Ketamine rapidly reduces depressive symptoms in people with treatment-resistant depression, but its effectiveness may diminish as the number of prior failed treatments increases. A systematic review of 18 randomized controlled trials found that ketamine and esketamine worked at both lower and higher stages of treatment resistance, yet effect sizes and duration of benefits were greater in studies involving patients with fewer prior antidepressant failures. Variability in how studies defined treatment resistance and measured outcomes prevented clear comparisons of efficacy across different resistance stages. The authors conclude that while ketamine remains broadly effective, more failed treatment trials may reduce its efficacy, and participant-level data are needed to clarify the relationship between resistance level and response.
A systematic review of five randomized-controlled trials found that ketamine-assisted psychotherapy (KAP) had a significant positive effect on primary outcome measures for adults with substance use disorders and treatment-resistant depression, but the data is mixed. The single trial examining KAP for treatment-resistant depression found no benefit. The review notes a lack of large, replicated clinical trials and no studies actively examining mechanisms of action. Evidence suggests temporary neural changes caused by ketamine, such as NMDAR inhibition and increased synaptic neuroplasticity, may affect treatment outcomes. Preliminary findings also suggest adjunct psychotherapy, changes in perspective, and spirituality may play a role.