Exploratory non-randomized clinical trial of subcutaneous esketamine in treatment-resistant depression: Effects of ketamine-assisted psychotherapy.

Publication date: Dec 01, 2026

Ketamine is an effective rapid-acting treatment for treatment-resistant depression (TRD), producing antidepressant effects within hours of administration. Because it induces states of heightened neuroplasticity and psychological openness, psychotherapy may enhance its therapeutic effects. This exploratory, nonrandomized, 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 sequentially allocated to esketamine alone (KET, n = 23) or esketamine plus KAP (n = 23). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory-II (BDI-II) during treatment and at follow-up assessments up to six months after protocol completion. Both groups showed significant reductions in depressive symptoms. MADRS scores were significantly lower in the KAP group at the seventh and eighth sessions (p = 0. 015 and p = 0. 041). At treatment completion, response and remission rates were 52. 2% and 34. 8% in the KET group versus 78. 3% and 78. 3% in the KAP group; the between-group difference was significant only for remission (p = 0. 007). BDI-II scores also indicated earlier subjective improvement in the KAP group. No significant between-group differences were observed during the six-month follow-up. These findings suggest that structured psychotherapeutic support may accelerate symptomatic improvement and increase remission rates during subcutaneous esketamine treatment for TRD, without improving the durability of response. Randomized controlled trials are needed to clarify the specific contribution of psychotherapy, investigate the mechanisms underlying this interaction, and optimize integrated treatment approaches.

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