title: Translational evaluation of JNJ-18038683, a 5-hydroxytryptamine type 7 receptor antagonist, on rapid eye movement sleep and in major depressive disorder.
abstract: In rodents 5-hydroxytryptamine type 7 (5-HT(7)) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT(7) receptor antagonist, (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT(7) blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drug-drug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS) < = 12] and from sites with no placebo response (MADRS > = 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.
authors.affiliation: Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92109, USA. pbonave1@its.jnj.com
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
authors.forename: Michelle
authors.initials: M
authors.lastname: Kramer
authors.forename: Peter
authors.initials: P
authors.lastname: De Boer
authors.forename: Jaskaran
authors.initials: J
authors.lastname: Singh
authors.forename: Sue
authors.initials: S
authors.lastname: Wilson
authors.forename: Kirk
authors.initials: K
authors.lastname: Bertelsen
authors.forename: Jianing
authors.initials: J
authors.lastname: Di
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shelton
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.forename: Lisa
authors.initials: L
authors.lastname: Dvorak
authors.forename: Ian
authors.initials: I
authors.lastname: Fraser
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Diane
authors.initials: D
authors.lastname: Nepomuceno
authors.forename: Abdellah
authors.initials: A
authors.lastname: Ahnaou
authors.forename: Wilhelmus
authors.initials: W
authors.lastname: Drinkenburg
authors.forename: Wenying
authors.initials: W
authors.lastname: Chai
authors.forename: Curt
authors.initials: C
authors.lastname: Dvorak
authors.forename: Steve
authors.initials: S
authors.lastname: Sands
authors.forename: Nicholas
authors.initials: N
authors.lastname: Carruthers
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D015283:Citalopram / Q000494:pharmacology; D015331:Cohort Studies; D018592:Cross-Over Studies; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D057809:HEK293 Cells; D019417:Hindlimb Suspension / Q000379:methods; D006801:Humans; D007035:Hypothermia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D012895:Sleep, REM / Q000187:drug effects*; D014233:Tricarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C576951:3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo(3,4-d)azepine 2-hydroxy-1,2,3-propanetricarboxylate; D000928:Antidepressive Agents; D001381:Azepines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014233:Tricarboxylic Acids; C104425:serotonin 7 receptor; D015283:Citalopram; D012701:Serotonin