Post hoc analyses of an open-label long-term study of esketamine nasal spray plus an oral antidepressant comparing results in older versus younger adults with treatment-resistant depression

Abstract

<h3>Introduction</h3> Major depressive disorder in the elderly is associated with lower response and remission rates, resulting in treatment-resistant depression (TRD). Furthermore, older patients are often more vulnerable to adverse drug effects. Recently published findings from a 4-week, phase 3 study of esketamine nasal spray (TRANSFORM-3), evaluated patients ≥65 years with TRD. SUSTAIN-2 was an up to one year, open-label safety and efficacy study of esketamine nasal spray in the same phase 3 program, which enrolled patients with TRD over 18 years old. In addition to patients directly enrolled in SUSTAIN-2, completers from TRANSFORM-3 (responders or non-responders) could continue into SUSTAIN-2. We present a post hoc comparison of depressive symptoms and safety between patients with TRD aged 18-64 years (younger) vs ≥65 years (older) in the SUSTAIN-2 study. <h3>Methods</h3> SUSTAIN-2 included 802 patients with TRD; 624 younger and 178 older. Patients received a new oral antidepressant and open-label, flexibly-dosed esketamine nasal spray (28 [only older patients], 56 or 84 mg) administered in two phases: induction (IND) (2X/week for 4 weeks; included direct-entry patients and transferred-entry non-responder patients) and optimization/maintenance (OP/MAINT) (weekly or bi-weekly for up to 48 weeks; included responders from the open-label IND phase of SUSTAIN-2 and transferred-entry responders from TRANSFORM-3). Post hoc analyses compared treatment outcomes and safety for both age groups for each study phase. Outcome measurements included change from baseline in each phase for the Montgomery–Åsberg Depression Rating Scale (MADRS) total score and patient-reported outcomes: Sheehan Disability Scale (SDS), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-Item (GAD-7). Remission (MADRS ≤12) and response (≥50% MADRS reduction from baseline) rates were also reported by phase. Key safety assessments included adverse events, labs, electrocardiograms (ECGs), blood pressure, and dissociation measured by Clinician-Administered Dissociative States Scale (CADSS). <h3>Results</h3> Baseline demographics, other than age (mean 49.0 [range: 18-64] and 69.0 [range: 65-86] for younger and older adults, respectively) and baseline hypertension (21.5% and 48.3% for younger and older adults, respectively), were similar between subgroups, including mean baseline MADRS total scores (IND: 31.4 and 30.7, in the younger and older groups respectively). The mean (SD) change from IND baseline in MADRS total scores following the IND phase was −16.6 (8.6) vs −15.4 (9.4), in younger and older patients respectively. Remission rates at the end of IND phase were 281/624 (46.5%) vs 76/155 (50.0%) and at the end of the OP/MAINT phase (up to week 48) rates were 270/477 (56.6%) vs 81/126 (64.3%) for younger and older patients respectively. Response rates at the end of IND were 485/624 (80.3%) vs 108/155 (71.1%) and at the end of OP/MAINT were 366/477 (76.7%) vs 95/126 (75.4%) for younger and older patients respectively. The mean (SD) change in the PHQ-9 following IND was –9.5 (6.4) vs −6.9 (7.2), in younger vs older patients respectively. Similarly, the mean change (SD) in the SDS following IND was –9.6 (7.8) vs –7.8 (8.4), in younger vs older patients respectively. The mean change (SD) in the GAD-7 following IND was –6.4 (5.9) vs –3.9 (5.3), in younger vs older patients respectively. In the IND phase, treatment emergent adverse events (TEAEs) ≥5% were seen in 537/624 (86.1%) and 116/155 (74.8%) of younger vs older patients respectively; TEAEs ≥10% included: dizziness (30.8% vs 23.2%), dissociation (24.0% vs 20.6%), nausea (22.9% vs 9.0%) headache (20.2% vs 7.1%), somnolence (12.3% vs 11.0%), hypoesthesia (11.5% vs <5%) in younger vs older patients respectively. In the OP/MAINT phase, TEAEs ≥5% occurred in 414/477 (86.8%) and 102/126 (81.0%) of younger vs older patients respectively; TEAEs ≥10% included: dizziness (22.0% vs 23.8%), headache (21.2% vs 10.3%), dissociation (19.3% vs 16.7%), nausea (15.3% vs 8.7%), somnolence (13.8% vs 15.1%) and viral upper respiratory infection (10.7% vs 15.1%), in younger vs older patients respectively. Treatment-emergent acute hypertension (defined as blood pressure ≥180/110 mm Hg) occurred in 13/624 (2.1%) vs 5/155 (3.2%) in the IND, and in 10/477 (2.1%) vs 8/126 (6.3%) in the OP/MAINT for younger vs older patients. <h3>Conclusions</h3> In this post hoc descriptive analysis, patients with TRD aged 18-64 and those ≥65 showed comparable treatment outcomes using esketamine nasal spray, including change in MADRS scores, response and remission rates. Safety and tolerability findings were comparable in both age groups, except for treatment-emergent acute hypertension, which was observed more often in the elderly. <h3>Funding</h3> Janssen Research & Development, LLC