The Relax Study - REduction of the autonomic stress response with AnXiolytics
A double blind randomized clinical trial of alprazolam vs. placebo on
social stress-induced hyperthermia response in healthy men

Acute stress elicits an autonomic stress response, causing body temperature to
rise in all organisms (stress-induced hyperthermia, SIH) . This autonomic
stress response also causes the blood pressure and heart rate to increase, and
plays an important part in the manifestation of anxiety disorders, when it is
activated inappropriately. Extensive animal research has shown that this SIH
response can be robustly blocked with a wide range of anxiolytic drugs.
Furthermore, the SIH response has excellent translational properties for
anxiety research, because the procedure and parameters are more or less
identical in animals as well as humans. So far, very little structural research
on the autonomic stress response in humans has been carried out. Therefore, the
RELAX study aims to reduce the SIH response in healthy men exposed to social
stress with one dose of the registered anxiolytic drug alprazolam. In addition,
we aim to reduce the stress-induced increase in blood pressure using an
automatic blood pressure monitor. Furthermore, we aim to correlate the
stress-induced hyperthermia response with the stress-induced cortisol response
by measuring saliva cortisol during the stress test. Moreover, we aim to
correlate the autonomic stress-induced temperature response to subjective
perceived anxiety levels in humans by using a set of anxiety/stress
questionnaires. The possibility to screen for stress and anxiety using
temperature measurements could be of great clinical value. Also, this
experiment would also provide evidence for a complete translational anxiety
model which can be identically carried out in animals as well as humans,
facilitating progress in anxiety research.

Study Objective
To determine whether alprazolam, a registered anxiolytic non-selective
benzodiazepine, can reduce the autonomic temperature increase induced with
social stress in healthy men. Secondary objectives are to determine whether
alprazolam can reduce the autonomic blood pressure increase, wether the SIH
response correlates with the stress-induced cortisol response (positive
control) and whether the SIH response correlates with subjective perceived
stress/anxiety levels.

Study Design
This is a small placebo-controlled, double-blind, randomized controlled trial
of alprazolam versus placebo in 24 adult male volunteers exposed to social
stress via the validated Trier Social Stress Test. Body temperature and blood
pressure will be measured throughout stress exposure using an ingested
telemetry pill and a automatic blood pressure monitor, and subjects will donate
saliva samples before, during and after the Trier Social Stress Test. Also,
volunteers complete anxiety/stress questionnaires twice.

6. Interventions
6.1 Telemetry pill
All participants receive and ingest a telemetry pill (Vitalsense Minimitter,
size 2.3 x 0.87 cm) on the day of the TSST, at least 2 hours before commencing
the TSST. Immediately after taking the pill, temperature data will be checked
to establish a good functioning of the telemetry pill. The pill will be present
until it leaves the alimentary tract after an average passage time of 1 day
which is sufficient for this study. The pill will leave the body without any
known hazard or discomfort. For details about the system and MDD/FDA approvals,
we refer to Appendix B.

6.2 Blood pressure monitor
All volunteers will be equipped with an automatic blood pressure monitor at
least 2 hours before commencing the TSST which will measure the blood pressure
at regular intervals.


6.3 Alprazolam group (index treatment)
Participants randomized to the alprazolam group receive a single oral dose of
alprazolam (1.0 mg) 1 hour before commencing the TSST.

6.4 Placebo control group
Participants randomized to the control group receive a single oral dose of
placebo
1 hour before commencing the TSST.

Trial medication (alprazolam or placebo) is handed out by the attending
investigator.
Volunteers and investigators are blinded for treatment allocation.

6.5 Stress procedure
6.5.1 General
All stress tests will be taken in the morning (8:00 until 14:00) since body
temperature and cortisol levels are subject to circadian rhythmicity. In
addition, we will make sure that volunteers are awake at least one hour before
starting by phone calls since a shorter period could influence stress
behaviour. Also, no heavy physical exercise should be exerted or large meals
should be taken on the morning before the stress procedure.

6.5.2 The Trier Social Stress Test
The Trier Social Stress Test is a procedure which was developed at the
University of Trier for induction of moderate psychosocial stress under
laboratory conditions (Kirschbaum, Pirke et al. 1993). In numerous studies in
Trier and other laboratories, the TSST has proven to elicit significant changes
in cardiovascular parameters, different endocrine axes as well as subjective
stress ratings. To ensure that the results obtained in response to this
challenge test remain comparable over time, it is necessary to standardize its
execution, so that every volunteer is challenged similarly during confrontation
with the Trier Social Stress Test. For a precise protocol of the Trier Social
Stress Test we refer to Appendix A of the study protocol (p 14), where all
details are written down. These procedures are standardized and validated.

Volunteers have no direct benefit of participation. No risks are associated
with the ingestable telemetry pill and alprazolam. The Trier Social Stress Test
is a standardized form of social stress with no extra burden for an academic
student.