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


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.

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Available from: Rachel G Klein
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    • "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). "
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    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
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    • "In particular, twin-based clinical and epidemiological studies showed that CSA and PD share a common genetic diathesis [28], [29]. Moreover, separation-anxious 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. "
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    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). "
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    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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