Clinical Experience With Substance P Receptor (NK1) Antagonists in Depression

Substance P (SP) belongs to the neurokinin (NK) family of neuropeptides and exerts its biologicaleffects 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 beenpostulated that this pathway may have important roles in a variety of centrally regulated pathophysiologicconditions, including depression. In animal models, central injection of SP was associated witha 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, severalclinical 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 depressionand anxiety symptoms that were quantitatively comparable with those seen with selective serotoninreuptake inhibitors (SSRIs) and significantly greater than those seen with placebo. These positive resultshave established a proof of concept that the inhibition of the SP-NK₁ receptor pathway may be apotentially useful novel treatment option for management of patients with depression. The apparentlack of benefit with SPAs versus placebo in subsequent dose-finding studies with aprepitant and compoundA is not surprising, considering the fact that the outcomes with an active control (SSRI) in thesetrials were also similar to those observed with placebo. Future trials with SPAs will focus on the identificationof appropriate patients and drug regimens and will also define the role of these agents in thetreatment of depression.