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

Summary & key facts

Researchers review evidence that a single intravenous, subanesthetic infusion of ketamine can produce rapid and sustained antidepressant effects in people with treatment-resistant depression. The paper says the biology of depression is still not well understood. It summarizes possible ketamine mechanisms, including blocking NMDA receptors, increasing AMPA receptor activity, activating pathways that help form synapses, and producing an active metabolite called hydroxynorketamine. The authors note that learning which molecular actions cause the good and bad effects of ketamine could help design better antidepressant drugs.

Key facts:

• Major depressive disorder’s underlying molecular causes are still poorly understood.
• Current antidepressant treatments have many shortcomings, which motivated research into alternatives.
• A single intravenous infusion of ketamine at a subanesthetic dose produced robust, rapid and sustained antidepressant effects in people with treatment-resistant depression.
• Proposed molecular actions of ketamine include inhibition of N-methyl-D-aspartate (NMDA) receptors and upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
• Ketamine appears to activate downstream synaptogenic signaling pathways that are involved in forming and strengthening synapses.
• An active ketamine metabolite called hydroxynorketamine has been identified and may play a role in its antidepressant effects.
• The paper emphasizes that understanding both ketamine’s beneficial and detrimental molecular effects is important for developing improved antidepressant agents.

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 Sadness or low mood