PMID- 23539641
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20190117
IS  - 1461-7285 (Electronic)
IS  - 0269-8811 (Linking)
VI  - 27
IP  - 5
DP  - 2013 May
TI  - Full central neurokinin-1 receptor blockade is required for efficacy in 
      depression: evidence from orvepitant clinical studies.
PG  - 424-34
LID - 10.1177/0269881113480990 [doi]
AB  - 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.
FAU - Ratti, Emiliangelo
AU  - Ratti E
AD  - Neurosciences Center for Excellence in Drug Discovery, GlaxoSmithKline, Verona, 
      Italy.
FAU - Bettica, Paolo
AU  - Bettica P
FAU - Alexander, Robert
AU  - Alexander R
FAU - Archer, Graeme
AU  - Archer G
FAU - Carpenter, David
AU  - Carpenter D
FAU - Evoniuk, Gary
AU  - Evoniuk G
FAU - Gomeni, Roberto
AU  - Gomeni R
FAU - Lawson, Erica
AU  - Lawson E
FAU - Lopez, Monica
AU  - Lopez M
FAU - Millns, Helen
AU  - Millns H
FAU - Rabiner, Eugenii A
AU  - Rabiner EA
FAU - Trist, David
AU  - Trist D
FAU - Trower, Michael
AU  - Trower M
FAU - Zamuner, Stefano
AU  - Zamuner S
FAU - Krishnan, Ranga
AU  - Krishnan R
FAU - Fava, Maurizio
AU  - Fava M
LA  - eng
SI  - ClinicalTrials.gov/NCT00880048
SI  - ClinicalTrials.gov/NCT00880399
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20130328
PL  - United States
TA  - J Psychopharmacol
JT  - Journal of psychopharmacology (Oxford, England)
JID - 8907828
RN  - 0 (Antidepressive Agents)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Neurokinin-1 Receptor Antagonists)
RN  - 0 (Piperidines)
RN  - IIU6V0W3JD (orvepitant)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antidepressive Agents/*therapeutic use
MH  - Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
MH  - Depressive Disorder, Major/diagnostic imaging/*drug therapy/metabolism
MH  - Double-Blind Method
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neurokinin-1 Receptor Antagonists/*metabolism
MH  - Piperidines/therapeutic use
MH  - Positron-Emission Tomography
MH  - Radioligand Assay
EDAT- 2013/03/30 06:00
MHDA- 2013/12/16 06:00
CRDT- 2013/03/30 06:00
PHST- 2013/03/30 06:00 [entrez]
PHST- 2013/03/30 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
AID - 0269881113480990 [pii]
AID - 10.1177/0269881113480990 [doi]
PST - ppublish
SO  - J Psychopharmacol. 2013 May;27(5):424-34. doi: 10.1177/0269881113480990. Epub 
      2013 Mar 28.