Esketamine nasal spray (ESK) is indicated, in conjunction with an oral antidepressant (OAD), for the management of treatment-resistant depression (TRD) in adults. Select US-based patients from an open-label, long-term extension safety study of ESK (NCT02782104) participated in this study through semi-structured interviews. The study evaluated patient-reported early health changes related to emotional health, daily functioning, and social functioning in adults with TRD treated with ESK plus OAD. Eligible patients were responders to ESK who had begun initial ESK treatment ≤30 months before enrollment and were currently receiving ESK plus OAD. Results from 23 patients (9 men, 14 women; mean age, 46 years) were analyzed. Patients described the degree to which ESK treatment changed the effects of depression on aspects of health as either being much improved or improved (91.8%, 156/170). Key characteristics noted regarding treatment with ESK plus OAD included degree of effectiveness (n = 11), rapid onset of action (n = 7), and side-effect profile (n = 5). All patients reported being either satisfied (52%) or very satisfied (48%) with ESK plus OAD treatment. Adverse events were consistent with the known safety profile of ESK. Study insights may help prepare patients with TRD and their clinicians to anticipate potential health changes experienced with ESK.