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142 Withdrawal Symptom Assessment in an Esketamine Safety Study in Patients with Treatment-resistant Depression
- Leah Aluisio, Lynn Yieh, Ewa Wajs, Allitia DiBernardo, Andrew Krystal, Wayne Drevets, Yun Wu, Jagadish Gogate, Ella Daly, Peter Zannikos, Valerie Curran, Guang Chen, Jaskaran Singh
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, p. 290
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Background:
SUSTAIN-2 (NCT02497287) was an open-label, phase III trial evaluating the safety of esketamine (ESK) nasal spray plus a newly initiated oral antidepressant (AD) for up to 1 year in adults with treatment-resistant depression (TRD). ESK is a schedule III drug that acts via glutamate receptor modulation. ESK is rapidly cleared from the plasma, and with intermittent dosing there is no accumulation. Thus, no withdrawal syndrome is expected. The current analysis assessed potential withdrawal symptoms in patients who discontinued ESK after long-term, intermittent use. In the absence of a glutamatergic-specific withdrawal scale, the Physicians Withdrawal Checklist1 (PWC-20) was used. The PWC-20 was designed to assess new or worsening benzodiazepine-like discontinuation symptoms after stopping non-SSRI anxiolytics.
Methods:ESK nasal spray was administered two times per week during a 4-week induction phase (IND). Responders entered the optimization/maintenance phase (O/M) where ESK nasal spray was dosed either weekly or every two weeks for up to 48 weeks. Patients entered a 4-week follow up period (F/U) after discontinuation from either phase, during which continuation of the AD was recommended. PWC-20 assessments were conducted at the last ESK dosing (endpoint of IND or O/M) and at weeks 1, 2 and 4 of F/U. Symptoms were rated using a 0-3-point scale (Not present = 0, Mild = 1, Moderate = 2, Severe = 3). To account for worsening of underlying depression, subset calculations were performed for depressive symptoms (PWC-DS: loss of appetite; anxiety or nervousness; irritability; dysphoric mood or depression; insomnia; fatigue, lethargy or lack of energy; restlessness or agitation; headaches; muscle aches or stiffness; weakness; difficulty concentrating or remembering; depersonalization-derealization) and withdrawal symptoms (PWC-WS: nausea and/or vomiting; diarrhea; poor coordination; diaphoresis; tremor or tremulousness; dizziness or light-headedness; increased acuity of sound, smell, or touch; paresthesias).
Results:Data on 357 patients entering F/U were included in the analysis (91 completed treatment during the IND phase and 141 were treated during O/M). The mean (SD) PWC-20 total scores (range 0-60) at treatment endpoint, Week 1, 2 and 4 were 7.2 (6.8), 7.5(7.0), 7.4 (7.1) and 7.2 (6.9), respectively. At these same assessment times, mean PWC-WS scores (range 0-24) were 0.9 (1.7), 1.0 (1.7), 1.0 (1.8), and 0.9 (1.8). Mean PWC-DS scores (range 0-36) were 6.3 (5.6), 6.5 (5.7), 6.5 (5.8), and 6.3 (5.7), respectively. Complete analysis of data from the entire SUSTAIN-2 dataset will be presented.
Conclusions:No indication of drug-specific withdrawal symptoms was seen after stopping up to 1-year of intermittent treatment with ESK nasal spray for TRD.
Funding Acknowledgements:Janssen Research and Development
144 Esketamine Nasal Spray for Management of Treatment-Resistant Depression: Number Needed to Treat, Number Needed to Harm, Likelihood to be Helped/Harmed
- Leslie Citrome, Allitia DiBernardo, Jaskaran Singh
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 291-292
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Background:
Targeting of glutamate receptors is a novel approach for the treatment of major depressive disorder (MDD). This study aimed to review the usefulness for esketamine nasal spray for the management of treatment-resistant depression (TRD) using the tools of evidence-based medicine: number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).
Methods:Data sources were four completed Phase 3 randomized, double-blind, placebo-controlled, studies, including two pivotal registration studies of esketamine nasal spray in TRD in non-elderly adults (acute flexible-dose study NCT02418585, maintenance study NCT02493868) Efficacy outcomes included acute response (≥50% decrease from baseline on Montgomery-Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12; and other thresholds using the MADRS and Clinical Global Impressions-Severity [CGI-S] scales), categorical shifts in MADRS and CGI-S scores, and avoidance of relapse/recurrence (observed relapse rates). NNT, NNH and LLH are calculated for combination of esketamine nasal spray and oral antidepressant (esketamine+AD) vs AD+placebo in patients with TRD.
Results:In the acute flexible-dose study of esketamine nasal spray (56-84 mg twice-weekly for 4 weeks), MADRS response with esketamine+AD vs AD+placebo at endpoint (rates 63.4% vs 49.5%, respectively) yielded an NNT value of 8, and MADRS remission at endpoint (48.2% vs 30.3%) resulted in a NNT vs AD+placebo of 6. NNH values vs AD+placebo were <10 for the adverse events (AE) of dissociation (26.1% vs 3.7%), vertigo (26.1% vs 2.8%), nausea (26.1% vs 6.4%), dizziness (20.9% vs 4.6%), and dysgeusia (24.3% vs 11.9%), the NNH values were 5, 5, 6, 7, and 9, respectively. Discontinuation rates due to AE (7.0% vs 0.9%) yielded a NNH of 17. LHH comparing MADRS remission vs discontinuation was 17/6, or approximately 3. The pattern of results was similar for the other acute studies and for the pooled data combining all 3 acute studies. Maintenance use of esketamine (dose 56-84 mg once-weekly or once-every-other-week) plus an oral AD demonstrated NNT values <10 for relapse and/or maintenance of remission in favor of esketamine+AD vs AD+placebo, a NNT of 4 was observed for outcome of relapse in patients with stable response at the time of randomization (relapse rates were 25.8% vs 57.6%, respectively). In the maintenance study, discontinuation rates due to an AE (2.6% vs 2.1%) yielded a non-significant NNH value of 178.
Conclusion:The low NNT values <10 for efficacy outcomes suggest potential benefits of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times more likely to result in acute remission vs discontinuation due to an AE.
Funding Acknowledgements:Janssen Global Services, LLC
156 Improvement in Disease Severity in Patients With Treatment-Resistant Depression Following Treatment With Intranasal Esketamine
- Abigail Nash, May Shawi, Jaskaran Singh, Ella Daly, Kimberly Copper, Pilar Lim, Rosanne Lane, Jagadish Gogate, Allitia DiBernardo, David Hough, Larry Alphs
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, pp. 95-96
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Background
Recognizing the importance not only of the clinician’s opinion but also of the patient’s experience and perspective, Sequenced Treatment Alternatives to Relieve Depression (STAR*D) utilized both clinician-reported and patient-reported outcomes in a large-scale multi-step study on antidepressant effectiveness in real-world settings. Both approaches indicate that <17% of Major Depressive Disorder (MDD) patients respond to novel oral treatments after two prior antidepressant failures. To address this low response rate and continue to investigate the use of patient-rated outcomes in clinical trials, an antidepressant with a new mechanism of action is being investigated for efficacy and safety utilizing both clinician-rated and patient-reported scales.
MethodsThis is a post-hoc analysis of a Janssen R&D Phase 2a clinical trial (ESKETINTRD2003). Subjects aged 20-64 withMDD without psychotic features (DSM IV) and a history of inadequate response to ≥2 antidepressants were randomized [3:1:1:1] to 1 week of twice-weekly treatment with intranasal placebo (n=33), esketamine 28 mg (n=11), 56 mg (n=11), or 84 mg (n=12). Participants taking oral antidepressants at study entry continued treatment during the study. Changes in depression severitywere measured using the Clinical Global Impression Severity (CGI-S) and the Patient Global Impression Severity (PGI-S) scales.
ResultsAt all esketamine doses (28 mg, 56 mg, 84 mg), subjects reported a one-point mean change in PGI-S from baseline to week one compared to no change on placebo (p-values 0.005, 0.001, 0.032 respectively). Similarly, mean CGI-S scores improved for subjects receiving esketamine at all doses (p-values 0.028, 0.004, 0.049 respectively) compared to no change inplacebo subjects. These data are consistent with previously reported data based on the Montgomery Åsberg Depression Rating Scale (MADRS) and support positive correlation between patient-reported and clinician-reported outcomes.
DiscussionInitial results from this Phase 2a study suggest clinically relevant improvement in depression symptoms in as early as one week when treated with twice-weekly intranasal esketamine as reported by both clinicians and patients. This work will help guide future investigations of esketamine in larger populations to provide better therapeutic options for treatment resistantMDD patients.
Funding AcknowledgementsJanssen