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A long-term prospective evaluation of first-degree relatives of panic patients who underwent the 35% CO2 challenge
BRIEF REPORTS A Long-Term Prospective Evaluation of First-Degree Relatives of Panic Patients Who Underwent the 35% CO2 Challenge Giampaolo Perna, Silvia Cocchi, Liliana Allevi, Riccardo Bussi, and Laura Bellodi 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. Biol Psychiatry 1999;45:365–367 © 1999 Society of Biological Psychiatry Key Words: Panic disorder, carbon dioxide, safety, genetic, provocation
Introduction
I
nhalations of gas mixtures containing 35% carbon dioxide (CO2) have been widely used as a laboratory model of panic disorder (PD). The inhalation of 35% CO2 in oxygen (O2) is a simple procedure and has been reported to provoke acute anxiety and possibly panic attacks in patients with PD stronger than in normal controls (Griez et al 1987; Gorman et al 1990; Perna et al 1994). The observation that CO2 sensitivity is not significantly related to age or severity of panic disorder (Perna et al 1994) suggests, that 35% CO2 hypersensitivity might be considered a trait marker of panic disorder possibly related to a familial– genetic vulnerability. A significant
From the Anxiety Disorders Clinical and Research Unit, Department of Neuropsychiatric Sciences, Istituto Scientifico H.S. Raffaele, Milan, Italy. Address reprint requests to Prof. L. Bellodi, Department of Neuropsychiatric Sciences, Istituto Scientifico H.S. Raffaele, 29 via Prinetti 20127, Milan, Italy. Received August 11, 1997; revised January 5, 1998; accepted January 9, 1998.
© 1999 Society of Biological Psychiatry
association between CO2 hypersensitivity and familial vulnerability for panic disorder in both panic patients (Perna et al 1996) and healthy subjects (Perna et al 1995; Coryell 1997) has been recently reported. Given these considerations, studies on relatives hypersensitive to 35% CO2 might be useful in the investigation of the etiopathogenetic mechanisms underlying PD, for example, considering them as affected phenotypes in segregation analysis. Therefore, it might be particularly important for ethical reasons to investigate the possibility that the 35% CO2 challenge might prime PD in subjects with an underlying familial vulnerability. The main aim of this prospective study was to investigate the long-term effects of 35% CO2 inhalation in a sample of first-degree relatives (FDR) of panic patients.
Methods and Materials All the subjects (n 5 45) included in the study come from 20 families, with 90 family members, of probands with PD who collaborated to a previous study on 35% CO2 reactivity in FDR of panic patients (Perna et al 1995). Each family was contacted by phone from two of us (GP and SC). The original group was composed by 25 families, but we were not able to come into contact with 4 of them, and 1 refused to participate in the study. Thirty-one healthy FDR (mean age 42.4 6 14.0 years, 18 male and 13 female) (age # 20 years: n 5 2; 21 years # age # 30 years: n 5 6; 31 years # age # 40 years: n 5 5; age $ 41 years: n 5 18) who were previously tested by a single-capacity inhalation with a gas mixture of 35% CO2 and 65% O2 agreed to participate to the study. FDR were previously tested by a single-capacity challenge with a gas mixture of 35% CO2 and 65% O2 between 31 and 50 months prior to current testing (mean months: 42.6 6 6.3). Relatives assessed were 16 parents, 4 siblings, and 11 children. At the time of the challenges, FDR were free from Axis I diagnoses according to the Diagnostic Interview Schedule, version III-R (DIS-R) (Robins et al 1989) and never experienced spontaneous panic attacks. Investigators who performed the challenges were blind to the diagnoses. Subjects were tested in a double-blind random design, described in detail elsewhere (Perna et al 1994), and the reactivity was assessed by a Visual Analogue Scale for Anxiety (VAS-A), evaluated as D% VAS-A (the percentage of maximum increment or decrement possible on the VAS-A scale) calculated as follows: a) if D VAS-A (post-CO2 VAS-A values minus pre-CO2 0006-3223/99/$19.00 PII S0006-3223(98)00030-4
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VAS-A values) was positive, then D% VAS-A 5 D VAS-A 3 100/(100 2 VAS-A before CO2); b) if DVAS-A was negative, then D% VAS-A 5 D VAS-A 3 100/VAS-A before CO2. According to the ideal threshold previously obtained by a receiver operating characteristic (ROC) analysis of the 35% CO2 challenge, the reaction was considered “positive” if D% VASA $ 26 and “negative” if D% VAS-A , 26 (Battaglia and Perna 1995). The comparison group was composed of 14 healthy FDR (mean age 41.9 6 23.9 years, 8 male and 6 female) (age # 20 years: n 5 2; 21 years # age # 30 years: n 5 4; 31 years # age # 40 years: n 5 3; age $ 41 years: n 5 5) who did not undergo the 35% CO2 challenge. Comparison relatives (5 parents, 4 siblings, and 5 children) were free from Axis I diagnoses between 35 and 50 months prior to current testing (mean months: 41.9 6 6.0), according to the DIS-R (Robins et al 1989) and never experienced spontaneous panic attacks. After obtaining written informed consent, all the FDR were personally interviewed at the hospital by two experienced psychiatrists (GP and SC), blind to the results of the 35% CO2 challenges, regarding the presence of anxiety disorders and/or spontaneous panic attacks using the DIS-R. Nonparametric Mann–Whitney tests and chi-square analyses were applied where appropriate. At the beginning of the follow-up, family history information of PD for the remaining 25 FDR of the 20 families examined were obtained using a modified Family History Method for Research Diagnostic Criteria (FH-RDC) (Andreasen et al 1977, 1986) adapted to generate psychiatric diagnoses according to DSM-III-R criteria. Probands (n 5 20) with PD were directly interviewed about their own diagnoses.
Results At the time of the challenge, 15 FDR (48%) showed a positive response to the 35% CO2 challenge, whereas 16 (52%) did not. Global mean pre and post values on the VAS-A were respectively 10.6 6 15.3 and 35.4 6 27.9, with a mean D% VAS-A score of 24.8 6 35.0. Positive and negative reactors were not significantly different for mean age (respectively 44.6 6 13.5 and 40.3 6 14.7 years) and sex distribution (respectively 6 female, 9 male and 7 female, 9 male). Among these subjects, only 1 (man aged 40 years at the time of current study), who previously had a positive reaction to the 35% CO2 challenge, developed 4 panic attacks during a period of 44 months after 35% CO2 inhalation. The attacks were separated one from another by at least 4 months, the first occurring 2 years after the 35% CO2 challenge was given. There were no significant effects of these attacks on the subject’s behavior or quality of life, and thus the patient did not qualify for a diagnosis of PD or other anxiety disorders. Among comparison relatives, none developed anxiety disorders or sporadic unexpected panic attacks during the follow-up period.
At the time of the challenge, all the probands (n 5 20) were diagnosed as having PD, as were 8 other relatives not included in the follow-up.
Discussion Our results suggest that the 35% CO2 challenge does not trigger PD or other anxiety or phobic disorders in healthy members of families containing patients with panic disorder. None of the 15 FDR with a previous positive reaction to the 35% CO2 challenge reported the development of PD, and only 1 (7%) reported sporadic unexpected panic attacks across a period of 3– 4 years after the challenge, thus suggesting that CO2 inhalation might not be able to trigger even sporadic unexpected panic attacks. The different rate of positive responses between this study (48%) and data reported in our previous study (22%) (Perna et al 1995), the samples of which were partially overlapping, is simply a reflection of differences in criteria defining the response, as also suggested by the similar mean D% VAS-A scores for the two samples. The present study confirms and extends, data from some recent studies reporting a negligible risk of priming anxiety disorders in healthy subjects with 35% CO2 inhalations (Harrington et al 1996; Perna et al 1997). The 35% CO2 challenge procedure seems to be safe also in first-degree relatives of panic patients, since none of them developed anxiety disorders in the follow-up period, and in the single subject who developed sporadic panic attacks, the occurrence was not proximal to the challenge, but occurred 2 years afterward. The reason why only 1 high-risk subject developed panic attacks may reflect the fact that in our sample only a few subjects were young enough to be still at risk for onset of PD. In addition, these healthy subjects came from families where the vulnerability to PD had already been expressed in a relevant number of other members (28/90, 31%) of the families included in the study. These findings are important for two main reasons. First, genetic factors play a relevant role in the etiology of PD, and some recent studies reported an association between CO2 hypersensitivity and familial vulnerability to PD (Perna et al 1995, 1996; Coryell 1997), thus the investigation of CO2 reactivity in relatives of panic patients might help the understanding of the etiopathogenetic mechanisms underlying PD. Second, given these data it is unlikely that CO2 hypersensitivity might simply be predictive for later development of PD or other anxiety disorders, strongly supporting the idea that CO2 hyperreactivity might be considered a trait marker of an underlying vulnerability to panic, as also suggested by the lack of a significant relationship between the clinical severity of
CO2 Stimulation in Panic Disorder
panic disorder and CO2 hypersensitivity (Perna et al 1994). In conclusion, our study indicates, that the 35% CO2 challenge does not prime the development of anxiety disorders in nonclinical members of families containing patients with PD, and thus 35% CO2 challenge might be considered a safe laboratory procedure in the study of the etiopathogenetic mechanisms underlying PD. The main limitation of the present study is the small number of healthy FDR with an age # 30 years (n 5 8) tested with the 35% CO2 challenge and thus, possibly at a higher risk for the development of PD. This finding needs to be confirmed by other observations, in particular in larger samples of healthy young relatives of panic patients. Finally, to complete the evaluation of the safety of this procedure, it might be useful to investigate if nonclinical subjects with a history of sporadic panic attacks might be at risk for developing the full-fledged disorder after the 35% CO2 challenge.
References Andreasen NC, Endicott J, Spitzer RL, Winokur G (1997): The family history method using diagnostic criteria: Reliability and validity. Arch Gen Psychiatry 34:1229 –1235. Andreasen NC, Rice J, Endicott J, Reich T, Coryell W (1986): The family history approach to diagnosis: How useful is it? Arch Gen Psychiatry 43:421– 429.
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Battaglia M, Perna G (1995): The 35% CO2 challenge in panic disorder: Optimization by receiver operating characteristic (ROC) analysis. J Psychiatr Res 29:111–119. Coryell WH (1997): Hypersensitivity to carbon dioxide as a disease specific trait marker. Biol Psychiatry 41:259 –263. Gorman JM, Papp LA, Martinez J, Goetz RR, Hollander E, Liebowitz MR, et al (1990): High dose carbon dioxide challenge test in anxiety disorder patients. Biol Psychiatry 28:743–757. Griez E, Lousberg H, van den Hout MA, van der Molen GM (1987): CO2 vulnerability in panic disorder. Psychiatry Res 20:87–95. Harrington PJ, Schmidt NB, Telch MJ (1996): Prospective evaluation of panic potentiation following 35% CO2 challenge in nonclinical subjects. Am J Psychiatry 153:823– 825. Perna G, Battaglia M, Garberi A, Arancio C, Bertani A, Bellodi L (1994): CO2/O2 challenge test in panic disorder. Psychiatry Res 52:159 –171. Perna G, Cocchi S, Bertani A, Arancio C, Bellodi L (1995): Sensitivity to 35% CO2 in healthy first-degree relatives of patients with panic disorder. Am J Psychiatry 152:623– 625. Perna G, Bertani A, Caldirola D, Bellodi L (1996): Family history of panic disorder and hypersensitivity to CO2 in panic disorder. Am J Psychiatry 153:1060 –1064. Perna G, Cocchi S, Politi E, Bellodi L (1997): CO2 challenge in non clinical subjects. Am J Psychiatry 153:886 – 887. Robins LN, Helzer JE, Cottler L (1989): NIHM Diagnostic Interview Schedule, Version III-R. St. Louis, MO: Washington University School of Medicine.
Introduction
I
nhalations of gas mixtures containing 35% carbon dioxide (CO2) have been widely used as a laboratory model of panic disorder (PD). The inhalation of 35% CO2 in oxygen (O2) is a simple procedure and has been reported to provoke acute anxiety and possibly panic attacks in patients with PD stronger than in normal controls (Griez et al 1987; Gorman et al 1990; Perna et al 1994). The observation that CO2 sensitivity is not significantly related to age or severity of panic disorder (Perna et al 1994) suggests, that 35% CO2 hypersensitivity might be considered a trait marker of panic disorder possibly related to a familial– genetic vulnerability. A significant
From the Anxiety Disorders Clinical and Research Unit, Department of Neuropsychiatric Sciences, Istituto Scientifico H.S. Raffaele, Milan, Italy. Address reprint requests to Prof. L. Bellodi, Department of Neuropsychiatric Sciences, Istituto Scientifico H.S. Raffaele, 29 via Prinetti 20127, Milan, Italy. Received August 11, 1997; revised January 5, 1998; accepted January 9, 1998.
© 1999 Society of Biological Psychiatry
association between CO2 hypersensitivity and familial vulnerability for panic disorder in both panic patients (Perna et al 1996) and healthy subjects (Perna et al 1995; Coryell 1997) has been recently reported. Given these considerations, studies on relatives hypersensitive to 35% CO2 might be useful in the investigation of the etiopathogenetic mechanisms underlying PD, for example, considering them as affected phenotypes in segregation analysis. Therefore, it might be particularly important for ethical reasons to investigate the possibility that the 35% CO2 challenge might prime PD in subjects with an underlying familial vulnerability. The main aim of this prospective study was to investigate the long-term effects of 35% CO2 inhalation in a sample of first-degree relatives (FDR) of panic patients.
Methods and Materials All the subjects (n 5 45) included in the study come from 20 families, with 90 family members, of probands with PD who collaborated to a previous study on 35% CO2 reactivity in FDR of panic patients (Perna et al 1995). Each family was contacted by phone from two of us (GP and SC). The original group was composed by 25 families, but we were not able to come into contact with 4 of them, and 1 refused to participate in the study. Thirty-one healthy FDR (mean age 42.4 6 14.0 years, 18 male and 13 female) (age # 20 years: n 5 2; 21 years # age # 30 years: n 5 6; 31 years # age # 40 years: n 5 5; age $ 41 years: n 5 18) who were previously tested by a single-capacity inhalation with a gas mixture of 35% CO2 and 65% O2 agreed to participate to the study. FDR were previously tested by a single-capacity challenge with a gas mixture of 35% CO2 and 65% O2 between 31 and 50 months prior to current testing (mean months: 42.6 6 6.3). Relatives assessed were 16 parents, 4 siblings, and 11 children. At the time of the challenges, FDR were free from Axis I diagnoses according to the Diagnostic Interview Schedule, version III-R (DIS-R) (Robins et al 1989) and never experienced spontaneous panic attacks. Investigators who performed the challenges were blind to the diagnoses. Subjects were tested in a double-blind random design, described in detail elsewhere (Perna et al 1994), and the reactivity was assessed by a Visual Analogue Scale for Anxiety (VAS-A), evaluated as D% VAS-A (the percentage of maximum increment or decrement possible on the VAS-A scale) calculated as follows: a) if D VAS-A (post-CO2 VAS-A values minus pre-CO2 0006-3223/99/$19.00 PII S0006-3223(98)00030-4
366
G. Perna et al
BIOL PSYCHIATRY 1999;45:365–367
VAS-A values) was positive, then D% VAS-A 5 D VAS-A 3 100/(100 2 VAS-A before CO2); b) if DVAS-A was negative, then D% VAS-A 5 D VAS-A 3 100/VAS-A before CO2. According to the ideal threshold previously obtained by a receiver operating characteristic (ROC) analysis of the 35% CO2 challenge, the reaction was considered “positive” if D% VASA $ 26 and “negative” if D% VAS-A , 26 (Battaglia and Perna 1995). The comparison group was composed of 14 healthy FDR (mean age 41.9 6 23.9 years, 8 male and 6 female) (age # 20 years: n 5 2; 21 years # age # 30 years: n 5 4; 31 years # age # 40 years: n 5 3; age $ 41 years: n 5 5) who did not undergo the 35% CO2 challenge. Comparison relatives (5 parents, 4 siblings, and 5 children) were free from Axis I diagnoses between 35 and 50 months prior to current testing (mean months: 41.9 6 6.0), according to the DIS-R (Robins et al 1989) and never experienced spontaneous panic attacks. After obtaining written informed consent, all the FDR were personally interviewed at the hospital by two experienced psychiatrists (GP and SC), blind to the results of the 35% CO2 challenges, regarding the presence of anxiety disorders and/or spontaneous panic attacks using the DIS-R. Nonparametric Mann–Whitney tests and chi-square analyses were applied where appropriate. At the beginning of the follow-up, family history information of PD for the remaining 25 FDR of the 20 families examined were obtained using a modified Family History Method for Research Diagnostic Criteria (FH-RDC) (Andreasen et al 1977, 1986) adapted to generate psychiatric diagnoses according to DSM-III-R criteria. Probands (n 5 20) with PD were directly interviewed about their own diagnoses.
Results At the time of the challenge, 15 FDR (48%) showed a positive response to the 35% CO2 challenge, whereas 16 (52%) did not. Global mean pre and post values on the VAS-A were respectively 10.6 6 15.3 and 35.4 6 27.9, with a mean D% VAS-A score of 24.8 6 35.0. Positive and negative reactors were not significantly different for mean age (respectively 44.6 6 13.5 and 40.3 6 14.7 years) and sex distribution (respectively 6 female, 9 male and 7 female, 9 male). Among these subjects, only 1 (man aged 40 years at the time of current study), who previously had a positive reaction to the 35% CO2 challenge, developed 4 panic attacks during a period of 44 months after 35% CO2 inhalation. The attacks were separated one from another by at least 4 months, the first occurring 2 years after the 35% CO2 challenge was given. There were no significant effects of these attacks on the subject’s behavior or quality of life, and thus the patient did not qualify for a diagnosis of PD or other anxiety disorders. Among comparison relatives, none developed anxiety disorders or sporadic unexpected panic attacks during the follow-up period.
At the time of the challenge, all the probands (n 5 20) were diagnosed as having PD, as were 8 other relatives not included in the follow-up.
Discussion Our results suggest that the 35% CO2 challenge does not trigger PD or other anxiety or phobic disorders in healthy members of families containing patients with panic disorder. None of the 15 FDR with a previous positive reaction to the 35% CO2 challenge reported the development of PD, and only 1 (7%) reported sporadic unexpected panic attacks across a period of 3– 4 years after the challenge, thus suggesting that CO2 inhalation might not be able to trigger even sporadic unexpected panic attacks. The different rate of positive responses between this study (48%) and data reported in our previous study (22%) (Perna et al 1995), the samples of which were partially overlapping, is simply a reflection of differences in criteria defining the response, as also suggested by the similar mean D% VAS-A scores for the two samples. The present study confirms and extends, data from some recent studies reporting a negligible risk of priming anxiety disorders in healthy subjects with 35% CO2 inhalations (Harrington et al 1996; Perna et al 1997). The 35% CO2 challenge procedure seems to be safe also in first-degree relatives of panic patients, since none of them developed anxiety disorders in the follow-up period, and in the single subject who developed sporadic panic attacks, the occurrence was not proximal to the challenge, but occurred 2 years afterward. The reason why only 1 high-risk subject developed panic attacks may reflect the fact that in our sample only a few subjects were young enough to be still at risk for onset of PD. In addition, these healthy subjects came from families where the vulnerability to PD had already been expressed in a relevant number of other members (28/90, 31%) of the families included in the study. These findings are important for two main reasons. First, genetic factors play a relevant role in the etiology of PD, and some recent studies reported an association between CO2 hypersensitivity and familial vulnerability to PD (Perna et al 1995, 1996; Coryell 1997), thus the investigation of CO2 reactivity in relatives of panic patients might help the understanding of the etiopathogenetic mechanisms underlying PD. Second, given these data it is unlikely that CO2 hypersensitivity might simply be predictive for later development of PD or other anxiety disorders, strongly supporting the idea that CO2 hyperreactivity might be considered a trait marker of an underlying vulnerability to panic, as also suggested by the lack of a significant relationship between the clinical severity of
CO2 Stimulation in Panic Disorder
panic disorder and CO2 hypersensitivity (Perna et al 1994). In conclusion, our study indicates, that the 35% CO2 challenge does not prime the development of anxiety disorders in nonclinical members of families containing patients with PD, and thus 35% CO2 challenge might be considered a safe laboratory procedure in the study of the etiopathogenetic mechanisms underlying PD. The main limitation of the present study is the small number of healthy FDR with an age # 30 years (n 5 8) tested with the 35% CO2 challenge and thus, possibly at a higher risk for the development of PD. This finding needs to be confirmed by other observations, in particular in larger samples of healthy young relatives of panic patients. Finally, to complete the evaluation of the safety of this procedure, it might be useful to investigate if nonclinical subjects with a history of sporadic panic attacks might be at risk for developing the full-fledged disorder after the 35% CO2 challenge.
References Andreasen NC, Endicott J, Spitzer RL, Winokur G (1997): The family history method using diagnostic criteria: Reliability and validity. Arch Gen Psychiatry 34:1229 –1235. Andreasen NC, Rice J, Endicott J, Reich T, Coryell W (1986): The family history approach to diagnosis: How useful is it? Arch Gen Psychiatry 43:421– 429.
BIOL PSYCHIATRY 1999;45:365–367
367
Battaglia M, Perna G (1995): The 35% CO2 challenge in panic disorder: Optimization by receiver operating characteristic (ROC) analysis. J Psychiatr Res 29:111–119. Coryell WH (1997): Hypersensitivity to carbon dioxide as a disease specific trait marker. Biol Psychiatry 41:259 –263. Gorman JM, Papp LA, Martinez J, Goetz RR, Hollander E, Liebowitz MR, et al (1990): High dose carbon dioxide challenge test in anxiety disorder patients. Biol Psychiatry 28:743–757. Griez E, Lousberg H, van den Hout MA, van der Molen GM (1987): CO2 vulnerability in panic disorder. Psychiatry Res 20:87–95. Harrington PJ, Schmidt NB, Telch MJ (1996): Prospective evaluation of panic potentiation following 35% CO2 challenge in nonclinical subjects. Am J Psychiatry 153:823– 825. Perna G, Battaglia M, Garberi A, Arancio C, Bertani A, Bellodi L (1994): CO2/O2 challenge test in panic disorder. Psychiatry Res 52:159 –171. Perna G, Cocchi S, Bertani A, Arancio C, Bellodi L (1995): Sensitivity to 35% CO2 in healthy first-degree relatives of patients with panic disorder. Am J Psychiatry 152:623– 625. Perna G, Bertani A, Caldirola D, Bellodi L (1996): Family history of panic disorder and hypersensitivity to CO2 in panic disorder. Am J Psychiatry 153:1060 –1064. Perna G, Cocchi S, Politi E, Bellodi L (1997): CO2 challenge in non clinical subjects. Am J Psychiatry 153:886 – 887. Robins LN, Helzer JE, Cottler L (1989): NIHM Diagnostic Interview Schedule, Version III-R. St. Louis, MO: Washington University School of Medicine.