Richard C Shelton, Robert E Litman, Howard Hassman, David P Walling, Salvador Ros Montalbán, Joan Salvà-Coll, John Zajecka, Oleksandr Sverdlov, Baltazar Gomez-Mancilla, Mark P Healy, Y Gopi Shanker, Maria Berkheimer, Thomas Faller, Florian von Raison, Carmen Serban, Jang-Ho Cha, S Nassir Ghaemi
{"title":"新型NR2B阴性变构调节剂Onfasprodil （MIJ821）在治疗抵抗性抑郁症患者中的快速起效和持续疗效：一项随机、安慰剂对照、概念验证的2期研究","authors":"Richard C Shelton, Robert E Litman, Howard Hassman, David P Walling, Salvador Ros Montalbán, Joan Salvà-Coll, John Zajecka, Oleksandr Sverdlov, Baltazar Gomez-Mancilla, Mark P Healy, Y Gopi Shanker, Maria Berkheimer, Thomas Faller, Florian von Raison, Carmen Serban, Jang-Ho Cha, S Nassir Ghaemi","doi":"10.4088/JCP.23m15246","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> Onfasprodil (MIJ821) is a highly potent and novel selective NR2B subunit negative allosteric modulator. This phase 2, randomized, placebo-controlled, proof-of-concept study evaluated efficacy and safety of onfasprodil in patients with treatment-resistant major depression (TRD).</p><p><p><b>Methods:</b> Adults with TRD who did not respond to ≥2 antidepressants were randomized (3:3:3:3:6:4) to receive a 40-minute intravenous infusion of onfasprodil 0.16 mg/kg weekly (n = 11), onfasprodil 0.16 mg/kg biweekly (n = 10), onfasprodil 0.32 mg/kg weekly (n = 10), onfasprodil 0.32 mg/kg biweekly (n = 9), placebo weekly (n=20), or ketamine 0.5 mg/kg weekly (n= 10) for 6 weeks. Primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score at 24 hours. Secondary end points were change in MADRS score at 48 hours and at final follow-up at 6 weeks. Safety and tolerability were assessed during the study.</p><p><p><b>Results:</b> Of 70 randomized patients, 53 (75.7%) completed the study. At 24 hours, adjusted mean differences versus placebo for pooled onfasprodil 0.16 mg/kg, 0.32 mg/kg, and ketamine groups were -8.25 (<i>P</i> = .001), -5.71 (<i>P</i> = .019), and -5.67 (<i>P</i> = .046), and at 48 hours, -7.06 (<i>P</i> = .013), -7.37 (<i>P</i> = .013), and -11.02 (<i>P</i> = .019), respectively. At Week 6, adjusted arithmetic mean MADRS difference between ketamine and placebo was -5.24 (80% CI, -10.42 to -0.06; <i>P</i>= .0974). At Week 6, the difference versus placebo on MADRS was -5.78 (<i>P</i>= .0427) for pooled 0.16 mg/kg and -4.24 (<i>P</i>= .1133) for pooled 0.32 mg/kg groups. The commonest treatment-emergent adverse events in the onfasprodil groups were dizziness (14.3%), transient amnesia (14.3%), and somnolence (11.4%). It had overall a good safety profile and was well tolerated.</p><p><p><b>Conclusion:</b> Onfasprodil appeared to be effective and well-tolerated across all dosing regimens in patients with TRD and demonstrated rapid onset of action (24 hours) with evidence of antidepressant effects to be maintained at Week 6, particularly for the lower-dose group.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT03756129.</p>","PeriodicalId":50234,"journal":{"name":"Journal of Clinical Psychiatry","volume":"86 3","pages":""},"PeriodicalIF":4.6000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Rapid Onset and Sustained Efficacy of Onfasprodil (MIJ821), a Novel NR2B Negative Allosteric Modulator, in Patients With Treatment-Resistant Depression: A Phase 2, Randomized, Placebo-Controlled, Proof-of-Concept Study.\",\"authors\":\"Richard C Shelton, Robert E Litman, Howard Hassman, David P Walling, Salvador Ros Montalbán, Joan Salvà-Coll, John Zajecka, Oleksandr Sverdlov, Baltazar Gomez-Mancilla, Mark P Healy, Y Gopi Shanker, Maria Berkheimer, Thomas Faller, Florian von Raison, Carmen Serban, Jang-Ho Cha, S Nassir Ghaemi\",\"doi\":\"10.4088/JCP.23m15246\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background:</b> Onfasprodil (MIJ821) is a highly potent and novel selective NR2B subunit negative allosteric modulator. This phase 2, randomized, placebo-controlled, proof-of-concept study evaluated efficacy and safety of onfasprodil in patients with treatment-resistant major depression (TRD).</p><p><p><b>Methods:</b> Adults with TRD who did not respond to ≥2 antidepressants were randomized (3:3:3:3:6:4) to receive a 40-minute intravenous infusion of onfasprodil 0.16 mg/kg weekly (n = 11), onfasprodil 0.16 mg/kg biweekly (n = 10), onfasprodil 0.32 mg/kg weekly (n = 10), onfasprodil 0.32 mg/kg biweekly (n = 9), placebo weekly (n=20), or ketamine 0.5 mg/kg weekly (n= 10) for 6 weeks. Primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score at 24 hours. Secondary end points were change in MADRS score at 48 hours and at final follow-up at 6 weeks. Safety and tolerability were assessed during the study.</p><p><p><b>Results:</b> Of 70 randomized patients, 53 (75.7%) completed the study. At 24 hours, adjusted mean differences versus placebo for pooled onfasprodil 0.16 mg/kg, 0.32 mg/kg, and ketamine groups were -8.25 (<i>P</i> = .001), -5.71 (<i>P</i> = .019), and -5.67 (<i>P</i> = .046), and at 48 hours, -7.06 (<i>P</i> = .013), -7.37 (<i>P</i> = .013), and -11.02 (<i>P</i> = .019), respectively. At Week 6, adjusted arithmetic mean MADRS difference between ketamine and placebo was -5.24 (80% CI, -10.42 to -0.06; <i>P</i>= .0974). At Week 6, the difference versus placebo on MADRS was -5.78 (<i>P</i>= .0427) for pooled 0.16 mg/kg and -4.24 (<i>P</i>= .1133) for pooled 0.32 mg/kg groups. The commonest treatment-emergent adverse events in the onfasprodil groups were dizziness (14.3%), transient amnesia (14.3%), and somnolence (11.4%). It had overall a good safety profile and was well tolerated.</p><p><p><b>Conclusion:</b> Onfasprodil appeared to be effective and well-tolerated across all dosing regimens in patients with TRD and demonstrated rapid onset of action (24 hours) with evidence of antidepressant effects to be maintained at Week 6, particularly for the lower-dose group.</p><p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT03756129.</p>\",\"PeriodicalId\":50234,\"journal\":{\"name\":\"Journal of Clinical Psychiatry\",\"volume\":\"86 3\",\"pages\":\"\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.4088/JCP.23m15246\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4088/JCP.23m15246","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
Rapid Onset and Sustained Efficacy of Onfasprodil (MIJ821), a Novel NR2B Negative Allosteric Modulator, in Patients With Treatment-Resistant Depression: A Phase 2, Randomized, Placebo-Controlled, Proof-of-Concept Study.
Background: Onfasprodil (MIJ821) is a highly potent and novel selective NR2B subunit negative allosteric modulator. This phase 2, randomized, placebo-controlled, proof-of-concept study evaluated efficacy and safety of onfasprodil in patients with treatment-resistant major depression (TRD).
Methods: Adults with TRD who did not respond to ≥2 antidepressants were randomized (3:3:3:3:6:4) to receive a 40-minute intravenous infusion of onfasprodil 0.16 mg/kg weekly (n = 11), onfasprodil 0.16 mg/kg biweekly (n = 10), onfasprodil 0.32 mg/kg weekly (n = 10), onfasprodil 0.32 mg/kg biweekly (n = 9), placebo weekly (n=20), or ketamine 0.5 mg/kg weekly (n= 10) for 6 weeks. Primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score at 24 hours. Secondary end points were change in MADRS score at 48 hours and at final follow-up at 6 weeks. Safety and tolerability were assessed during the study.
Results: Of 70 randomized patients, 53 (75.7%) completed the study. At 24 hours, adjusted mean differences versus placebo for pooled onfasprodil 0.16 mg/kg, 0.32 mg/kg, and ketamine groups were -8.25 (P = .001), -5.71 (P = .019), and -5.67 (P = .046), and at 48 hours, -7.06 (P = .013), -7.37 (P = .013), and -11.02 (P = .019), respectively. At Week 6, adjusted arithmetic mean MADRS difference between ketamine and placebo was -5.24 (80% CI, -10.42 to -0.06; P= .0974). At Week 6, the difference versus placebo on MADRS was -5.78 (P= .0427) for pooled 0.16 mg/kg and -4.24 (P= .1133) for pooled 0.32 mg/kg groups. The commonest treatment-emergent adverse events in the onfasprodil groups were dizziness (14.3%), transient amnesia (14.3%), and somnolence (11.4%). It had overall a good safety profile and was well tolerated.
Conclusion: Onfasprodil appeared to be effective and well-tolerated across all dosing regimens in patients with TRD and demonstrated rapid onset of action (24 hours) with evidence of antidepressant effects to be maintained at Week 6, particularly for the lower-dose group.
期刊介绍：
For over 75 years, The Journal of Clinical Psychiatry has been a leading source of peer-reviewed articles offering the latest information on mental health topics to psychiatrists and other medical professionals.The Journal of Clinical Psychiatry is the leading psychiatric resource for clinical information and covers disorders including depression, bipolar disorder, schizophrenia, anxiety, addiction, posttraumatic stress disorder, and attention-deficit/hyperactivity disorder while exploring the newest advances in diagnosis and treatment.
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