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).

METHOD:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467).

• Authors: Guy Griebel, Sandra Beeské, Stephen M Stahl
• Journal: The Journal of clinical psychiatry (J Clin Psychiatry) Vol. 73 Issue 11 Pg. 1403-11 (Nov 2012) ISSN: 1555-2101 [Electronic] United States
• PMID: 23146246 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Copyright 2012 Physicians Postgraduate Press, Inc.

Chemical References

• 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
• Anti-Anxiety Agents
• Antidepressive Agents
• Antidiuretic Hormone Receptor Antagonists
• Indoles
• Pyrrolidines
• Citalopram
• Paroxetine

Topics

• Adolescent
• Adult
• Anti-Anxiety Agents (adverse effects, therapeutic use)
• Antidepressive Agents (adverse effects, therapeutic use)
• Antidiuretic Hormone Receptor Antagonists
• Anxiety Disorders (drug therapy)
• Citalopram (adverse effects, therapeutic use)
• Clinical Trials, Phase II as Topic
• Depressive Disorder, Major (drug therapy)
• Double-Blind Method
• Female
• Humans
• Indoles (adverse effects, therapeutic use)
• Male
• Middle Aged
• Multicenter Studies as Topic
• Paroxetine (adverse effects, therapeutic use)
• Pyrrolidines (adverse effects, therapeutic use)
• Randomized Controlled Trials as Topic
• Recurrence
• Treatment Outcome
• Young Adult