SciELO - Scientific Electronic Library Online

vol.60 issue2BCorrelation of sleep macrostructure parameters and idiopathic epilepsiesStereotactic fibrinolysis of spontaneous intracerebral hematoma using infusion of recombinant tissue plasminogen activator author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand



  • English (pdf)
  • Article in xml format
  • How to cite this article
  • SciELO Analytics
  • Curriculum ScienTI
  • Automatic translation


Related links


Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282XOn-line version ISSN 1678-4227

Arq. Neuro-Psiquiatr. vol.60 no.2B São Paulo June 2002 



Alexandre M. Valença1, Antonio Egidio Nardi1, Isabella Nascimento1, Walter A. Zin2, Márcio Versiani1



ABSTRACT - OBJECTIVE: We aim to determine if a treatment with a dose of clonazepam - 2 mg/day, for 6 weeks, blocks spontaneous panic attacks and the ones induced by the inhalation of 35% carbon dioxide (CO2) in panic disorder (PD) patients. The CO2 challenge-test may be a useful addition tool for measuring the pharmacological response during the initial phase (6 weeks) in the treatment of PD. METHOD: Eighteen PD patients drug free for a week participated in a carbon dioxide challenge test. Fourteen had a panic attack and were openly treated for a 6-week period with clonazepam. At the end of the 6-week period they were submitted again to the CO2 challenge test. RESULTS: After 6 weeks of treatment with clonazepam, 12 of 14 PD patients (85.7%) did not have a panic attack after the CO2 challenge test. Just 2 of 14 patients (14.3%) had a panic attack after the CO2 challenge test. Ten of 14 (71.4%) PD patients had panic free status after clonazepam treatment. The 2 patients who had a panic attack in the sixth week, after the CO2 test, did not have panic free status after the treatment with clonazepam. CONCLUSION: The CO2-test may be a valid tool for testing and predicting the drug response.

KEY WORDS: panic disorder, benzodiazepine, carbon dioxide, clonazepam.


O teste com dióxido de carbono como uma medida adicional na mensuração da resposta terapêutica no transtorno de pânico

RESUMO - OBJETIVO: Desejamos determinar se o tratamento com clonazepam ¾ 2mg/dia, durante 6 semanas, bloqueia ataques de pânico espontâneos e os induzidos pela inalação de dióxido de carbono (CO2) a 35% em pacientes com transtorno de pânico (TP). O teste com CO2 talvez possa ser uma ferramenta adicional útil para medir a resposta farmacológica durante a fase inicial (6 semanas) do tratamento farmacológico no TP. MÉTODO: 18 pacientes com TP sem medicamento por uma semana participaram de um teste com CO2 a 35%. 14 pacientes tiveram um ataque de pânico e foram tratados de forma aberta por um período de 6 semanas com clonazepam. Ao final das 6 semanas, os pacientes foram submetidos novamente ao teste com CO2. RESULTADOS: Após 6 semanas de tratamento com clonazepam, 12 (85,7%) dos 14 pacientes não apresentaram ataques de pânico no teste com CO2 a 35%. Apenas 2 (14,3%) apresentaram ataques de pânico ao teste respiratório e não apresentaram remissão dos ataques de pânico espontâneos. 10 (71,4%) pacientes ficaram livres dos ataques de pânico espontâneos após o tratamento CONCLUSÃO: O teste com CO2 pode ser uma ferramenta válida para testarmos e predizermos a resposta terapêutica.

PALAVRAS-CHAVE: transtorno do pânico, benzodiazepínico, dióxido de carbono, clonazepam.



A panic attack is usually initiated by a sudden, surprising, unexpected rise of terror associated with many autonomic, especially cardio-respiratory symptoms1. The description of the natural history of panic disorder (PD) makes clear the central importance of the acute panic attack as the basis for all features of the illness2. A number of agents are reported to be capable of provoking acute panic attacks in PD patients under laboratory conditions: carbon dioxide3, sodium lactate4, caffeine5, isoproterenol6 and yohimbine6. These agents induce panic attacks in the laboratory that are very similar of spontaneous panic attacks. The understanding of the mechanism of action of a panicogenic agent may elucidate the underlying pathogenesis of panic disorder.

The inhalation of high concentrations of carbon dioxide (CO2) has consistently been shown to increase anxiety and induce panic attacks in PD patients7-10. CO2 induced panic attacks closely resemble the panic attack in PD patients experience outside the laboratory. Of the numerous agents capable of inducing panic attacks in patients with PD, CO2 offers significant advantages. It is easily administered, well tolerated, and one of the most reliable panicogenic agents11. The two most common methods used are the prolonged (15 minutes) inhalation of 7% CO2 and the one or two vital capacity inhalation of 35% CO2 and 65% O2. The 35% CO2 technique was found to differentiate between PD patients and controls, displaying enough specificity for PD11,12. The provocation of anxiety by CO2 may be a reliable marker of panic. Gaining insight into the mechanisms of CO2 provoked anxiety may in turn shed light on the pathophysiology of PD. This agent probably triggers some vulnerability that may represent the predisposition to the development of panic. CO2 challenge appears to be a possible biological marker for PD patients13. Klein14 proposed that many spontaneous panic attacks occur when the brain's suffocation monitor erroneously signals a lack of useful air, maladaptively triggering an evolved suffocation alarm system. Such a dysfunction would make an individual vulnerable to "false suffocation alarms", namely panic attacks. CO2 sensitivity would be an aspect of a hypersensitive suffocation detector.

Alprazolam15 and clonazepam16 are efficacious drugs for the treatment of panic disorder and mostly studied in association with CO2 provoked panic attacks. Clonazepam has some atypical features in comparison with other benzodiazepines, including the demonstration of elevated serotonin levels in the brain suggesting that this drug may also act by increasing the concentration of the neurotransmitter at synaptic receptor sites17. This possible particular mechanism of action may help to explain its efficacy in panic disorder.

We aim to determine if a treatment with a dose of clonazepam - 2 mg, for 6 weeks, blocks spontaneous panic attacks and the ones induced by the inhalation of 35% carbon dioxide in panic disorder patients. We also expect that the CO2 challenge-test could be a useful addition tool for measuring the pharmacological response during the initial phase (6 weeks) in the treatment of PD patients. It is expected that clonazepam should block CO2 induced anxiety attacks and other studies have reported similar results with chronic administration of clonazepam18 and acute19 and long term administration of alprazolam.20 In a preliminary report21 clonazepam was effective in blocking CO2 panic attacks after 10 days of treatment.



We randomly selected at the Laboratory of Panic & Respiration in the Federal University of Rio de Janeiro 18 PD subjects with agoraphobia who agreed to participate in this protocol. The diagnosis was obtained using the Structured Clinical Interview22 (SCID-I) for DSM-IV23. The study design of the investigation was explained to the patients and a signed voluntary written inform consent for their participation in this study was obtained. The protocol complying with the principles laid down in the Declaration of Helsinki was approved by our local Ethics Committee.

To participate in the study the subjects were required to be between the ages of 18 and 55 years and to report at least three panic attacks in the two weeks before the first challenge test day. All patients were free of psychotropic drugs for at least one week and have a negative urine test for benzodiazepines and other medications. All patients underwent physical examination and laboratory exams to ensure they were healthy enough to participate in a CO2 challenge test. They had no respiratory or cardiovascular abnormalities and were free of caffeine for one day.

The subjects were informed that the test could either cause sinus head pressure, dizziness, a mild headache or an increase in anxiety levels and that the symptoms would be quickly relieved when the test was finished. The possibility of a panic attack was not mentioned in order to avoid a bias linked to anticipatory anxiety features. The patients were informed that one inhalation was likely to induce unpleasant sensations, while the other was harmless.

As a part of the challenge test, patients received both 35% CO2 and atmospheric compressed (placebo test) air 20 minutes apart each other under double-blind conditions. The subjects were asked to exhale as fully as possible, place the mask on their face, take a fast vital capacity breath, inhaling either the 35% CO2 mixture or the atmospheric compressed air, holding their breath for 8 seconds and afterwards exhale. Immediately after, they were asked to repeat the fast vital capacity breath and hold it again for 8 seconds. The same procedure was repeated after 20 minutes using the gas not used before.

To measure the presence of a panic attack subjects were asked to complete the Diagnostic Symptom Questionnaire24 adapted for DSM-IV23 in which the presence and level of discomfort of panic symptoms experienced after the inhalations were rated on a 0 - 4 point scale (0= none , 4 = very severe). On the basis of the Diagnostic Symptom Questionnaire, a CO2-induced panic attack was defined as the following: 1) the presence of four or more DSM-IV panic attacks symptoms where either the presence or the increase in DSM-IV symptomatology was used for diagnosis; 2) at least one DSM-IV cognitive panic symptom (i.e. fear of dying, losing control, or going crazy); 3) sensation of panic or fear, resembling real-life panic attacks; and 4) an agreement of two medical doctors that the patient had a clinical panic attack. This criteria made the diagnosis of a panic attack reliable and with clinical significance.

After the CO2 challenge test, 14 PD patients who had a panic attack were selected to participate in the study. In an open trial, they received clonazepam (2mg/day, taken once a day) for 6 weeks, then the CO2 challenge test was repeated. The patients who did not have a panic attack after the first CO2 challenge test were excluded at baseline. They were treated with antipanic drugs by medical doctors of the Laboratory of Panic & Respiration.



The PD patients were 9 female and 5 male with a mean (± SD) age of 36.9 ± 8.7 years. Of this sample, 12 of 14 (85.7%) PD patients had agoraphobia and 2 (14.3%) had not. The mean (± SD) time duration of PD in the sample was 45.8 ± 71,4 months. After 6 weeks of treatment with clonazepam (2mg/day), 12 (85.7%) of 14 PD patients did not have a panic attack after the CO2 challenge test. Just 2 (14.3%) of 14 patients had a panic attack after the CO2 challenge test. Ten (71.4%) of 14 PD patients had panic free status after clonazepam treatment. Both of the 2 patients who had a panic attack in the sixth week, after the CO2 test, did not have panic free status after the treatment with clonazepam.



The original data of our trial is that the blockade of CO2 induced panic attacks was related to a clinical improvement of the PD patients, since 10 (71.4%) of 14 patients had panic free status after clonazepam treatment. We also observed that this open trial with clonazepam confirmed that when taken in a regimen of 6 weeks, blocked panic attacks evoked by inhalation of 35% CO2 in PD patients. After 6 weeks of treatment with clonazepam (2mg/day), 12 (85.7%)of 14 PD patients, who had had a panic attack after the CO2 challenge test at baseline, when were free of psychotropic drugs, did not have a panic attack after the second CO2 challenge test. Curiously, the 2 patients who had a panic attack after the CO2 challenge test, in the sixth week of the study, did not have panic free status, after using clonazepam (2mg/day) for 6 weeks.

Our finding is consistent with the observation that acute alprazolam19, 10 days treatment with clonazepam21, long term alprazolam20 treatment and 5-week treatment with clonazepam18,25 are effective in reducing CO2 induced panic attacks. Perhaps the most essential point in every CO2 study is the criteria used to define laboratorial panic attacks and the CO2 concentrations.

The chronic administration (11 weeks) of alprazolam (mean dose 3.1 mg) to eight panic disorder patients attenuated the anxiety induced by 5% CO2 inhalation.20 In a previous study26 it was found that a single dose of clonazepam blocked CO2 induced panic attacks significantly over placebo. A single dose of alprazolam (1mg) as a pretreatment reduced anxiety and panic provoked by the inhalation of 35% CO2 in patients with panic disorder19 .These patients did a 35% CO2 challenge test in two different occasions, with one week of interval between them, and received 1mg of alprazolam or placebo 90 minutes before the CO2 test. It was found that 7 in 10 patients had a panic attack after using placebo and only 1 in 10 patients had a panic attack after using alprazolam. Mono-amino-oxidase inhibitors27, tricyclic antidepressants28,29 and selective serotonin re-uptake inhibitors28,29 are also able to reduce CO2 reactivity.

It is possible that the response to antipanic treatment is correlated with a reduction to CO2 sensitivity. The 35% CO2 challenge test is an interesting neurobiologic probe into the pathophysiology of panic anxiety and an ideal way for the observation and experimental manipulation of different components of panic in a controlled setting.



The CO2-test may be a valid tool for testing and predicting the drug response. This trial provides evidence for the positive effect of clonazepam in carbon dioxide-induced panic attacks. The CO2 challenge test might be a laboratory instrument able to predict the efficacy of an antipanic medication in PD patients.



1. Klein DF, Klein HM. The status of panic disorder. Curr Opin Psychiatr 1988; 1:177-183.         [ Links ]

2. Klein DF, Gorman JM. A model of panic and agoraphobic development. Acta Psychiatr Scand 1987;76:87-95.         [ Links ]

3. Valença AM, Nardi AE, Nascimento I, Mezzasalma MA, Lopes FL, Zin WA. Carbon-dioxide induced panic attacks: a clinical-phenomenological study. Rev Bras Psiquiatria 2001;23:15-20.         [ Links ]

4. Lingjaerde A. Lactate-induced panic attacks: possible involvement of serotonine reuptake stimulation. Acta Psychiatr Scand 1985;72:206-208.         [ Links ]

5. Charney DS, Heninger GR, Jatlow PI. Increased anxiogenic effects of caffeine in panic disorder. Arch Gen Psychiatry 1985;42:233-243.         [ Links ]

6. Shear MK. Pathophysiology of panic: a review of pharmacologic provocative tests and naturalistic monitoring data. J Clin Psychiatry 1986;47(Suppl 6):18-26.         [ Links ]

7. Gorman JM, Askanazi J, Liebowitz MR, et al. Response to hyperventilation in a group of patients with panic disorder. Am J Psychiatry 1984;141:857-861.         [ Links ]

8. Sanderson WC, Wetzler S. Five percent carbon dioxide challenge: valid analogue and marker of panic disorder? Biol Psychiatry 1990;27:689-701.         [ Links ]

9. Griez E, de Loof C, Pols H, Zandbergen J, Lousberg H. Specific sensitivity of patients with panic attacks to carbon dioxide inhalation. Psychiatry Res 1990;31:193-199.         [ Links ]

10. Perna G, Battaglia M, Garberi A, Arancio C, Bertani A, Bellodi L. Carbon dioxide/oxygen challenge test in panic disorder. Psychiatry Res 1994;52:159-171.         [ Links ]

11. Papp LA, Klein DF, Martinez JM, et al. Diagnostic and substance specificity of carbon-dioxide-induced panic. Am J Psychiatry 1993;150:250-257.         [ Links ]

12. Verburg K, Griez E, Meijer J, Pols H. Discrimination between panic disorder and generalized anxiety disorder by 35% carbon dioxide challenge. Am J Psychiatry 1995;152:1081-1083.         [ Links ]

13. Griez E, Verburg K. Panic provocation with 35% carbon dioxide: the link with the respiratory system. In Bellodi L, Perna G(eds). The panic-respiration connection. Milan: MDM Medical Media Srl, 1998:35-51.         [ Links ]

14. Klein DF. False suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis. Arch Gen Psychiatry 1993;50:306-317.         [ Links ]

15. Chouinard G, Annable L, Fontaine R, Solyom L. Alprazolam in the treatment of generalized anxiety and panic disorders: a double-blind placebo-controlled study. Psychopharmacology 1982;77:229 -233.         [ Links ]

16. Fontaine R, Chouinard G. Antipanic effects of clonazepam. Am J Psychiatry 1984;141:149.         [ Links ]

17. Davidson JR, Moroz G. Pivotal studies of clonazepam in panic disorder. Psychopharm Bull 1998;34:169-174.         [ Links ]

18. Pols H, Zandbergen J, de Loof C, Griez E. Attenuation of carbon dioxide-induced panic after clonazepam treatment. Acta Psychiatr Scand 1991;84:585-586.         [ Links ]

19. Sanderson WC, Wetzler S, Asnis GM. Alprazolam blockade of CO2-provoked panic in patients with panic disorder. Am J Psychiatry 1994;151:1220-1222.         [ Links ]

20. Woods SW, Charney DS, Loke J, Goodman WK, Redmond E Jr, Heninger GR. Carbon dioxide sensitivity in panic anxiety. Arch Gen Psychiatry 1986; 43: 900-909.         [ Links ]

21. Nardi AE, Valenca AM, Zin WA, Nascimento I. Carbon dioxide induced panic attacks and short term clonazepam treatment: preliminary report. Arq Neuropsiquiatr 1999;57:361-365.         [ Links ]

22. First MB, Spitzer RL, Gibbon M, Williams JBM. Structured clinical interview diagnostic (SCID) for DSM-IV axis I Disorder-Clinician Version (SCID-CV), Washington, DC: American Psychiatric Press, 1997         [ Links ]

23. American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders ¾ DSM-IV, 4th ed. Washington, DC: American Psychiatric Press, 1994.         [ Links ]

24. Sanderson WC, Rapee RM, Barlow DH. The influence of an illusion of control on panic attacks via inhalation of 5.5% carbon dioxide-enriched air. Arch Gen Psychiatry 1989; 46:157-162.         [ Links ]

25. Beckett A, Fishman SM, Rosenbaum JF. Clonazepam blockade of spontaneous and CO2 inhalation-provoked panic in a patient with panic disorder. J Clin Psychiatry 1986; 47:475-476.         [ Links ]

26. Nardi AE, Valença AM, Nascimento I, Mezzasalma MA, Zin WA. Double-blind acute clonazepam vs placebo in carbon dioxide induced panic attacks. Psychiatry Res 2000;94:179-184.         [ Links ]

27. Perna G, Cocchi S, Bertani A, Arancio C, Bellodi L. Pharmacologic effect of toloxatone on reactivity to the 35 % carbon dioxide challenge: a single-blind, random, placebo-controlled study. J Clin Psychopharmacol 1994;14:414-418.         [ Links ]

28. Bertani A, Perna G, Arancio C, Caldirola D, Bellodi L. Pharmacologic effect of imipramine, paroxetine, and sertraline on 35 % carbon dioxide hypersensitivity in panic patients: a double-blind, random, placebo-controlled study. J Clin Psychopharmacol 1997;17:97-101.         [ Links ]

29. Perna G, Bertani A, Gabriele A, Politi E, Bellodi L. Modification of 35 % carbon dioxide hypersensitivity across one week of treatment with clomipramine and fluvoxamine: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 1997;17:173-178.         [ Links ]



1Laboratory of Panic & Respiration, Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil (UFRJ); 2Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, UFRJ. Supported by the Brazilian Council for Scientific and Technological Development (CNPq), Grant 300500/93-9.

Received 13 September 2001, received in final form 10 December 2001. Accepted 8 January 2002

Alexandre Martins Valença, MD - Rua da Cascata 13/ 501 - 20530-080 Rio de Janeiro RJ ¾ Brasil. FAX: 5521-523-6839. E-mail:

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License