A validation of the 7.5% CO₂ model of GAD using paroxetine and lorazepam in healthy volunteers

Abstract

The inhalation of 7.5% carbon dioxide (CO2) in healthy subjects produces an increase in blood pressure and heart rate, and increased feelings of anxiety, fear and tension (Bailey et al. 2005). As this state is similar to that of general anxiety rather than panic, we further validated this by examining the effects of anxiolytic medication. Two separate studies in healthy volunteers are described; study one is a double-blind, placebo-controlled study of a single dose of 2 mg lorazepam and study two describes the effects of 21 days of treatment with paroxetine. Gas challenges were air and 7.5% CO2 inhaled for 20 minutes, delivered on day 0 (before treatment) and day 21 (after treatment) in the paroxetine study. Subjective effects were measured using visual analogue scales and questionnaires. When compared with placebo, lorazepam 2 mg significantly reduced peak CO2-induced subjective fear, feelings of wanting to leave, tension and worry. In the paroxetine study, when compared with day 0, day 21 showed a significantly attenuated peak CO2-induced nervousness and a trend for reduced ratings of anxiety, fear, feel like leaving, tense and worried. In these studies we have shown that this CO2 model of anxiety is sensitive to lorazepam and to a lesser extent paroxetine. This gives support to its utility as an experimental model of general anxiety disorder in healthy volunteers.

Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder

“…As disorder-specific challenges are necessary to elicit ATD effects in patients with SSRI-remitted anxiety states Bell et al 2002;Bell et al 2005;Corchs et al 2009), it is possible that the CO 2 inhalation failed to induce a state similar to clinical GAD. The validity of this challenge as reported elsewhere (Bailey et al 2005;Bailey et al 2007), coupled with the clear CO 2 -induced anxiety responses versus air seen on STAI-S, GAD-related VAS, and POMS-TA outcome measures in this study and excellent separation on the convergent validity VAS measure, however, provides evidence supporting the effectiveness of this challenge. There is no evidence of ceiling effects (namely, maximal anxiety produced from 7.5% CO 2 inhalation alone) from inspection of the results.…”

“…The CO 2 inhalation followed established procedure (Bailey et al 2005;Bailey et al 2007), with a minimum duration of 12-min inhalation required. Gas delivery was single-blind, placebo-controlled (air vs. 7.5% CO 2 ).…”

“…Our Bristol research group has begun the validation of the chronic (20 min) 7.5% carbon dioxide (7.5% CO 2 ) inhalation technique, which induces GAD-spectrum symptoms (Bailey et al 2005;Bailey et al 2007) in contrast to single-breath 35% CO 2 that appears to induce symptoms of panic Hood et al 2006;Schruers et al 2000). In the work reported here, we combine ATD with this 7.5% CO 2 (versus air) challenge in subjects with SSRI-remitted GAD.…”

d-Cycloserine and performance under different states of anxiety in healthy volunteers

“…It has been used in studies of panic provocation (Nutt et al 1990;Bell et al 2002) and our previous CO 2 studies Bailey et al , 2007. The PSI was administered at baseline, for peak effects and at the end of gas inhalation.…”

“…The state produced by inhaling 7.5% CO 2 mimics the symptoms seen in generalised anxiety disorder, and some of these symptoms can be attenuated by anxiolytic medication (Bailey et al 2007). The control condition in this paradigm is air inhalation delivered in the same way.…”