Background: Regulatory agency approval of esketamine nasal spray (ESK), combined with oral antidepressant, for treatment-resistant depression (TRD) was based on data from phase 2/3 (≤ 1 yr) studies.

Methods: Adults with TRD who participated in phase 3 “parent” studies could continue ESK treatment by enrolling in a global, open-label, long-term extension study, SUSTAIN-3 (NCT02782104). Based on their status at parent study end, eligible participants entered a 4-wk induction phase (IND) followed by an optimization/maintenance phase (OP/MA) of variable length, or directly entered the OP/MA phase of SUSTAIN-3. ESK dosing was flexible, twice/wk during IND and individualized to depression severity during OP/MA.

Results: 1148 participants were enrolled. Mean (SD, range) age was 49.6 (12.28, 19-83) years. Total exposure to ESK in SUSTAIN-3 was 3,777.0 cumulative patient-yrs. Mean (SD, range) total duration of exposure was 42.9 (24.22, 0-79) mon. About 2/3 of participants were on 84 mg, ~1/3 on 56 mg, and < 3% on 28 mg as their final dose; most participants received ESK weekly or every other wk during OP/MA.

Common treatment-emergent adverse events (AEs, ≥ 20%) were headache, dizziness, nausea, dissociation, nasopharyngitis, somnolence, dysgeusia, and back pain. Incidence of increased blood pressure-related AEs did not rise over time. No events of treatment-emergent interstitial/ulcerative cystitis, respiratory depression, or hypertensive crisis were reported. Nine participants died: COVID-19 related (n = 3), pneumonia (n = 2), completed suicide, myocardial infarction, multiple injuries, unknown cause (1 each).

Mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score decreased during IND, and this reduction persisted during OP/MA (mean [SD] change from baseline to endpoint of each phase: IND -12.8 [9.73]; OP/MA 0.2 [9.93]), with 35.6% of participants in remission (MADRS ≤ 12) at IND endpoint, and 54.1%, 51.1%, 46.8%, 47.7%, and 46.9% at wks 56, 104, 160, 208, and 256, respectively.

Conclusions: Improvement in depression generally persisted among participants who remained on maintenance treatment; no new safety signals were identified during long-term treatment (up to 6.6 yrs). All-cause mortality and completed suicide rates were lower than expected based on published data from patients with TRD.

Disclosures: Janssen Research and Development, LLC: Employee (Self). Johnson and Johnson: Stock / Equity (Self).

17.3 Abstract not included.