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Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.

Publication ,  Journal Article
Ratti, E; Bettica, P; Alexander, R; Archer, G; Carpenter, D; Evoniuk, G; Gomeni, R; Lawson, E; Lopez, M; Millns, H; Rabiner, EA; Trist, D ...
Published in: J Psychopharmacol
May 2013

Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [(11)C]GR205171 binding indicated that oral orvepitant doses of 30-60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: -2.41, 95% confidence interval (CI) (-4.50 to -0.31) p=0.0245; 60 mg: -2.86, 95% CI (-4.97 to -0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: -1.67, 95% CI (-3.73 to 0.39) p=0.1122; 60 mg: -0.76, 95% CI (-2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.

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Published In

J Psychopharmacol

DOI

EISSN

1461-7285

Publication Date

May 2013

Volume

27

Issue

5

Start / End Page

424 / 434

Location

United States

Related Subject Headings

  • Radioligand Assay
  • Psychiatry
  • Positron-Emission Tomography
  • Piperidines
  • Neurokinin-1 Receptor Antagonists
  • Middle Aged
  • Male
  • Humans
  • Double-Blind Method
  • Depressive Disorder, Major
 

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Ratti, E., Bettica, P., Alexander, R., Archer, G., Carpenter, D., Evoniuk, G., … Fava, M. (2013). Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol, 27(5), 424–434. https://doi.org/10.1177/0269881113480990
Ratti, Emiliangelo, Paolo Bettica, Robert Alexander, Graeme Archer, David Carpenter, Gary Evoniuk, Roberto Gomeni, et al. “Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.J Psychopharmacol 27, no. 5 (May 2013): 424–34. https://doi.org/10.1177/0269881113480990.
Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, et al. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013 May;27(5):424–34.
Ratti, Emiliangelo, et al. “Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.J Psychopharmacol, vol. 27, no. 5, May 2013, pp. 424–34. Pubmed, doi:10.1177/0269881113480990.
Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013 May;27(5):424–434.
Journal cover image

Published In

J Psychopharmacol

DOI

EISSN

1461-7285

Publication Date

May 2013

Volume

27

Issue

5

Start / End Page

424 / 434

Location

United States

Related Subject Headings

  • Radioligand Assay
  • Psychiatry
  • Positron-Emission Tomography
  • Piperidines
  • Neurokinin-1 Receptor Antagonists
  • Middle Aged
  • Male
  • Humans
  • Double-Blind Method
  • Depressive Disorder, Major