Long-term safety and maintenance of response with esketamine nasal spray in treatment-resistant depression: final results of the SUSTAIN-3 study

This work was sponsored by Janssen Research & Development, LLC Aim: To assess long-term safety and efficacy of esketamine nasal spray in treatment-resistant depression (TRD). Methods: Adults with TRD who participated in a phase 3 “parent” study could continue esketamine, combined with oral antidepressant, by enrolling in SUSTAIN-3 (NCT02782104), an open-label extension study. Participants entered a 4-week induction phase (n=458) followed by an optimization/maintenance phase of variable duration, or directly entered at optimization/maintenance (n=690). Esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance. Results: Mean (SD) age was 49.6 (12.28) years; 66.6% were female, 86.8% white. Mean (SD) esketamine exposure was 42.9 (24.22) months (3,777.0 cumulative patient-years in SUSTAIN-3). Common AEs (≥20%) were headache, dizziness, nausea, dissociation, nasopharyngitis, somnolence, dysgeusia, and back pain. Nine participants died: COVID-related (n=3), pneumonia (n=2), completed suicide, myocardial infarction, multiple injuries, unknown cause (n=1 each). Mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score decreased during induction; this reduction persisted during optimization/maintenance (mean [SD] change from baseline to endpoint of each phase: induction -12.8 [9.73]; optimization/maintenance +0.2 [9.93]), with 35.6% of participants in remission (MADRS ≤12) at induction endpoint, and 54.1%, 51.1%, 46.8%, 47.7%, and 46.9% at weeks 56, 104, 160, 208, and 256, respectively. A similar trend was observed for functioning and associated disability, based on change from baseline to endpoint of each phase in Sheehan Disability Scale total score, a patient-reported outcome. Conclusions: Improvement in depression ratings generally persisted and no new safety signal was identified during long-term treatment (up to 6.6 years) with intermittently-dosed esketamine plus daily antidepressant.