Objective: Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more antidepressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary objective consisted in researching the relationship between response and previous use of electroconvulsive therapy. Methods: A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were followed up to 4 months after the administration. Results: Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation between outcome and any demographic or clinical traits evaluated. No differences were found between patients that previously received Electroconvulsive Therapy, and those that didn’t. 10 out of 16 patients responded (＞ 50% change in baseline MADRS scores), but only five achieved remission (＜ 12 points in the global MADRS score). We provide some recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects. Conclusion Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed to properly assess predictors of response outcome.