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dc.contributor.authorMoaddel, Ruin
dc.contributor.authorZanos, Panos
dc.contributor.authorFarmer, Cristan A
dc.contributor.authorKadriu, Bashkim
dc.contributor.authorMorris, Patrick J
dc.contributor.authorLovett, Jacqueline
dc.contributor.authorAcevedo-Diaz, Elia E
dc.contributor.authorCavanaugh, Grace W
dc.contributor.authorYuan, Peixiong
dc.contributor.authorYavi, Mani
dc.contributor.authorThomas, Craig J
dc.contributor.authorPark, Lawrence T
dc.contributor.authorFerrucci, Luigi
dc.contributor.authorGould, Todd D
dc.contributor.authorZarate, Carlos A
dc.date.accessioned2022-05-06T12:17:32Z
dc.date.available2022-05-06T12:17:32Z
dc.date.issued2022-05-02
dc.identifier.urihttp://hdl.handle.net/10713/18770
dc.description.abstractSubanesthetic-dose racemic (R,S)-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine's mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). A parallel targeted metabolomic analysis in plasma, hippocampus, and hypothalamus was carried out in mice receiving either 10 mg/kg of ketamine, 10 mg/kg of (2 R,6 R)-HNK, or saline. Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine's effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat.en_US
dc.description.urihttps://doi.org/10.1038/s41398-022-01941-xen_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofTranslational Psychiatryen_US
dc.rights© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.en_US
dc.titleComparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration.en_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41398-022-01941-x
dc.identifier.pmid35501309
dc.source.journaltitleTranslational psychiatry
dc.source.volume12
dc.source.issue1
dc.source.beginpage179
dc.source.endpage
dc.source.countryUnited States


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