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Distinct mechanism for antidepressant activity by blockade of central substance P receptors. 1998
M S Kramer, and
N Cutler, and
J Feighner, and
R Shrivastava, and
J Carman, and
J J Sramek, and
S A Reines, and
G Liu, and
D Snavely, and
E Wyatt-Knowles, and
J J Hale, and
S G Mills, and
M MacCoss, and
C J Swain, and
T Harrison, and
R G Hill, and
F Hefti, and
E M Scolnick, and
M A Cascieri, and
G G Chicchi, and
S Sadowski, and
A R Williams, and
L Hewson, and
D Smith, and
E J Carlson, and
R J Hargreaves, and
N M Rupniak
Merck Research Laboratories, West Point, PA 19456, USA. Mark_Kramer@merck.com
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.
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E Wyatt-Knowles, and
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