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Title: Full central neurokinin-1 receptor blockade is required for efficacy in depression: Evidence from orvepitant clinical studies
Authors: Ratti, E.
Bettica, P.
Alexander, R.
Archer, G.
Carpenter, D.
Evoniuk, G.
Gomeni, R.
Lawson, E.
Lopez, M.
Millns, H.
Rabiner, E.A.
Trist, D.
Trower, M.
Zamuner, S.
Krishnan, R. 
Fava, M.
Keywords: clinical trials
receptor occupancy
substance P
Issue Date: May-2013
Citation: Ratti, E., Bettica, P., Alexander, R., Archer, G., Carpenter, D., Evoniuk, G., Gomeni, R., Lawson, E., Lopez, M., Millns, H., Rabiner, E.A., Trist, D., Trower, M., Zamuner, S., Krishnan, R., Fava, M. (2013-05). Full central neurokinin-1 receptor blockade is required for efficacy in depression: Evidence from orvepitant clinical studies. Journal of Psychopharmacology 27 (5) : 424-434. ScholarBank@NUS Repository.
Abstract: 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 [11C]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. © The Author(s) 2013.
Source Title: Journal of Psychopharmacology
ISSN: 02698811
DOI: 10.1177/0269881113480990
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