Oral Esketamine Maintenance Treatment for Treatment-Resistant Depression: Clinical Outcomes During an Off-Label Treatment Program

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.