ORIGINAL ARTICLE

Cognitive Modulation of the Endocrine StressResponse to a Pharmacological Challenge
in Normal and Panic Disorder Subjects
James L. Abelson, MD, PhD; Israel Liberzon, MD; Elizabeth A. Young, MD; Samir Khan, PhD

Context: The hypothalamic-pituitary-adrenal (HPA) axis

may mediate the deleterious effects of stress on health.
It is sensitive to cognitive and emotional aspects of organism-environment interactions, such as familiarity, control, and social support. Scientific study of how such factors moderate human HPA axis activity has been limited.
Their relevance to HPA axis disturbances in psychiatricpatients is largely unexplored.
Objective: To determine whether cognitive manipulation can alter HPA axis activity in laboratory studies andwhether patients with panic disorder are differentially sensitive to the manipulated factors.
Design: Pharmacological activation paradigm (cholecystokinin-B agonist pentagastrin) by which we examined symptom and endocrine effects on subjects randomly assigned to a standard introduction or a cognitive
intervention.

cognitive intervention designed to reduce novelty, increase cognitive coping, and provide a sense of control.
Main Outcome Measures: Corticotropin (ACTH) andcortisol levels.
Results: The cognitive intervention significantly reduced cortisol (P = .02) and ACTH (P = .01) levels, despite pentagastrin’s robust stimulation of both hormones (P⬍.001). The intervention effect was evident inpatients and controls, who did not differ in basal HPA
axis activity or response to pentagastrin. They did differ
in panic symptom responses, which were unaffected by
the intervention, and in ACTH effects of the intervention. Patients’ exaggerated anxiety responses to pentagastrin were normalized by the intervention.

Participants: Recruited from university clinic andnewspaper advertisements. Fourteen patients withpanic disorder and 14 controls, individually matched
for age and sex.

Conclusions: Cognitive/emotional manipulation can substantially modulate HPA axis responses to pharmacological activation in humans, and HPA disturbances inpanic disorder may be secondary to manipulable cognitive/
emotional sensitivities. Further study of such factors as
novelty, control, and coping may help clarify the origins of HPA axis disturbance in psychiatric disorders andthe mediators linking psychosocial stress to disease.

Intervention: Half of each group received a 9-minuteArch Gen Psychiatry. 2005;62:668-675

Setting: Clinical research center.

T

Author Affiliations:
Department of Psychiatry and
Mental Health ResearchInstitute, Trauma, Stress andAnxiety Research Group,
University of Michigan,
Ann Arbor.

HE HYPOTHALAMIC - PITU itary-adrenal (HPA) axis is
critical to an organism’s capacity to mount an integrated biobehavioral response to environmental challenge1,2 andis an important mediator linking “stress”
to detrimental health consequences.3 It issensitive to social contexts and cognitive/
emotional inputs as it shapes behavioral
responses to environmental challenge.
Such inputs, and their processing throughsuprahypothalamic circuits to influence
hypothalamic outputs, have been wellstudied in animals.4,5 Similar cognitive/
emotional factors contribute to endo-(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, JUNE 2005
668

crine stress activation in humans. 6,7
However, psychiatric studies have rarely
examined the ways in which cognitive/
emotional factors with particular salienceto the HPA axis might shape neuroendocrine findings in clinical populations.
Deeper understanding of such modulators might help clarify the origins andmeaning of HPA axis abnormalities in psychiatric patients and could also facilitate
efforts to ameliorate the deleterious effects of stress on health.3
Novelty, unavailability of control orcoping responses, and lack of social buffering are cognitive/emotional factors
known to enhance HPA axis responses to

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challenge in animals.8-12 Inconsistent results have characterized parallel study of “psychological stress” in humans,13 but recent meta-analytic and theoretical reviews have helped link the animal and human work.
Meta-analysis of 208 acute stress studies suggests thatlack of access to behavioral responses that can control
outcomes clearly contributes to corticotropin (ACTH) andcortisol release in humans.7 Theoretical reviews also
highlight the primary salience of cognitive factors—
specifically defined as “acquired outcome expectancies”—in shaping stress responding.6,14 A “positive outcome expectancy” based on acquired control over apotential threat is the most reliable way to reduce neuroendocrine stress responses.6 Prior exposure (reduced
novelty),15,16 access to “help” (social support),17 and pastexperience suggesting that a challenge can be mastered(control)18 may all reduce HPA axis activation by enhancing positive outcome expectancies (coping).6,19 Training in stress management or coping can in fact reduce
HPA responses to acute challenge in humans,20 suggesting that we can perhaps develop specific, teachable techniques to actively ameliorate the detrimental health effects of stress.
Psychiatric neuroendocrine studies have not generally considered the potential impact of novelty, social support, and access to coping or control responses within
experimental paradigms. Differential sensitivity to suchfactors could account for some HPA abnormalities reported in psychiatric patients. This may be especially likely
in an illness such as panic disorder, where HPA axis findings have been inconsistent21-24 and cognitive expectancies may be particularly relevant to pathophysiologicalprocesses. Patients with panic disorder have a cognitive
bias for perception of environmental threat,25,26 whichshould heighten reactivity to novelty and undermine positive outcome expectancies and thus increase HPA axis
reactivity to pharmacological and psychosocial challenges. If salient situational variables like novelty varyin uncontrolled ways across experimental paradigms, andpatients and control subjects have differential sensitivity to such factors, inconsistent results can be expected.
Laboratory models in which cognitive/emotional modulators can be directly studied in humans are needed to
explore this possibility.
Pharmacological activation paradigms may be particularly useful because modulatory inhibition via cognitive/emotional factors may be most detectable after thesystem has been directly activated. The cholecystokinin-B (CCK-B) receptor agonist pentagastrin27 provides
an intriguing model because it releases ACTH and cortisol27,28 and triggers an anxiety response.29 Its anxiogenic and HPA effects are independent27,30-32 and allow
for multiple pathways through which modulatory inhibition could occur. Patients with panic disorder initiallyshowed an exaggerated HPA response to pentagastrin,
but interestingly, reducing novelty in the experimental
paradigm normalized this response.30
To further explore the role of cognitive/emotional factors in modulating responses to pharmacological activators, we examined the impact of a cognitive intervention (CI) on symptoms and HPA axis responses topentagastrin in patients with panic disorder and healthy(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, JUNE 2005
669

comparison subjects. The CI was designed to manipulate expectancies and facilitate stress management by increasing familiarity, control, and coping. We hypothesized that the CI would reduce the HPA axis responseto pentagastrin and ameliorate CCK-B and HPA “hypersensitivities” in patients with panic disorder.
METHODSDESIGN
Twenty-eight subjects (14 patients with panic disorder and 14
controls individually matched to patients for age and sex) received intravenous injection of placebo and pentagastrin following either standard instruction or a CI. Patient-control dyads were randomly assigned to condition. Analyses examinedthe effects of pentagastrin on HPA activation, CI effects, andpatient-control differences in sensitivity to activation and cognitive modulation.
Subjects entered a clinical research center twice, separated
by 1 to 7 days. They received placebo on the first visit and pentagastrin on the second but were told that they might receive
either substance on both visits or 1 of each in either order. This
preserved blind administration on both visits and separated thefirst exposure to the novel experimental context from the first
exposure to pentagastrin. Subjects and research center nurses
were blind to condition.

SUBJECTS
Subjects were recruited through clinic referrals and advertising and diagnosed using the Structured Clinical Interview for
DSM-IV. They were 18 to 37 years old, medically healthy, within
25% of ideal body weight, and not pregnant or lactating, andthey had no history of substance dependence or recent abuse(6 months), no recent exposure (within 1 month) to psychoactive medication, low levels of tobacco use (⬍20 cigarettes/d) and alcohol use (⬍5 drinks/wk), negative urine drug
screen results, and normal screening laboratory results. Females were premenopausal, not using birth control pills, andstudied within 8 days of menstruation onset. Control subjects
had no history of psychiatric disorder or spontaneous panic
attacks and no first-degree relatives with anxiety or affective
disorders. Patients had a primary diagnosis of panic disorder,
with at least 2 attacks in the prior month (mean±SD, 21±22
attacks). Nine had mild to moderate agoraphobia. Five had social anxiety disorder. One had obsessive compulsive disorder.
One had dysthymia. None had current depression. One had aprior depressive episode. Ten had never received psychopharmacological medications; 3 had past exposure but no daily medication for 3 years; 1 had discontinued use of a selective serotonin reuptake inhibitor, buspirone, and alprazolam 3 months
earlier. Subjects provided written, informed consent and were
paid $200 each.

PROCEDURES
Evaluations were completed 1 week before study. Subjects reported at 1 PM for experimental sessions. Use of food and tobacco was prohibited. The investigator administered instructions identically on each visit via a 5-minute audio tape forstandard instructions or a 9-minute tape and 5-minute discussion for the CI. Subjects were escorted to the clinical research
center. An intravenous catheter (saline drip) was inserted into
an antecubital vein at approximately 1:30 PM. Subjects rested
in bed for 1.5 hours, reading or watching TV, to accommodate

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to the setting. Baseline blood samples were obtained at 3 PM
and 3:28 PM. At 3:20 PM, the investigator entered the room
briefly, turning on a bedside infusion pump and, for subjects
in the CI condition, a light on top. He returned at 3:30 PM (behind a curtain, out of the subject’s awareness) to inject (over15 seconds) the placebo or pentagastrin (0.6 µg/kg; WyethAyerst, Philadelphia, Pa, or Calbiochem-Novabiochem,
Laufelfingen, Switzerland). Blood samples were obtained at 3,
5, 10, 20, 30, 45, and 60 minutes after the administration ofpentagastrin, drawn into vacuum tubes containing heparin (cortisol) or ethylenediaminetetraacetic acid (ACTH), and placedon ice. They were spun in a refrigerated centrifuge within 5 minutes; plasma was separated and stored at −70°C.

INSTRUCTIONSInstructions were presented via audio tape. The “standard”
introduction was unchanged from previous studies, fully describing the apparatus and procedures and listing the common side effects of pentagastrin. The CI added 2 techniques,labeled “coping” and “control,” intended to reduce anxious
distress. The coping component addressed the potentiallyfrightening misinterpretation of normal pentagastrin side effects as dangerous33 by increasing familiarity with themthrough detailed information (reducing novelty) and reassuring subjects that side effects were normal and not adverse or
dangerous reactions. It encouraged them to consciously attribute side effects to a safe, predictable response that would
run its course and resolve (active coping). The control component34 gave subjects the information that they could slow orstop the pentagastrin if they found it too uncomfortable. Referring to a light on the bedside infusion pump, we informed
subjects that if the light was lit, they could reduce flow by decreasing the pump rate with the dial or could stop it altogether
with the on/off switch. They were told that the data would be
most useful if they did not use these controls, but that they
were there for their use if needed. All subjects received thesame description of this apparatus, but the indicator light was
lit only for subjects receiving the CI. Drug was administereddirectly via bolus injection as previously described.35 No subjects used the pump controls. All were told that they could
terminate the experiment at any time. An institutional review
board approved all procedures.

MEASURES AND ASSAYS
Measures included the Sheehan Disability Scale, Beck Depression Inventory, Anxiety Sensitivity Index, and Spielberger State/
Trait Anxiety Inventory. Physical and emotional symptoms wererecorded at the time of each blood sample using an acute panic
inventory and visual analog scale. The modified acute panic inventory36 measured DSM-IV symptoms of panic on a 4-point
scale (none, mild, moderate, or severe). The visual analog scalemeasured feeling states on 100-mm visual analog lines (“notat all” to “most ever”). Primary dependent variables were panic
symptom intensity (sum of acute panic inventory symptom ratings) and subjective anxious distress (sum of visual analog scale
ratings of “anxious,” “nervous,” and “fearful” minus a ratingof “calm”).
Cortisol was assayed using the Coat-A-Count assay from Diagnostic Products Corporation (Los Angeles, Calif ), and ACTH
using the Allegro HS IRMA from Nichols Institute (San Juan
Capistrano, Calif ). Sensitivities were 6 pg/mL for ACTH and
0.2 µg/dL for cortisol. Coefficients of variation were less than
10%. Patient-control dyads were always run in the same assay.
Each assay run contained equal numbers of standard instruction and CI dyads.

(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, JUNE 2005
670

STATISTICAL ANALYSIS
One control (woman, CI) was excluded because of a loss of intravenous access at a critical point. Repeated-measures analyses
of variance were conducted separately on placebo and pentagastrin day data to examine the effect of diagnosis (controls vs patients) and instruction (standard vs CI) on infusion-inducedchanges (time) in symptom and log transformed neuroendocrine responses. We also assessed hormonal responses by calculating a peak response (postpentagastrin maximum minus meanbaseline) and area under the curve (AUC) response (area under
the postinjection curve minus time-corrected area under the preinjection curve, using trapezoidal approximation).27 The lattermeasures integrated secretory effects over the full course of theexperiment, especially when applied to the slowly responding
cortisol. Peak response captures more acute dynamics, especially when applied to the more rapidly responding ACTH. We
calculated peak symptom responses, for both panic symptom intensity and subjective anxious distress, by subtracting baselinemeans from postpentagastrin maximums. We conducted
diagnosis⫻instruction analyses of variance on symptom and hormonal response measures.
RESULTS

Patient and control groups were well-matched for sex (9men, 5 women each) and age (27.5 ± 5.78 years and27.3±5.74 years). Random assignment produced comparable sex ratios in the instruction groups (8 men, 6
women in CI; 10 men, 4 women in standard instructions; P=.69). The CI group was slightly older (29.8±5.20
years vs 25.2±5.29 years, t25 =2.25, P=.03). Patients weremore depressed, anxious, and impaired than controls(P⬍.003 for all measures). Within patients, the instruction groups did not differ (P⬎.31) on any severity measure (disability, state/trait anxiety, anxiety sensitivity, depression, frequency of panic, agoraphobia rating,clinician’s global severity impression). The CI patients
had a later age at onset (27.3±6.05 years vs 18.3±4.57
years, t12 =3.14, P=.009). Regression analyses revealed nosignificant relationships between age, age at onset, or any
illness severity measure and the magnitude of HPA response to pentagastrin. There were no effects of sex on
outcome measures; there were no significant differences between men and women in the CI effects.
PLACEBO DAY
Patients with panic disorder had greater panic symptom
intensity and higher subjective anxious distress ratings
than controls (diagnosis F 1,24 = 15.1, P = .001; andF1,23 = 35.9, P⬍.001, respectively). There were no subjective responses to placebo (no time effect for either variable, F3,72 =0.8, P=.48; F5,115 =2.1, P=.07). The latter trend
was due entirely to a drop in anxiety at the last time point,with a flat line across all earlier points. The CI had no
impact on placebo day symptoms (instructions, F1,24 =0.6,
P=.46 for panic symptom intensity; F1,23 =1.7, P =.20 for
subjective anxious distress; no significant interactions).
Cortisol levels declined over the course of the placebo day (time, F6,144 = 5.1, P⬍.001), reflecting a normal, diurnal rhythm. There were no cortisol differences
between patients and controls and no effects from the inWWW.ARCHGENPSYCHIATRY.COM©2005 American Medical Association. All rights reserved.
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PENTAGASTRIN DAY
On pentagastrin day, patients again showed elevated subjective ratings compared to controls (Figure 2), on bothmeasures (main effect of diagnosis, F1,24 = 12.9, P=.002;
F1,23 =23.1, P⬍.001). Pentagastrin increased symptoms
on both measures (time, F3,72 =91.3, P⬍.001; F5,115 =26.6,
P⬍.001), and did so to a greater degree and with slower
recovery in patients (diagnosis ⫻ time interaction,
F3,72 =4.99, P=.003; F5,115 = 3.81, P = .003). The CI had noeffect on either symptom measure (no effects involving
instructions were significant).
Patients had greater panic symptom responses to pentagastrin (peak minus baseline) than controls (diagnosis, F1,23 = 5.67, P = .03), confirming increased sensitivity. Cognitive intervention had no impact on peak panic
symptom response in either group (instruction, F1,23 =0.02,
P = .90; diagnosis ⫻ instruction interaction, F1,23 = 1.43,
P=.24). Similar analyses for subjective anxious distresswere not significant (diagnosis, F1,23 = 1.50, P = .23; instruction, F1,23 = 2.28, P = .14; diagnosis⫻ instruction interaction, F1,23 =2.73, P=.11). However, additional analyses confirmed the graphical impression (Figure 2) thatstandard instruction patients had elevated responses relative to other groups on this measure. Standard instruction patients had significantly elevated anxious distressresponses compared with CI patients (F1,12 =14.1, P=.003)
and compared with their matched controls (F1,12 =4.56,
P=.05).
Pentagastrin increased cortisol and ACTH in all groups(time, F6,138 =51.6, P⬍.001 for both hormones). The CI significantly reduced ACTH and cortisol levels in all groups
combined (instructions, F1,23 = 7.66, P = .01; F1,23 = 5.91,
P=.02, respectively). The CI significantly reduced the cortisol response to pentagastrin (instruction⫻time interaction, F6,138 =2.52, P=.02) in both patients and controls (nosignificant effects involving diagnosis). Patients and controls had identical overall cortisol levels, identical cortisol responses to pentagastrin, and identical reductions in
cortisol responses with CI (Figure 3).
The pattern for ACTH was more complex. The CI did
not reduce the overall magnitude of ACTH response topentagastrin (nonsignificant instruction⫻time interac(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, JUNE 2005
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Standard Instruction

ACTH Response, pg/dL

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0

Patients

Controls

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Patients, CI
Patients, Standard
Controls, CI
Controls, Standard

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24

ACTH, pg/dL

structions (no significant effects or interactions involving diagnosis or instructions). Levels of ACTH did not
decline with time (F6,144 =1.16, P=.33). They actually rosein patients receiving standard instructions, although thetime ⫻ instruction interaction did not reach significance (F6,144 =1.89, P = .09). We examined this more directly using ACTH peak response in a group⫻instruction
analysis of variance (Figure 1), which showed that the
instructions had opposite effects in patients and controls on placebo day (group ⫻ instruction interaction,
F1,24 = 5.1, P = .03). Patients receiving standard instructions had a significant rise from first sample to peak ACTH
level (paired t test, P = .02); patients receiving the CI did
not (P=.37). For controls, the opposite was seen: controls receiving the CI showed a significant rise from firstsample to peak ACTH (P = .01), but controls receiving
standard instructions did not (P=.34). Time-course data
are included in Figure 1.

22
20
18
16
14
12
–30

–2

+3

+5

+10

+20

+45

Time Relative to Injection, min

Figure 1. Corticotropin (ACTH) levels (bottom) and responses (top, peaklevel minus initial level) on placebo day for 14 patients with panic disorderand 14 matched controls (means ± SE). Half of each group received standard
instructions and half received a cognitive intervention (CI) designed toreduce anxious distress.

tion, F6,138 =1.74, P=.12), but it impacted patients and controls differently (significant diagnosis⫻ instruction interaction, F 1,23 = 4.28, P = .05), flattening the ACTH
response curve in patients alone (Figure 3).
Response measure analyses confirmed and clarified
these results (Figure 3; AUC response shown for cortisol, peak response shown for ACTH). For both AUC andpeak measures, ACTH and cortisol responses were smallerwith the CI than standard instructions (instruction effectfor peak response: ACTH, F1,23 =9.49, P =.005; cortisol,
F1,23 =4.30, P=.05; for AUC response: ACTH, F1,23 =8.19,
P =.009; cortisol, F1,23 =4.47, P=.05). Patients and controls did not differ on either measure for either hormone (P⬎.71 for diagnosis in all analyses). Interaction
effects were not significant (P⬎.46) for these measures.
However, because of the significant diagnosis⫻instruction
effect in the ACTH time-course data, due to greater CIrelated curve flattening in patients (Figure 3), we examined patients and controls separately on the ACTH peak
response measure. In patients with panic disorder, theCI significantly reduced peak ACTH response to pentagastrin, relative to standard instructions (F1,12 = 5.95,
P = .03), but it did not have this effect in controls(F1,12 =0.51, P=.49). In contrast, on a more integrated measure (cortisol total AUC), the CI significantly reduced
HPA axis activity in both patients (F1,12 =7.16, P=.02) andcontrols (F1,12 =5.42, P =.04).
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Patients, CI
Patients, Standard
Controls, CI
Controls, Standard

20
15
10
5

25

Panic Symptom Response

25

PA Symptom Intensity

Cognitive Intervention
Standard Instruction

30

30

20

15

10

5

0

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–5
–5

+5

+3

+10

Patients

Controls

Patients

Controls

Time Relative to Injection, min
180

200

160
140

Anxious Distress Response

Subjective Anxious Distress

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0

120
100
80
60
40

–50
20
0

–100
–30

–5

+3

+5

+10

+60

Time Relative to Injection, min

Figure 2. Panic attack (PA) symptoms (top) and anxiety (bottom) in 14 patients with panic disorder and 14 matched controls before and after pentagastrin
injection (means ± SE). Raw time-course data are presented on the left, and response scores (postpentagastrin peak minus baseline) are on the right. CI indicatescognitive intervention.

CORRELATIONS
Whether examined within all subjects or patients or controls alone, clinical variables (depression, state/trait anxiety, panic attack frequency, anxiety sensitivity) showedno significant relationships with any endocrine response measure. When we examined all subjects together or controls alone, we could find no significant relationships between either panic attack symptom
responses or subjective anxious distress responses to pentagastrin and any measure of ACTH or cortisol response. Examining patients alone, the anxious distressresponse (r = 0.63, P = .02, n = 14) and the panic symptom response (r=0.54, P=.05, n=14) both predicted the
ACTH peak response; however, these could be spurious
findings, given the number of correlations examined. They
could also be due to group differences produced by the
CI (they disappeared when we examined the 2 patient
instruction groups separately).
COMMENT

These data demonstrate that varying preparatory instructions can significantly alter HPA activity in a pharmacological activation paradigm, in healthy controls as well as
patients with panic disorder, indicating that cognitive vari(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, JUNE 2005
672

ables such as familiarity or novelty and access to control
or coping responses can modulate HPA axis activity in laboratory studies. An identical cognitive manipulation alsosignificantly modulated HPA axis activity in another panicogenic model—one involving a challenge agent that,in contrast to pentagastrin, has no direct effects on ACTH
and cortisol release (doxapram).37 In that model, HPA axis
activity is primarily shaped by psychosocial factors (doxapram does not directly activate this system), whereas in
the CCK-B model used here, there is direct pharmacological activation at the level of the pituitary.27,31,32,38-40
These data suggest that suprahypothalamic inputs carrying cognitive/emotional information should be considered active in all human studies of the HPA axis, regardless of the neuroendocrine level at which a given
probe is targeted. Careful attention to the expectancy milieu of an experimental paradigm may be critical to accurately understand HPA axis activity within it. These
results are consistent with extensive literature documenting the importance of novelty, expectancies, control, andcoping to human HPA axis stress responses6,7 and demonstrate the potential particular utility of pharmacological activation paradigms for studying inhibitory, cognitive modulation of the human HPA axis.
The mechanisms whereby a brief verbal exchange robustly reduced cortisol responses in this activation paraWWW.ARCHGENPSYCHIATRY.COM©2005 American Medical Association. All rights reserved.
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24

Cognitive Intervention
Standard Instruction

Patients, CI
Patients, Standard
Controls, CI
Controls, Standard

600

500

Cortisol AUC Response

Cortisol, µg/dL

20

16

12

8

400

300

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Patients

Controls

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Controls

Time Relative to Injection, min
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ACTH Response, pg/dL

120

ACTH, pg/dL

100
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40

80

60

40

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20
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Time Relative to Injection, min

Figure 3. Cortisol (top) and corticotropin (ACTH) (bottom) responses to pentagastrin in 14 patients with panic disorder and 14 controls (means ± SE). Left panels
contain raw data, and right panels show response scores (area under curve [AUC] response for cortisol, peak response for ACTH). CI indicates cognitive
intervention.

digm are of considerable interest but were not directly studied. The intervention specifically addressed factors known
from prior work to be salient to the HPA axis. It was designed to provide (1) detailed information about expectable physical sensations, (2) a cognitive tool to protect
against the misinterpretation of normal side effects as dangerous or unusual, and (3) a perception that control could
be asserted if distress was in fact experienced. It thus reduced novelty and enhanced coping and sense of control.
It may also have increased perceived social support (theinvestigator presenting the intervention was also present
immediately after pentagastrin injection). Animal and human work has shown that familiarity, access to control orcoping responses, and social buffering can all modulate HPA
axis activity.6-12 Our brief intervention could have reduced cortisol release through any or all of these factors.
Presumably, this type of psychological modulationmust impact hypothalamic and pituitary output after processing through suprahypothalamic circuits. Animal datasuggest that threats with immediate physiological relevance activate the hypothalamus fairly directly. Threats
with less immediate survival relevance are processed
through cortical and limbic pathways that allow interpretation of meaning and salience, influenced by past experience. When experience suggests that a challenge isfamiliar or can be managed or escaped, activation is modulated by extrahypothalamic (“top-down”) circuits.1,41(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, JUNE 2005
673

Our data are consistent with the hypothesis that complex psychological stimuli—in this case, a verbal discussion targeting expectancies and cognitive responses—
can provide inhibitory inputs to the HPA axis, likely after
processing through cortical and limbic pathways, to significantly modulate stress axis reactivity. The cognitive
inputs likely shape pituitary output via hypothalamic release of corticotropin-releasing hormone or vasopressin, after integration of multiple processing loops in the“hypothalamic continuum” (bed nucleus of the stria terminalis, preoptic area, and hypothalamus).41 Follow-up
work using pentagastrin, which may well have both direct, pharmacological (pituitary-level) components andindirect, psychological (cognitive/emotional responses to
its side effects) components to its HPA effects, could be
useful in tracing psychological activation and inhibition
pathways in humans, as well as in more precisely defining the specific cognitive/emotional factors that modulate human cortisol release.
Our results also demonstrate the potential relevance ofcognitive factors in interpreting data from challenge studies of psychiatric disorders. Neuroendocrine challenge studies have suggested that patients with panic disorder have
HPA axis abnormalities24 and hypersensitive CCK-B receptors.42 Pilot data suggested a link between these biological abnormalities by showing exaggerated ACTH responses to the CCK-B agonist pentagastrin30 in patients with
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panic disorder. However, the current data confirm subsequent evidence that patients with panic disorder in fact havenormal HPA axis responses to pentagastrin30 if they haveprior exposure to the experimental context and procedures, suggesting that specific psychological sensitivities
could shape the appearance of HPA axis and CCKreceptor abnormalities.
In the current study, patients with panic disorder hadcortisol responses to pentagastrin that were identical tothose of healthy comparison subjects. Patients did not differ from controls on any direct comparisons using hormonal data. The few differences detected involved CI effects. These findings suggest that patients with panic
disorder have normal sensitivity of CCK-B receptors andnormal pharmacological response elements within their
HPA axes. The data did show some subjective hypersensitivity to the CCK-B agonist in the patients with panic disorder (greater anxiety and panic symptom intensity), as
previously reported.36,42 However, the normal endocrine
responses argue against this being a consequence of differences in CCK-B receptor sensitivity. Intriguingly, the2 subjective measures, anxious distress and panic symptom intensity, did not change in parallel. Panic symptom
intensity, which is dominated by physical symptom ratings, was not reduced by the CI, but anxious distress, which
is purely emotional, was reduced in patients with panic
disorder and appeared “normalized.”
The failure of the CI to reduce panic symptom ratings could be consistent with the idea that cognitive factors are not key mediators of panic attacks produced by
CCK-B agonists43; but our data suggest that although thephysical “side effects” of CCK-B agonists may be resistant to cognitive manipulation, patients’ associated anxious distress responses are more malleable. The data suggest that a secondary emotional response to physical side
effects, rather than a CCK-specific pharmacological effect,
may account for these agents’ panicogenic potency. The
specific similarity of normal CCK-B side effects to thephysical manifestations of a panic attack may be the active factor. When patients with panic disorder were adequately coached to attribute the physical side effects toa normal drug effect, pentagastrin did not produce any
greater rise in anxious distress in them than it did in
healthy subjects, although they did start from a more anxious baseline.
The only endocrine differences detected between patients and controls involved CI effects. The CI decreased ACTH response on placebo day in patients but
not in controls and had a greater impact on peak ACTH
response following pentagastrin administration in patients than controls. The placebo day data suggest thatthe provision of detailed information and a sense of control, along with coaching in coping techniques, tended
to ameliorate an acute, neuroendocrine stress response
in patients that was not present in controls. On placeboday, patients may be showing a “first visit” effect, reacting with an exaggerated ACTH response to nonspecificaspects of the experimental procedures on first exposure to them, and this effect appeared correctable withcognitive preparation.
Patients with panic disorder may be hypersensitive tonovelty cues, and the intervention may have reduced this(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, JUNE 2005
674

sensitivity or blocked its impact on the HPA axis, perhaps via the indirect prefrontal and limbic pathways thatprocess complex stimuli and can inhibit hypothalamic output.4 Healthy subjects, lacking this hypersensitivity, do notshow a similar down modulation by the CI. Patients withpanic disorder may also have overreacted to the noveltyof pentagastrin side effects, so the impact of the intervention on their acute ACTH response to the drug could reflect the same process.
Peak placebo day ACTH levels, peak postpentagastrin ACTH, and anxious distress response to pentagastrin could all reflect novelty sensitivity. All were somewhat elevated in patients and significantly reduced by theintervention. Follow-up studies in panic should specifically examine novelty sensitivity and its modulation bycognitive preparation. If novelty sensitivity can explain
HPA axis abnormalities in this model, similar phenomena may be at work in other paradigms and disorders.
Clinical studies should examine paradigm differences incontext-dependent expectancies and preparation instructions and individual differences in novelty sensitivity andcontrol or coping expectancies. Any HPA axis abnormalities in psychiatric patients could result from heightened novelty sensitivity or impaired control or coping
expectancies, rather than specific pharmacological sensitivities to particular challenge agents.
As in prior work, pentagastrin’s hormonal and subjective effects were independent. Endocrine response magnitude was not linked to the intensity of symptoms elicited or anxiety induced and thus does not appear primarily
driven by these subjective experiences. The intervention reduced cortisol responses in controls without reducing anxiety, so it was clearly not anxiety reduction
itself that drove the cortisol modulation noted. This isconsistent with a meta-analysis showing that the natureof a threat and its controllability are more salient to HPA
axis activation than the intensity of negative affect or subjective distress.7
Follow-up is needed to determine whether subjective descriptions of cognitive factors manipulated by theintervention (familiarity, surprise, control, or coping)might show a more direct link to cortisol levels than
measures of physical side effects or anxious distress.
Follow-up work should also examine other stressresponsive biological systems (eg, noradrenergic systems) to determine whether activity elsewhere is moreclosely correlated with distress and anxiety.
The impact of brief cognitive manipulation on HPAaxis reactivity in both healthy subjects and patients withpanic disorder has important implications for researchon stress. It suggests that cognitive/emotional factors
shaped by experimental contexts and instructions can alter results in studies examining HPA axis reactivity inpsychiatric patients. Differential sensitivity to such variables may confound the interpretation of abnormal biological sensitivities to challenge agents.
This finding also suggests that psychologically mediated inhibition of the human stress-response system canbe studied experimentally. It may be possible to empirically develop stress inoculation procedures capable of reducing cortisol responses to predictable stressors, which
could help ameliorate cortisol-mediated deleterious efWWW.ARCHGENPSYCHIATRY.COM©2005 American Medical Association. All rights reserved.
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fects of stress on health. It also provides a tool for studying the mechanisms and pathways through which cognitive/emotional processes modulate behavioral,
endocrine, and physiological outputs from midbrain control centers.
Follow-up work is needed to replicate the CI effect ina larger group of healthy controls, determine the specificfactors within the intervention that are most salient to HPA
axis modulation, and see whether the same factors canmodulate reactivity in other HPA axis activation models,
both biological (eg, corticotropin-releasing hormone) andpsychological (eg, the Trier Social Stress Test).
Submitted for Publication: May 7, 2004; final revision
received October 27, 2004; accepted November 16, 2005.
Correspondence: James L. Abelson, MD, PhD, UH9D/
0118, University of Michigan, 1500 E Medical Center Dr,
Ann Arbor, MI 48109-0118 (jabelson@umich.edu).
Funding/Support: This research was supported by grants
R29/RO1MH52724 from the National Institute of Mental Health (Bethesda, Md) and clinical research center
grant MO1RR00042 from the National Institutes of Health(Bethesda, Md).
Previous Presentation: This study was presented at the34th Annual Meeting of the International Society of Psychoneuroendocrinology; September 8, 2003; New York
City, NY.
Acknowledgment: We thank Hedieh Briggs, MSW, andKathleen Jarvenpaa, RN, whose dedication and skill were
essential to the successful collection of these data.
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