Ketamine and esketamine maintenance treatment show promise in maintaining initial antidepressant effects, yet further research is needed to optimize long-term outcomes. This observational study aimed to assess long-term depression symptom severity, safety, and tolerability in a cohort of patients receiving at-home oral esketamine maintenance treatment. Between June 2017 and March 2024, 221 patients with severe treatment-resistant unipolar depression were enrolled directly or trial-transferred into an off-label induction treatment program. After 6 weeks of individually titrated oral esketamine (twice a week, max 3.0 mg/kg) administered in the clinic, 93 patients continued to maintenance treatment at home (max 3.0 mg/kg twice a week). Our primary outcome was change in depression symptom severity during maintenance treatment, measured by the 17-item Hamilton Depression Rating Scale (HDRS17). Mean exposure to esketamine in the maintenance phase was 20.8 months. We found no difference between the HDRS17 total score at the maintenance baseline and last-observation-carried-forward (mean difference = 0.825, 95% CI = -0.759 to 2.410, p = 0.302). Of the 26 initial responders (≥50% decrease in HDRS17 at the end of induction treatment), 23.1% met sustained response criteria throughout maintenance treatment. Of the 40 patients meeting minimal clinically important difference (MCID) criteria (≥27.1% decrease in HDRS17 at the end of induction treatment), 60.0% met sustained MCID criteria throughout maintenance treatment. Eleven patients (11.8%) successfully tapered off esketamine maintenance treatment. Twelve patients (12.9%) discontinued maintenance treatment (partly) due to adverse events. These findings suggest that oral esketamine maintenance home treatment may be associated with sustained symptom stability in patients with severe treatment-resistant depression (TRD), although causal inferences cannot be drawn from this observational study. Although some potential long-term side effects require monitoring and further examination, overall, treatment was safe and well-tolerated.
