Ketamine lowers depressive symptoms after surgery even when given only while patients are unconscious under general anesthesia

Ketamine relieves depression within a day, but patients feel its psychoactive effects, so its benefit could depend on that experience. We asked whether ketamine and esketamine lower depressive symptoms when every dose is given while patients are unconscious under general anesthesia. Under a registered plan, we coded each randomized trial's dosing from its Methods alone and pooled standardized differences (Hedges' g) one to three days after surgery or childbirth. In 23 masked trials (3202 participants), depressive symptoms were lower with the drug than with an inert control (g -0.61, confidence interval -0.81 to -0.4; Holm-adjusted p < 0.001), including trials that passed an integrity screen and strictly masked ones. In surgery, dosing awake patients did not enlarge the effect (difference 0.12, -0.24 to 0.48). Masked doses also lowered pain and caused fewer psychotomimetic events than awake doses; the one trial that randomized timing favored awake dosing. Ketamine's effect on depressive symptoms after surgery does not require patients to experience the drug.