Lack of Efficacy of the Substance P (Neurokinin1 Receptor) Antagonist Aprepitant in the Treatment of Major Depressive Disorder

Keller, Martin B.; Montgomery, Stuart; Ball, William A.; Morrison, Mary F.; Snavely, Duane; Liu, Guanghan; Hargreaves, Richard; Hietala, Jarmo; Lines, Christopher; Beebe, Katherine; Reines, Scott A.

doi:10.1016/j.biopsych.2005.07.013

Cited by 279 publications

(194 citation statements)

References 18 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…The SP antagonist MK-869 had significant antidepressant effects (39), supporting the concept that SP and its receptor (neurokinin-1R) are involved in the pathophysiology of depression (40), although MK-869 failed to demonstrate antidepressant effects in a subsequent trial (41). However, a different SP antagonist, L-759274, did demonstrate significant antidepressant effects (42).…”

mentioning

confidence: 74%

Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Evans

Lynch

Benton

et al. 2008

Biological Psychiatry

View full text Add to dashboard Cite

Background-Natural killer (NK) cells play an important role in innate immunity and are involved in the host defense against human immunodeficiency virus (HIV) infection. This study examines the potential role of three underlying regulatory systems that have been under investigation in central nervous system research as well as immune and viral research: serotonin, neurokinin, and glucocorticoid systems.

show abstract

mentioning

confidence: 74%

Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Evans

Lynch

Benton

et al. 2008

Biological Psychiatry

View full text Add to dashboard Cite

show abstract

“…Confirmation of this proposal was obtained by clinical findings that selective NK1R antagonists have antidepressant as well as anxiolytic efficacy in patients with major depressive disorder and with moderately high anxiety levels (Kramer et al, 1998(Kramer et al, , 2004Furmark et al, 2005). However, since some conflicting results have been obtained more recently (Keller et al, 2005), additional studies are necessary to better understand the precise mechanisms mediating such effects.…”

Section: Introductionmentioning

confidence: 86%

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Ebner

Singewald

Whittle

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Antagonists of the substance P (SP) preferring neurokinin 1 receptor (NK1R) represent a promising novel class of drugs for the treatment of stress-related disorders such as depression and anxiety disorders; however, the involved neuronal pathways releasing SP in response to stressors are ill defined. By using in vivo microdialysis in combination with a highly sensitive and selective radioimmunoassay we found that exposure to forced swim stress increased SP release in the rat lateral septum (LS), a key area in processing emotions and stress responses. Acute administration of the selective NK1R antagonist L-822429 injected either systemically or locally into the LS reduced passive and facilitated active stress-coping strategies in the forced swim test. This effect seems to be mediated by enhanced intraseptal serotonergic transmission via serotonin (5-HT)1A receptors since NK1R blockade reversed the swim stress-induced decrease to an increase in extracellular 5-HT efflux, and furthermore the behavioral effects of L-822429 were blocked by intraseptal 5-HT1A receptor antagonism. A direct heterosynaptic regulation by NK1R on 5-HT release from serotonergic fibers was ruled out by immunocytochemistry at the light and electron microscopic level indicating involvement of GABAergic interneuron(s) in this interaction. Taken together, our data identify the LS as a critical brain area for the involvement of SP transmission in the modulation of stress responses and demonstrate that NK1R blockade can elicit a functionally significant facilitatory effect on 5-HT transmission, which does not necessarily involve the previously proposed interaction with neuronal firing at the cell body level of raphe neurons.

show abstract

“…18 F]SPA-RQ shows with a K d of 67 pM an affinity to the NK1-receptor comparable with that of aprepitant and additionally a log P of 1.8 confirming a moderate brain penetrance [220]- [222]. It shows the highest binding in striatum, followed by amygdala, and parietal and occipital cortex [223].…”

Section: Non-peptide Neurokinin Receptor Ligandsmentioning

confidence: 81%

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

Pissarek¹

2014

WJNS

View full text Add to dashboard Cite

show abstract

Lack of Efficacy of the Substance P (Neurokinin1 Receptor) Antagonist Aprepitant in the Treatment of Major Depressive Disorder

Cited by 279 publications

References 18 publications

Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Selective Serotonin Reuptake Inhibitor and Substance P Antagonist Enhancement of Natural Killer Cell Innate Immunity in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

Contact Info

Product

Resources

About