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Science 11 September 1998:
Vol. 281. no. 5383, pp. 1640 - 1645
DOI: 10.1126/science.281.5383.1640
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Research Articles

Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors

Mark S. Kramer, * Neal Cutler, John Feighner, Ram Shrivastava, John Carman, John J. Sramek, Scott A. Reines, Guanghan Liu, Duane Snavely, Edwina Wyatt-Knowles, Jeffrey J. Hale, Sander G. Mills, Malcolm MacCoss, Christopher J. Swain, Timothy Harrison, Raymond G. Hill, Franz Hefti, Edward M. Scolnick, Margaret A. Cascieri, Gary G. Chicchi, Sharon Sadowski, Angela R. Williams, Louise Hewson, David Smith, Emma J. Carlson, Richard J. Hargreaves, Nadia M. J. Rupniak dagger

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.

M. S. Kramer is at Merck Research Laboratories, West Point, PA 19456, USA, and in the Department of Psychiatry and Human Behavior, Thomas Jefferson Medical College, Philadelphia, PA 19107, USA. N. Cutler and J. J. Sramek are at California Clinical Trials, Beverly Hills, CA 90211, USA. J. Feighner is at the Feighner Research Institute, San Diego, CA 92121, USA. R. Shrivastava is at the Eastside Medical Group, New York, NY 10021, USA. J. Carman is at Carman Research, Smyrna, GA 30080, USA. S. A. Reines, G. Liu, D. Snavely, and E. Wyatt-Knowles are at Merck Research Laboratories, West Point, PA 19456, USA. J. J. Hale, S. G. Mills, M. MacCoss, M. A. Cascieri, G. G. Chicchi, and S. Sadowski are at Merck Research Laboratories, Rahway, NJ 07065, USA. C. J. Swain, T. Harrison, R. G. Hill, F. Hefti, A. R. Williams, L. Hewson, D. Smith, E. J. Carlson, R. J. Hargreaves, and N. M. J. Rupniak are at the Merck Sharp & Dohme Neuroscience Research Centre, Harlow CM20 2QR, England. E. M. Scolnick is at Merck Research Laboratories, West Point, PA 19456, USA, and Merck Research Laboratories, Rahway, NJ 07065, USA.
M. Kramer and N. Rupniak are the principal contributors to the clinical and preclinical studies, respectively.
*   To whom correspondence concerning the clinical study should be addressed. E-mail: Mark_Kramer{at}merck.com

dagger    To whom correspondence concerning the preclinical studies should be addressed. E-mail: Nadia_Rupniak{at}merck.com

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