Abstract
Recently, ketamine has been demonstrated to exert rapid-acting antidepressant effects in patients with depression, including those with treatment-resistant depression, and this discovery has been regarded as the most significant advance in drug development for the treatment of depression in over 50 years. To overcome unwanted side effects of ketamine, numerous approaches targeting glutamatergic systems have been vigorously investigated. For example, among agents targeting the NMDA receptor, the efficacies of selective GluN2B receptor antagonists and a low-trapping antagonist, as well as glycine site modulators such as GLYX-13 and sarcosine have been demonstrated clinically. Moreover, agents acting on metabotropic glutamate receptors, such as mGlu2/3 and mGlu5 receptors, have been proposed as useful approaches to mimicking the antidepressant effects of ketamine. Neural and synaptic mechanisms mediated through the antidepressant effects of ketamine have been being delineated, most of which indicate that ketamine improves abnormalities in synaptic transmission and connectivity observed in depressive states via the AMPA receptor and brain-derived neurotrophic factor-dependent mechanisms. Interestingly, some of the above agents may share some neural and synaptic mechanisms with ketamine. These studies should provide important insights for the development of superior pharmacotherapies for depression with more potent and faster onsets of actions.
Highlights
Recent evidence clearly indicates that targeting glutamatergic transmission is an effective and useful approach to treating depression, as represented by recent ground-breaking clinical findings for the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine
Based on findings from these research activities, agents acting on both NMDA receptors and metabotropic glutamate receptors have been proposed as alternatives, and the efficacies of some of these agents have been tested in clinical studies, with both encouraging and discouraging outcomes [8,9,10,11,12]
Mechanisms other than NMDA receptor blockade may be involved in the antidepressant effects of ketamine, as mentioned above, NMDA receptor blockade has been considered to be the major mechanism by which ketamine acts, and some approaches with different effects on the NMDA receptor have been investigated to avoid the adverse effects of ketamine
Summary
Recent evidence clearly indicates that targeting glutamatergic transmission is an effective and useful approach to treating depression, as represented by recent ground-breaking clinical findings for the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Based on findings from these research activities, agents acting on both NMDA receptors and metabotropic glutamate (mGlu) receptors have been proposed as alternatives, and the efficacies of some of these agents have been tested in clinical studies, with both encouraging and discouraging outcomes [8,9,10,11,12]. First, after a brief description of the clinical outcomes of ketamine, the mechanisms underlying the antidepressant effects of ketamine that have been proposed to date will be discussed on both a molecular and a synaptic basis. The potential of possible alternatives, including agents acting on either NMDA receptors or mGlu receptors, will be discussed in the context of clinical evidence as well as their similarities to the efficacy and mechanisms of ketamine. Questions that remain to be solved so as to develop better pharmacotherapies from ketamine research will be raised
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