Background <p>Major Depressive Disorder (MDD) is a common and debilitating condition. Current treatments fail to provide adequate relief in roughly one-third of individuals, resulting in treatment-resistant depression (TRD). Ketamine has emerged as a promising intervention for TRD, offering rapid and sustained antidepressant effects. However, benefits often require maintenance dosing, and long-term outcomes remain unclear. This has promoted interest in adjunctive approaches such as ketamine-assisted psychotherapy (KAP), which combines ketamine with structured psychological support.</p> Methods <p>A comprehensive literature search was conducted via the OVID platform using Embase, Medline, Global Health, and APA PsycInfo. Keyword clusters related to “Ketamine,” “Diagnosis,” and “Psychotherapy” yielded 768 results. Screening followed PRISMA guidelines, resulting in 11 studies meeting inclusion criteria.</p> Results <p>The selected studies clustered into two thematic categories: structured, protocol-based interventions and individualized, experiential approaches. Across all studies, KAP was associated with reductions in depressive symptoms, with some improvements sustained up to six months. However, among the three studies with control groups, no significant differences were found between KAP and control conditions. Methodological heterogeneity—including variability in treatment protocols, outcome measures, and study designs—limits the ability to draw firm conclusions or identify mechanisms driving KAP’s effects.</p> Conclusion <p>KAP shows promise as a treatment for TRD, potentially offering meaningful and sustained symptom relief. However, limited evidence and methodological variability underscore the need for more rigorous research—particularly randomized controlled trials—to better understand its efficacy and mechanisms.</p>