Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial

Bevilacqua, Laura; Charney, Alex; Pierce, Charlotte R; Richards, Samantha; Jha, Manish K.; Glasgow, Andrew M; Brallier, Jess W.; Kirkwood, Katherine; Bagiella, Emilia; Charney, Dennis S.; Murrough, James W.

doi:10.1177/0269881120985147

Cited by 2 publications

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“…Although, the signaling molecule NO has also been thought to play a role in inflammation as well as in ketamine’s antidepressant effects [ 35 , 62 ], a recent study suggested that the NO pathway may not play a primary role in these effects [ 63 ]. Multiple factors affect NO levels, including arginase activity, amino acid levels, NOS activity, and the presence of specific endogenous NOS inhibitors, such as ADMA and/or SDMA [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration

et al. 2022

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Subanesthetic-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.

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Section: Discussionmentioning

confidence: 99%

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration

et al. 2022

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Ketamine: Mechanisms and Relevance to Treatment of Depression

Kim,

Suzuki,

Kavalali

et al. 2024

Annu. Rev. Med.

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Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine. Expected final online publication date for the Annual Review of Medicine, Volume 75 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial

Cited by 2 publications

References 11 publications

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration

Ketamine: Mechanisms and Relevance to Treatment of Depression

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