title: Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.
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 [(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.
authors.affiliation: Neurosciences Center for Excellence in Drug Discovery, GlaxoSmithKline, Verona, Italy.
authors.forename: Emiliangelo
authors.initials: E
authors.lastname: Ratti
authors.forename: Paolo
authors.initials: P
authors.lastname: Bettica
authors.forename: Robert
authors.initials: R
authors.lastname: Alexander
authors.forename: Graeme
authors.initials: G
authors.lastname: Archer
authors.forename: David
authors.initials: D
authors.lastname: Carpenter
authors.forename: Gary
authors.initials: G
authors.lastname: Evoniuk
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomeni
authors.forename: Erica
authors.initials: E
authors.lastname: Lawson
authors.forename: Monica
authors.initials: M
authors.lastname: Lopez
authors.forename: Helen
authors.initials: H
authors.lastname: Millns
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: David
authors.initials: D
authors.lastname: Trist
authors.forename: Michael
authors.initials: M
authors.lastname: Trower
authors.forename: Stefano
authors.initials: S
authors.lastname: Zamuner
authors.forename: Ranga
authors.initials: R
authors.lastname: Krishnan
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
mesh_terms: D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists / Q000378:metabolism*; D010880:Piperidines / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D011869:Radioligand Assay
chemical_list: D000928:Antidepressive Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; C584555:orvepitant