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 H. Feldman, Dan A. Oren, Anantha Shekhar, Joseph Pultz, Randy C. Dockens, Xiaoling Wu, Kimberly A. Gentile, Shu Pang Huang, Eileen Emison, Terrye Delmonte, Bernadette B. D'Souza, Daniel L. Zimbroff, Jack A. Grebb, Andrew W. Goddard, Elyse G. Stock

Research output: Contribution to journalArticle

107 Scopus citations

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 P5.015). 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. Depression and Anxiety 27:417-425, 2010.

Original languageEnglish (US)
Pages (from-to)417-425
Number of pages9
JournalDepression and anxiety
Volume27
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • Generalized anxiety disorder
  • HPA axis
  • Orticotropin-releasing factor
  • Plexin
  • Semaphorins

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Clinical Psychology

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    Coric, V., Feldman, H. H., Oren, D. A., Shekhar, A., Pultz, J., Dockens, R. C., Wu, X., Gentile, K. A., Huang, S. P., Emison, E., Delmonte, T., D'Souza, B. B., Zimbroff, D. L., Grebb, J. A., Goddard, A. W., & Stock, E. G. (2010). Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depression and anxiety, 27(5), 417-425. https://doi.org/10.1002/da.20695