Elsevier

Biological Psychiatry

Volume 73, Issue 12, 15 June 2013, Pages 1133-1141
Biological Psychiatry

Review
Rapid-Acting Glutamatergic Antidepressants: The Path to Ketamine and Beyond

https://doi.org/10.1016/j.biopsych.2013.03.026Get rights and content

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.

Section snippets

N-Methyl-D-Aspartate Receptor Antagonists as Rapid-Acting Antidepressants

The testing of glutamatergic drugs for the treatment of depression has a surprisingly long history. In 1959, Dr. George Crane reported on the effects of a tuberculosis antibiotic that was known to cause seizures and exacerbate psychosis, D-cycloserine. In his first case series, he found that D-cycloserine produced mood improvement in 30 of 37 tuberculosis patients suffering from depression, predominately within 2 weeks (10). When he replicated these findings in another case series, he

Glutamate and the Neurobiology of Depression

Glutamatergic neurotransmission emerged over a decade ago as an extremely important area for depression research (91). This progress was inevitable as glutamate neurons are important targets for monoamine systems previously implicated in depression neurobiology and treatment, cortical neuroimaging studies in depression describe alterations in glutamatergic connectivity, and glutamatergic functional connectivity is targeted by both psychotherapeutic and neurostimulation treatments for depression

From Glutamate Pathophysiology to Novel Therapeutics

This model of glutamate synaptic dysfunction in depression yields a number of testable hypotheses regarding the treatment of this disorder. Studies support the hypothesis that immunologic activation, perhaps mediated by glial dysfunction, contributes to the emergence of depression-like states that are responsive to the effects of NMDA receptor antagonists. For example, NMDA receptor antagonists appear to treat fatigue and dysphoric mood associated with multiple sclerosis and interferon

Discussion

Research on rapid-acting antidepressants is shaping expectations regarding what might be achieved through antidepressant treatment. Ketamine research has proved to unlock new insights into the neurobiology of depression and to point to new and otherwise unexpected classes of antidepressant medications. Fifty years of antidepressant research suggested that antidepressants needed to act on monoamine systems and that treatment required weeks to months to produce benefits in responding patients. It

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