Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond

Abstract

Traditional antidepressants require many weeks to reveal their therapeutic effects. However, the widely replicated observation that a single subanesthetic dose of the N-methyl-D-aspartate glutamate receptor antagonist ketamine produced meaningful clinical improvement within hours, suggested that rapid-acting antidepressants might be possible. The ketamine studies stimulated a new generation of basic antidepressant research that identified new neural signaling mechanisms in antidepressant response and provided a conceptual framework linking a group of novel antidepressant mechanisms. This article presents the path that led to the testing of ketamine, considers its promise as an antidepressant, and reviews novel treatment mechanisms that are emerging from this line of research.

Published by Elsevier Inc.

Figures

Figure 1

The effects of ketamine 0.5 mg/kg, i.v. and a saline placebo in patients with major depression (n=7). In this figure, the antidepressant effects of ketamine emerge after the psychotigenic and euphoric effects of ketamine abate. The top figure presents the reduction in Hamilton Depression Scale (HDRS) scores in patients administered ketamine, but not placebo. The middle figure presents the production of euphoria, as measured by a visual analog scale of “high”, following ketamine, but not saline. The bottom figure presents the production of psychosis, as measured by the Brief Psychiatric Rating Scale (BPRS) positive symptom subscale. The repeated measures ANOVA performed on each of these outcomes revealed highly significant ketamine by time interaction effects (p<.005 this figure is adapted from berman>et al. (32).

Figure 2

A summary of the antidepressant effects of ketamine from seven published studies (5 in unipolar major depression and 2 in bipolar depression*). The response rates are both impressive and consistent across studies. The data are collected from a total of 130 patients. This figure is adapted from aan het Rot et al. (36).

Figure 3

A figure illustrating a link between the neurobiology of depression and the mechanisms through which ketamine produces its antidepressant effects. A. Two consequences of glial deficits or dysfunction on glutamate neurotransmission are illustrated. It is hypothesized that glial loss elevates glutamate levels (blue circles) in the extracellular space. On the left side, this figure depicts how glutamate overflow may stimulate inhibitory presynaptic mGluR2 receptors, located at the periphery of these glutamate synapses. Through this mechanism, glial loss may depress glutamate neurotransmission, compromising functional connectivity. The right side of this figure shows elevated extracellular glutamate causing overstimulation of extrasynaptic NMDA receptors, particularly those containing the GluN2B subunit. Through this mechanism, glial loss may activate a signaling cascade responsible for loss of dendritic spines and dendritic regression, contributing to impaired functional connectivity. B. Ketamine is thought to produce its antidepressant effects by disinhibiting the release of glutamate by the presynaptic neuron, increasing the stimulation of the “go” pathway, i.e., postsynaptic AMPA receptors and signaling via the Akt/mTOR pathway (87). In addition, it blocks extrasynaptic NMDA receptors, reducing signaling via ElF2, which suppresses BDNF levels (103). Although other ketamine effects may contribute in important ways to its antidepressant effects, these converging effects of ketamine may contribute to its capacity to rapidly increase the number of dendritic spines and to restore aspects of functional connectivity.

Figure 3

A figure illustrating a link between the neurobiology of depression and the mechanisms through which ketamine produces its antidepressant effects. A. Two consequences of glial deficits or dysfunction on glutamate neurotransmission are illustrated. It is hypothesized that glial loss elevates glutamate levels (blue circles) in the extracellular space. On the left side, this figure depicts how glutamate overflow may stimulate inhibitory presynaptic mGluR2 receptors, located at the periphery of these glutamate synapses. Through this mechanism, glial loss may depress glutamate neurotransmission, compromising functional connectivity. The right side of this figure shows elevated extracellular glutamate causing overstimulation of extrasynaptic NMDA receptors, particularly those containing the GluN2B subunit. Through this mechanism, glial loss may activate a signaling cascade responsible for loss of dendritic spines and dendritic regression, contributing to impaired functional connectivity. B. Ketamine is thought to produce its antidepressant effects by disinhibiting the release of glutamate by the presynaptic neuron, increasing the stimulation of the “go” pathway, i.e., postsynaptic AMPA receptors and signaling via the Akt/mTOR pathway (87). In addition, it blocks extrasynaptic NMDA receptors, reducing signaling via ElF2, which suppresses BDNF levels (103). Although other ketamine effects may contribute in important ways to its antidepressant effects, these converging effects of ketamine may contribute to its capacity to rapidly increase the number of dendritic spines and to restore aspects of functional connectivity.

Figure 4

This figure depicts the impact of a Val66Met polymorphism in the BDNF gene on the effects of ketamine upon dendritic spine growth in rodents (figure A) and on improvement in depression (Hamilton Depression Scale Score: HamD Score). A. The left slide of this figure presents the results of two-photon microscopy of labeled layer 5 pyramidal neurons in slices from the prefrontal cortex. A robust proliferation of large and long dendritic spines is observed following ketamine administration in Wild Type (WT) animals. However, mice that have had the Met allele inserted into the BDNF gene (Met/Met), rendering that gene less effective, show 1) reduced dendritic spine density compared with the WT animals at baseline, and 2) markedly blunted increases in dendritic spine density following administration. *:p