Preliminary Non-Randomized Clinical Trial of Subcutaneous Esketamine in Treatment-Resistant Depression: Exploring Adjunctive Effects of Ketamine-Assisted Psychotherapy

Abstract Background Ketamine has emerged as an effective rapid-acting treatment for treatment-resistant depression (TRD), producing significant antidepressant effects within hours of administration. Given ketamine's capacity to induce states of heightened neuroplasticity and psychological openness, psychotherapy may represent a meaningful complement to its pharmacological effects - facilitating emotional processing, cognitive restructuring, and the consolidation of therapeutic gains. However, the adjunctive potential of structured psychotherapeutic support in ketamine-based interventions remains largely unexplored. Methods This preliminary, non-randomized, open-label clinical trial evaluated the adjunctive effects of ketamine-assisted psychotherapy (KAP) in an outpatient setting. Forty-six patients with TRD received eight weekly sessions of subcutaneous esketamine (0.5-1.0 mg/kg) and were allocated into two groups: esketamine without psychotherapeutic support (n = 23) and esketamine combined with structured KAP encompassing preparation, dosing accompaniment, and post-session integration (n = 23). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory-II (BDI-II) at multiple timepoints during treatment and at follow-up assessments up to six months after protocol completion. Results Both groups showed significant reductions in depressive symptoms throughout treatment. The KAP group demonstrated greater clinical improvement by the end of treatment, with between-group differences on the MADRS emerging at sessions 7 and 8. MADRS response and remission rates were 52.2% and 34.8% in the KET group, and 78.3% and 78.3% in the KAP group, respectively. BDI-II scores indicated earlier subjective improvement in the KAP group, with between-group differences emerging as early as the second session and persisting across multiple timepoints. No significant between-group differences were observed during the six-month follow-up, with both groups maintaining symptom reductions comparable to end-of-treatment levels. Conclusions These findings suggest that structured psychotherapeutic support may be associated with early clinical response and remission rates in subcutaneous esketamine treatment for TRD, potentially through facilitation of emotional processing, psychological flexibility, and behavioural change. Further controlled studies are needed to clarify the specific contribution of psychotherapy, investigate the mechanisms underlying this interaction, and optimize integrated treatment approaches for TRD. The trial was registered at https://ensaiosclinicos.gov.br/rg/RBR-1072m6nv . Keywords: esketamine; treatment-resistant depression; ketamine-assisted psychotherapy; innovative therapies.