Skip to main content
    • Aa
    • Aa
  • The International Journal of Neuropsychopharmacology, Volume 16, Issue 1
  • February 2013, pp. 1-11

Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder

  • David Michelson (a1), Richard Hargreaves (a1), Robert Alexander (a1), Paulette Ceesay (a1), Jarmo Hietala (a2), Christopher Lines (a1) and Scott Reines (a1)
  • DOI:
  • Published online: 21 March 2012

Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1–6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) −1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = −2.7, 95% CI −5.0 to −0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5–6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder.

Corresponding author
Author for correspondence: Dr D. Michelson, Merck Sharp & Dohme Corp., 351 North Sumneytown Pike, North Wales, PA 19454, USA. Tel.: (001) 267 305 6222Fax: (011) 267 305 6454Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

DS Baldwin , KI Ajel , M Garner (2010). Pharmacological treatment of generalized anxiety disorder. Current Top Behavioral Neuroscience 2, 453467.

M Bergstrom , R Hargreaves , D Burns , M Goldberg , (2004). Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biological Psychiatry 55, 10071012.

R Carson , M Channing , R Blasberg , B Dunn , (1993). Comparison of bolus and infusion methods for receptor quantitation: application to [18F]cyclofoxy and positron emission tomography. Journal of Cerebral Blood Flow and Metabolism 13, 2442.

J Culman , T Unger (1995). Central tachykinins: mediators of defense reaction and stress reactions. Canadian Journal of Physiology and Pharmacology 73, 885891.

JR Davidson (2009). First-line pharmacotherapy approaches for generalized anxiety disorder. Journal of Clinical Psychiatry 70(Suppl. 2), 2531.

K Ebner , SB Sartori , N Singewald (2009). Tachykinin receptors as therapeutic targets in stress-related disorders. Current Pharmaceutical Design 15, 16471674.

R Frank , R Hargreaves (2003). Clinical biomarkers in drug discovery and development. Nature Reviews in Drug Discovery 2, 566580.

T Furmark , L Appel , A Michelgård , K Wahlstedt , (2005). Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biological Psychiatry 58, 132142.

M Gail , R Simon (1985). Testing for qualitative interaction between effects and patient subsets. Biometrics 41, 361372.

M Hamilton (1959). The assessment of anxiety states by rating. British Journal of Medical Psychology 32, 5055.

M Hamilton (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662.

R Hargreaves (2008). The role of molecular imaging in drug discovery and development. Clinical Pharmacology and Therapeutics 83, 15.

PJ Hesketh , SM Grunberg , J Herrstedt , R de Wit , (2006). Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response. Support Care Cancer 14, 354360.

J Hietala , MJ Nyman , O Eskola , A Laakso , (2005). Visualization and quantification of neurokinin-1 (NK1) receptors in the human brain. Moleular Imaging and Biology 7, 262272.

M Keller , S Montgomery , W Ball , M Morrison , (2006). Lack of efficacy of the substance P (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biological Psychiatry 59, 216223.

M Kramer , A Winokur , J Kelsey , S Preskorn , (2004). Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29, 385392.

MS Kramer , N Cutler , J Feighner , R Shrivastava , (1998). Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 16401645.

A Lammertsma , S Hume (1996). Simplified reference tissue model for PET receptor studies. NeuroImage 4, 153158.

SJ Mathew , M Vythilingam , JW Murrough , CA Zarate , (2011). A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized,double-blind, placebo-controlled, proof-of-concept trial. European Neuropsychopharmacoogy 21, 221229.

A Raskin , J Schulterbrandt , N Reatig , JJ McKeon (1969). Replication of factors of psychopathology in interview, ward behavior and self-report ratings of hospitalized depressives. Journal of Nervous and Mental Disease 148, 8798.

O Solin , O Eskola , TG Hamill , J Bergman , (2004). Synthesis and characterization of a potent, selective, radiolabeled substance-P antagonist for NK1 receptor quantitation: ([18F]SPA-RQ). Molecular Imaging and Biology 6, 373384.

FD Tattersall , W Rycroft , M Cumberbatch , G Mason , (2000). The novel NK1 receptor antagonist MK-0869(L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets. Neuropharmacology 39, 652663.

J Tauscher , W Kielbasa , S Iyengar , F Vandenhende , (2010). Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder. European Neuropsychopharmacology 20, 8087.

RB Weisberg (2009). Overview of generalized anxiety disorder: epidemiology,presentation, and course. Journal of Clinical Psychiatry 70 (Suppl. 2), 49.

AS Zigmond , RP Snaith (1983).The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica 67, 361370.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *