Distinct mechanism for antidepressant activity by blockade of central substance P receptors.
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.
Kramer
M S
MS
Merck Research Laboratories, West Point, PA 19456, USA. Mark_Kramer@merck.com
Cutler
N
N
Feighner
J
J
Shrivastava
R
R
Carman
J
J
Sramek
J J
JJ
Reines
S A
SA
Liu
G
G
Snavely
D
D
Wyatt-Knowles
E
E
Hale
J J
JJ
Mills
S G
SG
MacCoss
M
M
Swain
C J
CJ
Harrison
T
T
Hill
R G
RG
Hefti
F
F
Scolnick
E M
EM
Cascieri
M A
MA
Chicchi
G G
GG
Sadowski
S
S
Williams
A R
AR
Hewson
L
L
Smith
D
D
Carlson
E J
EJ
Hargreaves
R J
RJ
Rupniak
N M
NM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000077608:Aprepitant; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000502:physiology; D017374:Paroxetine / Q000627:therapeutic use; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012701:Serotonin / Q000502:physiology; D013315:Stress, Psychological / Q000188:drug therapy; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014828:Vocalization, Animal / Q000187:drug effects
D018687:Antidepressive Agents, Second-Generation; C114226:L 760735; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D012701:Serotonin; D013373:Substance P; D017374:Paroxetine; D009638:Norepinephrine