Sublingual Dexmedetomidine for Agitation Associated with Schizophrenia or Bipolar Disorder: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed

Leslie Citrome, Robert Risinger, Lavanya Rajachandran, Heather Robison, Leslie Citrome, Robert Risinger, Lavanya Rajachandran, Heather Robison

Abstract

Introduction: The objective was to use the evidence-based medicine metrics of number needed to treat, number needed to harm, and likelihood to be helped or harmed to appraise the clinical efficacy and tolerability of sublingual dexmedetomidine in adults with agitation associated with schizophrenia or bipolar disorder.

Methods: Sublingual dexmedetomidine data for this post hoc analysis were obtained from two similarly designed, double-blind, randomized, placebo-controlled studies of adults with schizophrenia or bipolar disorder. Response to treatment was defined as a ≥ 40% reduction from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC). Tolerability was assessed by evaluating rates of adverse events.

Results: The number needed to treat (95% confidence interval) estimate versus placebo for PEC response at 2 h post-dose was 3 (2, 3) for the sublingual dexmedetomidine 180-µg group (n = 125) and 3 (3, 4) for the 120-µg group (n = 129) in the study of patients with schizophrenia and 3 (2, 3) for the sublingual dexmedetomidine 180-µg group (n = 126) and 4 (3, 6) for the 120-µg group (n = 126) in the study of patients with bipolar disorder. Number needed to harm values versus placebo were greater than 10 for all adverse events except somnolence, where the number needed to harm (95% confidence interval) was 7 (5, 10) for all doses pooled from both studies. In all instances, likelihood to be helped or harmed values were greater than 1 for efficacy versus applicable tolerability outcomes.

Conclusions: The number needed to treat, number needed to harm, and likelihood to be helped or harmed of sublingual dexmedetomidine support a favorable benefit-risk profile in adults with acute agitation associated with schizophrenia or bipolar disorder.

Trial registration: ClinicalTrials.gov, https://ichgcp.net/clinical-trials-registry/NCT04268303 , NCT04268303.

Clinicaltrials: gov, https://ichgcp.net/clinical-trials-registry/NCT04276883 , NCT04276883.

Keywords: Agitation; Bipolar disorder; Number needed to treat; Schizophrenia; Sublingual dexmedetomidine.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Time course of number needed to treat versus placebo for sublingual dexmedetomidine (all diagnoses and doses pooled) based on Positive and Negative Syndrome Scale-Excited Component response
Fig. 2
Fig. 2
Number needed to treat and 95% confidence intervals for response versus placebo for sublingual dexmedetomidine, 120 µg or 180 µg, inhaled loxapine, 5 or 10 mg, intramuscular ziprasidone, 10 or 20 mg, intramuscular olanzapine, 10 mg, and intramuscular aripiprazole, 9.75 mg. All data pooled from available studies as reported elsewhere. Not shown are data for haloperidol 6.5–7.5 mg or lorazepam 2 mg administered intramuscularly, where the NNT (95% CI) for response versus placebo has been reported as 4 (3, 5) and 4 (3, 7); refer to Fig. 1 in Citrome L. J Clin Psychiatry. 2007;68(12):1876–85

References

    1. Garriga M, Pacchiarotti I, Kasper S, et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry. 2016;17(2):86–128. doi: 10.3109/15622975.2015.1132007.
    1. Sacchetti E, Valsecchi P, Tamussi E, Paulli L, Morigi R, Vita A. Psychomotor agitation in subjects hospitalized for an acute exacerbation of Schizophrenia. Psychiatry Res. 2018;270:357–364. doi: 10.1016/j.psychres.2018.09.058.
    1. Alderfer BS, Allen MH. Treatment of agitation in bipolar disorder across the life cycle. J Clin Psychiatry. 2003;64(Suppl 4):3–9.
    1. Martinez-Raga J, Amore M, Di Sciascio G, et al. 1st International experts’ meeting on agitation: conclusions regarding the current and ideal management paradigm of agitation. Front Psychiatry. 2018;9:54. doi: 10.3389/fpsyt.2018.00054.
    1. Pacciardi B, Calcedo A, Messer T. Inhaled loxapine for the management of acute agitation in bipolar disorder and schizophrenia: expert review and commentary in an era of change. Drugs R D. 2019;19(1):15–25. doi: 10.1007/s40268-019-0262-3.
    1. Patel MX, Sethi FN, Barnes TRE, et al. Joint BAP NAPICU evidence-based consensus guidelines for the clinical management of acute disturbance: de-escalation and rapid tranquillisation. J Psychiatric Intensive Care. 2018;14(2):89–132. doi: 10.20299/jpi.2018.008.
    1. Wasserstein RL, Lazar NA. The ASA Statement on p-values: context, process, and purpose. Am Stat. 2016;70(2):129–133. doi: 10.1080/00031305.2016.1154108.
    1. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988;318(26):1728–1733. doi: 10.1056/NEJM198806303182605.
    1. Altman DG. Confidence intervals for the number needed to treat. BMJ. 1998;317(7168):1309–1312. doi: 10.1136/bmj.317.7168.1309.
    1. Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67(5):407–411. doi: 10.1111/ijcp.12142.
    1. Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry. 2007;68(12):1876–1885. doi: 10.4088/JCP.v68n1207.
    1. Citrome L. Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder. Int J Clin Pract. 2012;66(3):318–325. doi: 10.1111/j.1742-1241.2011.02890.x.
    1. Pratts M, Citrome L, Grant W, Leso L, Opler LA. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand. 2014;130(1):61–68. doi: 10.1111/acps.12262.
    1. Citrome L, Juday T, Frech F, Atkins N., Jr Lemborexant for the treatment of insomnia: direct and indirect comparisons with other hypnotics using number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Clin Psychiatry. 2021 doi: 10.4088/JCP.20m13795.
    1. Citrome L, DiBernardo A, Singh J. Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Affect Disord. 2020;271:228–238. doi: 10.1016/j.jad.2020.03.106.
    1. Citrome L, Sánchez Del Rio M, Dong Y, et al. Benefit-risk assessment of galcanezumab versus placebo for the treatment of episodic and chronic migraine using the metrics of number needed to treat and number needed to harm. Adv Ther. 2021;38(8):4442–4460. doi: 10.1007/s12325-021-01848-x.
    1. Weerink MAS, Struys M, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 2017;56(8):893–913. doi: 10.1007/s40262-017-0507-7.
    1. Preskorn SH, Risinger R, Kakar R, Yocca FD. Double-blind, placebo-controlled, single ascending dose, study to determine the efficacy, safety, and pharmacokinetics of a BXCL501 (sublingual dexmedetomidine) in agitation associated with schizophrenia or related. Neuropsychopharmacology. 2019;44:114.
    1. Citrome L, Preskorn SH, Lauriello J, et al. Sublingual dexmedetomidine for the treatment of acute agitation in adults with schizophrenia or schizoaffective disorder: a randomized placebo-controlled trial. J Clin Psychiatry. (In Press)
    1. Preskorn SH, Zeller S, Citrome L, et al. Effect of sublingual dexmedetomidine vs placebo on acute agitation associated with bipolar disorder: a randomized clinical trial. JAMA. 2022;327(8):727–736. doi: 10.1001/jama.2022.0799.
    1. Montoya A, Valladares A, Lizán L, San L, Escobar R, Paz S. Validation of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room. Health Qual Life Outcomes. 2011;9:18. doi: 10.1186/1477-7525-9-18.
    1. Citrome L. Dexmedetomidine sublingual film for agitation. Curr Psychiatry. 2022;21(6):34–38. doi: 10.12788/cp.0255.
    1. American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 5. Arlington: APA (American Psychiatric Association); 2013.
    1. Guy W. ECDEU assessment manual for psychopharmacology. Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976.
    1. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology. 2002;26(4):494–504. doi: 10.1016/S0893-133X(01)00365-7.
    1. Battaglia J, Lindborg SR, Alaka K, Meehan K, Wright P. Calming versus sedative effects of intramuscular olanzapine in agitated patients. Am J Emerg Med. 2003;21(3):192–198. doi: 10.1016/S0735-6757(02)42249-8.
    1. Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117(6):412–419. doi: 10.1111/j.1600-0447.2008.01194.x.
    1. Citrome L. Relative vs. absolute measures of benefit and risk: what's the difference? Acta Psychiatr Scand. 2010;121(2):94–102. doi: 10.1111/j.1600-0447.2009.01449.x.

Source: PubMed

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