Preliminary evidence of anxiolytic effects of the CRF₁ receptor antagonist R317573 in the 7.5% CO₂ proof-of-concept experimental model of human anxiety

Abstract

We have validated the use of prolonged inhalation of 7.5% carbon dioxide (CO(2)) as a human model of anxiety and have shown that drugs from two prototypical classes of anxiolytics, benzodiazepines and a serotonin reuptake inhibitor, attenuate CO(2)-induced symptoms (Bailey et al., 2007a). Preclinical evidence suggests that drugs acting at the corticotropin-releasing factor (CRF) system may be useful for the treatment of depression, anxiety, and other stress-related disorders (Valdez, 2006), hence we have now examined the effects of a CRF(1) receptor antagonist in the 7.5% CO(2) model. In a randomized double-blind, placebo-controlled, study in 32 healthy participants we examined the effects of 7 days of treatment with the CRF(1) receptor antagonist, R317573, at a dose that shows a favourable safety profile and is comparable with those effective in preclinical models (40 mg). On day 8, eight of the placebo-treated group received lorazepam (LZP) 2 mg as a positive control. All participants underwent 20 min inhalation of 7.5% CO(2)-enriched air. Subjective reports of peak gas effects were assessed using visual analogue scales and questionnaires. The mean age of participants was 26 years, and 13 were male. The peak effects of CO(2) were expressed as a difference from baseline scores obtained while breathing air alone. Compared with placebo (PLAC), both drug groups showed a decrease in all subjective symptoms, total score on the panic symptom inventory (CRF 11 [2.6], PLAC 16.4 [3.1], LZP 2.9 [3.0]) and a generalized anxiety disorder symptom scale (CRF 2.2 [1.5], PLAC 8.2 [2.2], LZP 1.1 [1.5]). We have shown that a drug that acts to inhibit the CRF(1) receptor shows efficacy in the 7.5% CO(2) model of anxiety in healthy participants.

The CRH1 Antagonist GSK561679 Increases Human Fear But Not Anxiety as Assessed by Startle

“…*po0.05, **po0.01, ***po0.001. a proof-of-concept study using 7.5% CO 2 to induce anxiety (Bailey et al, 2011). One possibility is that GSK561679 is anxiolytic in some tests but not in the NPU test.…”

“…Specifically, CRF 1 antagonists may reduce responses to acute rather than chronic stress (Koob and Zorrilla, 2012). However, minimal research has examined this issue in humans (Bailey et al, 2011;Binneman et al, 2008), and the current study fills this gap by examining the effects of a CRF 1 antagonist GSK561679 (Verucerfont) on startle, a validated, cross-species marker, in healthy individuals (Grillon, 2008).…”

Update on Corticotropin-Releasing Factor Pharmacotherapy for Psychiatric Disorders: A Revisionist View

“…A CRF 1 antagonist (R317573/JNJ19567470/CRA5626) also recently showed activity in rodent (Shekhar et al, 2011) and human (Bailey et al, 2011) panic models. These models reflect a dynamic, active response to an acute stressor and, from a face validity perspective, may reflect more the symptoms of specific subtypes of anxiety disorders rather than of generalized anxiety disorder.…”

Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

“…In a clinical model of generalized anxiety induced by 20-min inhalation of 7.5% CO 2 , preliminary studies in 12 healthy subjects showed that R317573 (40 mg once daily) given for 7 days significantly reduced panic symptom score and generalized anxiety compared to placebo. 194 Positron emission tomography (PET) studies indicated that the acute administration of R317573 at 30 and 200 mg results in dose-related changes in regional glucose metabolism in regions relevant to mood and anxiety disorders. 195 A recent clinical study using functional magnetic resonance imaging showed that an acute oral administration of CRF 1 antagonist, GW876008 (single dose of 20 or 200 mg orally) dampened the amygdala activation produced by the anticipation of visceral pain compared to placebo drug in IBS female patients.…”