Article

Carbon Dioxide Hypersensitivity in Separation-Anxious Offspring of Parents with Panic Disorder

Virginia Commonwealth University, Department of Psychiatry, Richmond, VA, USA.
Biological psychiatry (Impact Factor: 10.26). 02/2010; 67(12):1171-7. DOI: 10.1016/j.biopsych.2009.12.014
Source: PubMed

ABSTRACT

Similar patterns of vulnerability to carbon dioxide (CO(2)) inhalation have been reported in adults with panic disorder (PD) and children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence of familial risk for PD on CO(2) responses in children with SAD. We hypothesized that offspring with SAD of parents with PD would have distinct CO(2) responses.
Two hundred twelve 9- to 20-year-old offspring of parents with or without PD were exposed to maintained 5% CO(2) inhalation in the participants' homes. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were monitored during baseline and 15-min maintained CO(2) breathing.
As hypothesized, significant offspring SAD x parent PD interactions were obtained for anxiety symptoms, respiratory frequency, tidal volume, and a panting index during CO(2) inhalation. Offspring with both SAD and parental PD exhibited more anxiety symptoms at termination of 5% CO(2) breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology.
Youth with both SAD and parental PD have respiratory responses to CO(2) similar to adult PD. They might be a subtype of SAD at particularly high risk for adult PD.

Full-text

Available from: Rachel G Klein
Carbon Dioxide Hypersensitivity in Separation-
Anxious Offspring of Parents with Panic Disorder
Roxann Roberson-Nay, Donald F. Klein, Rachel G. Klein, Salvatore Mannuzza, John L. Moulton III,
Mary Guardino, and Daniel S. Pine
Background: Similar patterns of vulnerability to carbon dioxide (CO
2
) inhalation have been reported in adults with panic disorder (PD) and
children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence
of familial risk for PD on CO
2
responses in children with SAD. We hypothesized that offspring with SAD of parents with PD would have distinct
CO
2
responses.
Methods: Two hundred twelve 9- to 20-year-old offspring of parents with or without PD were exposed to maintained 5% CO
2
inhalation in
the participants’ homes. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were
monitored during baseline and 15-min maintained CO
2
breathing.
Results: As hypothesized, significant offspring SAD parent PD interactions were obtained for anxiety symptoms, respiratory frequency,
tidal volume, and a panting index during CO
2
inhalation. Offspring with both SAD and parental PD exhibited more anxiety symptoms at
termination of 5% CO
2
breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology.
Conclusions: Youth with both SAD and parental PD have respiratory responses to CO
2
similar to adult PD. They might be a subtype of SAD
at particularly high risk for adult PD.
Key Words: At risk, carbon dioxide hypersensitivity, panic disorder,
respiratory frequency, separation anxiety disorder, tidal volume
U
ncued panic attacks, the defining clinical features of
panic disorder (PD), have been the focus of active
research. An early view proposed hyperventilation as the
proximate causal mechanism of panic attacks. During hyperven-
tilation, more carbon dioxide (CO
2
) is eliminated than produced,
thus inducing respiratory alkalosis, a putative panicogen. The
hyperventilation hypothesis was previously tested by having
patients with PD hyperventilate both in room air and in 5%
CO
2
-enriched air (1). Five percent CO
2
was chosen because this
level approximates the usual lung concentration of CO
2
.Itwas
predicted that breathing 5% CO
2
air would prevent panic by
respiratory alkalosis, whereas hyperventilating in ambient air
would induce panic. Surprisingly, the opposite was found. The
connection between PD and CO
2
hypersensitivity has now been
well-documented, characterized by perturbed ventilation and
increased panic attacks and anxiety symptoms (2–11). Perturbed
ventilation includes increased respiratory frequency, coupled
with lowered tidal volume (8–9,12–14). This respiratory re-
sponse pattern during CO
2
exposure is akin to “panting,” which
decreases gas exchange by increasing the dead space proportion
of each breath.
Klein hypothesized a specific, evolved suffocation alarm system
(15). The initial adaptive response to smothering (e.g., maternal
overlay of neonate or sudden exposure to high CO
2
environ-
ment) would be hyperventilation combined with escape and
protest. However, if hyperventilation and escape failed, because
the asphyxiating environment was inescapable, panting would
be the default adaptive response, in an attempt to prevent a
further rise in partial pressure of CO
2
and increased respiratory
acidosis. Klein hypothesized that a hypersensitive suffocation
alarm system would lead to false alarms manifested as “uncued”
panic attacks (15).
Family studies suggest that CO
2
hypersensitivity represents a
vulnerability marker for PD. For instance, increased minute
ventilation has been observed in relatives of PD probands
compared with relatives of low-risk subjects (16). Healthy rela-
tives of PD patients also report more anxiety compared with
healthy relatives of healthy subjects after inhalation of 35% CO
2
(17). Moreover, patients with PD who are hypersensitive to CO
2
are three times more likely to have a first-degree relative with PD
than those without CO
2
hypersensitivity (18). A recent twin study
showed higher concordance for CO
2
-induced panic attacks
among monozygotic than dizygotic twins (55.6% vs. 12.5%) (19).
Given that the major source of familial risk for PD seems to be
genetic (19,20), heritable aspects of CO
2
-hypersensitivity and PD
might overlap significantly. Findings from a recent population-
based twin study of shared genetic influence for CO
2
hypersen-
sitivity and uncued panic attacks support this hypothesis (21).
This study also suggests that, among adults, a prior history of
separation anxiety disorder (SAD) moderates the association
between genetic risk for PD and CO
2
-hypersensitivity. A more
recent adult twin study by the same team found that genetic
factors strongly influence the covariation among childhood
separation anxiety disorder, CO
2
hypersensitivity, and adult PD
(22). The familiality of anxiety disorders and the putative rela-
tionship between PD and SAD prompted the current study that
relates CO
2
hypersensitivity to familial risk for PD in children
with SAD.
Studies examining CO
2
hypersensitivity in children with anx-
iety disorders or at risk for PD have relied on maintained 5% CO
2
protocols that expose subjects to room air, followed by 5%
From the Virginia Commonwealth University (RR-N), Department of Psychi-
atry, Richmond, Virginia; New York State Psychiatric Institute and Colum-
bia University (DFK); New York University Child Study Center (RGK, SM,
JLM), New York; Nathan S. Kline Institute for Psychiatric Research (SM,
MG), Orangeburg; Freedom from Fear (MG), Staten Island, New York;
Section on Development and Affective Neuroscience (DSP), National
Institute of Mental Health Intramural Research Program, Bethesda,
Maryland.
Address correspondence to Roxann Roberson-Nay, Ph.D., Virginia Com-
monwealth University, Department of Psychiatry, PO Box 980126, Rich-
mond, VA 23298; E-mail: rrobersonnay@vcu.edu.
Received Feb 17, 2009; revised Nov 26, 2009; accepted Dec 11, 2009.
BIOL PSYCHIATRY 2010;67:1171–11770006-3223/$36.00
doi:10.1016/j.biopsych.2009.12.014 © 2010 Society of Biological Psychiatry
Page 1
CO
2
-enriched air for various time periods (23–25). Clinical
samples of children with anxiety disorders have been found to
request termination of the CO
2
task at higher rates, report more
panic symptoms, and exhibit more rapid respiratory rate in
response to CO
2
than healthy peers (23). Children with SAD
exhibit signs of CO
2
hypersensitivity consisting of relatively
greater reports of dyspnea and steeper respiratory frequency
slopes (24), much like patients with PD during exposure to
maintained 5% CO
2
. In contrast, this response does not occur in
children with social phobia. Children with generalized anxiety
disorder do not differ from healthy subjects on respiratory-rate or
dyspnea response to CO
2
but do report increased anxiety. In
sum, SAD but not social phobia or generalized anxiety disorder
is more consistently associated with CO
2
hypersensitivity.
Only a subset of children with SAD develop PD (26,27). It
might be that it is those individuals at familial risk for later-life PD
who selectively exhibit respiratory correlates of PD at an early
age. We hypothesized that children with SAD who also have
parents with PD would experience greater symptomatic change
and respiratory perturbations (i.e., increased respiratory rate and
decreased tidal volume) during CO
2
inhalation, compared with
other offspring (i.e., offspring without SAD who are at high risk
for PD [parents have PD], offspring with SAD who are at low risk
for PD [no parental PD], and offspring with neither risk factor [no
SAD and no parental PD]). We also tested the hypothesis that,
during CO
2
breathing, conversion to panting respiration, indexed
by a decreasing ratio of tidal volume to respiratory frequency
over time, would be significantly greater in offspring at genetic
risk for PD and SAD than in the other offspring groups.
We previously reported the separate main effects of offspring
SAD and parental PD on CO
2
effects in a partial sample of 142
offspring (24). This sample was too small to test an SAD
parental PD interaction. This report is based on the completed
sample of 212 offspring from this same high-risk study.
Methods and Materials
Participants
Two hundred twelve biological offspring of 135 families were
recruited, with at least one parent with a lifetime diagnosis of PD
(n 57 PD families; n 88 offspring) or neither parent with
a history of PD (n 78 PD families; n 124 offspring). Of the
57 families in which at least one parent met criteria for PD (n
mothers 47; n fathers 11), there was only 1 family in which
both the father and mother had a history of PD. Age of PD onset
was 27.30 years (SD 9.69) for mothers and 28.73 for fathers
(SD 9.40). Twenty of 47 mothers (41.7%) and 5 of 11 fathers
(45.5%) with PD were currently symptomatic. Demographic data of
parents with and without PD did not differ significantly (Table 1).
Subjects also included offspring of parents with a history of
major depression (MD). In a series of separate analyses, parental
MD was not associated with any measure of offspring CO
2
hypersensitivity. Therefore, parental MD was not included in the
statistical models, and this report focuses on whether measures
of CO
2
sensitivity are influenced by an interaction between
offspring SAD and parental PD, regardless of parental MD.
Offspring (n 212) were classified on the basis of the
presence or absence of a lifetime parental diagnosis of PD and
cross-classified on the basis of current SAD, irrespective of other
ongoing anxiety disorders. The four cross-tabulated groups
were: 1) offspring with both SAD and PD (SAD/PD, n 13);
2) offspring with SAD but no parental PD (SAD/PD, n 10);
3) offspring with parental PD but not SAD (SAD/PD, n 75);
and 4) offspring with neither SAD nor parental PD (n 114,
SAD/PD). As presented in Table 2, the four risk groups did
not differ significantly on gender composition or percent of
parents with a history of MD, but children with SAD (SAD/
PD and SAD/PD) were younger than those without SAD
(SAD/PD and SAD/PD).
Fourteen subjects had missing respiratory data, due to tech-
nical difficulties. The 198 offspring with respiratory data came
from 126 families. Those included in respiratory data analyses
were: 1) SAD/PD, n 11; 2) SAD/PD, n 9; 3)
SAD/PD, n 69; and 4) SAD/PD, n 109. The 14
subjects with missing respiratory data were included in all
analyses of symptom-based responding to CO
2
. The 14 offspring
without respiratory data did not differ significantly from the
others with regard to demographic data or psychopathology
measures, p values .05.
Offspring exclusionary criteria were psychosis, mania, perva-
sive developmental disorder, use of psychotropic medication,
IQ 70, or an acute medical condition. Parents with PD were
past or current outpatients identified via chart review from the
New York State Psychiatric Institute (New York, New York),
Long Island Jewish Medical Center (New Hyde Park, New York),
or Freedom From Fear (Staten Island, New York). Approximately
one-half of healthy parents were recruited through a pediatric
dental clinic, with the remaining one-half recruited through
acquaintances of parents. Inclusion/exclusion criteria were the
same for parent and comparison parents with the exception that
comparison parents could not qualify for a past or present mood
or anxiety disorder.
Full disclosure of study procedures was provided to all
families. Written informed consent was obtained from parents
and offspring 18 years and older. Offspring ages 9 –17 provided
assent. Participants were informed that the CO
2
task would
include periods of breathing room-air and a 5% CO
2
-enriched air
mixture and that they might experience anxiety during CO
2
inhalation. This study was approved by an institutional review
board.
Table 1. Parent Demographic Data
Parent Diagnostic Group
PD (n 78) PD (n 57)
Mother’s Ethnicity n (%)
African-American 5 (6.9) 2 (3.8)
Asian/Pacific islander 2 (2.8) 1 (1.9)
Caucasian 62 (86.1) 46 (88.5)
Latino/Latina 3 (4.2) 3 (5.8)
Father’s Ethnicity n (%)
African-American 6 (8.3) 3 (5.8)
Asian/Pacific islander 1 (1.4) 1 (1.9)
Caucasian 60 (83.3) 46 (88.5)
Latino/Latina 4 (5.6) 2 (3.8)
Mother’s Age, mean yrs (SD) 45.68 (5.41) 46.04 (5.91)
Father’s Age, mean yrs (SD) 47.39 (6.55) 48.69 (7.11)
Family SES n (%)
1 (11–17) 4 (5.6) 2 (3.8)
2 (18–31) 31 (43.1) 20 (38.5)
3 (32–47) 26 (36.1) 22 (42.3)
4 (48–63) 9 (12.5) 5 (9.6)
5 (64) 2 (2.8) 3 (5.8)
Score on 5-factor Hollingshead scale (33); denotes presence of panic
disorder (PD), and denotes absence of PD. Missing demographic data for
6PD families and 5 PD families.
SES, socioeconomic status.
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Diagnostic Evaluations
Parental Diagnoses. Both parents were individually admin-
istered the Structured Clinical Interview for DSM-IV disorders
(SCID) (28) by trained clinicians blind to all family information.
In the event a parent was unable to complete a clinical interview,
the spouse or ex-spouse served as the informant and completed
the Family Informant Schedule and Criteria revised for DSM-IV
(29). All biological mothers (total n 135) completed the SCID.
Of the 139 biological fathers (four families had two offspring with
different biological fathers), 73 completed the SCID, with the
remaining 66 cases evaluated with spouse or ex-spouse’s inter-
views. Clinicians provided clinical narratives that detailed current
and lifetime history of DSM-IV diagnoses. Integrity and reliability
of parent clinical interviews was monitored through audiotapes
as well as expert review of clinical narrative summaries. Details
concerning these procedures and diagnostic reliability are pub-
lished elsewhere (23,24).
Offspring Diagnoses. Offspring diagnosis was based on
parent and child report. Parents and offspring were interviewed
in their home approximately 1 month before the CO
2
procedure
was completed. Trained psychologists blind to parent diagnoses
administered the Parent As Respondent Informant Schedule (30)
to parents and a child version to offspring. Different staff
conducted parent and offspring interviews. Fidelity of clinical
interviews was monitored through audiotapes. Clinicians wrote
clinical narrative summaries documenting DSM-IV diagnoses,
which were blindly reviewed by an expert clinician for accuracy.
A review by two raters of randomly selected parent and child
interviews (50 child and parent interviews) yielded acceptable
reliability for anxiety and mood disorders (␬⬎.65). Diagnoses
were coded as present if either the parent or the child report
indicated the presence of a psychiatric disorder.
CO
2
Procedure
Participants wore a face mask that covered their mouth and
nose throughout the experimental procedure. The face mask was
connected via gas-impermeable tubing to a three-way stopcock
valve, allowing the experimenter to switch manually from room-
air to the 5% CO
2
mixture. Connected to this valve was a large
multi-liter balloon reservoir located behind the participant. Dur-
ing the 25-min procedure, offspring breathed room air for 10
min, and 5% CO
2
-enriched air for 15 min. Participants were
unaware of this schedule. The face mask included an occlusion
pressure system device that transmitted inhalation and exhala-
tion data to a laptop computer with spirometry software. This
device computed respiratory frequency and tidal volume values.
The procedure was conducted in the home in a quiet room
selected by the family. Both a physician and technician, blind to
diagnostic status of parents and offspring, supervised it. Before
the procedure was initiated, children were instructed to signal if
they wished to terminate the CO
2
inhalation task for any reason.
The physician and technician remained in the room during the
entire CO
2
procedure, and reiterated that the child could signal if
she/he wished to discontinue. Parents were in an adjacent room
unless they or the child requested that they remain.
Assessment of Symptomatic Response to Maintained 5%
CO
2
. A trained technician who recorded presence/absence as
well as intensity of anxiety symptoms administered the Acute
Panic Inventory (API), modified and validated for children and
adolescents (21). The API assesses 23 symptoms rated on a 0 –3
scale with 0 absent, 1 mild, 2 moderate, and 3-severe.
Participants were asked to point to the rating that best-described
their symptom severity. The API change scores were created by
subtracting baseline API scores (i.e., before attachment of face-
mask and delivery of CO
2
) from APIs assessed at three time
points: 1) after attachment of facemask and assessment of
additional baseline respiratory physiology before CO
2
adminis-
tration (during room air breathing), 2) after 5 min of CO
2
exposure, and 3) at the end of CO
2
breathing.
The technician rated panic attacks during CO
2
inhalation. A
panic attack was operationally defined as an episode of peak
anxiety during which at least four somatic/cognitive symptoms
were reported, similar to previous studies. As in prior studies,
panic attacks required an increase in self-rated anxiety and
increases of 1 point or more on at least four API symptoms
(7,23,24).
Assessment of Ventilatory Response to Maintained 5%
CO
2
. Respiratory frequency (fR) and tidal volume (V
T
) were
continuously measured during room-air and CO
2
exposure with
breath-by-breath spirometry. The average of the initial 10 min of
room air breathing represents baseline values. Mean scores for fR
Table 2. Offspring Risk Group Characteristics
Risk Group
F/
2
p
SAD/PD
n 114
SAD/PD
n 75
SAD/PD
n 10
SAD/PD
n 13
% Female (n) 50.9 (58) 52 (39) 60 (6) 69.2 (9) 1.81 .61
Mean Age, yrs (SD) 15.6 (3.0) 15.2 (3.1) 13.2 (3.3) 12.3 (1.9) 6.4 .001
Age Range, yrs 9–20 9–19 9–18 10–16
% Offspring with a Parent with
Lifetime MD (n) 67.5 (77) 62.7 (47) 90.0 (9) 61.5 (8) 3.17 .37
% Offspring with Comorbid Anxiety
or Depressive Disorder (n)
GAD .0 12.0 (9) 20.0 (2) 23.1 (3)
PD .0 1.3 (1) .0 .0
SoPh 16.7 (19) 16.0 (12) 20.0 (2) 23.1 (3)
PTSD .0 .0 .0 .0
OCD .0 2.7 (2) .0 7.7 (1)
MD .0 8.0 (6) .0 .0
Dysthymia .0 1.3 (1) .0 7.7 (1)
SAD, separation anxiety disorder; PD, panic disorder; MD, major depression, single episode or recurrent episodes; GAD, generalized anxiety disorder; SoPh,
social phobia/social anxiety disorder; PTSD, post-traumatic stress disorder; OCD, obsessive compulsive disorder.
R. Roberson-Nay et al. BIOL PSYCHIATRY 2010;67:1171–1177 1173
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Page 3
and V
T
measured during CO
2
exposure were computed across
the first 10 30-sec epochs of the 15-min exposure. A panting
index was also created by dividing V
T
values by their corre-
sponding fR values. Analyses were restricted to the first 5 min of
the 15-min inhalation task, because ventilatory measures are
highly linear for the first 5 min, with values plateauing after
approximately 5 min of exposure to CO
2
-enriched air. This CO
2
procedure has been used previously in adults with PD and
pediatric studies of CO
2
hypersensitivity (6,23,24).
Data Analyses
Age was included as a covariate in all analyses, given that
offspring with SAD (mean 12.68, SD 2.57) were younger
than those without SAD [mean 15.44, SD 3.00; t (210) 4.21,
p .001].
To examine API change scores, the SAS Mixed procedure was
used (31). This method allows for inclusion of random effects
(i.e., parent– child clusters) and fixed effects (e.g., parental PD,
offspring SAD). The unstructured covariance structure was spec-
ified.
Exact logistic regression was used to examine panic attack
response (yes/no) in offspring. This method was chosen over
asymptotic methods, which might be unreliable when sample
sizes are small or the data are sparse, skewed, or heavily tied.
The SAS Mixed procedure was also used to analyze continu-
ous, repeated measures of fR and V
T
. The analysis included
random effects and fixed effects. The first order autoregressive
(i.e., type ar[1]) covariance structure was specified. Several
variables were entered as covariates in statistical models, includ-
ing baseline fR and V
T
values (respectively), offspring age, and
offspring body mass index.
Panting index values did not approximate a normal Gaussian
curve, demonstrating significant positive skew. Thus, the SAS
GLIMMIX procedure, which allows for random and fixed effects
as well as non-normal distributions, was used to examine panting
index values (31). A distribution and log link function specified
and the first-order autoregressive covariance structure was ap-
plied. A baseline V
T
/fR ratio was created with measures assessed
during the baseline phase and entered as a covariate. Offspring
age and body mass index also were entered as covariates.
All tests of interactions, main effects, and follow-up contrasts
are based on two-tailed tests of significance. Main effects for
offspring SAD and parental PD are not interpreted in the
presence of a significant offspring SAD parental PD interac-
tion. Dependent measure estimates presented in the text and
tables are adjusted for variables included in the particular
analysis. Throughout, indicates the presence of a disorder,
and indicates its absence. All analyses were conducted with
SAS version 9.2 (SAS, Cary, North Carolina). Statistical signifi-
cance was defined as .05. Although we rely on two-tailed
tests of significance for follow-up contrasts, our contrasts are
directional. To bring promising data patterns to notice, p values
.05 and .10 are reported as trends.
Results
Although most offspring completed the entire 15 min of CO
2
exposure, 18% terminated prematurely, creating a range of 65
sec–15 min of CO
2
-breathing. No differences were found among
the four risk groups in amount of exposure to the CO
2
-enriched
air (p .77).
Interaction Effects of Offspring SAD and Parental PD on
Offspring CO
2
Sensitivity Symptomatic Anxiety Responses
API. Analysis of the repeated API change scores supported
the hypothesized SAD PD Trial interaction [F (2468) 5.43,
p .005], indicating that the change in anxiety symptoms during
the respiratory assessment varied as a function of both offspring
SAD and parental PD across time (Figure 1). Follow-up analysis
of the three-way interaction indicated that offspring in the
SAD/PD group reported more symptoms on the API initially
while wearing the facemask and breathing room air compared
with SAD/PD and SAD/PD offspring [t (468) ⫽⫺3.00,
p .003; t (468) ⫽⫺2.46, p .01, respectively]. No difference
was detected between offspring in the SAD/PD and SAD/
PD groups [t (468) ⫽⫺1.49, p .14] on anxiety symptoms
while wearing the facemask and breathing room air.
A trend was noted for the SAD/PD versus SAD/PD
offspring contrast after 5-min exposure to 5% CO
2
[t (468) 1.76,
p .08], with the high-risk group reporting more anxiety
symptoms. The SAD/PD offspring group did not differ from
the SAD/PD or SAD/PDoffspring groups [t (468)
1.58, p .12; t (468) ⫽⫺.53 p .60, respectively] after 5 min
of 5% CO
2
breathing. At the end of CO
2
breathing, however, the
SAD/PD group had greater elevations in anxiety symptoms
compared with the SAD/PD and SAD/PD groups
[t (468) ⫽⫺2.76, p .006; t (468) ⫽⫺2.74, p .006], with a
statistical trend observed for the SAD/PD and SAD/PD
group contrast [t (468) ⫽⫺1.83, p .07].
Panic Attack Response. Offspring with SAD at high risk for
PD (SAD/PD) had a rate of panic attacks threefold higher (4
of 11, 36.4%) than the other groups, (e.g., SAD/PD: 11% [1 of
9]; SAD/PD: 10% [7 of 69]; SAD/PD: 11% [11 of 109]). But
results of the conditional exact test did not yield a significant SAD
PD interaction, as indicated by a nonsignificant exact median
unbiased estimate of the coefficient (1.38, p .58).
To increase statistical power, the high-risk group (SAD/
PD) was contrasted against all other risk groups combined in a
second analysis. The exact median unbiased estimate of the
coefficient for risk group status was significant (1.61, p .05),
with the high-risk group being approximately five times more
likely to experience a panic attack response compared with
offspring with only one or no risk factor.
Figure 1. Acute Panic Inventory (API) scores generated with the SAS mixed
model procedure. Estimated API scores are adjusted for all variables (i.e.,
baseline API, offspring age, Parental panic disorder [PD], Offspring separa-
tion anxiety disorder [SAD], and Trial effect) in the model. CO
2
, carbon
dioxide.
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Respiratory Responses to CO
2
Respiratory frequency and V
T
means and SE values across the
10 30-sec epochs are graphically depicted in Figure 2. Tests of
interactions for respiratory rate, tidal volume, and the panting
index are presented in Table 3, and follow-up contrasts are
presented in Table 4.
CO
2
Effects on Respiratory Frequency. As hypothesized, a
significant two-way interaction between offspring SAD and pa-
rental PD was found. Cell contrasts showed that the SAD/PD
group had higher fR during CO
2
breathing, relative to offspring
with only parental PD (SAD/PD). No significant differences
were found between the SAD/PD and SAD/PD or SAD/
PD groups.
CO
2
Effects on Tidal Volume. A significant Offspring SAD
Parental PD interaction on V
T
was obtained. The SAD/PD
offspring group exhibited lower V
T
compared with the SAD/
PD group. A statistical trend was detected for the SAD/PD
and SAD/PD contrast. No statistically significant difference
was detected between the SAD/PD and SAD/PD groups.
CO
2
Effects on Panting Index. A significant Offspring SAD
Parental PD interaction on the panting ratio was found (Figure 3).
Risk group contrasts indicated that the SAD/PD offspring
exhibited lower panting ratios, indicating progressively more
panting, compared with SAD/PD and SAD/PD offspring.
No significant differences were found between SAD/PD
offspring and SAD/PD offspring.
Discussion
The current study extends previous findings on enhanced
vulnerability to maintained 5% CO
2
inhalation in SAD. This is the
first study to test whether parental PD moderates the association
between childhood SAD and CO
2
hypersensitivity. Offspring of
PD parents with SAD were postulated to represent a distinct
clinical group, possibly at particularly high risk for PD, as
Figure 2. (A) Estimated respiratory frequency and (B) tidal volume values of
offspring with and without SAD of parents with or without a history of PD
across 5 min of 5% CO
2
inhalation. Respiratory frequency and tidal volume
values are adjusted for all variables (i.e., baseline, offspring age, offspring
body mass index, Parental PD, Offspring SAD, and Trial effect) in the model.
Abbreviations as in Figure 1.
Table 3. Predictors of Offspring fR, V
T
, and Panting Index During Maintained 5% CO
2
Inhalation
Predictor Variable
fR V
T
Panting Index
df F p df F p df F p
Fixed Effects
PD SAD trial 9,1702 1.76 .07 9,1702 1.51 .14 9,1651 .68 .72
PD SAD 1,1702 4.11 .04 1,1702 10.36 .001 1,1651 11.75 .001
PD trial 9,1702 .84 .58 9,1702 1.21 .28 9,1651 .58 .81
SAD trial 9,1702 .95 .48 9,1702 .64 .77 9,1651 .6 .79
PD 1,1702 .01 .92 1,1702 .91 .34 1,1651 .19 .66
SAD 1,1702 4.71 .03 1,1702 .44 .51 1,1651 .03 .86
Trial 1,1702 7.71 .001 1,1702 5.59 .001 1,1651 .58 .82
Covariates
Baseline 1,1702 460.09 () .001 1,1702 546.07 () .001 1,1651 244.67 () .001
Age 1,1702 37.62 () .001 1,1702 16.30 () .001 1,1651 34.92 () .001
BMI 1,1702 3.14 () .08 1,1702 1.69 () .19 1,1651 .39 () .53
Parent and offspring disorders are not mutually exclusive. denotes a positive association, and denotes a negative association between the
independent and dependent variables.
fR, respiratory rate; V
T
, tidal volume; CO
2
, carbon dioxide; PD, panic disorder; SAD, separation anxiety disorder; BMI, body mass index.
Table 4. Offspring SAD Parental PD Interaction Contrasts
fR V
T
Panting
Index
tptptp
Contrast
SAD/PD vs. SAD/PD⫺⫺1.34 .18 .32 .75 .47 .64
SAD/PD vs. SAD/PD⫹⫺2.87 .01 1.85 .06 2.68 .01
SAD/PD vs. SAD/PD⫺⫺.98 .33 2.17 .03 1.95 .05
Parent and offspring disorders are not mutually exclusive. Abbreviations
as in Table 3.
R. Roberson-Nay et al. BIOL PSYCHIATRY 2010;67:1171–1177 1175
www.sobp.org/journal
Page 5
manifest by CO
2
-hypersensitivity. In this study, parental PD
alone was not associated with CO
2
hypersensitivity in offspring;
however, it had significant influence on CO
2
response in the
offspring with SAD. Also, offspring with both SAD and parental
PD exhibited greater panic symptoms compared with SAD/
PD and SAD/PD offspring during threat (i.e., wearing
facemask during ambient air breathing). This finding for the
“threat” epoch extends our previous analysis in PD offspring by
showing that an enhanced level of anxiety symptoms occurs
before CO
2
inhalation predominantly among offspring with both
parental PD and offspring SAD.
Offspring with both risk factors also differed from all other
risk groups at the end of CO
2
-breathing. In fact, only offspring
with both SAD of parental PD exhibited increased elevations in
anxiety symptoms from 5 min of CO
2
breathing to termination of
CO
2
breathing, whereas all other risk groups’ endorsements
remained stable or decreased. A high rate of panic attacks also
emerged in this high-risk group (36%), compared with the other
three groups, who all exhibited rates in the 10%–11% range.
However, for this dichotomous index, the SAD PD interaction
was not significant, likely reflecting low power to detect an
interactive effect. The panic attack rate in the SAD/PD group
is similar to the rate reported in adult PD patients (30%–40%)
(6,8,32) during 5% CO
2
exposure; similarly, the rate of panic
attacks in the other three offspring groups is comparable to that
typically observed in adult healthy subjects (8,32).
Results for measures of respiratory physiology were less
consistent, because of the unexpected responsiveness of the
SAD/PD group. An SAD PD interaction was found for both
fR and V
T
, as hypothesized. Interactions for the respiratory
measures were driven by an SAD effect manifest only in the PD
but not PD stratum. Specifically, offspring with both SAD and
parental PD had the highest CO
2
-induced respiratory rate cou-
pled with reduced tidal volume, differing from offspring who had
parents with PD but no SAD, on measures of respiratory rate and
tidal volume. The high-risk offspring group also differed from
SAD/PD offspring on tidal volume. Unexpectedly, the
SAD/PD group did not differ from the SAD/PD group on
any respiration related measures. Post hoc analysis of a panting
index also suggests that youth with SAD at genetic risk for PD
might be attempting to reduce CO
2
levels by engaging in rapid,
shallow breathing. It should be noted that, again, not all be-
tween-group contrasts were significant, with the SAD/PD
group and SAD/PD group not differing significantly. Never-
theless, results from analyses of respiratory physiology indicate
that parental PD moderates the association between SAD and
respiratory physiology and that the ventilatory patterns observed
here are consistent with those identified among adult PD pa-
tients.
To date, much of the research examining disorder-specific
markers has yielded disappointing results. Some of the markers
investigated among the anxiety disorders include autonomic
indicators such as heart rate, heart rate variability, and skin
conductance as well as stress-related endocrine indexes such as
cortisol. None have demonstrated diagnostic specificity; rather,
each tends to be associated with global changes in arousal, and
each relates to some extent to the presence of high levels of
anxiety symptoms as opposed to any specific anxiety disorder or
symptom profile. To understand better the etiologic or patho-
physiological underpinnings of specific anxiety disorders, detec-
tion of disorder-specific markers might prove essential. In the
case of childhood SAD, respiratory system dysregulation caused
by CO
2
holds promise as a distinct objective marker.
A limitation of this study is that we did not systematically
record whether parents remained in the room with the child
during CO
2
breathing. It seems unlikely that this factor affected
outcomes, because SAD main effects on CO
2
-induced respiratory
perturbations also have been observed in studies using labora-
tory settings in which parents are not present during testing (23).
Although our results are generally supportive of study hypothe-
ses, tests of offspring SAD and parent PD interactions relied on
relatively small cell sizes, and contrasts directly comparing
children with both risk factors with children with one or no risk
factor did not consistently support differences, despite the pres-
ence of a significant interaction. At the same time, it is all the
more striking that support for interaction effects were obtained
with small samples. Ideally, future studies should seek to collect
larger samples and implement longitudinal follow-ups to clarify
the distinction between separation anxiety with and without
parental PD, with regard to course and comorbidity and possibly
treatment and prevention.
This work was supported by the National Institute of Mental
Health Grant R01 MH-59171 and a Grant from the Nick Traina
Foundation.
The authors report no biomedical financial interests or po-
tential conflicts of interest.
1. Gorman, JM, Fyer MR, Goetz R, Askanazi J, Liebowitz MR, Fyer AJ, et al.
(1984): Ventilatory physiology of patients with panic disorder. Arch Gen
Psychiatry 45:31–39.
2. Kent JM, Papp LA, Martinez JM, Browne ST, Coplan JD, Klein DF, et al.
(2001): Specificity of panic response to CO
2
inhalation in panic disorder:
A comparison with major depression and premenstrual dysphoric dis-
order. Am J Psychiatry 158:58 67.
3. Papp LA, Klein DF, Gorman JM (1993): Carbon dioxide hypersensitivity,
hyperventilation, and panic disorder. Am J Psychiatry 150:1149 –1157.
4. Sanderson WC, Rapee RM, Barlow DH (1989): The influence of an illusion
of control on panic attacks induced via inhalation of 5.5% carbon diox-
ide-enriched air. Arch Gen Psychiatry 46:157–162.
5. Klein DF (1998): Panic and phobic anxiety: Phenotypes, endopheno-
types, and genotypes. Am J Psychiatry 155:1147–1149.
6. Gorman JM, Fyer MR, Goetz R, Askanazi J, Liebowitz MR, Fyer AJ, et al.
(1988): Ventilatory physiology of patients with panic disorder. Arch Gen
Psychiatry 45:31–39.
7. Gorman JM, Kent J, Martinez J, Browne S, Coplan J, Papp LA (2001):
Physiological changes during carbon dioxide inhalation in patients with
Figure 3. Log-transformed panting ratio (respiratory frequency/tidal vol-
ume [V
T
/fR]) values across 5 min of 5% CO
2
breathing for offspring with and
without SAD of parents with or without a history of PD. Panting ratio values
are adjusted for all variables (i.e., baseline, offspring age, offspring body
mass index, Parental PD, Offspring SAD, and Trial effect) in the model. Other
abbreviations as in Figure 1.
1176 BIOL PSYCHIATRY 2010;67:1171–1177 R. Roberson-Nay et al.
www.sobp.org/journal
Page 6
panic disorder, major depression, and premenstrual dysphoric disorder:
Evidence for a central fear mechanism. Arch Gen Psychiatry 58:125–131.
8. Papp LA, Martinez JM, Klein DF, Coplan JD, Norman RG, Cole R, et al.
(1997): Respiratory psychophysiology of panic disorder: Three respira-
tory challenges in 98 subjects. Am J Psychiatry 154:1557–1565.
9. Pain MC, Biddle N, Tiller JW (1988): Panic disorder, the ventilatory re-
sponse to carbon dioxide and respiratory variables. Psychosom Med
50:541–548.
10. Sasaki I, Akiyoshi J, Sakurai R, Tsutsumi T, Ono H, Yamada K, Fujii I (1996):
Carbon dioxide induced panic attack in panic disorder in Japan. Prog
Neuropsychopharmacol Biol Psychiatry 20:1145–1157.
11. Lousberg H, Griez E, van den Hout MA (1988): Carbon dioxide chemo-
sensitivity in panic disorder. Acta Psychiatr Scand 77:214 –218.
12. Goetz RR, Klein DF, Gully R, Kahn J, Liebowitz MR, Fyer AJ, et al. (1993):
Panic attacks during placebo procedures in the laboratory. Physiology
and symptomatology. Arch Gen Psychiatry 50:280 –285.
13. Papp LA, Martinez JM, Klein DF, Coplan JD, Gorman JM (1995): Rebreath-
ing tests in panic disorder. Biol Psychiatry 38:240 –245.
14. Zandbergen J, Pols H, de Loof C, Griez EJ (1991): Ventilatory response to
CO
2
in panic disorder. Psychiatry Res 39:13–19.
15. Klein DF (1993): False suffocation alarms, spontaneous panics, and re-
lated conditions. An integrative hypothesis. Arch Gen Psychiatry 50:306
317.
16. Coryell W, Fyer A, Pine D, Martinez J, Arndt S (2001): Aberrant respiratory
sensitivity to CO
2
as a trait of familial panic disorder. Biol Psychiatry
49:582–587.
17. van Beek N, Griez E (2000): Reactivity to a 35% CO
2
challenge in healthy
first-degree relatives of patients with panic disorder. Biol Psychiatry
47:830 835.
18. Perna G, Cocchi S, Bertani A, Arancio C (1995): Sensitivity to 35% CO
2
in
healthy first-degree relatives of patients with panic disorder. Am J Psy-
chiatry 152:623– 625.
19. Bellodi L, Perna G, Caldirola D, Arancio C, Bertani A, Di Bella D (1998):
CO
2
-induced panic attacks: A twin study. Am J Psychiatry 155:1184
1188.
20. Hettema JM, Neale MC, Kendler KS (2001): A review and meta-analysis of
the genetic epidemiology of anxiety disorders. Am J Psychiatry 158:
1568 –1578.
21. Battaglia M, Pesenti-Gritti P, Spatola CAM, Ogliari A, Tambs K (2008): A
twin study of the common vulnerability between heightened sensitivity
to hypercapnia and panic disorder. Am J Med Genet 147B:586 –593.
22. Battaglia M, Pesenti-Gritti P, Medland SE, Ogliari A, Tambs K, Spatola
CAM (2009): A genetically informed study of the association between
childhood separation anxiety, sensitivity to CO(2), panic disorder, and
the effect of childhood parental loss. Arch Gen Psychiat 66:64 –71.
23. Pine DS, Coplan JD, Papp LA, Klein RG, Martinez JM, Kovalenko P, et al.
(1998): Ventilatory physiology of children and adolescents with anxiety
disorders. Arch Gen Psychiatry 55:123–129.
24. Pine DS, Klein RG, Coplan JD, Papp LA, Hoven CW, Martinez J, et al.
(2000): Differential carbon dioxide sensitivity in childhood anxiety dis-
orders and nonill comparison group. Arch Gen Psychiatry 57:960 –967.
25. Pine DS, Klein RG, Roberson-Nay R, Mannuzza S, Moulton JL III, Wolde-
hawariat G, et al. (2005): Response to 5% carbon dioxide in children and
adolescents: Relationship to panic disorder in parents and anxiety dis-
orders in subjects. Arch Gen Psychiatry 62:73– 80.
26. Aschenbrand SG, Kendall PC, Webb A, Safford SM, Flannery-Schroeder E
(2003): Is childhood separation anxiety disorder a predictor of adult
panic disorder and agoraphobia? A seven-year longitudinal study. JAm
Acad Child Adolesc Psychiatry 42:1478 –1485.
27. Klein RG (1995): Is panic disorder associated with childhood separation
anxiety disorder? Clin Neuropharmacol 18:7–14.
28. Spitzer RL, Williams JB, Gibbon M, First MB (1992): The Structured Clini-
cal Interview for DSM-III-R (SCID). I: History, rationale, and description.
Arch Gen Psychiatry 49:624 629.
29. Mannuzza S, Fyer AJ (1990): Family Informant Schedule and Criteria
(FISC), July 1990 Revision. New York: New York State Psychiatric Institute,
Anxiety Disorders Clinic.
30. Kentgen LM, Klein RG, Mannuzza S, Davies M (1997): Test-retest reliabil-
ity of maternal reports of lifetime mental disorders in their children. J
Abnorm Child Psychol 25:389 –398.
31. Littell RC, Milliken GA, Stroup WW, Wolfinger RD (2002): SAS System for
Mixed Models. Cary, North Carolina: SAS Institute.
32. Rassovsky Y, Abrams K, Kushner MG (2006): Suffocation and respiratory
responses to carbon dioxide and breath holding challenges in individ-
uals with panic disorder. J Psychsom Rev 60:291–298.
33. Hollingshead AB, Redlich FC (1958): Social Class and Mental Illness: A
Community Study. New York: John Wiley & Sons.
R. Roberson-Nay et al. BIOL PSYCHIATRY 2010;67:1171–1177 1177
www.sobp.org/journal
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  • Source
    • "Whether the susceptibility to experiencing panic symptoms following CO 2 inhalation reflects a perturbation within neural circuits responsible for respiratory functioning is not known, but it is a possibility (Klein, 1993). An abnormality in respiratory physiology may not be detectable, however, because there is some evidence to suggest that vulnerable persons engage in subtle respiratory maneuvering to avoid absorption of CO 2 into the blood (Coryell et al., 2001; Roberson-Nay et al., 2010). Moreover, the respiratory measures that might underlie subjective hypersensitivity to breathing CO 2 enriched air have produced mixed findings, most notably tidal volume (i.e., measurement of the air expired in a breath). "
    [Show abstract] [Hide abstract] ABSTRACT: Carbon dioxide (CO2) hypersensitivity is hypothesized to be a robust endophenotypic marker of panic spectrum vulnerability. The goal of the current study was to explore the latent class trajectories of three primary response systems theoretically associated with CO2 hypersensitivity: subjective anxiety, panic symptoms, and respiratory rate (fR).Methods Participants (n=376; 56% female) underwent a maintained 7.5% CO2 breathing task that included three phases: baseline, CO2 air breathing, and recovery. Growth mixture modeling was used to compare response classes (1..n) to identify the best-fit model for each marker. Panic correlates also were examined to determine class differences in panic vulnerability.ResultsFor subjective anxiety ratings, a three-class model was selected, with individuals in one class reporting an acute increase in anxiety during 7.5% CO2 breathing and a return to pre-CO2 levels during recovery. A second, smaller latent class was distinguished by elevated anxiety across all three phases. The third class reported low anxiety reported during room air, a mild increase in anxiety during 7.5% CO2 breathing, and a return to baseline during recovery. Latent class trajectories for fR yielded one class whereas panic symptom response yielded two classes.LimitationsThis study examined CO2 hypersensitivity in one of the largest samples to date, but did not ascertain a general population sample thereby limiting generalizability. Moreover, a true resting baseline measure of fR was not measured.Conclusions Two classes potentially representing different risk pathways were observed. Implications of results will be discussed in the context of panic risk research.
    Full-text · Article · Nov 2014 · Journal of Behavior Therapy and Experimental Psychiatry
  • Source
    • "In particular, twin-based clinical and epidemiological studies showed that CSA and PD share a common genetic diathesis [28,29] . Moreover, separationanxious offspring of parents with panic disorder (PD) presents ventilatory responses to hypercapnia similar to those observed in panic patients [30]. In the same vein, preclinical studies showed that respiratory responses to hypercapnia are facilitated in both mice and rats exposed to unstable familial environment (repeated cross-fostering) [31] and maternal separations [32,33,34,35,36] respectively. "
    [Show abstract] [Hide abstract] ABSTRACT: Plenty of evidence suggests that childhood separation anxiety (CSA) predisposes the subject to adult-onset panic disorder (PD). As well, panic is frequently comorbid with both anxiety and depression. The brain mechanisms whereby CSA predisposes to PD are but completely unknown in spite of the increasing evidence that panic attacks are mediated at midbrain's dorsal periaqueductal gray matter (DPAG). Accordingly, here we examined whether the neonatal social isolation (NSI), a model of CSA, facilitates panic-like behaviors produced by electrical stimulations of DPAG of rats as adults. Eventual changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST) respectively. Male pups were subjected to 3-h daily isolations from post-natal day 2 (PN2) until weaning (PN21) allotting half of litters in individual boxes inside a sound-attenuated chamber (NSI, n = 26) whilst siblings (sham-isolated rats, SHAM, n = 27) and dam were moved to another box in a separate room. Non-handled controls (CTRL, n = 18) remained undisturbed with dams until weaning. As adults, rats were implanted with electrodes into the DPAG (PN60) and subjected to sessions of intracranial stimulation (PN65), EPM (PN66) and FST (PN67-PN68). Groups were compared by Fisher's exact test (stimulation sites), likelihood ratio chi-square tests (stimulus-response threshold curves) and Bonferroni's post hoc t-tests (EPM and FST), for P<0.05. Notably, DPAG-evoked panic-like responses of immobility, exophthalmus, trotting, galloping and jumping were markedly facilitated in NSI rats relative to both SHAM and CTRL groups. Conversely, anxiety and depression scores either did not change or were even reduced in neonatally-handled groups relative to CTRL, respectively. Data are the first behavioral evidence in animals that early-life separation stress produces the selective facilitation of panic-like behaviors in adulthood. Most importantly, results implicate the DPAG not only in panic attacks but also in separation-anxious children's predispositions to the late development of PD.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Such elicitation occurs very rarely in normal subjects or other anxiety disorders, and does not occur during infusions of such stressors as physostigmine, insulin, 5HTP, etc. (Brambilla et al., 1995; den Boer and Westenberg, 1990; Di Lorenzo et al., 1987; Rapaport et al., 1991; Strawn et al., 2008). Hypersensitivity to elevated CO 2 may also help identify childhood groups at familial risk for subsequent development of panic disorder (Roberson-Nay et al., 2010; Spatola et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO2, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO2 were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1mg/kg), and alprazolam (0.3mg/kg) injections. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO2, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO2 were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO2, which might be related to CO2 induced panic.
    Full-text · Article · Jun 2011 · Brain research
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