How does ketamine elicit a rapid antidepressant response?

Summary & key facts

This review summarizes research on how a single low dose of ketamine can produce a very fast antidepressant effect. In patients, a low intravenous dose often eases core depression symptoms within about two hours and can last up to two weeks. Animal studies suggest ketamine works by blocking NMDA receptors that are active at rest, which then lowers eEF2 kinase activity, allows rapid production of BDNF protein, and boosts synaptic AMPA responses. The work points to hippocampus and prefrontal cortex as likely sites, but the exact brain circuits and how short-term changes lead to longer effects are still unclear.

Key facts:

• A single low (sub-psychotomimetic) intravenous dose of ketamine can reduce core symptoms of major depression within about two hours in patients, with effects reported to last up to two weeks.
• Preclinical (animal) studies found ketamine’s rapid antidepressant-like effects require rapid protein synthesis of brain-derived neurotrophic factor (BDNF), but do not require new BDNF gene transcription.
• Ketamine’s proposed molecular chain in animals: blockade of resting NMDA receptor currents (driven by spontaneous glutamate release) → deactivation of eEF2 kinase → reduced eEF2 phosphorylation → rapid translation of BDNF protein and increa
• Experiments showed that drugs or genetic manipulations that inhibit eEF2 kinase can produce fast antidepressant-like effects in mice, and ketamine does not produce these effects in eEF2 kinase knockout mice, supporting a role for this pathw
• Memantine, another NMDA receptor antagonist, is a poor blocker of resting NMDA currents in physiological conditions, does not decrease eEF2 kinase signaling or raise BDNF protein in the same way, and has failed to show antidepressant effica
• Most of the detailed molecular and synaptic findings come from animal experiments. The review notes that the exact synaptic circuits mediating ketamine’s rapid antidepressant effects in humans remain unresolved.

Topics

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

Categories

Health Sciences Medicine Pharmacology

Tags

Anesthesia Antagonist Antidepressant Depression (economics) Economics Glutamate receptor Glutamatergic Hippocampus Internal medicine Ionotropic effect Ketamine Macroeconomics Medicine Neuroscience NMDA receptor Onset of action Pharmacology Psychology Psychotomimetic Receptor

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood