Clinical trial NCT02972554: Does Propranolol Attenuate Inflammatory Responses to a Psychological Stressor?
Official title: Beta-Blockers and Inflammatory Responses to Acute Psychosocial Stress
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Stress, Psychological
Inflammation
Cortisol
Sympathetic Nervous System
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
First posted: 2016-11-23
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 25
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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)

Primary outcomes:
measure: Change in Interleukin-6 (IL-6)
timeFrame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 30-min post-stressor; 60-min post-stressor; 90-min post-stressor
Secondary outcomes:
measure: Change in Salivary Cortisol
timeFrame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor; 30-min post-stressor
measure: Change in Salivary Alpha Amylase
timeFrame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 15-min post-stressor
measure: Change in Pre-Ejection Period
timeFrame: 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
measure: Change in Respiratory Sinus Arrhythmia
timeFrame: 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
measure: Change in Negative, High Arousal Emotion
timeFrame: Pre-drug baseline; 60-min post-drug administration baseline before stressor; 2-min before the stressor; 1-min post-stressor
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Howell Hall
state: North Carolina
Study officials:
affiliation: University of North Carolina at Chapel Hill, Psychology & Neuroscience
name: Keely A Muscatell, Ph.D
role: PRINCIPAL_INVESTIGATOR
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