Introduction
For over half a century, the pharmacological treatment of depression was dominated by a single idea: that depression results from a deficit of monoamine neurotransmitters -- serotonin, norepinephrine, and dopamine -- and that the solution is to increase their availability. SSRIs, SNRIs, and their predecessors all work on this principle. They also share a critical limitation: they take weeks to work, and roughly one-third of patients do not respond adequately even after multiple medication trials. Ketamine shattered this paradigm. A single intravenous infusion can produce antidepressant effects within hours -- even in patients who have failed every other treatment.
The Discovery
Ketamine was synthesized in 1962 by Calvin Stevens at Parke-Davis and approved as a human anesthetic in 1970. It works primarily by blocking NMDA (N-methyl-D-aspartate) receptors, a type of glutamate receptor central to synaptic plasticity and learning.
The first hint of antidepressant properties came from researchers at Yale University in the 1990s who were studying ketamine's cognitive effects. Robert Berman and colleagues conducted the first controlled study, published in Biological Psychiatry in 2000. Seven patients with major depression received either a single intravenous ketamine infusion (0.5 mg/kg over 40 minutes) or saline placebo in a randomized, double-blind crossover design. Patients showed significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion. The effect was rapid, robust, and unlike anything seen with conventional antidepressants.
