Mechanisms of ketamine action as an antidepressant

Summary & key facts

Clinical studies show that a single low dose of ketamine can lift depression symptoms fast and for a time afterwards. Researchers are trying to figure out how this happens in the brain. Animal and lab studies point to several possible steps: blocking certain glutamate receptors, changing activity of inhibitory brain cells, activating other glutamate receptors, and turning on molecular pathways that help synapses (the connections between nerve cells) get stronger. Some recent work suggests that parts made when the body breaks down ketamine might help too. Understanding these steps could help scientists make new medicines that keep the fast benefit but cause fewer side effects and less risk of abuse. However, many findings come from basic research in animals or cells, so we do not yet fully know which exact steps are most important in people.

Key facts:

• Many clinical trials have found that one low, non-anesthetic dose of ketamine can reduce depression symptoms rapidly, sometimes within hours, and the benefit can last beyond the immediate effects.
• Widespread use of ketamine for depression is limited because it can cause dissociation (a feeling of being disconnected) and has potential for abuse.
• Lab and animal studies suggest several possible brain actions that might explain ketamine’s antidepressant effect: blocking a type of glutamate receptor called the NMDA receptor, especially certain subtypes or locations; reducing activity of inhibitory neurons that normally dampen brain signals; and stopping burst firing in a brain area called the lateral habenula.
• Other studies point to a role for AMPA receptors (another glutamate receptor) and to downstream molecular signals that help synapses strengthen, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mTOR, and GSK-3.
• Some recent work found that ketamine metabolites, especially one called (2R,6R)-hydroxynorketamine, might produce antidepressant effects without directly blocking NMDA receptors, suggesting different or additional ways ketamine can work.
• The proposed mechanisms are not mutually exclusive. They might act together to cause quick changes in synaptic strength, which could underlie the lasting antidepressant effects seen in patients.
• Because much of the mechanistic evidence comes from preclinical studies in animals and cells, there is still uncertainty about which mechanisms are most important in people and which can be safely targeted by new drugs.

Topics

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

Categories

Health Sciences Medicine Pharmacology

Tags

Action (physics) Antidepressant Hippocampus Ketamine Medicine Neuroscience Pharmacology Physics Psychiatry Psychology Quantum mechanics

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood