Ketamine and the next generation of antidepressants with a rapid onset of action

Abstract

Existing treatments for major depressive disorder (MDD) usually take weeks to months to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement even after months of treatment. In addition, increased risk of suicide attempts is a major public health concern during the first month of standard antidepressant therapy. Thus, improved therapeutics that can exert their antidepressant effects within hours or a few days of their administration are urgently needed, as is a better understanding of the presumed mechanisms associated with these rapid antidepressant effects. In this context, the N-methyl-D-aspartate (NMDA) antagonist ketamine has consistently shown antidepressant effects within a few hours of its administration. This makes it a valuable research tool to identify biomarkers of response in order to develop the next generation of fast-acting antidepressants. In this review, we describe clinical, electrophysiological, biochemical, and imaging correlates as relevant targets in the study of the antidepressant response associated with ketamine, and their implications for the development of novel, fast-acting antidepressants. We also review evidence that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA throughput may represent a convergent mechanism for the rapid antidepressant actions of ketamine. Overall, understanding the molecular basis of this work will likely lead to the ultimate development of improved therapeutics for MDD.

Figure 1. Potential targets for ketamine and similar agents induce rapid and sustained antidepressant effects

Glutamate is packaged into presynaptic vesicles by the vesicular glutamate transporters (VGLUTs), which critically modulate glutamate concentration in the synaptic vesicles and its consequent release in the synaptic cleft. Also, presynaptic group II mGluR modulation controls glutamate accumulation in the synaptic vesicles. Glutamate clearance from the extracellular space occurs through the high-affinity EAATs presented in the glia and presynaptic neuron. The EAATs play a key role in maintaining adequate neuronal function by reducing potentially toxic extracellular glutamate levels. Notably, ketamine’s rapid antidepressant effects have been shown to be modulated by AMPA relative to NMDA throughput. Excessive glutamate also stimulates the extrasynaptic NMDA receptors, which antagonizes the activation of neurotrophic cascades. The potential sustained (sub-acute) antidepressant effects of ketamine are hypothesized to be mediated by increases in CREB and BDNF expression, as well as the anti-apoptotic protein Bcl-2. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid); NMDA (N-methyl-D-aspartate); VGLUTs (vesicular Glu transporters); metabotropic Glu receptors (mGluRs); EAAT (excitatory amino-acid transporters); BDNF (brain-derived neurotrophic factor); CREB (cAMP response element binding); B-cell lymphoma 2 (Bcl-2)