM, Meltzer-Brody S, Sloan EK, Lindquist KA, Muscatell KA. β-Adrenergic Contributions to Emotion and Physiology During an Acute Psychosocial Stressor. Psychosom Med. 2021 Nov-Dec 01;83(9):959-968. doi: 10.1097/PSY.0000000000001009.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT02972554
• Other Study ID Numbers: 16-2498
• First Posted: November 23, 2016
• Results First Posted: December 19, 2018
• Last Update Posted: December 19, 2018
• Last Verified: January 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Inflammation; Stress, Psychological; Pathologic Processes; Behavioral Symptoms; Propranolol; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents