Research Article

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

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Science  11 Sep 1998:
Vol. 281, Issue 5383, pp. 1640-1645
DOI: 10.1126/science.281.5383.1640

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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.

  • * To whom correspondence concerning the clinical study should be addressed. E-mail: Mark_Kramer{at}merck.com

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

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