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Heightened activation of the hypothalamic-pituitary-adrenal
axis and the resultant increase in cortisol secretion has been shown
to be linked with psychiatric disorders such as depression and psychosis.
However studies that have examined the effects of direct administration
of cortisol (hydrocortisone) have yielded inconsistent findings
with some showing an elevation in mood and/or cognition and others
showing a decline. In this investigation the effects of cortisol
and placebo administration on subjective mood stress and anxiety
were examined. It is hypothesized that cortisol administration will
induce higher levels of negative affect in humans. Using a placebo-controlled
double-blind within-subject design we administered 100mg (stress-level)
of hydrocortisone orally to healthy right-handed males between the
ages of 18 and 35 years. Subjective reports of mood and anxiety
were assessed using the Symptom Checklist (SCL-90-R) and the State-trait
Anxiety Inventory (STAI). The SCL-90 and STAI were completed before
and two hours after the drug administration. The scores from the
SCL-90 and STAI administered in the placebo and drug conditions
of the procedure were compared using paired samples t tests to determine
whether self-reported anxiety and mood were affected by acute stress-level
cortisol elevation. The results indicated that the mean levels of
state and trait anxiety as measured by the STAI did not significantly
decline from baseline after the administration of hydrocortisone.
However a significant decrease on the SCL-90-R scale for symptoms
of somatization was found after hydrocortisone administration. These
findings did not lend support to our hypothesis that higher levels
of negative affect will be induced in humans following cortisol
administration. This study is part of a larger study that is being
conducted to examine the effects of acute stress on memory encoding
and retrieval in humans using functional Magnetic Resonance Imaging
(fMRI).
There is an extensive body of research showing that
increased activation of the hypothalamic-pituitary-adrenal axis
is linked with psychopathology especially depression (Halbreich
et al. 1985; Lupien et al. 1999). Further the HPA axis is one of
the neural systems that mediates the biological response to stress
in mammals (Sapolsky 1998). Exposure to stressful experiences results
in activation of the HPA axis and a cascade of biochemical events
that includes the release of cortisol (a glucocorticoid) from the
adrenal glands. Salivary cortisol levels can thus be measured as
an index of the adrenocorticol stress responses. Previous correlational
studies have investigated the effects of mood and daily stressors
on salivary cortisol levels and the results indicate that increasing
stress results in increased cortisol secretion (Smyth et al. 1998).
It has also been shown that there is an association between reductions
in salivary cortisol and mood improvement (Cruess et al. 2000).
However there has been little experimental research on the effects
of stress hormone administration to human subjects. Several published
reports on the effects of cortisol (hydrocortisone) administration
to humans have yielded fairly consistent results with respect to
memory and other cognitive functions (Lupien et al. 2002; Monk et
al. 2002). Administration of cortisol generally leads to a reduction
in cognitive performance. However findings on mood changes after
hydrocortisone administration are inconsistent with some studies
showing an increase in self-reported euphoria (high spirits) activation
and concentration (Plihal et al. 1996) while others have shown no
effect on mood (Watchel et al. 2001). The main limitation of these
previous investigations is their reliance on brief self-report measures
of affective state. The chief aim of the present study is to further
explore the effects of hydrocortisone administration on mood and
self-reported anxiety using standardized and more comprehensive
measures of mood. The study tested the hypothesis that individuals
who receive acute cortisol administration will report higher levels
of anxiety and will also experience increased negative affect as
measured by the State-Trait Anxiety Inventory (STAI) and the Symptom
Checklist-90-R (SCL-90-R). This present study is part of a larger
study that is being conducted to examine the effects of acute stress
on memory encoding and retrieval in humans using functional Magnetic
Resonance Imaging (fMRI). Preliminary results from functional imaging
data suggest that hydrocortisone administration suppresses neural
activation in multiple brain regions. Therefore it is plausible
that these changes in brain activity due to cortisol administration
will affect mood and anxiety levels.
Participants
Six healthy right-handed males between the ages of
18 and 35 years (mean = 22 years SD = ±4 years) took part
in the study. Informed consent was obtained from each participant.
Subjects were required to be fluent in English and have no history
of neurological psychiatric or neuroendocrine disturbances.
Procedures
Using a double-blind design subjects were administered
100mg of hydrocortisone or placebo by a nurse in the General Clinical
Research Center (GCRC) at the Emory University Hospital. Two saliva
samples were collected from the subjects prior to drug administration
to obtain a value of their baseline salivary cortisol levels. Following
drug administration saliva samples were collected once every 15
minutes until 10 samples had been collected to monitor salivary
cortisol levels. Standardized subjective effects questionnaires
were administered before and two hours after the drug administration.
The effect of hydrocortisone on the subjective responses to the
standardized questionnaires was compared across the cortisol and
placebo conditions using paired samples t tests for a repeated measures
design. The significance level for all statistical analyses was
set at p < 0.05.
Measures
The State-Trait Anxiety Inventory (STAI) incorporates
40 items on a four point Likert scale and was used to measure anxiety
in the study. The inventory evaluates qualities such as level of
nervousness worry apprehension and tension (Spielberger & Sydeman
1994). The Symptom Checklist-90-R (SCL-90-R) was also utilized and
is a 90 item self-report symptom inventory. This measure is designed
to screen for symptoms of psychopathology including anxiety phobic
anxiety and depression (Derogatis & Lazarus 1994). Cortisol
Assay Cortisol assays were completed with the Clinical Assays GammaCoat
Cortisol 125I RIA Kit (DiaSorin Stillwater MN). Sensitivity of this
kit for salivary cortisol is 0.05 µg/dL and inter- and intraassay
coefficients of variation are 6.0 and 3.5% respectively.
Administration of 100mg of hydrocortisone induced
a significant increase in salivary cortisol levels compared to the
placebo condition (see Fig. 1).
Figure 1. Change in salivary levels of cortisol following
oral administration of 100mg of hydrocortisone or placebo. Average
salivary cortisol levels were computed across subjects (n=6). Two
saliva samples were collected from the subjects prior to drug administration
to obtain a value of their baseline salivary cortisol levels. Following
drug administration, saliva samples were collected once every 15
minutes until 10 samples had been collected to monitor salivary
cortisol levels. Approximately two hours passed between saliva samples
one and ten.
Paired samples t-tests (within subjects) were conducted
to evaluate whether subjects administered cortisol showed decreases
in level of mood and anxiety. The results indicated that the mean
levels of state anxiety as measured by the STAI did not significantly
decline from baseline (M=24.83 SD=2.23) after the administration
of cortisol (M=25.17 SD=4.17) t (5)= -.229 p>0.05. Mean levels
of state anxiety did not significantly decline from baseline after
the administration of placebo. The results indicated that the mean
levels of trait anxiety as measured by the STAI did not significantly
decline from baseline (M=30.17 SD=4.83) after the administration
of cortisol (M=29.5 SD=4.51) t (5)= .632 p>0.05. Mean levels
of trait anxiety did not significantly decline from baseline after
the administration of placebo. These findings are illustrated in
Figure 2.
Figure 2. Changes in the average State-Trait Anxiety Inventory (STAI)
scores across the cortisol and placebo conditions. Average scores
on the STAI were obtained from subjects (n=6), and were separated
into State Anxiety and Trait Anxiety components. Paired samples
t-tests (within subjects) revealed that there were no significant
differences in STAI scores across the cortisol and placebo conditions.
T- tests comparing scores from the placebo and drug
condition revealed that oral hydrocortisone administration did not
induce any subjective change in anxiety depression hostility or
psychotic symptoms as defined by the SCL-90-R (p>0.05). On the
contrary hydrocortisone did produce a significant decrease (M=1.83)
on the SCL-90-R scale for symptoms of somatization measured at baseline
(t(5)=3.051 p=.028). In order to further explore this relationship
the correlation between peak cortisol value (in the cortisol condition)
and the somatization score was derived. This correlation is illustrated
in Figure 3.
Figure 3. The relationship between peak cortisol values and the
participants’ self-reported symptoms of somatization within
the cortisol condition. Peak salivary cortisol levels have a significant
negative correlation with the symptoms of somatization reported
by subjects prior to drug administration. This association suggests
that the higher the peak salivary cortisol levels, the lower the
number of somatization symptoms that were reported by subjects at
baseline.
In the present study hycrocortisone administration resulted in
significant increases in cortisol levels; increases that were commensurate
with exposure to a significant stressor. But our findings did not
lend support to the hypothesis that cortisol administration alone
induces higher levels of negative affect in humans. There were no
significant differences between the cortisol and placebo conditions
in any of the scales from the self-report measures of mood. ·
On the contrary we found a significant decrease in self-reported
symptoms of somatization following cortisol administration. Thus
the research participants reported fewer somatic symptoms under
conditions of heightened cortisol. This finding while contradictory
to our initial hypothesis is consistent with previous reports. Further
the overall pattern of findings is compatible with Schacter's (1975)
theory that situational factors determine the individual's subjective
reactions to changes in physical state or arousal. Specifically
Schacter proposed that cognitive interpretations derived from the
immediate situation influence the individual's psychological interpretation
of changes in physical state induced by drugs. When situational
cues are interpreted as negative increased arousal is attributed
to negative feelings. But when cognitive interpretations of the
situation are benign increased physiological arousal is not attributed
to negative emotions and may even be interpreted as reflecting a
positive emotional state. In the present and previous studies of
cortisol administration the participants may have attributed any
perceived change in physical state to the experimental context rather
than their own emotional state (Erdmann & Janke 1978). Thus
the altered physical state induced by cortisol administration did
not result in changes in self-reported mood. Also the decrease in
self-reported somatic symptoms associated with cortisol is in accordance
with the phenomenon of stress-induced analgesia where conditions
of stress can lead one to temporarily experience reduced physical
discomfort (Sapolsky 1998). · Limitations with our study
include small sample size the exclusion of females and the possibility
that our psychological measures were not sensitive to the acute
changes in mood that may be induced by cortisol administration.
Further research is needed to clarify the effects of hydrocortisone
administration on mood in humans. In particular experimental studies
that manipulate expectations or mood in conjunction with the administration
of cortisol/placebo may be particularly informative. Cortisol administration
may only induce negative mood in situations that are interpreted
as threatening to the individual.
This research was supported by the Howard Hughes Medical Institute
under Grant No. 52003727. Additional funding was provided by the
National Science Foundation agreement # IBN-9876754 and an Emory
University URC grant.
My research this summer involved exploring the effects
that cortisol a substance the human body makes when it experiences
stress can have on people's mood and anxiety. Using six healthy
men between the ages of 18 and 35 gave them 100mg of hydrocortisone
(cortisol) to swallow and monitored the levels of cortisol in their
body by collecting 12 saliva samples (the first two within five
minutes and the next 10 once every fifteen minutes)over approximately
three hours. I gave them questionnaires about their mood and anxiety
just before they swallowed the hydrocortisone. Two hours later once
cortisol levels in their saliva had a chance to peak I gave them
the same questionnaire. I then looked at their responces to see
if the cortisol made them feel more anxious or in a worse mood like
I had predicted. The subjects also had a day where they came in
and were given a sugar pill (placebo) in place of the hydrocortisone
without telling them which week they received what and without knowing
myself what they swallowed that day (placebo-controlled double-blind
study) to see if their responses on the questionnaires changed significantly
from their responses when they had hydrocortisone. Turns out neither
the hydrocortisone nor sugar pill significantly decreased their
anxiety levels but rather significantly decreased their reports
of feeling discomfort in parts of their body (somatization). More
research is needed to further study the possible effects that elevated
cortisol levels in the body will have on people's mood and anxiety
levels.
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