title: The vasopressin V(1b) receptor antagonist SSR149415 in the treatment of major depressive and generalized anxiety disorders: results from 4 randomized, double-blind, placebo-controlled studies.
abstract: OBJECTIVE
  These studies were designed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b) receptor antagonist, SSR149415, in the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).
  
  
  METHODS
  Studies were randomized 8-week, double-blind, placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415, placebo, and escitalopram 10 mg/day or paroxetine 20 mg/day, conducted from August 2006 through February 2008. Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for MDD or GAD. Baseline Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) total scores were ≥ 24 and 18, respectively, and in the GAD trial baseline Hamilton Anxiety Rating Scale (HARS) score was ≥ 22. Primary efficacy variables included changes from baseline in total score on HDRS or HARS and MADRS, and the secondary variable included changes in the Clinical Global Impressions-Severity of Illness score (CGI-S). A 4-week, double-blind, placebo-controlled study evaluating the effect of 100- and 250-mg twice daily doses of SSR149415 on the hypothalamic-pituitary-adrenal (HPA) axis in MDD patients was also conducted.
  
  
  RESULTS
  In the GAD trial, SSR149415 did not separate from placebo on the primary (HARS-100 mg: P = .29; 250 mg: P = .21) and secondary (CGI-S-100 mg: P = .18; 250 mg: P = .24) outcome measures, while paroxetine demonstrated efficacy (HARS: P = .003; CGI-S: P = .01). In 2 MDD trials, SSR149415-treated patients did not show significant improvement from baseline on any outcome measure compared with placebo-treated patients (HDRS-100 mg: P = .21 and .48, respectively; 250 mg: P = .22 and P = .46, respectively; CGI-S-100 mg: P = .64 and P = .82, respectively; 250 mg: P = .33 and P = .08, respectively). In the third MDD study, SSR149415 250 mg (P = .04), but not escitalopram (P = .15), demonstrated significant improvement compared to placebo on the HDRS total score at week 8. SSR149415 had no deleterious effects on the HPA axis.
  
  
  CONCLUSIONS
  These studies demonstrate that SSR149415 may not be useful for the treatment of GAD and that its antidepressant potential needs to be further evaluated.
  
  
  BACKGROUND
  ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467).
authors.affiliation: Sanofi, Exploratory Unit, 1 avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. guy.griebel@sanofi.com
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Sandra
authors.initials: S
authors.lastname: Beeské
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Stahl
mesh_terms: D000293:Adolescent; D000328:Adult; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D065092:Antidiuretic Hormone Receptor Antagonists; D001008:Anxiety Disorders / Q000188:drug therapy*; D015283:Citalopram / Q000009:adverse effects / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D017374:Paroxetine / Q000009:adverse effects / Q000627:therapeutic use; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; D015283:Citalopram; D017374:Paroxetine