Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression A Randomized Clinical Trial

被引:458
作者
Daly, Ella J. [1 ]
Singh, Jaskaran B. [2 ]
Fedgchin, Maggie [1 ]
Cooper, Kimberly [3 ]
Lim, Pilar [4 ]
Shelton, Richard C. [5 ]
Thase, Michael E. [6 ]
Winokur, Andrew [7 ,8 ]
Van Nueten, Luc [9 ]
Manji, Husseini [1 ]
Drevets, Wayne C. [1 ]
机构
[1] Janssen Res & Dev LLC, Dept Neurosci, 1125 Trenton Harbourton Rd, Titusville, NJ 08560 USA
[2] Janssen Res & Dev LLC, Dept Neurosci, San Diego, CA USA
[3] Janssen Res & Dev LLC, Dept Neurosci, Spring House, PA USA
[4] Janssen Res & Dev LLC, Dept Quantitat Sci, Titusville, NJ USA
[5] Univ Alabama Birmingham, Sch Med, Dept Psychiat, Birmingham, AL USA
[6] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA
[7] Inst Living, Hartford, CT USA
[8] UConn Hlth, Dept Psychiat, Farmington, CT USA
[9] Janssen Res & Dev, Dept Neurosci, Beerse, Belgium
关键词
HIGH PLACEBO-RESPONSE; REPORT QIDS-SR; MAJOR DEPRESSION; DOUBLE-BLIND; QUICK INVENTORY; KETAMINE; DESIGN; SYMPTOMATOLOGY; DISORDERS; MECHANISMS;
D O I
10.1001/jamapsychiatry.2017.3739
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
IMPORTANCE Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. OBJECTIVE To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). DESIGN, SETTING, AND PARTICIPANTS This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. INTERVENTIONS In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. MAIN OUTCOMES AND MEASURES The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. RESULTS Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). CONCLUSIONS AND RELEVANCE In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.
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页码:139 / 148
页数:10
相关论文
共 47 条
  • [1] American Psychiatric Association, 2013, DIAGN STAT MAN MENT, DOI [DOI 10.1176/APPI.BOOKS.9780890425596, 10.1176/appi.books.9780890425596]
  • [2] World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects
    [J]. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2013, 310 (20): : 2191 - 2194
  • [3] [Anonymous], 1976, DHEW PUBL
  • [4] [Anonymous], AM PSYCH ASS PRACT G
  • [5] Antidepressant effects of ketamine in depressed patients
    Berman, RM
    Cappiello, A
    Anand, A
    Oren, DA
    Heninger, GR
    Charney, DS
    Krystal, JH
    [J]. BIOLOGICAL PSYCHIATRY, 2000, 47 (04) : 351 - 354
  • [6] Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS)
    Bremner, JD
    Krystal, JH
    Putnam, FW
    Southwick, SM
    Marmar, C
    Charney, DS
    Mazure, CM
    [J]. JOURNAL OF TRAUMATIC STRESS, 1998, 11 (01) : 125 - 136
  • [7] Combining multiple comparisons and modeling techniques in dose-response studies
    Bretz, F
    Pinheiro, JC
    Branson, M
    [J]. BIOMETRICS, 2005, 61 (03) : 738 - 748
  • [8] Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ)
    Chandler, Gregory M.
    Iosifescu, Dan V.
    Pollack, Mark H.
    Targum, Steven D.
    Fava, Maurizio
    [J]. CNS NEUROSCIENCE & THERAPEUTICS, 2010, 16 (05) : 322 - 325
  • [9] A sequential enriched design for target patient population in psychiatric clinical trials
    Chen, Yeh-Fong
    Zhang, Xiangmin
    Tamura, Roy N.
    Chen, Chiung M.
    [J]. STATISTICS IN MEDICINE, 2014, 33 (17) : 2953 - 2967
  • [10] Evaluation of performance of some enrichment designs dealing with high placebo response in psychiatric clinical trials
    Chen, Yeh-Fong
    Yang, Yang
    Hung, H. M. James
    Wang, Sue-Jane
    [J]. CONTEMPORARY CLINICAL TRIALS, 2011, 32 (04) : 592 - 604