Psychology › Therapy & treatment › Psychiatric medicine: drugs and brain treatments
Ketamine and esketamine for depression
2000; Spravato 2019· Therapy or method
Mixed evidenceSome support; effects smaller or less consistent than once thought.
An anesthetic that, at low doses, can lift severe depression within hours instead of weeks, though the effect often fades.
See it on the Psychology map →What it says
Ketamine has been an approved anesthetic since 1970. In 2000 a Yale team, including Robert Berman, Dennis Charney and John Krystal, reported that one low-dose intravenous infusion eased depression within hours. It blocks NMDA receptors for glutamate, the brain's main excitatory messenger, which appears to trigger rapid growth of synaptic connections. In 2019 the FDA approved esketamine nasal spray (Spravato) for treatment-resistant depression, given in a clinic with two hours of monitoring. Off-label infusion clinics have multiplied since.
Why it matters
It was the first antidepressant with a genuinely new mechanism in decades and showed depression can lift in hours, redirecting drug research.
The evidence
Status: mixed. Controlled trials repeatedly show fast effects, but blinding is hard because patients feel its dissociative 'floating' sensations. Benefits often fade within a week or two without repeat doses.
Open questions
Exactly how it works is debated, and the risks of long-term repeated use, including bladder damage and misuse, are not well known.
Connections (2)
▸Ketamine and esketamine for depression target glutamate among Neurotransmitters, the brain's chemical messengersWell replicated
The connection
Most antidepressants act on serotonin or norepinephrine. Ketamine instead blocks NMDA receptors, a main receiver for glutamate, the brain's chief excitatory messenger. This seems to trigger a brief glutamate surge and rapid growth of synaptic connections in mood circuits, which may explain its speed.
Who showed it and when
Ronald Duman and George Aghajanian's labs at Yale showed in 2010 that ketamine regrows synapses in rats within a day.
The evidence
In rats, blocking the downstream signaling protein mTOR blocks both synapse growth and the antidepressant effect. Human evidence is indirect, from brain imaging and blood markers.
Open questions
A 2018 Stanford study found an opioid blocker dampened ketamine's effect, hinting at opioid involvement; other teams disputed this. The mechanism remains debated.
▸Ketamine and esketamine for depression rapidly relieve treatment-resistant Depression and mood disordersMixed evidence
The connection
For people whose depression has not improved after two or more antidepressants, ketamine or esketamine can reduce symptoms, including suicidal thoughts, within hours to a day. Effects usually fade over days to weeks, so treatment means repeated doses under medical supervision.
Who showed it and when
Yale's 2000 study, then NIMH trials led by Carlos Zarate (2006); Johnson & Johnson's Spravato nasal spray won FDA approval in March 2019.
How solid is it?
Multiple randomized trials show rapid effects, but blinding is weak; only one of esketamine's three short-term Phase 3 trials met its main goal.
Open questions
How long benefits last with ongoing use, the risk of misuse, and whether loosely regulated infusion clinics are safe are open questions.