Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study.

Importance: The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) versus non-treatment-resistant major depressive disorder. Even among patients with TRD who initially respond, the majority (70%) relapse within 6 months.

Objective: To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD.

Design: Phase 3, open-label, single-arm long-term extension study (SUSTAIN-3) conducted from June 2016 to December 2022.

Setting: Outpatient.

Participants: Adults with TRD who participated in ≥1 of 6 phase 3 "parent" studies continued esketamine by either entering a 4-week induction phase followed by an optimization/maintenance phase of variable duration (n=458), or directly entering the optimization/maintenance phase of SUSTAIN-3 (n=690), based on their individual response to study drug at the endpoint of the parent study.

Interventions: Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance (weekly, every-other-week, or every-4-weeks), under direct supervision by site staff.

Main outcomes and measures: To assess long-term safety of esketamine. Efficacy endpoint included change in depressive symptoms, assessed by Montgomery-Åsberg Depression Rating Scale (MADRS).

Results: 1,148 patients were enrolled. Total exposure to esketamine was 3,777 cumulative patient-years. Mean (median, range) exposure to esketamine in SUSTAIN-3 was 42.9 (45.8, range 0-79) months. The most common adverse events were headache (36.9%), dizziness (33.9%), nausea (33.6%), dissociation (25.5%), nasopharyngitis (23.8%), somnolence (23.1%), dysgeusia (20.2%), and back pain (20.0%). During the study, 5.3% and 6.4% of participants discontinued due to lack of efficacy or adverse event, respectively. Nine participants died: COVID-19 related (n=3), pneumonia (n=2), and completed suicide, myocardial infarction, multiple injuries, unknown cause (n=1 each). Mean MADRS total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from baseline-to-phase endpoint of each phase: induction: -12.8 [9.73]; optimization/maintenance: +0.2 [9.93]). 35.6% of participants were in remission at the induction endpoint, and 48.5% and 49.6% at week 112 and optimization/maintenance endpoint, respectively.

Conclusions and relevance: In the SUSTAIN-3 final dataset, no new safety signals were identified during long-term treatment with intermittently-dosed esketamine, combined with oral antidepressant, and improvement in depression generally persisted among participants who remained on maintenance treatment. These results add to the accumulated evidence on TRD treatment with esketamine.