A Review of the Mechanism of Antagonism of N-methyl-D-aspartate Receptor by Ketamine in Treatment-resistant Depression

Summary & key facts

This paper reviews how ketamine, a drug that blocks a brain receptor called NMDA, might quickly reduce depressive symptoms in people whose depression does not respond to usual treatments. The authors explain a chain of ideas: ketamine may raise glutamate levels, spur growth of tiny branches on brain cells, increase a growth protein called BDNF, and turn on a cell-growth pathway called mTOR. These changes could help brain connections work better and may explain why a single injection of ketamine can ease severe depression symptoms fast. The paper describes possible mechanisms, but it does not prove long-term benefit or safety for everyone.

Key facts:

• Depression involves more than the usual chemicals like serotonin and dopamine. The NMDA receptor, a molecule on brain cells that helps control signals, also seems important in depression.
• Ketamine is a drug that blocks the NMDA receptor. The paper says this action is linked to its fast effects on depression symptoms.
• A single injection of ketamine can work rapidly to reduce depressive symptoms, and in some reports can quickly reduce severe suicidal thinking.
• Blocking NMDA with ketamine may raise glutamate, a brain chemical that can trigger growth changes in brain cells.
• Those growth changes include more and longer dendrites, which are tiny branches on nerve cells. More branches can help form new connections between cells, a process called synaptogenesis.
• Ketamine’s effects may also raise levels of brain-derived neurotrophic factor (BDNF) and activate mTOR, a pathway that helps build and strengthen connections. Together, these changes might improve how brain circuits work in depression.
• The paper is a review of ideas and evidence about how ketamine might work. It outlines possible mechanisms but does not prove they cause lasting recovery or that ketamine is safe for all people in the long term.

Abstract

The biochemical processes involved in depression go beyond serotonin, norepinephrine, and dopamine. The N-methyl-D-aspartate (NMDA) receptor has a major role in the neurophysiology of depression. Ketamine, one of the prototypical NMDA antagonists, works rapidly in controlling depressive symptoms, including acutely suicidal behavior, by just a single injection. Ketamine may rapidly increase the glutamate levels and lead to structural neuronal changes. Increased neuronal dendritic growth may contribute to synaptogenesis and an increase in brain-derived neurotrophic factor (BDNF). Activation of the mechanistic target of rapamycin (mTOR), as well as increased levels of BDNF, may increase long-term potentiation and result in an improvement in the symptoms of depression. The mechanisms of ketamine's proposed effect as an off-label treatment for resistant depression are outlined in this paper.

Topics

Neurotransmitter Receptor Influence on Behavior Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

Antidepressant Brain-derived neurotrophic factor Depression (economics) Dopamine Economics Epistemology Glutamate receptor Hippocampus Internal medicine Ketamine Long-term potentiation Macroeconomics Mechanism (biology) Medicine Neuroscience Neurotrophic factors NMDA receptor Norepinephrine Pharmacology Philosophy Psychology Receptor Synaptogenesis Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood