Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism

Summary & key facts

This review explains how ketamine can act as a fast antidepressant for people whose depression did not get better with usual treatments. A single low-dose intravenous infusion of ketamine can give strong and quick mood improvement that can last longer than expected. Scientists are studying several ways ketamine might work: blocking one kind of brain receptor, boosting another receptor, turning on signals that help brain cells make new connections, and a breakdown product called hydroxynorketamine. Learning these details could help design safer, faster antidepressant medicines, but the exact reasons for ketamine’s benefits and side effects are still not fully known.

Key facts:

• Researchers found that one low-dose intravenous infusion of ketamine can produce strong, rapid, and sometimes sustained antidepressant effects in people whose depression did not respond to standard treatments.
• Ketamine’s effects are partly linked to blocking the NMDA receptor, which is a protein on brain cells that helps control signals from the brain chemical glutamate.
• Other important actions go beyond blocking NMDA receptors. Ketamine appears to increase activity at AMPA receptors, which help brain cells respond to glutamate, and this may be important for its antidepressant effect.
• Ketamine also activates signalling pathways that help form new synapses, meaning it may help build or strengthen connections between brain cells.
• A ketamine breakdown product called hydroxynorketamine is active in the brain and may contribute to the antidepressant effect, so researchers are studying it as a separate target.
• The molecular reasons for both ketamine’s therapeutic effects and its harmful side effects are not yet fully understood, and learning more could guide the development of better antidepressant drugs with fewer downsides.

Abstract

The molecular mechanisms underlying major depressive disorder remain poorly understood, and current antidepressant treatments have many shortcomings. The recent discovery that a single intravenous infusion of ketamine at a subanesthetic dose had robust, rapid and sustained antidepressant effects in individuals with treatment-resistant depression inspired tremendous interest in investigating the molecular mechanisms mediating ketamine’s clinical efficacy as well as increased efforts to identify new targets for antidepressant action. We review the clinical utility of ketamine and recent insights into its mechanism of action as an antidepressant, including the roles of N-methyl-d-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor upregulation, activation of downstream synaptogenic signalling pathways and the production of an active ketamine metabolite, hydroxynorketamine. Emerging knowledge of the molecular mechanisms underlying both ketamine’s positive therapeutic and detrimental side effects will aid the development of a new generation of much-needed superior antidepressant agents.

Topics

Neuroscience and Neuropharmacology Research Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

AMPA receptor Antidepressant Biochemistry Biology Epistemology Glutamate receptor Hippocampus In vitro Internal medicine Ketamine Mechanism (biology) Mechanism of action Medicine Neuroscience NMDA receptor Pharmacology Philosophy Psychology Receptor

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood