Efficacy and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression Who Completed a Second Induction Period: Analysis of the Ongoing SUSTAIN-3 Study

Abstract

Background Treatment-resistant depression (TRD) is a chronic illness requiring long-term treatment. Esketamine nasal spray (ESK) has been studied in several long-term trials of patients with TRD, including SUSTAIN-1 (NCT02493868) and SUSTAIN-3 (NCT02782104). This subgroup analysis of SUSTAIN-3 evaluated patients with TRD who received a second induction (IND) and maintenance treatment with ESK plus oral antidepressant (AD) after a relapse in SUSTAIN-1. Methods Patients aged 18–64 years who achieved stable remission or response with ESK and subsequently relapsed after randomization to continue ESK or switch to placebo nasal spray (PBO) in SUSTAIN-1 and entered the IND phase of SUSTAIN-3 were included in this interim analysis. Response (≥50% improvement in total score from baseline for Montgomery–Åsberg Depression Rating Scale [MADRS] and Patient Health Questionnaire 9-item [PHQ-9]), remission (MADRS score ≤12; PHQ-9 total score <5), changes in depression rating scores (measured as mean change from baseline), and safety were evaluated (incidence of treatment-emergent and serious adverse events [AE]). Results Of the 96 eligible patients who entered IND in SUSTAIN-3, 32 (33.3%) were taking ESK+AD at the time of relapse in SUSTAIN-1 and 64 (66.7%) were taking AD+PBO. Substantial improvements in depressive symptoms were observed over the second IND phase in both groups and were maintained over the optimization/maintenance (OP/M) phase. MADRS response rates following a second IND were 71.9% and 73.4% for previously relapsed (PR) ESK+AD and PR-AD+PBO, respectively; remission rates were 62.5% and 60.9%, respectively. During the IND and OP/M phases, 58.3% and 83.3% of patients experienced a treatment-emergent AE, respectively. No patients discontinued due to an AE during the second IND. Conclusions Patients with TRD benefitted from receiving a second IND and maintenance treatment with ESK and no new safety signals were identified. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-023-01026-3.

Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database

“…The most common AEs of ESK-NS was dissociation, described as the distortion of time and space, illusions, derealization, and depersonalization, which could be assessed by the Median Clinician-Administered Dissociative States Scale (CADSS). However, in clinical trials, dissociation was transient and resolved spontaneously without the need for concomitant (Jeon et al, 2022;Zaki et al, 2023). ESK-NS may cause sedation or loss of consciousness and diminished or less apparent breathing (Titusville, 2024).…”

“…In the SUSTAIN-2 study, 42/802 (5.2%) patients reported suicidality-related treatmentemergent adverse events (TEAEs), three patients reported suicidal behavior, and one suicided (Jeon et al, 2022). In the SUSTAIN-3 study, one participant died by suicide 4 days after the most recent ESK-NS dose, and 49 participants (of 1,144, 4.3%) reported new occurrences of suicidal ideation (Zaki et al, 2023). However, esketamine/antidepressant groups reported more suicidal ideation than placebo/antidepressant groups in TRANSFORM-1 (Fedgchin et al, 2019).…”

“…Although the overall tolerability of ESK-NS in short-term and long-term clinical trials is well, ESK-NS marketing authorization triggered many concerns, including the lack of convincing evidence about its safety and the risk of suicide and abuse ( Cristea and Naudet, 2019 ; Fedgchin et al, 2019 ; Vanina Popova et al, 2019 ; Fu et al, 2020 ; Ionescu et al, 2020 ; Ochs-Ross et al, 2020 ; Wajs et al, 2020 ; Castro et al, 2023 ). In the phase III studies completed, the most common AEs included dizziness, dissociation, nausea, and headache ( Fu et al, 2020 ; Wajs et al, 2020 ).…”