Rapid antidepressant effects: moving right along

Abstract

Available treatments for depression have significant limitations, including low response rates and substantial lag times for response. Reports of rapid antidepressant effects of a number of compounds, including the glutamate N-methyl-D-aspartate receptor antagonist ketamine, have spurred renewed translational neuroscience efforts aimed at elucidating the molecular and cellular mechanisms of action that result in rapid therapeutic response. This perspective provides an overview of recent advances utilizing compounds with rapid-acting antidepressant effects, discusses potential mechanism of action and provides a framework for future research directions aimed at developing safe, efficacious antidepressants that achieve satisfactory remission not only by working rapidly but also by providing a sustained response.

Figure 1

Potential cellular and molecular mechanisms underlying the rapid-acting antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) blockade. (1) Pharmacological blockade of the NMDA receptor. Various agents with pharmacological properties leading to NMDAR antagonism have been demonstrated as having rapid antidepressant effects. The NMDAR is an ionotropic glutamate receptor that is both ligand and voltage dependent and is non-selective to cations. The flux of calcium through the NMDAR has been demonstrated as having a crucial role in synaptic plasticity. (2) Changes in glutamatergic transmission. Changes in neurotransmission downstream of NMDAR blockade are thought to contribute to changes in synaptic potentiation and efficacy that are implicated in the antidepressant effects of NMDAR blockade. The ‘disinhibition’ hypothesis has suggested that blocking the tonic NMDAR-induced firing of GABAergic (gamma-amino-butyric acid) interneurons leads to general disinhibition of glutamatergic pyramidal cells, and a subsequent increase in excitation and synaptic efficacy. The increased glutamate release from pyramidal cells is hypothesized to contribute to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activation and activity-dependent release of brain-derived neurotrophic factor (BDNF).^,, Another theory posits that administration of NMDAR antagonists leads to blockade of NMDAR activation normally triggered by spontaneous neurotransmission. The selective suppression of this form of NMDAR activation by spontaneous release of glutamate is hypothesized to contribute to inability to activate eukaryotic elongation factor 2 (eEF2) kinase, which subsequently results in attenuation of eEF2 phosphorylation and de-repression of BDNF translation^, (depicted in (3)). (3) Dendritic spine remodeling/synthesis. Structural remodeling at the synapse is implicated downstream of the changes in glutamatergic transmission and induction of local, dendritic protein synthesis. The upstream changes in glutamatergic signaling due to disinhibition of GABAergic interneurons and inhibitory tone are thought to contribute to activation of the mammalian target of rapamycin (mTOR) signaling pathway, which is important in controlling the translational machinery. In this scenario, NMDAR blockade activates signaling via the mTOR pathway, contributing to an increase in local dendritic translation of proteins important in dendritic spine synthesis and synaptic remodeling, including structural components at the synapse and the neurotrophin BDNF. (4) BDNF secretion and TrkB activation. Secretion of BDNF leads to signaling through its cognate receptor TrkB; signaling cascades downstream of TrkB activation are implicated in dendrite complexity, spine synthesis and remodeling, synaptogenesis and various forms of synaptic plasticity. TrkB-mTOR signaling also contributes to feed-forward stimulation of synaptogenesis by increasing synaptic protein synthesis, including that of BDNF.^, (5) BDNF trafficking. The BDNF Val66Met polymorphism impacts trafficking of BDNF and its subsequent secretion. Specifically, the Met allele impairs transport of both BDNF mRNA transcripts as well as BDNF protein, contributing to a decrease in activity-dependent BDNF secretion.^– (6) Mood-related circuitry and rapid antidepressant effects. Alterations in synaptic plasticity and synaptogenesis may converge to increase synchronization and strength of key, mood-related circuits in the cortico-limbic system. Targeting these key connections is thought to underlie the ability to effect rapid and sustained antidepressant efficacy.