Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies

Pham, Thu Ha; Gardier, Alain M.

doi:10.1016/j.pharmthera.2019.02.017

Cited by 129 publications

(67 citation statements)

References 378 publications

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“…and stimulation of mammalian target of rapamycin (mTOR) modifies the number and function of synaptic connections [38]. However, ketamine's mechanism of action is more complex and includes also non-glutamatergic actions such as interactions with the monoaminergic system [39], potentiation of the inhibitory effects of GABA [40], and interactions with ion channels [41][42][43]. Ketamine has also antagonistic effect on cholinergic neurons [44].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

Kryst

Kawalec

Mitoraj³

et al. 2020

Pharmacol. Rep

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Background Due to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains. Methods Electronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed. Results A total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = − 0.89; 95% CI − 1.24; − 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2-3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = − 0.70; 95% CI − 1.15; − 0.25 or SMD = − 0.81; 95% CI − 1.41; − 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo. Conclusions Our meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.

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Section: Discussionmentioning

confidence: 99%

Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

Kryst

Kawalec

Mitoraj³

et al. 2020

Pharmacol. Rep

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“…NMDAR antagonist, displays fast antidepressant activity in both rodent models of anxiety/depression and in depressed patients. 28,65,66 We also found that genes associated with glutamate synaptic transmission were downregulated in the midbrain of FGR mice. VTA glutamate neurons generally project to NAc and lateral habenular nucleus (LHb).…”

mentioning

confidence: 63%

“…The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR) is a glutamate receptor and ion channel protein found in neurons including dopamine neurons, GABA neurons, and glutamate neurons. 27,28 Two ligands, NMDA and glycine, bind to NMDAR and activate the NMDAR-related signaling pathway. 29 NMDA receptors have been strongly implicated in excitotoxicity, and NMDAR-induced excitotoxicity is believed to contribute to the cell death associated with certain neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Fetal growth restriction mice are more likely to exhibit depression‐like behaviors due to stress‐induced loss of dopaminergic neurons in the VTA

Tian

Sun

et al. 2020

FASEB j.

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Fetal growth restriction (FGR) is a severe perinatal complication that can increase risk for mental illness. To investigate the mechanism by which FGR mice develop mental illness in adulthood, we established the FGR mouse model and the FGR mice did not display obvious depression‐like behaviors, but after environmental stress exposure, FGR mice were more likely to exhibit depression‐like behaviors than control mice. Moreover, FGR mice had significantly fewer dopaminergic neurons in the ventral tegmental area but no difference in serotoninergic neurons in the dorsal raphe. RNA‐seq analysis showed that the downregulated genes in the midbrain of FGR mice were associated with many mental diseases and were especially involved in the regulation of NMDA‐selective glutamate receptor (NMDAR) activity. Furthermore, the NMDAR antagonist memantine can relieve the stress‐induced depression‐like behaviors of FGR mice. In summary, our findings provide a theoretical basis for future research and treatment of FGR‐related depression.

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“…Recently (March 2019) a nasal preparation of the (S)-enantiomer (esketamine) received FDA approval after successful phase 3 trials. Moreover, new approaches for fast-onset and effective antidepressants via modulation of the glutamatergic-NMDA system are now subject of intense research efforts [6,36]. One may expect a new range of novel antidepressants with as main attribute a fast onset of action.…”

Section: Slow Onset Of Actionmentioning

confidence: 99%

Introductory Chapter: Antidepressants - Preclinical, Clinical and Translational Aspects

Olivier¹

2019

Antidepressants - Preclinical, Clinical and Translational Aspects

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Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies

Cited by 129 publications

References 378 publications

Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

Fetal growth restriction mice are more likely to exhibit depression‐like behaviors due to stress‐induced loss of dopaminergic neurons in the VTA

Introductory Chapter: Antidepressants - Preclinical, Clinical and Translational Aspects

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