Key PointsQuestionWhat are the mediators of repeated ketamine administration for chronic pain relief?FindingsIn this cohort study of 329 patients with treatment-resistant pain, pretreatment depression was the only mediator of chronic pain relief with ketamine.MeaningDepression as a mediator for refractory chronic pain relief provides radically new insights on how ketamine reduces pain primarily by dampening depression and reinforces the need for systematic depression assessment of patients with treatment-resistant pain.