Elsevier

Biological Psychiatry

Volume 45, Issue 7, 1 April 1999, Pages 923-927
Biological Psychiatry

Techniques and Methods
The 35% CO2 inhalation procedure: test–retest reliability

https://doi.org/10.1016/S0006-3223(98)00241-8Get rights and content

Abstract

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.

Introduction

Procedures that provoke symptoms of a specific illness have obvious value as tools for the study of that illness and may have important clinical uses as well. Among the mental disorders such procedures have probably been most widely applied in the study of panic disorder. These have included hyperventilation, the infusion of lactate, and the inspiration of carbon dioxide, either at low concentrations in rebreathing apparati, or at higher concentrations in single breaths.

The last of these procedures is likely to come into wider use as a research tool, due in part to its simplicity and, in part, to its apparent sensitivity and specificity to panic disorder. The proportion of individuals who develop brief panic attacks following a single breath of 35% CO2 has robustly separated patients with unmedicated panic disorder from well control subjects van den Hout and van der Molen 1987, Gorman et al 1990, Perna et al 1994a, Caldirola et al 1997 and from patients with major depressive disorder (Perna et al 1995a), obsessive–compulsive disorder Griez et al 1990, Perna et al 1995b, and generalized anxiety disorder (Verburg et al 1995). Moreover, medications effective in the treatment of panic disorder have blocked the panicogenic effects of 35% CO2Pols et al 1991, Sanderson et al 1994, Perna et al 1994b. This effect manifests soon after treatment with tricyclic antidepressants or serotonin reuptake inhibitors begins, well before the antipanic effect of these drugs would be expected Bertani et al 1997, Perna et al 1997.

The subjective response to CO2 inhalation also shows promise as a marker for risk status. Two studies have shown that relatives of panic disorder patients are more likely to experience a panic attack after a single breath of 35% CO2 than are individuals without a family history of panic disorder Perna et al 1995c, Coryell 1997. Another found that panic disorder probands who respond to 35% CO2 inhalation with panic attacks had higher familial loadings for panic disorder than did probands with negative test results (Perna et al 1996). Further evidence that the subjective response to doses of CO2 is genetically influenced derive from a recent twin study in which monozygotic twins were significantly more concordant for a positive test result than were dizygotic twins (Bellodi et al 1998).

The potential utility of this procedure clearly warrants attention to its reliability. To our knowledge, there has been no formal effort to quantify the stability over time of test results. The following does this with additional data from a previously described study of never-ill individuals at high risk for panic disorder (Coryell 1997). Subjects who had a first-degree relative treated for panic disorder, but who lacked a personal history of panic attacks, were substantially more likely to report panic attacks after CO2 inhalation than were either never-ill subjects with a family history of affective disorder, or never-ill subjects with a family history of neither condition. Those subjects underwent the same inhalation procedure after variable intervals, but the results of repeat testing were not described in the earlier report. The following provides these results with a focus on the reproducibility of findings.

Section snippets

Subjects

Advertisements were used to recruit subjects into three groups. Inclusion criteria required that all participants were 18–34 years of age, lacked a personal history of any Research Diagnostic Criteria disorder (Spitzer et al 1978), had never experienced panic attacks, and had never sought professional help for emotional problems. Subjects considered to be at high risk for panic disorder (HR-PD) described at least one first-degree relative who met DSM-III-R criteria for panic disorder and who

Results

The subjects at high risk for affective disorder did not differ from the low-risk control subjects by post-CO2 symptoms scores on either testing occasion. For simplicity these two groups are combined in the following analyses and designated simply as “control subjects.” Twelve HR-PD subjects and 31 control subjects completed the initial inhalation procedure, and none of these failed to return for the repeat procedure. Two control subjects (both at high risk for affective disorder) and 1 HR-P

Discussion

The central findings generated by the first session of testing were clearly reproducible in the second session, yet the within-individual reliability of categorical test results was poor. This instability appeared to arise from variations in sensitivity rather than changes in specificity. Thus, a positive test result with either session was a valid indicator of high-risk status, whereas a negative result in either session was not a strong sign of low-risk status. If replicated, these findings

Acknowledgements

This work was supported by NIMH grant MH 56132.

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