title: Distinct mechanism for antidepressant activity by blockade of central substance P receptors.
abstract: The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.
authors.affiliation: Merck Research Laboratories, West Point, PA 19456, USA. Mark_Kramer@merck.com
authors.forename: M S
authors.initials: MS
authors.lastname: Kramer
authors.forename: N
authors.initials: N
authors.lastname: Cutler
authors.forename: J
authors.initials: J
authors.lastname: Feighner
authors.forename: R
authors.initials: R
authors.lastname: Shrivastava
authors.forename: J
authors.initials: J
authors.lastname: Carman
authors.forename: J J
authors.initials: JJ
authors.lastname: Sramek
authors.forename: S A
authors.initials: SA
authors.lastname: Reines
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Snavely
authors.forename: E
authors.initials: E
authors.lastname: Wyatt-Knowles
authors.forename: J J
authors.initials: JJ
authors.lastname: Hale
authors.forename: S G
authors.initials: SG
authors.lastname: Mills
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: C J
authors.initials: CJ
authors.lastname: Swain
authors.forename: T
authors.initials: T
authors.lastname: Harrison
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: F
authors.initials: F
authors.lastname: Hefti
authors.forename: E M
authors.initials: EM
authors.lastname: Scolnick
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: G G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: A R
authors.initials: AR
authors.lastname: Williams
authors.forename: L
authors.initials: L
authors.lastname: Hewson
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.forename: E J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000077608:Aprepitant; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000502:physiology; D017374:Paroxetine / Q000627:therapeutic use; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012701:Serotonin / Q000502:physiology; D013315:Stress, Psychological / Q000188:drug therapy; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: D018687:Antidepressive Agents, Second-Generation; C114226:L 760735; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D012701:Serotonin; D013373:Substance P; D017374:Paroxetine; D009638:Norepinephrine