Ketamine in neuropsychiatric disorders: an update

Abstract

The discovery of ketamine as a rapid-acting antidepressant led to a new era in the development of neuropsychiatric therapeutics, one characterized by an antidepressant response that occurred within hours or days rather than weeks or months. Considerable clinical research supports the use of-or further research with-subanesthetic-dose ketamine and its (S)-enantiomer esketamine in multiple neuropsychiatric disorders including depression, bipolar disorder, anxiety spectrum disorders, substance use disorders, and eating disorders, as well as for the management of chronic pain. In addition, ketamine often effectively targets symptom domains associated with multiple disorders, such as anxiety, anhedonia, and suicidal ideation. This manuscript: 1) reviews the literature on the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; 2) describes similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; 3) discusses the day-to-day use of ketamine in the clinical setting; 4) provides an overview of ketamine use in other psychiatric disorders and depression-related comorbidities (e.g., suicidal ideation); and 5) provides insights into the mechanisms of ketamine and therapeutic response gleaned from the study of other novel therapeutics and neuroimaging modalities.

Fig. 1. Current hypothesized mechanisms of ketamine.

Ketamine’s rapid-acting antidepressant-like actions appear to be mediated primarily through NMDAR antagonism and AMPAR activity. Blockade of NMDARs by racemic ketamine and esketamine on GABAergic interneurons decreases the inhibition of pyramidal neurons, leading to increased glutamate release. This increased probability of glutamate release activates downstream mechanisms that activate mTORC1 signaling, leading to upregulation of synaptic density, PSD-95, and GluA1-containing AMPAR surface insertion. In addition, blockade of extrasynaptic NMDARs dephosphorylates eEF2, leading to increased BDNF translation and mTORC1 activity. Ketamine has also been hypothesized to bind to mu-opioid receptors, though the exact downstream mechanisms are unknown. Lastly, ketamine can block LHb bursting activity through NMDAR antagnosim on LHb neurons. Overall, these changes lead to improved E/I balance between glutamate and GABA in order to elicit therapeutic effects. Abbreviations: AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, BDNF brain-derived neurotrophic factor, eEF2 eukaryotic elongation factor, E/I Excitatory/inhibitory, GABA γ-aminobutyric acid, GAD glutamate decarboxylase, Glu glutamate, HNK hydroxynorketamine, LHb lateral habenula, mGluR metabotropic glutamate receptor, mRNA messenger ribonucleic acid, mTORC1 mechanistic target of rapamycin complex 1, NMDAR N-methyl-D-aspartate receptor, PSD-95 post-synaptic density 95, TrkB tropomyosin receptor kinase B. Adapted with permission from [170].