title: Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression.
abstract: The efficacy and safety of a selective NK(1) antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK(1)) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18-60, scoring >/=25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring >/=4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n=66) or placebo (n=62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (p<0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, p<0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial (p=0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK(1) antagonists (aprepitant and L-759274). NK(1) antagonism is a replicated and generally well-tolerated antidepressant mechanism.
authors.affiliation: Merck Research Laboratories, West Point, PA, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kramer
authors.forename: Andrew
authors.initials: A
authors.lastname: Winokur
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kelsey
authors.forename: Sheldon H
authors.initials: SH
authors.lastname: Preskorn
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Rothschild
authors.forename: Duane
authors.initials: D
authors.lastname: Snavely
authors.forename: Kalyan
authors.initials: K
authors.lastname: Ghosh
authors.forename: William A
authors.initials: WA
authors.lastname: Ball
authors.forename: Scott A
authors.initials: SA
authors.lastname: Reines
authors.forename: Dennis
authors.initials: D
authors.lastname: Munjack
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Apter
authors.forename: Lynn
authors.initials: L
authors.lastname: Cunningham
authors.forename: Mitchel
authors.initials: M
authors.lastname: Kling
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bari
authors.forename: Albert
authors.initials: A
authors.lastname: Getson
authors.forename: Yih
authors.initials: Y
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D004341:Drug Evaluation; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D010555:Personality Inventory; D011569:Psychiatric Status Rating Scales; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D064729:Neurokinin-1 Receptor Antagonists