Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study

Abstract

Importance: The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) vs 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 the long-term safety of esketamine. Efficacy endpoints included the change in depressive symptoms, assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).

Results: A total of 1148 patients were enrolled. Total exposure to esketamine was 3777 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). The 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]). A total of 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.

Trial registration: clinicaltrials.gov identifier: NCT02782104.

Keywords: efficacy; esketamine; long-term; safety; treatment-resistant depression.

Figure 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%, eg, investigator/sponsor decision, employment/school, personal reasons). ^cA participant was considered to have completed the study if they actively participated in the induction or optimization/maintenance phase until esketamine was approved in the respective country and accessible through the local healthcare system funding or until the end of December 2022, whichever was earlier. 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. 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. Data for the induction phase are reported elsewhere.

Figure 2.

Mean (± SE) Montgomery-Åsberg Depression Rating Scale Total Score (Observed Cases). BL (IND), baseline (induction phase); BL (OP/MA), baseline (optimization/maintenance phase); MADRS, Montgomery-Åsberg Depression Rating Scale. 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 score at later timepoints likely reflects the smaller number of participants at these timepoints, as reflected in the corresponding sample sizes. Data for the induction phase are reported elsewhere.

Figure 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 0 to 7: 0 = not assessed; 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. Data for the induction phase are reported elsewhere.