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
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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, Oct 08, 2015
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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.
    PLoS ONE 03/2014; 9(3):e90726. DOI:10.1371/journal.pone.0090726 · 3.23 Impact Factor
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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.
    Brain research 06/2011; 1396:54-59. DOI:10.1016/j.brainres.2011.04.042 · 2.84 Impact Factor
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    ABSTRACT: Respiratory abnormalities are commonly associated with anxiety in general and panic attacks in particular. Panic patients very often complain of dyspnea, shortness of breath and hyperventilation during acute panic attacks. Panic attacks may be provoked in the laboratory. The results from provocative tests using sodium lactate, caffeine, CO2, yohimbine and isoproterenol suggest that panic patients have a special sensitivity to these substances. Hyperventilation appears to be a secondary but pathophysiologically important event in triggering panic attacks. It seems more likely that hyperventilation or other respiratory deviations are symptoms, not causes of panic attacks. This present paper reviewed literature studies about the association between anxiety and respiration, using Medline from 1980 to 1995.
    Jornal brasileiro de psiquiatria 08/1996; 45(8):491-496.
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