Ketamine-50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms

Abstract

Over the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine's effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine's complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine's rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine's action.

Keywords: Anesthesia; Depression; Dose; Ketamine; Rapid-acting antidepressant; Subanesthetic.

Fig. 1

Ketamine acts as a non-competitive blocker N-methyl-d-aspartate receptor (NMDAR) ion channels. Racemic ketamine contains two optical stereoisomers: S( +) and R(−)-ketamine. Both isomers act as non-competitive blockers, sharing the ability to enter NMDAR ion channels and to exhibit a trapping block. S-ketamine is often preferred in clinical anesthesia because it has a higher affinity for NMDARs than R-ketamine

Fig. 2

Some of the current and emerging clinical uses of ketamine along with examples of commonly used doses. Clinical applications not yet commonly adopted are followed by an asterix

Fig. 3

An overview of some of the proposed molecular mechanisms underlying ketamine’s rapid antidepressant action. a The disinhibition hypothesis. Ketamine preferentially blocks N-methyl-d-aspartate receptors (NMDARs) on gamma-aminobutyric acid (GABA)-ergic inhibitory interneurons, leading to a decrease in the inhibitory tone exerted on excitatory pyramidal neurons. Increased glutamate release acts on postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) and induces cellular effects such as the release of brain-derived neurotrophic factor (BDNF) and activation of its receptor tropomyosin receptor kinase B (TrkB) and the regulation of downstream pathways important for synaptic plasticity and protein synthesis. Downstream effects include activation of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) and regulation of AMPAR dynamics and scaffolding proteins such as postsynaptic density protein 95 (PSD95). b Hydroxynorketamine metabolites may modulate postsynaptic AMPAR signaling, leading to various downstream effects. c Inhibition of glycogen synthase kinase 3 β (GSK3β) by ketamine reduces phosphorylation of PSD95, which augments AMPAR signaling by reducing the internalization of AMPAR subunits, among other effects. d Ketamine may also block extrasynaptic NMDARs, normally tonically activated by glutamate, and induce mTOR activity. e The blockade of spontaneous NMDAR-mediated neurotransmission can have effects that lead to the disinhibition of BDNF translation via eukaryotic elongation factor 2 (eEF2)-dependent mechanisms

Fig. 4

Emerging hypotheses of ketamine’s action. a The metabolism of ketamine to its hydroxynorketamine metabolites, and particularly (2R,6R)-hydroxynorketamine, is responsible for mediating the rapid antidepressant effects. b Ketamine disrupts neuronal homeostasis, which triggers self-correcting mechanisms. c Ketamine regulates both circadian and homeostatic processes of sleep to elicit antidepressant effects. d The hypothesis of encoding, consolidation and renormalization in depression (ENCORE-D) proposes that ketamine alters neural encoding of information, the consolidation of synaptic change, and the renormalization of synaptic strength during sleep to elicit acute and sustained antidepressant effects