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

Abstract

Patients with treatment-resistant depression (TRD) have higher rates of relapse and pronounced decreases in daily functioning and health-related quality of life compared to patients with major depressive disorder who are not treatment-resistant, underscoring the need for treatment choices with sustained efficacy and long-term tolerability. Adults with TRD who participated in ≥1 of 6 phase 3 "parent" studies could continue esketamine treatment, combined with an oral antidepressant, by enrolling in phase 3, open-label, long-term extension study, SUSTAIN-3. Based on their status at parent-study end, eligible participants entered a 4-week induction phase followed by an optimization/maintenance phase, or directly entered the optimization/maintenance phase of SUSTAIN-3. Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance. At the interim data cutoff (01 December 2020), 1148 participants were enrolled, 458 at induction and 690 at optimization/maintenance. Mean (median) cumulative duration of maintenance esketamine treatment was 31.5 (37.7) months (totaling 2769 cumulative patient-years). Common treatment-emergent adverse events (≥20%) were headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from the baseline to the endpoint of each phase: induction -12.8 [9.73]; optimization/maintenance +1.1 [9.93]), with 35.6% and 46.1% of participants in remission (MADRS total score ≤12) at induction and optimization/maintenance endpoints, respectively. Improvement in depression ratings generally persisted among participants who remained in maintenance treatment, and no new safety signal was identified during long-term treatment (up to 4.5 years) using intermittent-dosed esketamine in conjunction with daily antidepressant.

Trial registration: ClinicalTrials.gov NCT02782104.

Fig. 1. SUSTAIN-3 Participant Disposition.

^aOne each: scheduling conflicts; multiple reasons (mainly, feeling better, wanted to start working again, adverse events, and time requirements of study); withdrew consent; participant’s choice despite investigator’s advice to continue; relocation; and death on study day 26 due to completed suicide, 4 days after the last dose of esketamine. ^bOther reasons (each ≤1%, e.g., investigator/sponsor decision, employment/school, personal reasons, death [4 participants, as described in Supplementary Material]). Note: Participants were eligible to enroll into the Induction Phase or the Optimization/Maintenance Phase based on their status at the end of the parent study (refer to Table S2). Participants received open-label esketamine nasal spray (28 mg [only an option for participants ≥65 years], 56 mg, or 84 mg) twice per week during the Induction Phase, and weekly, every other week, or every 4 weeks, based on clinical global impression - severity (CGI-S) and tolerability, during the Optimization/Maintenance Phase.

Fig. 2. Mean (±SE) Montgomery–Åsberg Depression Rating Scale Total Score (Observed Cases).

IND Induction, OP/MA optimization/Maintenance. Note: Responders from the induction phase of the SUSTAIN-3 study and responders from parent studies were to enter the optimization/maintenance phase. The greater variability of the mean MADRS total score at later time points likely reflects the smaller number of participants at these timepoints, as reflected in the corresponding sample sizes.

Fig. 3. Clinical global impression–severity (CGI-S): frequency distribution over time.

a Induction Phase. b Optimization/Maintenance Phase. Notes: Every-8-week data are presented. The visits with fewer than 10 participants are not presented. The CGI-S evaluates the severity of psychopathology on a scale of 1 to 7: 1 = normal (not at all ill); 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients.