Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression

UMMS Affiliation

Department of Psychiatry

Publication Date


Document Type



Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; *Drug Evaluation; Drug Tolerance; Female; Humans; Male; Middle Aged; Personality Inventory; Psychiatric Status Rating Scales; Receptors, Neurokinin-1; Time Factors; Treatment Outcome




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.

DOI of Published Version



Neuropsychopharmacology. 2004 Feb;29(2):385-92. Link to article on publisher's site

Journal/Book/Conference Title

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Related Resources

Link to Article in PubMed

PubMed ID