Articlebronze2010

Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder

Vladimir Coric · Howard Feldman · Dan A. Oren · Anantha Shekhar · Joseph A. Pultz · Randy C. Dockens +10 more

172 citations0/0 files storedDepression and Anxiety

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Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes Treatment of Major Depression Stress Responses and Cortisol

Abstract

BACKGROUND: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). METHOD: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. RESULTS: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). CONCLUSIONS: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.

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References

1960A RATING SCALE FOR DEPRESSION 1998The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10 1959THE ASSESSMENT OF ANXIETY STATES BY RATING 2006Human and economic burden of generalized anxiety disorder 2004Stress Burden and the Lifetime Incidence of Psychiatric Disorder inYoung Adults

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2015Emerging drugs for the treatment of anxiety 2018Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders 2009Sheehan Suicidality Tracking Scale (Sheehan-STS): Preliminary Results from a Multicenter Clinical Trial in Generalized Anxiety Disorder.2012Classical and novel approaches to the preclinical testing of anxiolytics: A critical evaluation 2023Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions

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