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Modulation by Muscarinic Antagonists of the Response to Carbon Dioxide Challenge in Panic Disorder
Marco Battaglia, MD;
Silvana Bertella, MD;
Anna Ogliari, MD;
Laura Bellodi, MD;
Enrico Smeraldi, MD
Arch Gen Psychiatry. 2001;58:114-119.
ABSTRACT
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Background Panic attacks can be induced in persons with panic disorder by inhalation
of carbon dioxide. Hypercapnia also elicits a reflex hyperventilation, which
is controlled in part by cholinergic mechanisms. This study investigated whether
the exaggerated response to carbon dioxide in panic disorder (PD) can be modulated
by antagonists of muscarinic cholinergic receptors.
Methods Twelve patients with PD received biperiden hydrochloride (a muscarinic
antagonist that crosses the blood-brain barrier), pirenzepine hydrochloride
(a muscarinic antagonist that does not cross the blood-brain barrier), or
placebo 2 hours before a 35% carbon dioxide–65% oxygen respiratory challenge
(vs air as a placebo) on 3 separate days, in a double-blind, random crossover
design.
Results According to patients' self-ratings of subjective anxiety, inhalation
of the carbon dioxide/oxygen mixture provoked a significant and intense response
after treatment with pirenzepine and placebo. After biperiden treatment, however,
hypercapnia elicited a response profile similar to that elicited by air, whereby
subjective anxiety remained similar to preinhalation levels.
Conclusions Consistent with the hypothesis of the study, a centrally active muscarinic
antagonist can block the response to carbon dioxide commonly observed in subjects
with PD.
INTRODUCTION
IN SUBJECTS who are susceptible to panic disorder (PD), the administration
of carbon dioxide (CO2) provokes a sudden increase in ventilation
followed quickly by a surge in anxiety1, 2, 3, 4, 5, 6
similar to what occurs in spontaneous attacks. Such effects are usually not
elicited in normal control subjects2 or patients
with psychiatric disorders other than PD,3 whereas
the administration of sodium lactate provokes flashbacks in subjects with
posttraumatic stress disorder.7
The evidence of hypersensitivity to CO2 led to the hypothesis
that PD is a disturbance in a suffocation alarm system4
in which a physiological misinterpretation of suffocative stimuli produces
respiratory distress, hyperventilation, and panic. Although the involvement
of central chemoceptors, and of various neurotransmitters including norepinephrine,
serotonin, and  -aminobutyric acid, have been invoked in PD,5, 8, 9 the central mechanisms
underlying laboratory-induced panic remain undescribed. Only limited efforts
have been made to link the functional bases of the normal reflex ventilatory
response to CO2 with the CO2 hypersensitivity characteristic
of patients with PD.
In mammals and humans, the physiologic reflex response to heightened
concentrations of inhaled CO2 (hypercapnia) is an increase in ventilatory
rate and arousal.10 This effect of CO2 is independent of its effects on hydrogen ion concentrations in the
extracerebral fluids.10, 11 Central
chemosensitivity has been localized to the ventral medulla, an area rich in
muscarinic receptors.12 Direct stimulation of
this area by CO2 elicits hyperventilation, which can be dramatically
decreased by the topical application of muscarinic antagonists.12, 13
Other physiological studies also suggest that ventilatory neurons are activated
through muscarinic mechanisms.11, 14
Functional magnetic resonance imaging studies of men breathing a 5% CO2 gas mixture showed significant metabolic and cerebral flow changes
localized primarily to the ventral medulla.15
One study16 of normal volunteers investigated
the roles of peripheral vs central muscarinic receptors in mediating the physiologic
response to CO2 inhalation. Subjects were treated with intravenous
placebo, pirenzepine hydrochloride (a muscarinic antagonist that does not
cross the blood-brain barrier), and biperiden hydrochloride (a muscarinic
antagonist that crosses the blood-brain barrier) before undergoing progressive
hyperoxic hypercapnia. There were no significant differences in the delta
( ) minute ventilation to the end-tidal CO2pressure
ratio among the 3 treatments, but the difference in the hypercapnic ventilatory
response between biperiden and placebo had a significant negative correlation
with the hypercapnic response after placebo.16
Although central muscarinic receptors play no prominent or consistent role
in the physiologic hypercapnic reflex in normal subjects, they can be important
in those individuals who have greater chemosensitivity to hypercapnia.16 Central cholinergic receptors can, therefore, contribute
to the central CO2-sensing mechanisms in humans, but the degree
of their involvement seems to vary among individuals.
This study was performed to investigate whether the response to hypercapnic
stimulation in subjects with PD could be modified by the administration of
muscarinic antagonists.
SUBJECTS AND METHODS
SUBJECTS
Subjects were recruited consecutively from outpatients of an anxiety
treatment facility at San Raffaele Hospital, Milan, Italy. They had to be
aged 18 through 35 years and have a clinical diagnosis of PD based on the DSM III-R,17 which was confirmed
independently by the Mental Health Diagnostic Interview Schedule Revised.18, 19, 20
Exclusion criteria were cardiocirculatory and respiratory disorders,
personal or familial history of aneurysm, hypertension (systolic blood pressure,
>160 mm Hg; diastolic blood pressure, >100 mm Hg), pregnancy, epilepsy, intolerance
of or hypersensitivity to biperiden or pirenzepine, glaucoma or ocular hypertension,
gastrointestinal tract stenosis, megacolon or dysfunctions in gut motility,
urinary retention, prostatic hypertrophia, and history of alcohol, benzodiazepine,
or other drug dependence.
With these criteria, 15 subjects were recruited during 13 months. After
the first or second 35% CO2–65% oxygen (O2) (hereafter
referred to as CO2 mixture) challenge,
3 subjects found the test excessively anxiogenic and dropped out. Therefore,
this study is based on the 12 subjects who completed the protocol. Although
we used the Italian version of the Mental Health Diagnostic Interview Schedule,
Revised19 interview, for which reliability data
are available,19, 20 all 12 subjects
also satisfied the DSM-IV diagnosis of PD,21 according to reviews of interviews and clinical information.
All had already been treated for PD with short half-life benzodiazepines at
some time in their life. None had taken tricyclic antidepressants, selective
serotonin reuptake inhibitors, or monoamine oxidase inhibitors. At the time
of recruitment, 5 subjects were taking benzodiazepines (alprazolam, chlordemethildiazepam,
etizolam, bromazepam) at a mean daily dose of 0.5 mg alprazolam-equivalent.
For these subjects, tapering was initiated, with monitoring of possible symptoms
of withdrawal each second day.
In the week before the experiment, the severity of PD was assessed using
the Panic-Associated Symptoms Scale, with scores ranging from 0 to 28.22
At initiation of the protocol, subjects had to have been free of psychotropic
drugs for at least 2 weeks, and receive no medications for at least 1 week.
Subjects were asked to refrain from consuming alcohol for at least 36 hours
and xanthine-containing beverages for at least 8 hours, from smoking for at
least 6 hours, and from eating for at least 2 hours before the tests. After
complete description, an informed consent was obtained. The procedure of the
CO2 mixture challenge has been approved by our hospital's Ethical
Committee. More than 600 subjects in Europe have undergone the challenge without
adverse events.
PROCEDURES
All subjects received orally 100 mg of pirenzepine hydrochloride, 4
mg of biperiden hydrochloride, and placebo at 48-hour intervals before undergoing
a CO2 mixture/air challenge on 3 different days, in a double-blind,
random crossover design.
Pirenzepine is a muscarinic antagonist used to treat gastric ulcer.
The low lipid solubility largely prevents passage of the blood-brain barrier.23 After oral administration, it reaches peak plasma
concentrations within 2 to 2.5 hours. The mean elimination half-life is 11
hours.
Biperiden is a muscarinic antagonist used as an antiparkinsonian agent.
It easily penetrates the blood-brain barrier and distributes in high concentrations
to the brainstem.24 After oral administration,
it reaches peak plasma concentrations within 2 hours, and declines biphasically,
with half times of 1.5 and 24 hours.24, 25
Two hours after administration of placebo, pirenzepine, or biperiden,
subjects underwent the CO2 mixture/air respiratory challenge.2
Once inhaled, CO2 quickly permeates the blood-brain barrier
and stimulates the central nervous system.5
Responders experience an intense increase in anxiety, usually described as
closely resembling a spontaneous panic attack1, 2, 5
and lasting from a few seconds to less than 1 minute. A receiver operating
characteristic analysis showed that this challenge discriminates between patients
with PD and healthy controls on the basis of subjective anxiety after the
test, with a positive predictive power of 91% and a negative predictive power
of 75%.26
The following 2 gas mixtures were used: compressed air as placebo, and
a mixture of 35% CO2 and 65% O2 mixture. Both gases
were inhaled through the same self-administration mask connected to a respirometer
to measure vital capacity and gas volume delivered at each inhalation.
Subjects were informed before the challenge that they would inhale 2
different harmless gas mixtures containing different percentages of O2 and CO2, that the procedure might elicit some sensations
of discomfort ranging from a few physical symptoms to a clear sensation of
anxiety, and that the aim of the study was to investigate whether the drug
they had received could influence their response to the challenge.The possibility
that a full panic attack might take place was not mentioned, however, to avoid
possible negative cognitive biases related to expectation.2, 3, 26, 27
After vital capacity was measured, subjects inhaled 1 vital capacity
of CO2 mixture, or compressed air, in a randomly assigned order,
at an interval of 30 minutes between both inhalations. At the end of each
inhalation, subjects were asked to hold their breath for 4 seconds. According
to this standardized procedure,2, 3, 26, 27
the test is considered valid if the subject inhales at least 80% of the vital
capacity.
MEASURES
Immediately before and after each inhalation of compressed air or CO2 mixture, subjects were asked to score themselves on a Visual Analog
Scale for Anxiety (VASA). Like the visual analog scales commonly used in assessments
of behavioral psychotherapy,28 the VASA depicts
on a 10-cm line the degree of global subjective anxiety, following a continuum
from 0 (no anxiety present at all) to 100 (the worst anxiety ever imaginable),
and has been used consistently and reliably in several studies of panic provocation.3, 26, 29, 30, 31, 32
Likewise, subjects were asked to score themselves on the Panic Symptom
List III-R (PSL-III-R29), a self-rating questionnaire
assessing on a 5-point scale (0 indicates absent; 4, very intense) each of
the 13 DSM-III-R and DSM-IV
panic symptoms (total score range, 0-52).
Evaluation of responses was made according to the following standard2, 26, 30, 32 procedures:
global anxiety reactivity was evaluated as the percentage of maximum increment
or decrement possible on the VASA scale (% VASA; range of values, -100
to 100) calculated as follows: (1) if postinhalation VASA values minus preinhalation
values ( VASA score) was positive, then % VASA = ( VASA
x 100)/(100 - VASA before inhalation); and (2) if VASA
was negative, then % VASA = ( VASA x 100)/(VASA before
inhalation).
By taking into account the pretest baseline value of anxiety, this transformation
allows us to calculate symmetrically for positive and negative values
the maximum possible increment or decrement of anxiety after inhalation.
Similarly, the rating at the PSL-III-R was transformed as follows: (1)
if postinhalation PSL-III-R values minus preinhalation values ( PSL-III-R
score) was positive, then % PSL-III-R = ( PSL-III-R x
100)/(52 - PSL-III-R before inhalation), where % PSL-III-R is
the percentage of maximum increment or decrement possible on the PSL-III-R;
and (2) if PSL-III-R was negative, then % PSL-III-R = (
PSL-III-R x 100)/(PSL-III-R before inhalation).
Receiver operating characteristic analyses showed that measuring the
challenge response with transformed % VASA and % PSL-III-R values
yields better information content than measuring with untransformed values.26
Criteria for qualitative assessment of response to the challenge reflected
standardized procedures derived by receiver operating characteristic analyses26, 30: reaction to any gas mixture inhalation
was considered an induced attack when it included a sensation of fear or panic
with a % VASA of at least 26 and an increment of at least 2 points
on the PSL-III-R for at least 4 symptoms of a panic attack.
DATA ANALYSES
Given the small sample size, % VASA and % PSL-III-R values
obtained after challenge administration were analyzed in 2 separate Friedman
analyses of variance.
Contrasts between % VASA and % PSL-III-R after CO2 mixture plus biperiden vs CO2 mixture plus placebo, and
after CO2 mixture plus biperiden vs CO2 mixture plus
pirenzepine were made by means of the Wilcoxon matched-pairs test, with nominal 
set at .025.
Responses to different gas mixtures across different treatments measured
categorically (ie, presence or absence of provoked attack) were compared by
means of the Cochran Q test.
Analyses were performed using the Statistica package,33
with all test outcomes 2-tailed. Unless otherwise indicated, data are given
as mean ± SD.
RESULTS
There were 6 men and 6 women in the study group. Mean age was 27.35
± 5.1 years, and mean age at onset of PD was 19.9 ± 6.1 years.
Mean Panic-Associated Symptom Scale score was 9.3 ± 4.3 in the week
before the experiment (mild to moderate severity of symptoms). According to
clinical records, one man had qualified for alcohol abuse 4 years before the
experiment, but abuse and dependence were definitely ruled out at the time
of the study. None of the subjects who were still taking benzodiazepines at
the time of recruitment had experienced symptoms of withdrawal during the
tapering or the drug-free periods before the experiment.
The 3 subjects who dropped out did not differ from those who completed
the protocol for sociodemographic features, age at onset, duration and current
severity of PD, or medication history.
Biperiden, but not pirenzepine or placebo, modulated the response to
CO2 mixture measured as % VASA and % PSL-III-R values
obtained after the challenge in the 3 pharmacological treatments (Figure 1 and Figure 2). There was no anxious reaction to compressed air inhalation,
regardless of treatment.
These responses did not differ between those patients who had (5 patients
[41.7%]) vs those who had not (7 patients [58.3%]) received psychotropic medication
(ie, benzodiazepine therapy) recently (Mann-Whitney test for % VASA
[patients with vs those without recent medication]: after CO2 mixture
plus placebo, U = 14.5 [P
= .63]; after CO2 mixture plus biperiden, U
= 16.0 [P = .81]. Mann-Whitney test for %
PSL-III-R: after CO2 mixture plus placebo, U = 11.0 [P = .29]; after CO2 mixture
plus biperiden, U = 17.0 [P
= .93]).
When blind codes were opened at the end of the experiment, the random
orders of administration of gas mixtures (compressed air and then CO2 mixture, or CO2 mixture and then compressed air) across
3 different days could be arranged into 5 different sequences, whereas the
orders of administration of treatments had 6 sequences. The orders of administration
of gas mixtures (on 5 levels) and treatments (on 6 levels) were used for coding
group memberships as independent variables in a set of Kruskall-Wallis analyses
of variance that analyzed % VASA and % PSL-III-R after CO2 mixture inhalation in each of the 3 treatments. Differences were nonsignificant
when the responses to CO2 mixture were grouped according to the
order of administration of gas mixtures (values closest to significance observed
for % VASA after CO2 mixture and pirenzepine, H4,12 = 4.03 [P = .40]; for %
PSL-III-R, H4,12 = 3.47 [P = .48]). Similarly, differences were nonsignificant when the responses
to CO2 mixture were grouped according to the order of administration
of treatments (values closest to significance observed for % VASA after
CO2 mixture and placebo, H5,12
= 8.8 [P = .12]; for % PSL-III-R, H5,12 = 8.7 [P = .12]), in harmony
with findings of previous studies.3, 26
Qualitative responses to the experiment with CO2 mixture
yielded 9 patients (75%) and 7 patients (58%) who developed provoked panic
attacks after placebo and pirenzepine, respectively, and no provoked panic
attacks after biperiden, whereas there were no panic attacks with compressed
air, regardless of the pharmacologic treatment (Cochran Q test, Q5 = 39.7 [P<.001]).
COMMENT
The data reveal that the exaggerated response to CO2 observed
in subjects with PD can be modulated through blockade of central muscarinic
receptors by biperiden. Consistently, the effect of intravenous biperiden
in blocking the ventilatory reponse to CO2 in normal subjects correlates
with the degree of hypercapnic ventilatory response at baseline.16
It has been hypothesized4, 26
that individual sensitivities to increasing concentrations of inhaled CO2 may reflect a continuously distributed, possibly evolutionarily derived,
developmental trait. The magnitude of the response to the CO2 challenge
among individuals may parallel such a distribution, with patients with PD
at one extreme.4, 26 It is suggested
that muscarinic receptors can account at least partially for such individual
variability.
It appears unlikely, however, that dysfunction of any single neurotransmitter
system, or stimulation of the medullary chemoceptor(s) by CO2 alone,
can account for the complex phenomenology of panic attacks and PD. A neuroanatomical
model connecting the acute attack, anticipatory anxiety, and phobic avoidance
components of PD to the brainstem, limbic system, and prefrontal cortex, respectively,
has been offered.5 According to this model,
stimulation of the medullary chemoceptor(s) by CO2 can provoke
a dose-dependent increase in the firing rate of the locus ceruleus,5, 34 an area with a pivotal role in anxiety,5, 8 perhaps through the projections of the
medullary nucleus reticularis gigantocellularis.5, 35
Through connections of the locus ceruleus to the hippocampus and to the prefrontal
cortex, other salient features of PD, such as anticipatory anxiety and phobic
avoidance, can be primed and promoted4, 5
after the onset of 1 or more acute attack(s) generated in the brainstem.
Some pathologic conditions also allow some links to be drawn between
extreme variations in sensitivity to CO2, muscarinic receptor function,
and anxiety. In congenital central hypoventilation syndrome, which is often
associated with a hypoplastic or absent arcuate nucleus at the ventral medullary
surface,36 children cannot perceive ambient
CO2variations, and have significantly less anxiety symptoms than
age-matched controls.37 Insensitivity to the
suffocation stimulus that occurs when children rebreathe their own exalations
in the prone position during sleep makes liable infants subject to sudden
infant death syndrome. A significant decrease in binding of the muscarinic
antagonist tritiated quinuclidinyl benzilate to muscarinic receptors in the
arcuate nucleus has been demonstrated in these infants.38
This led researchers to hypothesize that sudden infant death syndrome is intrinsically
associated with a dysfunction of muscarinic receptors in the arcuate nucleus,
the same muscarinic receptors that might constitute all or part of the central
chemoceptor mediating responses to hypercapnia.38
Some limitations and caveats need to be taken into account in this study.
First, this is a small patient sample. Second, measures of subjective increase
in anxiety39 have been the only index of response
adopted here; assessments of ventilation would have been desirable to better
delineate the role of chemosensitivity in CO2vulnerability.6 Third, the inclusion of objective measures of peripheral
anticholinergic effects would have been valuable; the central effect of biperiden
as the only explanation for the different response from pirenzepine would
have been more reliably interpreted in the presence of similar peripheral
anticholinergic effects of biperiden and pirenzepine. Fourth, beyond double-blindedness
and randomization, we have not controlled for the possible effect of patients'
expectations of the challenge. Generally, however, it has been shown that
patients' expectancy has little influence on the challenge outcome.32 Fifth, although none of the subjects had spontaneously
reported any effects that could be linked specifically to central cholinergic
blockade (eg, drowsiness) in the 2 hours after administration of biperiden,
we have not systematically controlled for possible nonspecific effects that
might have contributed to blunting the response to CO2 with this
drug.
General caveats include the only partial overlap between the diagnosis
of PD and CO2-induced panic,30 suggesting
at least partially different determinants for these 2 phenotypes.40
Moreover, the 35% CO2–65% O2 mixture is
considered a robust stimulus, but it may be less specific than lower concentrations
of CO2. Stimulation with different gas concentrations may provide
different results to those reported herein, and the short-term reliability
of the test is unknown.
Attenuation of the response to CO2 mixture inhalation in
patients with PD can be achieved with a variety of agents. These include tricyclic
antidepressants and selective serotonin reuptake inhibitors,41
usually after 7 to 30 days of treatment, and benzodiazepines,29
but the data presented herein show very substantial reduction in responsiveness
to CO2 mixture inhalation after a single dose of biperiden, a drug
which is not considered therapeutic for PD.
Although it must be remembered that the global anxiety response to laboratory
provocation of panic is a complex index that is likely to be affected by different
neurochemical pathways, to our knowledge this is the first report to show
a specific role for acetylcholine, a neurotransmitter that is not usually
associated with PD. Likewise, the ability of biperiden to modulate the response
to CO2 does not necessarily suggest an intrinsic role of cholinergic
mechanisms in the pathophysiology of PD and calls for further investigations
in larger samples of patient and nonpatient subjects.
AUTHOR INFORMATION
Accepted for publication June 20, 2000.
An interim evaluation of part of these data was presented at a Workshop
on the Panic and Respiration Connection, Milan, Italy, February 10, 1998.
The statistical consultation of Andrea Fossati, MD, and Clelia Di Serio,
PhD, is gratefully acknowledged.
From the Developmental Psychopathology Unit, Department of Psychology,
University Vita-Salute San Raffaele (Drs Battaglia and Ogliari), and the Department
of Neuropsychiatric Sciences, Istituto Scientifico San Raffaele Hospital (Drs
Battaglia, Ogliari, Bellodi, and Smeraldi), Milan, and the Department of Child
Psychiatry, Istituto Scientifico Eugenio Medea, Bosisio Parini, Lecco (Dr
Bertella), Italy.
Corresponding author and reprints: Marco Battaglia, MD, Department
of Neuropsychiatric Sciences, Istituto Scientifico San Raffaele Hospital,
29 via Prinetti, 20127 Milan, Italy (e-mail: marco.battaglia{at}hsr.it).
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25 = 38.85 (n = 12; P<.001); 
.002); and 