Hypersensitivity to inhalation of carbon dioxide and panic attacks

ELSEVIER Psychiatry Research 57 (1995) 267-273

PSYCHIATRY

RESEARCH

Hypersensitivity to inhalation of carbon dioxide and panic attacks

Giampaolo Perna, Angela Gabriele, Daniela Caldirola, Laura Bellodi*

Istituto Scientifico H. San Raffaeie, Department of Neuropsychiatric Sciences, Anxiety Disorders Clinical and Research Unit, University of Milan, 29 via Prinetti, 20127, Milan, Italy

Received 19 September 1994; revision received 28 December 1994; accepted 27 February 1995

Abstract

Thirteen healthy subjects with infrequent panic attacks and without agoraphobia who did not meet DSM-III-R criteria for panic disorder, 43 patients with panic disorder, and 43 healthy control subjects who never experienced panic attacks underwent one vital capacity inhalation of 35% C02. Healthy subjects with infrequent panic attacks reacted similarly to patients with panic disorder and more strongly than healthy subjects who never experienced panic attacks. The results suggest that (a) subjects with sporadic unexpected panic attacks and patients with panic disorder belong to the same spectrum of vulnerability and (b) CO2 hypersensitivity might be a trait marker of panic attacks rather than of a clinical diagnosis of panic disorder.

Keywords: Panic disorder; Agoraphobia; Anxiety; Genetic vulnerability

1. Introduction

Since 1980, the DSM-III and then DSM-III-R criteria (American Psychiatric Association, 1980,

1987) have been the most widely used systems of diagnostic classification in psychiatry. The anxiety disorders sections of both editions of DSM-III in- clude panic disorder (PD) as a distinct diagnostic

entity characterized by the presence of recurrent panic attacks. The frequency of panic attacks required for a PD diagnosis remains an open ques- tion since the DSM-III/DSM-III-R criteria mainly

rely upon arbitrary threshold decisions (Frances et al., 1993).

* Corresponding author, Tel: +39 2 26433315; Fax: +39 2 26433265.

Epidemiological studies reported that up to 35%

of subjects from the general population have ex-

perienced sporadic unexpected panic attacks (Nor- ton et al., 1985; von Korff et al., 1985; Faravelli et al., 1989; Weissman, 1990; Katemdahl and Realini, 1993; Eaton et al., 1994), and data from

the literature suggest that subjects with sporadic unexpected panic attacks who do not meet DSM- IIUDSM-III-R criteria for PD resemble full- fledged PD patients in their demographic

characteristics (von Korff et al., 1985; Katemdahl and Realini, 1993), depression and anxiety scores (Norton et al., 1985; Katon et al., 1986), risk for depression (Bucholz and Dinwiddie, 1989) and

phobic avoidance (Norton et al., 1985; Aronson and Logue, 1987; Katerndahl, 1990), prevalence of mitral valve prolapse (Dager et al., 1986), and

0165-1781/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-1781(95)02723-A

268 G. Perna et al. /Psychiatry Research 57 (1995) 267-273

reactivity to lactate infusion (Cowley et al., 1987). Moreover, Noyes et al. (1986) reported a higher prevalence of subjects with sporadic unexpected panic attacks in families of PD patients than in families of patients with generalized anxiety disorder, and Torgersen (1983) reported a significantly higher concordance for anxiety disorders with panic attacks in monozygotic co-twins compared with dizygotic co-twins. These data suggest that subjects with sporadic unexpected panic attacks might share the same vulnerability present in PD patients.

Carbon dioxide (CO,) inhalation is a procedure widely used to provoke acute anxiety in PD patients. The inhalation of a gas mixture of 35% CO, and 65% O2 is a safe and simple procedure that has been reported to induce acute anxiety and possibly panic attacks in PD patients more fre- quently than in normal volunteers (Fyer et al., 1987; Griez et al., 1987; Zandbergen et al., 1990; Papp et al., 1993; Perna et al., 1994) and patients with other anxiety disorders, including social phobia (Papp et al., 1993) and obsessive-compulsive disorder (Griez et al., 1990a, 1990b; Perna et al., 1995a). In addition, the absence of a significant influence of the clinical severity of PD suggests that CO, hypersensitivity might be a biological marker, possibly related to the presence of the phenomenon of panic attacks rather than the presence of the full-fledged clinical disorder (Pema et al., 1994).

In the present study, we assessed the reactivity to 35% CO2 inhalation and the family history of anxiety disorders in a group of subjects with sporadic unexpected panic attacks without agoraphobia to test the idea of a “panic spectrum” characterized by unexpected panic attacks as the basic clinical phenomenon, by a high familial vulnerability to PD, and by hypersensitivity to CO2 inhalation as a laboratory trait marker of vulnerability.

2. Methods

2.1. Subjects Three groups of subjects were included in this

study: (1) 43 patients with PD, (2) 13 subjects with

sporadic unexpected panic attacks (HSP), and (3) 43 healthy subjects who never experienced unexpected panic attacks (HS). PD patients were recruited consecutively over 4 months at the Anxi- ety Disorders Clinical and Research Unit at the Department of Neuropsychiatric Sciences of S. Raffaele Hospital, Milan. Healthy subjects with/without sporadic panic attacks were recruited over 1 year by advertisements placed around the University of Milan.

Diagnoses were made by the Diagnostic Inter- view Schedule, Version III-R (DIS-R; Robins et al., 1989); interviewers were psychiatrists or residents in psychiatry who had been trained in the use of the DIS-R, and information collected with the DIS-R was scored by a computer program (Marcus et al., 1990). According to the DIS-R, healthy subjects with/without sporadic panic attacks had never fulfilled criteria for any lifetime Axis I psychiatric diagnosis. The HSP group com- prised subjects who satisfied DSM-III-R criteria a, c, d, and e for PD but had never satisfied criterion b as required for a PD diagnosis.

The possible presence of a family history of anxiety disorders in the families of each subject was assessed with the Family History-Research Diag- nostic Criteria (Andreasen et al., 1977), and diagnoses were made according to DSM-III-R criteria. Consensus diagnoses for the relatives were obtained by two experienced psychiatrists who were unaware of the clinical diagnosis of the subjects being interviewed.

Exclusion criteria for all subjects were significant cardiocirculatory and respiratory disorders, personal or family history of cerebral aneurysm, significant hypertension (systolic blood pressure > 180 mmHg, diastolic blood pressure > 100 mmHg), pregnancy, or epilepsy - all as deter- mined by direct physical examination and careful collection of medical histories. Another exclusion criterion for the patients was the presence of an Axis I psychiatric disorder other than PD.

At the time of the challenge test, all subjects had to have been free of psychotropic medications for 2 weeks. They were asked to refrain from alcoholic beverages for 236 h, beverages containing xan- thine for L 8 h, and food or smoking for r2 h

G. Perna et al. /Psychiatry Research 57 (1995) 267-273 269

before the test. All the participants gave their informed consent to the study after a detailed explanation of the procedure.

2.2. Apparatus. Two different gas mixtures were used: compress-

ed air (placebo) and a mixture of 35% COZ and 65% OZ. Both gases were inhaled through the same self-administration mask. Vital capacity was evaluated by a respirometer (Wright respirometer Mark 20, Ferraris Medical Limited) connected to the self-administration mask. The same respirometer measured the gas volume delivered in each inhalation.

2.3 Procedure All subjects were tested in a double-blind, ran-

domized, crossover design, according to the method described by Griez et al. (1987) and described in detail elsewhere (Pema et al., 1994). Subjects were informed that they would be inhaling two harmless gas mixtures containing different percen- tages of CO, and O2 (but were not told that one was compressed air) and that they might experi- ence some discomfort, ranging from a few neurovegetative symptoms to a definite sensation of anxiety. The possibility of a panic attack was not mentioned to avoid any negative cognitive bias related to expectation. We believed that the very brief nature (a few seconds to a few minutes) of the panic reaction provoked by 35% CO2 inhalation, which completely disappeared within a few minutes, justified the decision not to warn subjects about the possible occurrence of a panic attack. Vital capacity was measured and baseline anxiety assessed by the State-Trait Anxiety Inventory for state anxiety (STAI-1; Spielberger et al., 1970). Subjects then inhaled one vital capacity of the 35% COz/65% O2 mixture or of compressed air, in a randomly assigned order, at an interval of 25-30 min. At the end of each inhalation, subjects were asked to hold their breath for 4 s. Tests were considered valid only if subjects had inhaled at least 80% of the previously measured vita1 capacity.

Immediately before and after each inhalation (air or C02/02 mixture), anxiety was evaluated by a self-rating questionnaire that measured the 13

DSM-III-R panic symptoms on a 5-point scale. Assessment included a total symptom score (TSS: range = O-52) and a Visual Analogue Scale for Anxiety (VAS-A: degree of global subjective anxiety from 0 [no anxiety present] to 100 [the worst anxiety ever imaginable]).

The reaction to the 35% COz challenge was considered a provoked panic attack, as defined by Sanderson et al. (1989), when it included all three of the following criteria: (1) a sensation of fear or panic; (2) an increment of at least 1 point on the self-rating questionnaire for at least four symptoms, including (3) at least one of the DSM-III-R cognitive symptoms (fear of dying, going crazy, or losing control).

2.4. Data analyses Differences in continuously distributed vari-

ables among the three groups were assessed by analysis of variance (ANOVA) and post hoc Student’s t test with Bonferroni’s correction. In addition, x2 analyses were used to compare rates of CO*-induced panic, rates of subjects with positive family history for PD, and sex distributions in the three groups of subjects. When two groups were compared, Student’s t test or x2 analysis was performed with Bonferroni’s correction where appropriate. CO2 reactivity was evaluated quan- titatively as AVAS-A or ATSS (postinhalation values minus preinhalation values) by an ANOVA with repeated measures in which procedure (CO2 vs. air) was a repeated measures factor, diagnosis (PD vs. HSP vs. HS) was the grouping factor, and VAS-A or TSS score was the dependent variable. Pearson’s correlation coefficients were used to assess the presence of a correlation between panic attack frequency and CO, reactivity, expressed as AVAS-A or as ATSS.

3. Results

Table 1 presents the clinical and demographic characteristics of the study groups. No significant differences for age and sex distribution were found in the three groups. The mean number of panic attacks per week in the last month among PD patients was 2.1 (SD = 4.6), while HSP subjects did

270 G. Pema et al. /Psychiatry Research 57 (1995) 267-273

Table I Clinical and demographic characteristics

PD patients (II = 43)

Subjects with sporadic panic attacks (n = 13)

Subjects without sporadic panic attacks (n = 43)

Age (years) Sex (“IO males) Positive family history for PD (%) Age at first panic attack (years) Number of panic attacks/week in

last month

Agoraphobia Absent (%) Mild (%) Moderate (%) Severe (%)

STAI-1 score

31.1 f 8.6 32.1 zt 11.6 28.0 zt 6.1 17 (39.5) 5 (38.5) 17 (39.5) 13 (30.2) 4 (30.8) I (2.3) 25.4 zt 7.1 22.5 zt 7.4 2.1 f 4.6 0 0

7 (16.3) 13 (loo) 43 (100) 20 (46.5) 8 (18.6) 8 (18.6)

50.7 f 13.3 33.2 & 8.7 33.8 +z 7.5

Nofe. Data are presented as mean f SD or as number of subjects with percent in parentheses. PD, panic disorder; STAI-I, State- Trait Anxiety Inventory for state anxiety.

not report any panic attack during the last month. The mean number of panic attacks that had oc- curred after the first panic attack in HSP subjects was 6.5 (SD = 8.7). The PD patients and HSP subjects did not differ significantly in the age at which a panic attack had first been experienced. ANOVA showed a significant effect of diagnosis (F = 3 1.7; df = 2,96; P c 0.001) for STAI-1 scores. Post hoc comparisons showed significantly greater STAI- 1 scores in PD patients than in HS and HSP subjects; STAI-1 scores in HS and HSP subjects did

not differ significantly from each other. The three groups had different patterns of distribution for rates of positive family history for PD (x2 = 12.9, df = 2, P < 0.001). PD patients (30%) and HSP subjects (31%) had similar rates of positive family history for PD, both higher than the rate in HS subjects (2%).

Table 2 presents AVAS-A, ATSS, and provoked panic attack findings after inhalation of 35% CO2 versus air. ANOVA revealed a significant diagnosis x procedure interaction for both AVAS-A

Table 2 Reactivity to 35% CO* challenges in PD patients and in subjects with or without sporadic unexpected panic attacks

PD patients (n = 43)

Subjects with sporadic panic attacks (n = 13)

Subjects without sporadic panic attacks (n = 43)

AVAS-A After air After CO*

ATSS After air After CO2

Provoked panic attacks (%)

-5.2 f 18.9 -2.4 zk 18.2 -3.3 zt 6.9 46.7 f 25.6 38.9 f 32.0 3.3 * 17.1

-2.1 f 7.4 1.6 f 4.1 -0.1 f 1.3 12.2 f 7.4 11.2 zt 5.0 3.8 f 4.3 20 (46.5) 7 (53.8) I (2.3)

Note. Data are presented as mean f SD or as number of subjects with percent in parentheses. PD, panic disorder; TSS, total symptom score; VAS-A, Visual Analogue Scale for Anxiety.

G. Perna et al. /Psychiatry Research 57 (1995) 267-273 271

(F= 32.1; df = 2, 96; P c 0.001) and TSS scores (F= 14.9; df = 2, 96; P c 0.001). Post hoc comparisons showed (a) similar reactions in the PD and HSP groups, both more pronounced than reactions in the HS group, and (b) stronger reactions to 35% CO2 than to air in PD and HSP groups.

Finally, there were different patterns of distribution (x2 = 25.5, df = 2, P c 0.001) for rates of panic to 35% CO2 inhalation in the three groups. Post hoc 2 x 2 x2 analyses showed similar rates of provoked panic in the PD and HSP groups, both significantly higher than the rate in the HS group. No participants in the study experienced panic attacks after compressed-air inhalation.

No significant correlation emerged between number of panic attacks per week in the last month and AVAS-A or ATSS score in the PD group. There was also no significant correlation between the number of panic attacks experienced after the first panic attack and AVAS-A or ATSS score in the HSP group.

4. Discussion

Our data confirm the ability of 35% CO2 inhalation to induce acute anxiety in patients with PD and show that subjects with sporadic unexpected panic attacks, not satisfying DSM-III-R

criteria for PD, resemble PD patients in their response to 35% CO*. PD patients and HSP subjects were similar in age, gender distribution, and age at first panic attack. Moreover, the compar- able positive family history of PD rates in the PD and HSP groups support the idea that both PD patients and subjects with sporadic unexpected panic attacks belong to the same spectrum of vulnerability and share an underlying biological or psychological defect that makes them susceptible to panic attacks (Cowley et al., 1987), a defect that may be genetic in nature (Torgersen, 1983).

PD patients and HSP subjects differ in baseline anxiety levels and agoraphobic avoidance, thus confirming that these two clinical features are not significantly related to CO2 hypersensitivity (Pema et al., 1994). Since hypersensitivity to CO, might be considered a marker of vulnerability to panic, the lack of relatedness of agoraphobia to

CO2 sensitivity supports the primacy of panic attacks versus agoraphobia in PD.

These results have important clinical and research implications. In agreement with much of the research literature, our findings suggest that PD patients and subjects with infrequent unexpected panic attacks belong to the same spectrum of vulnerability. Thus, the threshold for the diagnosis of PD, as defined by DSM-III-R criteria, may be too restrictive; perhaps, any person who has experienced unexpected panic attacks suffers from some form of the same diathesis or illness. In addition, our results suggest that hypersensitivity to CO*, possibly related to a deranged suffocation alarm monitor (Klein, 1993, 1994), might be a biological marker of vulnerability to panic not related to panic attack frequency, to the presence of agoraphobia, or to baseline anxiety (Pema et al., 1994). Thus, these data support the idea that hypersensitivity to carbon dioxide might be a trait marker specifically related to unexpected panic attacks.

Data from the literature suggest that CO2 hypersensitivity is related not only to PD but also to some other anxiety disorders. Patients with social phobia (Gorman et al., 1990; Papp et al., 1993) and situational simple phobia (Verburg et al., in press a) react to CO2 more strongly than com- parison subjects, whereas patients with generalized anxiety disorder (Holt and Andrews, 1989; Ver- burg et al., in press b) and obsessive-compulsive disorder (Griez et al., 1990a; Pema et al., 1995a) do not show hypersensitivity to CO*. In addition, some data suggest that CO2 hypersensitivity might be the expression of underlying familial vulnerability to panic (Pema et al., 1995b). In view of these considerations, we can speculate that sporadic unexpected panic attacks and disorders such as panic disorder, social phobia, and situational simple phobia all belong to the same spectrum of vulnerability. All these disorders might have a similar mode of onset - that is, an unexpected panic attack possibly related to an abnor- mal sensitivity to CO,.

Some limitations must be recognized. Given the small number of subjects with unexpected sporadic panic attacks, we cannot exclude the possibility of a Type 1 error and, since retrospective diagnoses

212 G. Perna et al. /Psychiatry Research 57 (1995) 267-273

rely on probands’ memories, we also cannot exclude the possibility that some of the subjects with unexpected sporadic panic attacks may have been, in fact, “hidden” PD patients in the past.

In conclusion, if our results are confirmed in numbers of subjects, hypersensitivity to CO2 might be viewed as a “trait marker” of vulnerability to unexpected panic attacks, and thus subjects with unexpected panic attacks might be considered in biological and genetic studies as part of the same spectrum of vulnerability to PD.

Acknowledgments

The authors thank A. Bertani, M.D., and C. Arancio, M.D., for research assistance.

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Hypersensitivity to inhalation of carbon dioxide and panic attacks

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