title: A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies.
abstract: Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD.
authors.affiliation: Lilly UK, Windlesham, Surrey, UK.
authors.forename: Anke
authors.initials: A
authors.lastname: Post
authors.affiliation: Lilly UK, Windlesham, Surrey, UK.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Smart
authors.affiliation: Eli Lilly, Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Krikke-Workel
authors.affiliation: P1vital Limited, Oxfordshire, UK.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.affiliation: University of Oxford, Oxford, UK.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Harmer
authors.affiliation: P1vital Limited, Oxfordshire, UK.|University of Oxford, Oxford, UK.
authors.forename: Michael
authors.identifier: 0000-0001-9108-3144
authors.initials: M
authors.lastname: Browning
authors.affiliation: Lilly UK, Windlesham, Surrey, UK.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Jackson
authors.affiliation: Innovative Clinical Research-SICR, Ft. Lauderdale, FL, USA.
authors.forename: Rishi
authors.initials: R
authors.lastname: Kakar
authors.affiliation: Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mohs
authors.affiliation: Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Statnick
authors.affiliation: Lilly UK, Windlesham, Surrey, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Wafford
authors.affiliation: Lilly UK, Windlesham, Surrey, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Barth
authors.affiliation: Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005133:Eye Movements / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011714:Pyrans / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D013141:Spiro Compounds / Q000627:therapeutic use*; D055815:Young Adult; D000094942:Nociceptin Receptor
chemical_list: D014151:Anti-Anxiety Agents; C000625550:LY2940094; D009292:Narcotic Antagonists; D011714:Pyrans; D011957:Receptors, Opioid; D013141:Spiro Compounds; D002707:Chlordiazepoxide; D000094942:Nociceptin Receptor