Elsevier

Psychoneuroendocrinology

Volume 85, November 2017, Pages 123-133
Psychoneuroendocrinology

Review
Pharmacological challenge studies with acute psychosocial stress

https://doi.org/10.1016/j.psyneuen.2017.08.020Get rights and content

Highlights

  • Researchers conduct drug challenges studies with acute psychosocial stress to: i) determine the effectiveness of psychiatric medications, ii) investigate the neurochemical mechanisms involved in stress, and iii) determine whether drugs of abuse relieve responses to stress.

  • Most anxiolytic medications reduce subjective responses to stress, whereas single doses of antidepressants do not.

  • Several neurotransmitter systems are involved in the stress response, including serotonin, norepinephrine, GABA, glutamate, opioids, and endocannabinoids.

  • Some nonmedical drugs such as alcohol and cannabinoids reduce responses to stress, whereas other drugs (caffeine, nicotine, and amphetamines) do not.

  • Subjective ratings of anxiety are the most sensitive indices of drug effects on stress, and cortisol levels second to those.

  • Cardiovascular indices of stress are not related to either subjective or hormonal responses.

Abstract

Chronic stress is known to affect many psychiatric disorders, and studies of responses to acute stress may reveal processes that ultimately lead to maladaptive responses to chronic stress. Many studies have used simulated public speaking tasks to induce stress in the laboratory and, of interest to this review, the tasks have been used to assess the effects of both therapeutic and nonmedical drugs on stress reactivity. Here we review 38 studies that examined effects of single doses of drugs on subjective, cardiovascular and hormonal responses to an acute social stressor in healthy volunteers. Most studies have used the Trier Social Stress Test (TSST), or variations on it involving public speaking or mental arithmetic. Pharmacological studies with the TSST (ph-TSST) have been conducted for three main reasons: i) to determine the clinical effectiveness of psychiatric medications to reduce stress responses, ii) to investigate the neurochemical mechanisms involved in the stress response, and iii) to determine whether drugs of abuse relieve, or occasionally worsen, responses to acute stress. The review indicates that standard anxiolytic medications consistently reduce subjective responses to the TSST, whereas single doses of antidepressants produce mixed effects. Mechanistic studies indicate that several neurotransmitter systems are involved in the stress response, including serotonin, norepinephrine, GABA, glutamate, opioids, and endocannabinoids. Among drugs of abuse, alcohol and cannabinoids exert some stress-dampening effects, whereas caffeine, nicotine, and amphetamines tend to increase stress responses. Comparing outcome measures of the responses to stress, subjective ratings of anxiety are among the most sensitive indices of the stress response, with cortisol levels second and cardiovascular responses least sensitive. We conclude that the TSST is a valuable tool to study the clinical effectiveness of medications for stress-related disorders, and that it is important to use standardized procedures to enable comparisons across studies.

Introduction

Stress is a critical determinant of many psychiatric disorders (Selye, 1936, McEwen, 2000, Charney, 2004, de Kloet et al., 2005, Kendler, 2016). Studying responses to acute psychosocial stressors, and the effects of drug pretreatments on these responses to these stressors, may provide a window to understanding the consequences of chronic stress and ways to modulate its maladaptive effects. The Trier Social Stress Test (TSST; Kirschbaum et al., 1993) and similar public speaking tasks are commonly used in laboratory studies to assess acute responses to stress, and to investigate effects of psychoactive drugs on the stress response (Kudielka et al., 2007). In these drug challenge studies, subjects are pre-treated with a drug or a placebo, and then participate in the task, which involves a brief preparation period followed by a speaking monologue and a math task performed in front of an audience that provides no positive feedback. The outcome measures usually include three categories: i) self-reports of anxiety or tension, ii) cardiovascular responses such as heart rate and blood pressure, and iii) levels of the stress hormone cortisol in saliva or blood. The procedure is believed to induce an acute social evaluative threat, and researchers have studied the effects of drugs on public speaking tasks for three main reasons: i) to determine the clinical effectiveness of approved or potential psychiatric medications in reducing responses to acute stress, ii) to investigate the neurochemical receptor mechanisms involved in the stress response, and iii) to determine whether drugs of abuse are effective in ‘self-medicating’ or relieving negative aspects of acute stress responses. In this review, we discuss studies that have used drug challenge procedures with the TSST or similar tasks in each of these categories. We review the extent to which the TSST findings correspond to clinical expectations, or inform us about underlying neurochemical or hormonal processes involved in the response. We also review the extent to which the three categories of outcome measures (subjective, cardiovascular and hormonal) are related to each other, or independent. Campbell and Ehlert (2012) examined the correspondence between physiological and subjective responses in 49 studies that used the TSST. They found that cortisol responses and perceived emotional stress variables were correlated in just 25% of the studies, suggesting that these measures are controlled by separate factors, which is a theme throughout this review. We also review key components of the procedure, or of the subject populations, that may affect the outcome and interpretation of the studies.

The results of studies using the TSST have been summarized in several recent reviews (Kudielka et al., 2007; Allen et al., 2017; Goodman et al., 2017; Zorn et al., 2017; Liu et al., 2017). These reviews confirm that the task reliably induces several indices of responses to social stress, and they identify several variables that can influence TSST responses, including, for example, sex, menstrual cycle phase and hormones, age, genotype, time of day of testing, psychiatric diagnosis, symptomatic state (Zorn et al., 2017) and even the presence of a pet dog (e.g., Kertes et al., 2017). The fact that many variables can influence the stress response somewhat complicates the interpretation of pharmacological challenge studies with the TSST (referred to here as ph-TSST), because the drugs could affect the perception or impact of the stress indirectly, by influencing other variables. Here, we review recent ph-TSST to identify evidence of anxiolytic or stress-dampening effects, and to determine the co-relationships among different outcome measures of the stress response.

We have grouped the ph-TSST studies into three categories of i) approved or potential psychiatric medications (Table 1), ii) mechanistic studies (Table 2), and iii) drugs of abuse (Table 3). We conducted a PubMed search using the words [TSST OR Trier OR social stress OR public speaking] AND [alcohol OR benzodiazepine OR barbiturate OR stimulant OR opioid OR cannabinoid OR caffeine OR antidepressant OR anxiolytic OR analgesic OR serotonin OR GABA OR noradrenaline OR caffeine OR nicotine] AND (healthy OR human OR volunteer). Of the 110 results we selected 38 studies that met our inclusion criteria of studies with healthy volunteers who received a drug or placebo pretreatment before a public speaking task, providing measures of subjective ratings, cardiovascular measures or hormonal responses. The findings are separated into three sections based on the apparent purpose of the studies, but there is much overlap between the sections (e.g., medications that are abused).

The procedures used in the studies reviewed here follow essentially the same basic design, but differ in outcome measures, demographic characteristics of the participants, drug and doses, and phase of the stress response studied (i.e., anticipation, stress response and recovery). Most studies used the TSST, but some used variations involving either a simulated public speaking task or mental arithmetic task instead of the full TSST. In this review we will not focus on methodological differences unless they appear to influence the interpretation. Most of the studies use a between-subject design in which participants are randomly assigned to receive either placebo or a drug. Some, but not all, of the studies include a no-stress control session. The subject samples include healthy men and women, cigarette smokers, and alcohol drinkers. The measures of subjective or mood response to the stress procedure include visual analog measures (VAMS) of anxiety, calm, tension, confidence and other adjectives, the Spielberger Trait Anxiety Inventory (STAI; Spielberger et al., 1983), and self-report measures of somatic symptoms such as perspiration, dry mouth, palpitation, among others (Zuardi et al., 1993, Hetem et al., 1996). Other self-report measures include ratings of how threatening subjects considered the procedure to be. Physiological indices of stress include heart rate (HR), blood pressure (BP), electrodermal activity (EDA; skin conductance or other measures of sweating), and plasma epinephrine levels. Hormonal measures include cortisol (usually salivary), adrenocorticotropic hormone (ACTH) and salivary alpha amylase. In some studies, researchers recorded the participants’ performance during the tasks to determine whether the drug impaired, or improved, their performance. With so many possible sources of variability it becomes difficult to compare directly across studies. Nevertheless, some patterns emerge from the range of studies.

Section snippets

Benzodiazepines

Benzodiazepines are the current standard of care for anxiety disorders and, as such, would be expected to reliably dampen responses to an acute laboratory stressor. Surprisingly, however, benzodiazepines have mixed effects on responses to social evaluative stress tasks. Several early studies examined the effects of the prototypic benzodiazepine diazepam on responses to stress. McNair et al. (1982) tested the effects of 5 and 10 mg diazepam in healthy young adults on subjective anxiety and palmar

Analgesics

Analgesics by definition reduce reactivity to physical pain, but there is growing evidence that they may also reduce reactivity to psychological or social ‘pain’ (Eisenberger and Lieberman, 2004). Social pain and physical pain have overlapping neural processes with important evolutionary functions, and it is recognized that opioids as well as anti-depressants have regulatory effects on both physical and social forms of pain. Further, there is a large body of evidence implicating the opioid

Drugs of abuse

Stress is known to play an important role in the etiology of drug abuse (Sinha, 2001). Specifically, it is widely believed that people use drugs to ‘self-medicate’, i.e., to relieve unpleasant psychological states (Khantzian, 1985, Khantzian, 2013), including states of stress or anxiety related to discrete life events (Cappell and Herman, 1972, Sayette, 1999). Thus, several studies have examined the effects of drugs of abuse on reactivity to the TSST, as one test of the self-medication theory.

Conclusions

This review focused on ph-TSST studies that were conducted for one of three reasons: i) to determine the clinical effectiveness of approved or potential psychiatric medications in reducing responses to acute stress, ii) to investigate the neurochemical receptor mechanisms involved in the stress response, and iii) to determine whether drugs of abuse are effective in ‘self-medicating’ or relieving responses to acute stress. In general, classic anxiolytic drugs such as the benzodiazepines reduce

Conflict of interest statement

Dr. de Wit has received support unrelated to this review from the following sources: Consulting fees from Pfizer, Marinius and Jazz Pharmaceuticals; gift of a study drug from Indivior; and support for a research study from Insys Therapeutics.

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