Signaling pathways underlying the rapid antidepressant actions of ketamine

Summary & key facts

This paper reviews how a single dose of ketamine can ease depression symptoms much faster than standard antidepressants. Studies in animals and people show ketamine briefly blocks a certain brain receptor, which causes a burst of the chemical glutamate. That burst then turns on other receptors and cell signals that help brain cells make new connections and proteins. Those new connections in the frontal part of the brain are linked to faster mood improvement, but most evidence comes from animal experiments and the exact picture in people is still being worked out.

Key facts:

• Ketamine can reduce depression symptoms within hours in many patients, while standard antidepressants usually take weeks to start working.
• In animal studies, ketamine briefly blocks NMDA receptors, which are parts of nerve cells that respond to the brain chemical glutamate.
• Blocking those NMDA receptors causes a short surge of glutamate. That surge activates AMPA receptors, another type of glutamate receptor, and starts a chain of signals.
• Those signals include the release of a growth protein called BDNF and activation of the mTOR pathway. BDNF and mTOR help nerve cells make new proteins and strengthen or form new connections.
• Animal experiments show ketamine reverses stress-related loss of connections in the prefrontal cortex, a brain area involved in mood and thinking.
• Some experiments blocked BDNF or the mTOR pathway and found that ketamine no longer produced the fast antidepressant effects, which supports their role in ketamine’s action.
• Most detailed evidence about these signaling steps comes from studies in rodents, so researchers say we cannot be completely sure the same steps happen in people.
• Because ketamine can cause side effects and its mood benefits often last only days to weeks, scientists say more research is needed to make safer and longer-lasting treatments based on these pathways.

Topics

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

Categories

Health Sciences Medicine Pharmacology

Tags

Antidepressant Cognition Hippocampus Internal medicine Ketamine Medicine Milnacipran Neuroscience NMDA receptor Prefrontal cortex Psychology Receptor Synapse Synaptogenesis

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood