Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics

Abstract

Ketamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent antidepressant effects of ketamine in treatment-resistant depression. Moreover, preclinical and biomarker studies have begun to elucidate the mechanism underlying the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets. This article discusses the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants.

Keywords: BDNF; biomarker; depression; mTOR; synaptic plasticity.

Figure 1

A schematic representation of the proposed neurobiological model of depression. In this model, prolonged stress and depression alter prefrontal glutamate release and reduce glutamate uptake, leading to increased extracellular glutamate and excitotoxicity. High levels of extracellular glutamate precipitate neuronal atrophy through dendritic retraction, reduced dendritic arborization, decreased spine density, and reduced synaptic strength. An example of the effect of prolonged stress on dendritic arborization and length in rats is shown on the right.

Figure 2

Prefrontal synaptic connectivity during normal mood, depression, and after remission of depression. In euthymic individuals, stimulus and circuit activities maintain and regulate synaptic strength. Following prolonged stress and depression, an overall synaptic dysconnectivity is observed along with significant reduction in glutamate neurotransmission, excitatory amino acids transporters (EAATs), BDNF expression and release, and mTORC1 signaling. Ketamine’s rapid restoration of prefrontal synaptic connectivity is believed to result from the following consecutive events. (1) Blockade of NMDA receptors located on inhibitory GABAergic interneurons, leading to a stimulus-independent widespread prefrontal glutamate surge. (2) Activation of AMPA receptors combined with blockade of extrasynaptic NMDA receptors. (3) Increased BDNF release and activation of mTORC1 signaling, which in turn increases protein synthesis and AMPA cycling. Abbreviations: ⦿, activate; ∅, block; , decrease; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; GABA, γ-aminobutyric acid; mTORC1, mammalian target of rapamycin complex 1.