Zaki Naim, Chen Li Nancy, Lane Rosanne, Doherty Teodora, Drevets Wayne C, Morrison Randall L, Sanacora Gerard, Wilkinson Samuel T, Young Allan H, Lacerda Acioly L T, Paik Jong-Woo, Popova Vanina, Fu Dong-Jing
Department of Neuroscience, Johnson & Johnson, Titusville, NJ, United States.
Department of Clinical Biostatistics, Johnson & Johnson, Titusville, NJ, United States.
Int J Neuropsychopharmacol. 2025 Jun 6;28(6). doi: 10.1093/ijnp/pyaf027.
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.
To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD.
Phase 3, open-label, single-arm long-term extension study (SUSTAIN-3) conducted from June 2016 to December 2022.
Outpatient.
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.
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.
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).
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.
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.
clinicaltrials.gov identifier: NCT02782104.
与非难治性重度抑郁症相比，难治性抑郁症（TRD）的复发率和自杀风险更高。即使在最初有反应的TRD患者中，大多数（70%）在6个月内复发。
评估艾氯胺酮鼻喷雾剂联合口服抗抑郁药治疗TRD患者的长期安全性和有效性。
2016年6月至2022年12月进行的3期开放标签单臂长期扩展研究（SUSTAIN-3）。
门诊。
参与6项3期“母体”研究中至少1项的成年TRD患者，根据他们在母体研究终点对研究药物的个体反应，要么进入为期4周的诱导期，随后是可变持续时间的优化/维持期（n = 458），要么直接进入SUSTAIN-3的优化/维持期（n = 690）。
鼻内给予艾氯胺酮的剂量是灵活的，诱导期每周两次，优化/维持期根据抑郁严重程度个体化给药（每周、每两周或每四周一次），由研究点工作人员直接监督。
评估艾氯胺酮的长期安全性。疗效终点包括通过蒙哥马利-阿斯伯格抑郁评定量表（MADRS）评估的抑郁症状变化。
共纳入1148例患者。艾氯胺酮的总暴露量为3777累积患者年。SUSTAIN-3中艾氯胺酮的平均（中位数，范围）暴露时间为42.9（45.8，范围0 - 79）个月。最常见的不良事件是头痛（36.9%）、头晕（33.9%）、恶心（33.6%）、解离感（25.5%）、鼻咽炎（23.8%）、嗜睡（23.1%）、味觉障碍（20.2%）和背痛（20.0%）。在研究期间，分别有5.3%和6.4%的参与者因疗效不佳或不良事件而停药。9名参与者死亡：与COVID-19相关（n = 3）、肺炎（n = 2）以及自杀、心肌梗死、多处受伤、死因不明（各n = 1）。诱导期MADRS总分均值下降，且在优化/维持期持续存在（各阶段从基线到阶段终点的平均[标准差]变化：诱导期：-12.8 [9.73]；优化/维持期：+0.2 [9.93]）。共有35.6%的参与者在诱导期终点达到缓解，在第112周和优化/维持期终点分别为48.5%和49.6%。
在SUSTAIN-3最终数据集中，间歇性给药的艾氯胺酮联合口服抗抑郁药进行长期治疗期间未发现新的安全信号，且持续接受维持治疗的参与者中抑郁症状普遍持续改善。这些结果为艾氯胺酮治疗TRD的累积证据增添了内容。
clinicaltrials.gov标识符：NCT02782104。
