The article you requested is
Clinical Experience With Substance P Receptor (NK1) Antagonists in Depression
J Clin Psychiatry 2002;63(suppl 11):25-29
© Copyright 2015 Physicians Postgraduate Press, Inc.
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Substance P (SP) belongs to the neurokinin (NK) family of neuropeptides and exerts its biological
effects via interaction with the NK1 receptor. The SP-NK1 receptor system is one of the best-characterized neurotransmitter pathways in both the central and peripheral nervous systems. It has been
postulated that this pathway may have important roles in a variety of centrally regulated pathophysiologic
conditions, including depression. In animal models, central injection of SP was associated with
a series of anxiety-like behaviors, and this response could be abolished by pretreatment with SP (NK1)
receptor antagonists (SPAs). On the basis of these and other encouraging preclinical results, several
clinical trials have examined the potential of SPAs in the treatment of depression. In phase 2 trials,
therapy with the SPAs aprepitant (MK-0869) and compound A resulted in improvements in depression
and anxiety symptoms that were quantitatively comparable with those seen with selective serotonin
reuptake inhibitors (SSRIs) and significantly greater than those seen with placebo. These positive results
have established a proof of concept that the inhibition of the SP-NK1 receptor pathway may be a
potentially useful novel treatment option for management of patients with depression. The apparent
lack of benefit with SPAs versus placebo in subsequent dose-finding studies with aprepitant and compound
A is not surprising, considering the fact that the outcomes with an active control (SSRI) in these
trials were also similar to those observed with placebo. Future trials with SPAs will focus on the identification
of appropriate patients and drug regimens and will also define the role of these agents in the
treatment of depression.