Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review

  title={Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review},
  author={Patricio Molero and Josep Antoni Ramos-Quiroga and Roc{\'i}o Mart{\'i}n-Santos and Eva Calvo-S{\'a}nchez and Luis Guti{\'e}rrez-Rojas and J. Javier Meana},
  journal={CNS Drugs},
Ketamine and its enantiomer S-ketamine (esketamine) are promising candidates to produce a rapid-onset antidepressant effect in treatment-resistant depression. Ketamine causes continued blockade of the glutamate N-methyl-d-aspartate (NMDA) receptor, though this might not primarily mediate the antidepressant effect. Alternative hypotheses include selectivity for the NMDA receptor subtype containing the NMDA receptor subunit 2B (NR2B), inhibition of the phosphorylation of the eukaryotic elongation… 
Antidepressant Actions of Ketamine and Its Two Enantiomers
Recent findings on the antidepressant actions of two enantiomers of ketamine are discussed, including (R,S), which has been reported to have a greater potency and longer-lasting antidepressant effects than (S)-ketamine in rodent models of depression.
Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers
An overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers for predicting response to and/or monitoring of therapeutic outcome with ketamine is provided.
Repurposing Potential of Ketamine: Opportunities and Challenges
This review discusses repurposing ketamine for potential therapeutic use and about the safety concerns related to ketamine and esketamine.
Rapid-Acting Antidepressants.
The preclinical and clinical literature strongly suggests that rapid-acting antidepressants are the current focus of antidepressant drug discovery, and promising clinical findings exist for several compounds including ketamine and other NMDA receptor antagonists, scopolamine, and psilocybin.
Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action
Coadministration of ketamine for MDD with other psychotropic agents, for example benzodiazepines, may attenuate antidepressant effects and limited evidence exists for these effects and should be evaluated on a case-by-case basis.
Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments
Ketamine and other potentially novel glutamate-based treatments for treatment-resistant depression are reviewed, including N-methyl-D-aspartate receptor antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators.
Rapid-acting antidepressants.
A Randomized Trial of the N-methyl-d-aspartate Receptor Glycine Site Antagonist Prodrug 4-chlorokynurenine in Treatment-Resistant Depression.
In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied, with generally minimal associated adverse events.
Discovery of Novel and Potent N-Methyl-d-aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models.
A series of furan-2-carboxamide analogues are reported as novel NMDAR-positive allosteric modulators (PAMs) and provided potential opportunities for discovering of new antidepressants.


Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds.
Clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3).
Mechanisms of ketamine action as an antidepressant
Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects
In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamines (esketamine), and findings suggest that, unlike S- ketamine, R -ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3.
Convergent Mechanisms Underlying Rapid Antidepressant Action
Proposed mechanisms of the antidepressant action of ketamine include N-methyl-d-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites.
NMDAR inhibition-independent antidepressant actions of ketamine metabolites
It is shown that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice.
Ketamine for Treatment-Resistant Unipolar Depression
The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression.
Mechanistic Target of Rapamycin–Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model
ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression
The evidence and proposed therapeutic mechanisms for both NMDAR antagonists and agonists are critically reviewed, and several theories on how both activation and inhibition of N MDARs appear to have antidepressant effects are collated.
Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial.
This pilot study showed that a sub-anaesthetic dose of i.v. ketamine is well-tolerated in TRD, and may have rapid and sustained antidepressant properties, and riluzole did not prevent relapse in the first month following ketamine.
Reply to: Antidepressant Actions of Ketamine Versus Hydroxynorketamine