Fear responding to 35% CO(2) challenge as a vulnerability marker for later social anxiety symptoms

The majority of biological challenge studies have focused on panic disorder though there is a small literature suggesting that patients with social anxiety disorder (SAD) show comparable responding. These cross-sectional studies suggest that CO₂ reactivity may be a marker of vulnerability to social anxiety. However, the nature of this association is unclear due to design limitations in this literature. The present report prospectively evaluated whether response to a 20% CO₂ challenge was predictive of later changes in social anxiety symptoms. A large non-clinical sample of young adults (N = 404) screened for axis I disorders completed a 20% CO₂ challenge and were followed for approximately 18 months. Consistent with the vulnerability hypothesis, those showing greater reactivity to the CO₂ challenge showed increased social anxiety symptoms over time. This significant association was maintained after controlling for gender and trait anxiety. These data provide novel evidence suggesting that CO₂ sensitivity is predictive of the development of social anxiety symptoms.     

Vulnerability to 35% CO2 of panic disorder patients with a history of respiratory disorders

Patients with panic disorder often report a history of respiratory pathology. Furthermore, panic disorder patients are vulnerable to CO2 challenges. The increased CO2 vulnerability displayed by panic disorder patients may be related to lifetime respiratory pathology. We examined whether panic disorder patients with a history of respiratory disorders are more vulnerable to a 35% CO2 challenge than those without such a history. Ninety-six patients with panic disorder were interviewed about their lifetime respiratory status (asthma, bronchitis and various other respiratory conditions) and underwent the challenge. Immediately before and after the CO2 inhalation, the patients filled out the Visual Analogue Scale for Anxiety (VAS-A) and the Panic Symptom List (PSL). We found no differences between the two panic disorder groups on anxiety (VAS-A), panic symptoms (PSL) or panic attacks after the CO2 challenge. Our results suggest that having a PD is an important factor in CO2 vulnerability independent of a history of respiratory disorders.     

Psychopathological profile of 35% CO2 challenge test-induced panic attacks: a comparison with spontaneous panic attacks

Our aim was to describe the clinical features of 35% CO2-induced panic attacks in patients with panic disorder (PD) (Diagnostic and Statistical Manual and Mental Disorders, Fourth Edition) and compare them with the last spontaneous panic attack in patients with PD who had not had a panic attack after the 35% CO2 challenge test. We examined 91 patients with PD submitted to the CO2 challenge test. The test consisted of exhaling as fully as possible, took a fast vital capacity breath, held their breath for 8 seconds, exhaled, and then repeated the fast vital capacity breath, again holding for 8 seconds. The patients inhaled the 35% CO2/65% O2 mixture or atmospheric compressed air, randomly selected in a double-blind design. Scales were applied before and after the test. A total of 68.1% (n = 62) patients with PD had a panic attack (responders) after the CO2 test (chi2(1) = 25.87, P = .031). The last spontaneous panic attack and the symptom profile from the patients with PD who had not had a panic attack after the test (n = 29, 31.9%) were described to compare. The responders had more respiratory symptoms (chi2(1) = 19.21, P < .001), fulfilling the criteria for respiratory PD subtype (80.6%); the disorder started earlier (Mann-Whitney, P < .001), had a higher familial prevalence of PD (chi2(1) = 20.45, P = .028), and had more previous depressive episodes (chi2(1) = 27.98, P < .001). Our data suggest that there is an association between respiratory PD subtype and hyperreactivity to a CO2 respiratory challenge test. The responders may be a subgroup of respiratory PD subtype with future diagnostic and therapeutic implications.     

Anxiety sensitivity and 35% CO2 reactivity in patients with panic disorder

Objective: The present study examines the possible relationships between anxiety sensitivity (AS) and reactivity to the 35% carbon dioxide (CO₂) challenge in panic disorder (PD). Methods: One-hundred eight patients with PD underwent the 35% CO₂ challenge and completed the Anxiety Sensitivity Index (ASI). Multiple regression analyses were applied to evaluate the role of AS as a predictor of CO₂-induced anxiety. Results: Fifty-six patients with PD showed high AS scores, whereas 48 showed medium scores and 4 low scores. ASI scores significantly predicted symptomatological reaction to CO₂ but not subjective induced anxiety. Conclusion: These findings suggest that the fear of anxiety-related bodily sensations was related to the symptomatological reactivity to CO₂ but did not seem to play a crucial role in the modulation of the subjective anxiogenic/panicogenic response to hypercapnia in patients with PD.     

Reactivity to a 35% CO2 challenge in healthy first-degree relatives of patients with panic disorder.

BACKGROUND: The effects of a 35% CO2 challenge were examined in healthy first-degree relatives of panic disorder patients and in healthy control subjects matched for age and gender. METHODS: One single inhalation of a 35% CO2/65% O2 challenge was administered to 50 first-degree relatives of panic disorder patients and 50 control subjects. RESULTS: The first-degree relatives were more reactive to the 35% CO2 challenge than the control subjects. CONCLUSIONS: These findings indicate that being a member of a family with a panic disorder patient is, in itself an important factor in CO2 hypersensitivity among subjects who have never experienced a panic attack. Both panic disorder patients and their first-degree relatives have a tendency to be more reactive to the CO2 challenge.     

A segregation study of panic disorder in families of panic patients responsive to the 35% CO2 challenge.

BACKGROUND: A genetic component has a role in the etiology of Panic Disorder (PD) and a familial association between PD and CO2 hypersensitivity have been repeatedly described. METHODS: Complex segregation analysis was performed on a sample of 165 families of PD probands and on the subgroup homogeneous for CO2 hypersensitivity, using Regressive Logistic Models. The only relatives considered to be affected were those with PD. Relatives have been diagnosed according to Family History Method. RESULTS: A Mendelian hypothesis was compatible with our data, without distinction between different models of transmission. The Akaike's Information Criterion values indicated that the Additive model was the most parsimonious, with a gene frequency of .0005, incomplete penetrance and a phenocopy rate of .00029. By subdividing the families according to the probands' responses to CO2 inhalations, probands of 134 families were hypersensitive to CO2. The analysis performed on this subgroup supported the existence of a SML with a best fit for a Dominant model. CONCLUSIONS: A SML account for genetic transmission in PD families and 35% CO2 challenge test may individuate a genetically homogeneous subgroup of patients with PD.     

Temporal and structural dynamics of anxiety sensitivity in predicting fearful responding to a 35% CO2 challenge

The current study assessed the incremental prediction of anxiety sensitivity (AS) in both taxonic (categorical) and dimensional representations at various time points before and after a single vital capacity inhalation of a 35% CO₂, 65% balanced O₂ gas mixture. Participants were 128 young adults screened for a history of panic attacks. By controlling for traitwise factors including state anxiety and testing both categorical and continuous conceptualizations of the AS construct at various timepoints, the present report was able to evaluate the temporal and structural dynamics of AS in relation to fearful responding to the challenge. Relevant variables were evaluated in a hierarchical linear regression framework, and it was found that a continuous conceptualization of AS provided incremental predictive validity above and beyond trait anxiety immediately post-challenge, while a categorical representation of AS was equivalent to a continuous model of AS at post-challenge but outperformed a continuous model at follow-up. These data provide basic but important evidence suggesting that AS is uniquely associated with anxious responding to a 35% CO₂ challenge, and that categorical representations of AS should be considered in biological challenge studies.     

Social anxiety symptoms uniquely predict fear responding to 35% CO(2) challenge

The vast majority of biological challenge studies have focused on panic disorder though there is a small literature suggesting that patients with social anxiety disorder (SAD) show comparable responding. The SAD literature is potentially confounded, however, by the fact that many patients with SAD experience panic attacks. These patients also show elevated negative affect and anxiety sensitivity, factors that are also associated with increased fear responding to challenge. By controlling for these factors, the present report was able to evaluate whether social anxiety symptoms were uniquely associated with fearful responding to a 35% CO(2) challenge. A large nonclinical sample of young adults (N=120) screened for a history of panic attacks completed a 35% CO(2) challenge. Those high (versus low) in social anxiety showed approximately 2.5 times greater risk for experiencing substantial increases in anxiety in response to the challenge. This significant association was maintained after controlling for anxiety sensitivity and general negative affect. These data provide novel evidence suggesting that social anxiety symptoms are uniquely associated with anxious responding to 35% CO(2) challenge and this sensitivity appears to precede the development of panic attacks.     

Response to repeated CO2 in individuals with elevated anxiety sensitivity: replication with 20% CO2.

The present report replicates and extends previous work examining response patterns to repeated presentation of CO2. In previous studies, two distinct response patterns to repeated presentation of 35% CO2 were noted, representing habituation and nonhabituation of anxiety. In this report, 21 participants who had never experienced a panic attack but who reported high levels of anxiety sensitivity were presented with 12 trials of 20% CO2, followed by a trial involving inhalation of room air (to examine dishabituation) and two more trials of 20% CO2. Results indicated that 67% of the sample reported habituation of anxiety. Reductions in anxiety across inhalations were paralleled by changes in tidal volume, perceived panic symptom severity, and feelings of panic. Notable dishabituation was observed in the nonhabituation sample. Results are discussed in the light of basic learning processes underlying the treatment of Panic Disorder (PD).     

Effects of low pulmonary CO2 on panic anxiety

In order to investigate the possible role of hyperventilation in the pathogenesis of panic, 11 panic patients and eight normal controls underwent a hyperventilation provocation test. The word "hyperventilation" itself was not used; the subjects were told the test was meant to measure the amount of carbon dioxide in their expired air. End tidal pCO2 was reduced to less than half of its initial value, resulting in a significant increase in physical symptoms, both in patients and controls. However, there proved to be no significant increase in subjective anxiety. It is suggested, that hypocarbia alone is not sufficient to provoke anxiety in panic disorder patients.     

Response to 35% CO2 in patients with chest pain and angiographically normal coronary arteries.

OBJECTIVES: Several interview studies have suggested that panic disorder (PD) exists in patients with angiographically normal coronary arteries (NCA). Interview studies require corroboration by other studies in order to validate them. The purpose of this study is to test whether response to the inhalation of 35% CO2 reliably discriminates between PD and non-panic disorder patients in this population. METHOD: Three groups were studied: six with NCA and PD, five with NCA and no PD, and ten in the control group. All subjects breathed room air, then 35% CO2 in a single-blind fashion. Each completed the Acute Panic Inventory (API) before and during the procedure. RESULTS: The NCA-panic group scored significantly higher than the other two groups on the Acute Panic Inventory from baseline to post-inhalation. CONCLUSION: Despite several methodological limitations including a relatively small number people in each cells, 35% CO2 was shown to trigger more intense responses in panic patients, thus helping to validate the interview findings.     

Reduction of CO2-induced anxiety in patients with panic attacks after repeated CO2 exposure

The authors compared the subjective reaction of 13 panic patients and eight control subjects to a 35% CO2 challenge, a treatment known to produce physical symptoms comparable to those of natural or lactate-induced panic, and to placebo treatment (inhalation of air). They found that patients had higher placebo scores than control subjects, patients tended to get highly anxious on CO2 and control subjects did not, and CO2-induced subjective anxiety in patients decreased as the number of CO2-induced exposures to interoceptive anxiety symptoms increased. The data support a behavioral account of the effects of anxiogenics.     

A long-term prospective evaluation of first-degree relatives of panic patients who underwent the 35% CO2 challenge.

BACKGROUND: This follow-up study investigated the potential priming effect of the 35% CO2 challenge on the development of anxiety disorders and/or panic attacks in healthy first-degree relatives of panic patients across a period of 3-4 years subsequent to the challenge. METHODS: Thirty-one relatives who underwent the 35% CO2 challenge 3-4 years before and 14 relatives, free from psychiatric diagnoses in the same period, were directly reevaluated for the presence of anxiety disorders and panic attacks. RESULTS: None developed anxiety disorders and only 1, among relatives previously tested with the 35% CO2 challenge, reported sporadic panic attacks. CONCLUSIONS: The 35% CO2 challenge is a safe research paradigm in the investigation of healthy subjects with a familial vulnerability to panic, and CO2 hypersensitivity might be considered a trait marker of an underlying familial vulnerability to panic disorder.     

Hypothalamic-pituitary-adrenal axis function following a 35% CO2 inhalation in healthy volunteers

RATIONALE: The hypothalamic-pituitary-adrenal axis (HPA axis) is a central component of the brain's neuroendocrine response to stress. The extent of increase in cortisol secretion, provides an index of the HPA axis activity, and in this way, objectively reflects perceived stress. In healthy subjects, the 35% CO(2) inhalation does hardly induce stress, as expressed in anxiety. However, inconsistent results have been found in studies investigating the cortisol response following CO(2) inhalation. Clarity has to be reached about the normal reaction to this challenge, especially because this model is still a very valuable method to study central aspects of panic. OBJECTIVES: The present study aimed to test the hypothesis that a single breath of 35% CO(2) would not induce cortisol release in healthy volunteers. METHODS: In the current study, 20 healthy subjects underwent both a 35% CO(2) and a placebo inhalation in a randomised, single blind fashion. Cortisol levels were determined in saliva samples, taken at regular intervals. RESULTS: No differences were found between the CO(2) and the placebo condition. In both conditions a significant time effect was found, which can be subscribed to normal variation in the circadian rhythm. Furthermore, only modest subjective anxiety scores were found in the CO(2) condition. CONCLUSIONS: These results provide biological evidence for the hypothesis that healthy subjects are not affected by the 35% CO(2) challenge in a clinically significant way. Characteristic, PD patients react much stronger to the inhalation. Thus, in addition to psychological parameters, healthy subjects also constitute an ideal comparison group with regard to endocrinological parameters.     

Response to 5% carbon dioxide in children and adolescents: relationship to panic disorder in parents and anxiety disorders in subjects

BACKGROUND: Carbon dioxide (CO(2)) sensitivity is postulated to be a familial risk marker of panic disorder (PD). Exaggerated responses to CO(2) inhalation have been reported in adults with PD and their unaffected adult relatives, as well as in clinic-referred children with anxiety disorders. OBJECTIVE: To test in a family-based design whether CO(2) hypersensitivity is a familial risk marker for PD and associated with current anxiety disorders in children and adolescents. SETTING AND PARTICIPANTS: One hundred forty-two offspring (aged 9-19 years) of parents with PD, major depressive disorder, or no disorder. Forty-five (32%) had a current anxiety disorder, excluding specific phobia. DESIGN AND MAIN OUTCOME MEASURES: Parents and offspring received diagnostic assessments. Offspring underwent 5% CO(2) inhalation at home. Panic symptoms and panic attacks were rated with the Acute Panic Inventory at baseline, while anticipating CO(2) delivery ("threat"), and during CO(2) inhalation. Respiratory rate and volume were measured with spirometry. RESULTS: No group differences were found in Acute Panic Inventory ratings at baseline or in respiratory measures during threat. Risk for PD was not associated with CO(2) sensitivity (panic symptoms and respiratory physiologic response). During CO(2) inhalation, offspring with anxiety disorders, relative to offspring without anxiety disorders, experienced significantly more panic symptoms and panic attacks, as well as elevated respiratory rates. During threat, panic symptoms were significantly and independently associated with both parental PD and offspring anxiety disorders. CONCLUSIONS: No support was obtained for CO(2) hypersensitivity as a familial risk marker for PD in children and adolescents. Links between childhood anxiety disorders and CO(2) sensitivity were replicated. Familial risk for PD in children and adolescents may be associated with vulnerability to anticipatory anxiety.     

Yohimbine premedication and 35% CO2 vulnerability in healthy volunteers

Summary A group of 20 healthy volunteers underwent a 35% carbon dioxide / 65% oxygen air-placebo controlled challenge test twice, premedicated 1 h before with either 20 mg yohimbine or placebo, following a double-blind randomized crossover design. Contrary to expectation the anxiety response to carbon dioxide was not higher when premedicated with yohimbine compared to premedication with placebo. Possible implications of this finding are discussed, with reference to general chemical models of panic.     

35% Carbon dioxide and breath-holding challenge tests in panic disorder: a comparison with spontaneous panic attacks

Respiration and its control mechanisms may represent an important system involved in abnormal anxiety. Our aim was to compare the demographic and clinical features of patients with panic disorder (PD) with agoraphobia (DSM-IV) who had a panic attack after both the 35% carbon dioxide (CO(2)) test and the breath-holding test (CPA group), and compare them with PD patients who did not have a panic attack after both tests (NPA group). We examined 76 patients with PD who were administered a 35% CO(2)test and a breath-holding test within a 1-week interval. Anxiety scales were applied before and after each test. A panic attack was induced in 50 (65.8%) patients during the CO(2)test (chi(2) = 28.44, df = 1, P<.001) and in 40 (52.6%) patients during the breath-holding test (chi(2) = 15.35, df = 1, P = .036). All patients who had a panic attack during the breath-holding test also had a panic attack during the CO(2)test (n = 40; CPA group). Twenty-six (34.2%) patients with PD did not have a panic attack after both respiratory tests (NPA group). The CPA group had more (chi(2) = 21.67, df = 1, P = .011) respiratory PD subtype. In the CPA group, the disorder started earlier (Mann-Whitney, P<.001), had a higher familial prevalence of PD (chi(2) = 18.34, df = 1, P = .028), and had more previous depressive episodes (chi(2) = 23.59, df = 1, P<.001). Our data suggest that there is an association between respiratory PD subtype and the response to respiratory challenge tests: CO(2)and breath-holding. The CPA may be confirmed as a subgroup of respiratory PD subtype.     

The 35% CO2 inhalation procedure: test-retest reliability.

The subjective response to a single-breath, 35% carbon dioxide challenge test shows promise as a tool for the study of panic disorder and may comprise a trait marker for that disorder. Little has been done to measure the reliability of test results, however. Subjects took a single breath at 35% CO2 and completed a self-rating of anxiety symptoms immediately thereafter. This procedure was repeated after a mean interval of 29 days. One group, considered at high risk for panic disorder, consisted of well, first-degree relatives of individuals treated for panic disorder. The control group included well subjects at high risk for affective disorder and subjects who had family histories negative for both affective disorder and panic disorder. On both testing occasions, subjects at high risk for panic disorder had symptom scores that were significantly higher than those of control subjects. Group differences in the portions who experienced a panic attack were dependent on the symptom threshold used to define an attack. A lower threshold was optimal with the second testing and a single, positive test result appeared to be more meaningful than a single negative result. The majority of individual symptom ratings were highly correlated across tests. Ratings for "smothering sensations," in particular, correlated highly across tests and consistently discriminated high-risk from control subjects. The sources of test result variability are unclear and warrant more investigation before the tests can be clinically useful. Research efforts should seek optimal thresholds to define positive test results within given data sets.