manifest by CO
-hypersensitivity. In this study, parental PD
alone was not associated with CO
hypersensitivity in offspring;
however, it had significant influence on CO
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
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
-breathing. In fact, only offspring
with both SAD of parental PD exhibited increased elevations in
anxiety symptoms from 5 min of CO
breathing to termination of
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
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
, 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
-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
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-
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
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
breathing. It seems unlikely that this factor affected
outcomes, because SAD main effects on CO
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
The authors report no biomedical financial interests or po-
tential conflicts of interest.
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Figure 3. Log-transformed panting ratio (respiratory frequency/tidal vol-
/fR]) values across 5 min of 5% CO
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.