Carbon dioxide test as an additional clinical measure of treatment response in panic disorder

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 (CO 2 ) in panic disorder (PD) patients. The CO 2 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 CO 2 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 CO 2 challenge test. Just 2 of 14 patients (14.3%) had a panic attack after the CO 2 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 CO 2 test, did not have panic free status after the treatment with clonazepam. Conclusion: The CO 2 -test may be a valid tool for testing and predicting the drug response.

Clonazepam in the treatment of psychiatric disorders: an update

“…Response rates: clonazepam/sertraline 41% versus placebo/sertraline 4% (week 1); clonazepam/ sertraline 63% versus placebo/sertraline 32% (week 3); (P r 0.05) Pollack et al (2003) 60 R, DB, PC 12-week study: paroxetine (titrated to 40 mg/day by week 4) + placebo or clonazepam for 5 weeks [mean dose titrated to 1.6 mg/day by week 5] and then discontinued [3-week taper] or continued for 7 weeks Remission at endpoint: clonazepam/paroxetine (with tapered clonazepam discontinuation) 50% versus clonazepam/paroxetine (with ongoing treatment) 20% versus clonazepam/placebo 18% Clonazepam/paroxetine displayed earlier onset of response with significant advantage in the PD Severity Scale from weeks 1-5 versus placebo/ paroxetine (P < 0.05); no additional benefit in maintaining benzodiazepine after week 5 Jacobs et al (1997) 144 R, DB, PC 6-week regimen of clonazepam (titrated to 4 mg/day by week 3; dose maintained for 3 weeks) (followed by r 6-week tapered withdrawal) SF-36 Mental Health Component Summary scale mean improvement: clonazepam improved score by 8.9 versus 3.9 with placebo (P = 0.03) Clonazepam also improved work productivity versus placebo Nardi et al (2000) 22 R, DB, PC Single dose clonazepam 2 mg % Patients with a CO 2 challenge-induced panic attack: after single-dose clonazepam 2 mg 18% had a mild attack versus 82% of placebo recipients with moderate-severe attack Valenca et al (2002b) 34 DB, PC Placebo before CO 2 challenge then clonazepam 2 mg/day for 6 weeks OR clonazepam 2 mg before CO 2 challenege then placebo for 6 weeks % Patients with a CO 2 challenge-induced panic attack: 21%, 6% and 11% with clonazepam versus 80%, 75% and 67% with placebo after acute dosing and 2 and 6 weeks of treatment, respectively Wulsin et al (1999) 27 R, DB, PC 4-week flexible dose (1-4 mg/day) then 2-week taper Response rates at 4 weeks: HAM-A total scores r 50% of baseline score: clonazepam 58% versus placebo 14% (P = 0.038); weekly panic attack frequency 0% or 50% decrease from baseline: clonazepam 67% versus placebo 47% (P = 0.44) Valenca et al (2003) 34 R, PC Clonazepam 2 mg/day for 6 weeks % Patients panic-free at endpoint: clonazepam 78% versus placebo 8% (P < 0.001) Panic attack remission and reduction in anxiety and was equally effective in respiratory and non-respiratory subtypes Non-placebo-controlled studies Worthington et al (1998) Nardi et al (2005) 67 Open, UC Clonazepam 1-4 mg/d for 3 years % Patients panic-free at endpoint: > 95% of patients with respiratory and non-respiratory PD subtypes were free of panic attacks after 3 years Respiratory subgroup had a faster response at 8 weeks and equivalent response in follow-up period Valenca et al (2002a) 14 Open, UC Clonazepam 2 mg/day for 6 weeks % Patients with a CO 2 challenge-induced panic attack: of those who had a panic attack after CO 2 challenge at baseline 14% had a panic attack after CO 2 challenge after 6 weeks of clonazepam treatment Nardi et al (1999) Clonazepam (n = 10, mean dose 2.7 mg/ day) or alprazolam (n = 3; mean 2.5 mg/day) continued for 1-6 months Clonazepam reduced physiological expression of arousal but failed to show a beneficial effect on the course of PTSD 13 control Patients meeting PTSD diagnostic criteria 6 months after trauma: 69% (n = 9) of benzodiazepine patients versus 15% (n = 2) of controls …”

“…CO 2 -induced panic attacks CO 2 increases anxiety and induces panic attacks in PD patients (Valenca et al, 2002a). Moreover, CO 2 -induced panic appears to be a valid analogue of spontaneous panic attacks (Nardi et al, 1999).…”

“…In an open trial, 12 of 14 PD patients (86%) who had had a panic attack after CO 2 challenge-test at baseline did not have a panic attack after the CO 2 challenge-test after 6 weeks of clonazepam 2 mg/day (Valenca et al, 2002a). In a trial in 22 PD patients, a CO 2 challenge-test induced a panic attack (mild) in only 18% of patients after singledose clonazepam 2 mg compared to 82% of placebo recipients (moderate-severe attack) .…”

Predictors of pharmacotherapy response in anxiety disorders

“…However, Baker et al [49] failed to find an effect of HRV on treatment response, but observed a normalization of sleep pattern in responders to clonazepam and placebo. Valença et al [50,51] showed that patients taking clonazepam were less sensitive to the CO 2 -challenge test (responded less frequently with a panic attack) and that this effect was related to clinical improvement.…”

Clonidine in respiratory panic disorder subtype

“…Modalities for which there is considerable evidence of efficacy in the treatment of PD include cognitive behavioral therapies 3 and pharmacotherapy. Medications from several classes have been shown to be effective in PD treatment: selective serotonin reuptake inhibitors -SSRI 4 , tricyclic antidepressants 5 high-potency benzodiazepines 6,7 and monoamine-oxidase inhibitors -MAO-I 8 . It has been hypothesized that the alpha 2 -adrenergic receptor agonist clonidine also may be useful in the treatment of PD 9,10 .…”