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One in five people will likely suffer from major depressive disorder (MDD) during their life. Thirty percent of those with MDD will experience Treatment Resistant Depression (TRD), which is characterized by a failure to respond to two adequately administered trials of antidepressants. Esketamine is a rapidly acting intranasal antidepressant. Present-day Esketamine research has limited data in real-world populations. This study aimed to assess Esketamine treatment in a real-world community-based population. This naturalistic retrospective study included 94 individuals age 18 and above diagnosed with TRD, treated with Esketamine in an outpatient setting. The treatment was given in a single clinic, from January 2021 to January 2023, following approval of the Institutional Internal Review Board. The treatment included an acute phase (biweekly treatment, continuing 4-8 weeks), followed by a maintenance phase (once a week to once a month, for 6-12 months). Dosing ranged from 28 mg to 84 mg. Demographic and clinical data were retrospectively gathered. Depressive symptoms were assessed using the Quick Inventory of Depressive Symptomatology, at baseline and during each treatment phase. All patients completed the acute phase. About 60% completed the maintenance phase. Linear improvement of depressive symptoms was revealed in both phases. A sub-analysis of patients with comorbid personality disorder revealed a similar improvement pattern in the acute phase with milder improvement during the maintenance phase, compared to the other patients. This study supports the use of Esketamine for TRD, including patients with comorbid personality disorder and previous electroconvulsive therapy., Competing Interests: Declaration of competing interest None of the authors reports any financial or other conflict of interest with regard to this study. The authors furthermore confirm that this manuscript or parts thereof have not been published and are not under consideration for publication elsewhere. They also confirm that all of them contributed significantly to the study. They furthermore, confirm giving their approval to all statements and declarations included in this submission., (Copyright © 2024 Elsevier Ltd. All rights reserved.)