Ketamine, long used as an anesthetic, was first identified in 2000 as a fast-acting antidepressant. A single dose alleviates depressive symptoms, including anhedonia, within hours, and effects last for days. Research in animals indicates ketamine rapidly influences brain regions involved in punishment and reward processing, reverses negative affective biases in memories, and promotes stress resilience. Translating these findings to humans is ongoing, with emerging evidence suggesting similar mechanisms in healthy volunteers and patients. Clinical use is limited by acute side effects and unknown long-term safety. Understanding ketamine's mechanisms may guide development of safer rapid-acting antidepressants.
A single sub-anesthetic dose of ketamine reduces activity in the lateral habenula, a small midbrain structure involved in aversive learning, when healthy volunteers expect or experience unpleasant stimuli a day later. In a randomized trial with 70 adults, those who received ketamine showed attenuated habenula responses during an aversive Pavlovian conditioning task measured with 7-Tesla functional neuroimaging. Preliminary evidence suggests that reduced habenula activity during aversive learning may weaken the emotional impact of negative memories. These results support preclinical models of how ketamine may rapidly relieve depression by acting on the human habenula.