An overview of the efficacy and safety of brexpiprazole for the treatment of schizophrenia in adolescents

REFERENCES

• Solmi M, Radua J, Olivola M, et al. Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies. Mol Psychiatry. 2022;27(1):281–295. doi: 10.1038/s41380-021-01161-7
   PubMed Web of Science ®Google Scholar
• Giedd JN, Blumenthal J, Jeffries NO, et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 1999;2(10):861–863. doi: 10.1038/13158
   PubMed Web of Science ®Google Scholar
• Johnson SB, Blum RW, Giedd JN. Adolescent maturity and the brain: the promise and pitfalls of neuroscience research in adolescent health policy. J Adolesc Health. 2009;45(3):216–221. doi: 10.1016/j.jadohealth.2009.05.016
   PubMed Web of Science ®Google Scholar
• Arain M, Haque M, Johal L, Mathur P, Nel W, Rais A, Sandhu R, Sharma S. Maturation of the adolescent brain. Neuropsychiatr Dis Treat 2013;9:449–461.
   PubMed Web of Science ®Google Scholar
• Martinotti G, De Risio L, Vannini C, et al. Substance-related exogenous psychosis: a postmodern syndrome. CNS Spectr. 2021;26(1):84–91. doi: 10.1017/S1092852920001479
   PubMed Web of Science ®Google Scholar
• Martinotti G, Chiappini S, Mosca A, et al. Atypical antipsychotic drugs in dual disorders: Current evidence for clinical practice. Curr Pharm Des. 2022;28(27):2241–2259. doi: 10.2174/1381612828666220623092853
   PubMed Web of Science ®Google Scholar
• Kendler KS, Ohlsson H, Sundquist J, et al. Prediction of onset of substance-induced psychotic disorder and its progression to schizophrenia in a Swedish national sample. Am J Psychiatry. 2019;176(9):711–719. doi: 10.1176/appi.ajp.2019.18101217
   PubMed Web of Science ®Google Scholar
• Crump CJ, Good ME, Abuelazm H, El-Mallakh RS. Advances in the pharmacotherapeutic management of juvenile-onset schizophrenia. Expert Opin Pharmacother 2023;24(9):1039–1052, 2023. doi: 10.1080/14656566.2023.2208269
   PubMed Web of Science ®Google Scholar
• Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44(7):660–669. doi: 10.1001/archpsyc.1987.01800190080012
   PubMed Web of Science ®Google Scholar
• Toda M, Abi-Dargham A. Dopamine hypothesis of schizophrenia: making sense of it all. Curr Psychiatry Rep. 2007;9(4):329–336. doi: 10.1007/s11920-007-0041-7
   PubMedGoogle Scholar
• El-Mallakh RS, Rhodes P, Dobbins K. The case for case management in schizophrenia. Prof Case Manag 2019;24(5):273–276.
   PubMed Web of Science ®Google Scholar
• Talpur AR, Elsayed OH, El-Mallakh RS. Does Coronavirus-19 infection during pregnancy increase the risk for subsequent schizophrenia in the offspring? Univ Louisville J Resp Infect 2023;7(1):Article 9. doi: 10.55504/2473-2869.1268
   Google Scholar
• Opler MG, Susser ES. Fetal environment and schizophrenia. Environ Health Perspect. 2005 Sep;113(9):1239–42. doi: 10.1289/ehp.7572
   PubMed Web of Science ®Google Scholar
• Fan CH, Hsu SC, Hsiao FH, et al. The association of social support and symptomatic remission among community-dwelling schizophrenia patients: A cross-sectional study. Int J Environ Res Public Health. 2021 Apr 9;18(8):3977. doi: 10.3390/ijerph18083977
   PubMed Web of Science ®Google Scholar
• Hollis C. Adolescent schizophrenia. Adv Psychiatr Treat. 2000;6(2):83–92. doi: 10.1192/apt.6.2.83
   Google Scholar
• Centers for Medicare & Medicaid Services (CMS) Medicaid Integrity Group. Atypical Antipsychotic Medications: Use in Pediatric Patients. Fact Sheet, published October 2015, https://www.cms.gov/medicare-medicaid-coordination/fraud-prevention/medicaid-integrity-education/pharmacy-education-materials/downloads/atyp-antipsych-pediatric-factsheet11-14.pdf accessed 29 August 2023
   Google Scholar
• Sommi RW, Rege B, Wehr A, et al. Aripiprazole Lauroxil Dosing Regimens: Understanding Dosage Strengths and Injection Intervals. CNS Spectr. 2022 Jun;27(3):262–267. doi: 10.1017/S1092852920002072
   PubMed Web of Science ®Google Scholar
• Harlin M, Chepke C, Larsen F, et al. Aripiprazole plasma concentrations delivered from two 2-month long-acting injectable formulations: An indirect comparison. Neuropsychiatr Dis Treat 2023;19:1409–1416. doi: 10.2147/NDT.S412357
   PubMed Web of Science ®Google Scholar
• Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, “just the facts”: what we know in 2008 part 1: Overview. Schizophr Res. 2008;100:4–19. doi: 10.1016/j.schres.2008.01.022
   PubMed Web of Science ®Google Scholar
• GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry 2022;9:137–150. doi: 10.1016/S2215-0366(21)00395-3
   Web of Science ®Google Scholar
• Food and Drug Administration. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research. FDA Approves REXULTI (Brexpiprazole) for Pediatric Patients 13 to 17 Years of Age for the Treatment of Schizophrenia Utilizing Extrapolation of the Adult Effectiveness Data. FDA News: Issue 1–4, January 14, 2022, https://www.ascpt.org/resources/ascpt-news/view/articleid/27576/fda-news-issue-1-4-january-2022 accessed 29 August 2023
   Google Scholar
• Sleem A, El-Mallakh RS. Adaptive changes to antipsychotics: How to avoid the consequences. Curr Psychiatry 2022;21(7):46–50,52. doi: 10.12788/cp.0262
   Google Scholar
• Siwek M, Wojtasik-Bakalarz K, Krupa AJ, Chrobak AA. Brexpiprazole-pharmacologic properties and use in schizophrenia and mood disorders. Brain Sci. 2023;13(3):397. doi: 10.3390/brainsci13030397
   PubMed Web of Science ®Google Scholar
• Strzelczyk AA, Jarończyk M, Chilmonczyk Z, et al. Intrinsic activity and comparative molecular dynamics of buspirone analogues at the 5-HT1A receptors. Biochem Pharmacol. 2004;67(12):2219–2230. doi: 10.1016/j.bcp.2004.02.026
   PubMed Web of Science ®Google Scholar
• Citrome L, Stensbøl TB, Maeda K The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders? Expert Rev Neurother. 2015 Oct;15(10):1219–1229. doi: 10.1586/14737175.2015.1086269.
   PubMed Web of Science ®Google Scholar
• Celada P, Puig M, Amargós-Bosch M, Adell A, Artigas F. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci. 2004;29(4):252–265.
   PubMed Web of Science ®Google Scholar
• Mnie-Filali O, Faure C, Lambás-Señas L, El Mansari M, Belblidia H, Gondard E, Etiévant A, Scarna H, Didier A, Berod A, Blier P, Haddjeri N. Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy. Neuropsychopharmacology. 2011;36(6):1275–1288. doi: 10.1038/npp.2011.13
   PubMed Web of Science ®Google Scholar
• Andrews GD, Lavin A. Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors. Neuropsychopharmacology. 2006;31(3):594–601. doi: 10.1038/sj.npp.1300818
   PubMed Web of Science ®Google Scholar
• Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507–517. doi: 10.1056/NEJMoa1507598
   PubMed Web of Science ®Google Scholar
• Eaves S, Rey JA. Brexpiprazole (Rexulti): A new monotherapy for schizophrenia and adjunctive therapy for major depressive disorder. PT (Pharmacy and Therapeutics) 2016;41(7):418–422.
   Google Scholar
• Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, McQuade RD, Carson WH, Nyilas M, Sanchez R, Eriksson H. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: A phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry 2015;76(9):1224–1231. doi: 10.4088/JCP.14m09688
   PubMed Web of Science ®Google Scholar
• Bauer M, Hefting N, Lindsten A, Josiassen MK, Hobart M. A randomised, placebo-controlled 24-week study evaluating adjunctive brexpiprazole in patients with major depressive disorder. Acta Neuropsychiatr 2019;31(1):27–35. doi: 10.1017/neu.2018.23
   PubMed Web of Science ®Google Scholar
• Hobart M, Skuban A, Zhang P, Augustine C, Brewer C, Hefting N, Sanchez R, McQuade RD. A randomized, placebo-controlled study of the efficacy and safety of fixed-dose arexpiprazole 2 mg/d as Adjunctive treatment of adults with major depressive disorder. J Clin Psychiatry 2018;79(4):17m12058. doi: 10.4088/JCP.17m12058
   PubMed Web of Science ®Google Scholar
• Hobart M, Skuban A, Zhang P, et al. Efficacy and safety of flexibly dosed brexpiprazole for the adjunctive treatment of major depressive disorder: a randomized, active-referenced, placebo-controlled study. Curr Med Res Opin. 2018;34(4):633–642. doi: 10.1080/03007995.2018.1430220
   PubMed Web of Science ®Google Scholar
• Weiller E, Weiss C, Watling CP, et al. Functioning outcomes with adjunctive treatments for major depressive disorder: A systematic review of randomized placebo-controlled studies. Neuropsychiatr Dis Treat 2017;14:103–115. doi: 10.2147/NDT.S146840
   PubMed Web of Science ®Google Scholar
• Hobart M, Zhang P, Weiss C, Meehan SR, Eriksson H. Adjunctive brexpiprazole and functioning in major depressive disorder: A pooled analysis of six randomized studies using the Sheehan Disability Scale. Int J Neuropsychopharmacol 2019;22(3):173–179. doi: 10.1093/ijnp/pyy095
   PubMed Web of Science ®Google Scholar
• Correll CU, He Y, Therrien F, et al. Effects of brexpiprazole on functioning in patients with schizophrenia: post hoc analysis of short- and long-term studies. J Clin Psychiatry. 2022;83(2):20m13793. doi: 10.4088/JCP.20m13793
   PubMed Web of Science ®Google Scholar
• Drake RJ, Husain N, Marshall M, et al. Effect of delaying treatment of first-episode psychosis on symptoms and social outcomes: a longitudinal analysis and modelling study. Lancet Psychiatry. 2020;7(7):602–610. doi: 10.1016/S2215-0366(20)30147-4
   PubMed Web of Science ®Google Scholar
• Enders JR, Reddy SG, Strickland EC, McIntire GL. Identification of metabolites of brexpiprazole in human urine for use in monitoring patient compliance. Clin Mass Spectrometry 2017;6:21–24, doi: 10.1016/j.clinms.2017.11.001
   Google Scholar
• Wang Y, Wang X, Larsen F, et al. Population pharmacokinetic analysis of brexpiprazole to support its indication and dose selection in adolescents with schizophrenia. J Clin Pharmacol. 2023 Nov;63(11):1290–1299. doi: 10.1002/jcph.2307
   PubMed Web of Science ®Google Scholar
• Atkinson SD, Shah A, Burgess MV, Hefting N, Chen D, Ward CL. Safety and tolerability of brexpiprazole in adolescents with schizophrenia: A long-term, open-label study. JAACAP Open (J Am Acad Child Adoles Psychiatry Open) 2024. https://doi.org/10.1016/j.jaacop.2024.04.005.
   Google Scholar
• Kane JM, Skuban A, Hobart M, et al. Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res. 2016;174(1–3):93–98. doi: 10.1016/j.schres.2016.04.013
   PubMed Web of Science ®Google Scholar
• Antoun Reyad A, Girgis E, Mishriky R. Efficacy and safety of brexpiprazole in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials. Int Clin Psychopharmacol. 2020;35(3):119–128. doi: 10.1097/YIC.0000000000000308
   PubMed Web of Science ®Google Scholar
• Safer DJ. A comparison of risperidone-induced weight gain across the age span. J Clin Psychopharmacol. 2004;24(4):429–436. doi: 10.1097/01.jcp.0000130558.86125.5b
   PubMed Web of Science ®Google Scholar
• De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU. Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: A systematic review of randomized, placebo-controlled trials and guidelines for clinical practice. Eur Psychiatry 2011;26(3):144–158.
   PubMed Web of Science ®Google Scholar
• Lee TT, Demick DS, Worthington MA, Summers AT, El-Mallakh RS. The short form of the serotonin transporter and the safety of antidepressants when administered to pediatric populations. Curr Trends Neurol 2020;14:73–83.
   Google Scholar
• Harrison JN, Cluxton-Keller F, Gross D. Antipsychotic medication prescribing trends in children and adolescents. J Pediatr Health Care. 2012;26(2):139–145. doi: 10.1016/j.pedhc.2011.10.009
   PubMed Web of Science ®Google Scholar
• Dennis M, Spiegler BJ, Juranek JJ, Bigler ED, Snead OC, Fletcher JM. Age, plasticity, and homeostasis in childhood brain disorders. Neurosci Biobehav Rev. 2013;37(10 Pt 2):2760–2773. doi: 10.1016/j.neubiorev.2013.09.010
   PubMed Web of Science ®Google Scholar
• Ali Z, Roque A, El-Mallakh RS A unifying theory for the pathoetiologic mechanism of tardive dyskinesia. Med Hypoth 2020;140:109682. 10.1016/j.mehy.2020.109682
   PubMed Web of Science ®Google Scholar
• Solmi M, Pigato G, Kane JM, et al. Clinical risk factors for the development of tardive dyskinesia. J Neurol Sci. 2018 Jun 15;389:21–27. doi: 10.1016/j.jns.2018.02.012
   PubMed Web of Science ®Google Scholar
• Chouinard G, Samaha AN, Chouinard VA, et al. Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychother Psychosom. 2017;86(4):189–219. doi: 10.1159/000477313
   PubMed Web of Science ®Google Scholar
• Kane JM, Schooler NR, Marcy P, Correll CU, Achtyes ED, Gibbons RD, Robinson DG. Effect of long-acting injectable antipsychotics vs usual care on time to first hospitalization in early-phase schizophrenia: A randomized clinical trial. JAMA Psychiatry 2020;77(12):1217–1224. doi: 10.1001/jamapsychiatry.2020.2076.
   Google Scholar
• Correll CU, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, Nyilas M, Carson WH, Sanchez R, Eriksson H. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: A 6-Week randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2015;172(9):870–880. doi: 10.1176/appi.ajp.2015.14101275
   PubMed Web of Science ®Google Scholar
• Robinson DG, Gallego JA, John M, et al. A randomized comparison of aripiprazole and risperidone for the acute treatment of first-episode schizophrenia and related disorders: 3-month outcomes. Schizophr Bull. 2015;41(6):1227–1236. doi: 10.1093/schbul/sbv125
   PubMed Web of Science ®Google Scholar
• Alderson HL, Semple DM, Blayney C, et al. Risk of transition to schizophrenia following first admission with substance-induced psychotic disorder: a population-based longitudinal cohort study. Psychol Med. 2017;47(14):2548–2555. doi: 10.1017/S0033291717001118
   PubMed Web of Science ®Google Scholar
• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: A unifying hypothesis. Schizophr Res. 2018;194:78–85. doi: 10.1016/j.schres.2017.04.016
   PubMed Web of Science ®Google Scholar
• Lombardozzi G, Trovini G, Amici E, et al. Brexpiprazole in patients with schizophrenia with or without substance use disorder: An observational study. Front Psychiatry. 2023;14:1321233. doi: 10.3389/fpsyt.2023.1321233
   PubMed Web of Science ®Google Scholar
• Chiappini S, Cavallotto C, Mosca A, et al. Investigating the effectiveness of brexpiprazole in subjects with schizophrenia spectrum illness and co-occurring substance use disorder: a prospective, multicentric, real-world study. Pharmaceuticals (Basel). 2024;17(4):535. doi: 10.3390/ph17040535
   PubMedGoogle Scholar
• Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868–872. doi: 10.1176/appi.ajp.2020.177901
   PubMed Web of Science ®Google Scholar
• Findling RL, Cavuş I, Pappadopulos E, et al. Ziprasidone in adolescents with schizophrenia: results from a placebo-controlled efficacy and long-term open-extension study. J Child Adolesc Psychopharmacol. 2013;23(8):531–544. doi: 10.1089/cap.2012.0068
   PubMed Web of Science ®Google Scholar
• Findling RL, Landbloom RP, Mackle M, et al. Safety and efficacy from an 8 week double-blind trial and a 26 week open-label extension of asenapine in adolescents with schizophrenia. J Child Adolesc Psychopharmacol. 2015;25(5):384–396. doi: 10.1089/cap.2015.0027
   PubMed Web of Science ®Google Scholar
• Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol 2015;79(3):357–69. doi: 10.1111/bcp
   PubMed Web of Science ®Google Scholar
• Schreiner MS. Paediatric clinical trials: redressing the imbalance. Nat Rev Drug Discov. 2003;2(12):949–961. doi: 10.1038/nrd1253
   PubMed Web of Science ®Google Scholar
• Ollivier C, Mulugeta YL, Ruggieri L, Saint-Raymond A, Yao L. Paediatric extrapolation: A necessary paradigm shift. Brit J Pharmacol 2019;85(4):675–679.
   Web of Science ®Google Scholar
• Kalaria SN, Farchione TR, Uppoor R, Mehta M, Wang Y, Zhu H. Extrapolation of efficacy and dose selection in pediatrics: A case example of atypical antipsychotics in adolescents with schizophrenia and bipolar I disorder. J Clin Pharmacol 2021;61(Suppl 1):S117–S124. doi: 10.1002/jcph.1836
   PubMedGoogle Scholar
• United States Food and Drug Administration. Multi-disciplinary review and evaluation NDA 205422, S-007 brexpiprazole in pediatric patients with schizophrenia aged 13 to 17; 30 June 2021. https://www.fda.gov/media/155985/download. Accessed 12 September 2023.
   Google Scholar
• Hard ML, Mills RJ, Sadler BM, et al. Pharmacokinetic profile of a 2-month dose regimen of aripiprazole lauroxil: a phase I study and a population pharmacokinetic model. CNS Drugs. 2017;31(7):617–624. doi: 10.1007/s40263-017-0447-7
   PubMed Web of Science ®Google Scholar
• Miceli JJ, Glue P, Alderman J, Wilner K. The effect of food on the absorption of oral ziprasidone. Psychopharmacol Bull. 2007;40(3):58–68.
   PubMedGoogle Scholar
• Citrome L. Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol. 2014;10(6):893–903. doi: 10.1517/17425255.2014.908185
   PubMed Web of Science ®Google Scholar
• Taddeo D, Egedy M, Frappier JY. Adherence to treatment in adolescents. Paediatr Child Health 2008;13(1):19–24. doi: 10.1093/pch/13.1.19
   PubMed Web of Science ®Google Scholar
• Both C, Mechler K, Niemeyer L, Jennen-Steinmetz C, Hohmann S, Schumm L, Dittmann RW, Häge A. Medication adherence in adolescents with psychiatric disorders. Z Kinder Jugendpsychiatr Psychother 2021;49(4):295–306. doi: 10.1024/1422-4917/a000813
   PubMed Web of Science ®Google Scholar
• Villiera JB, Katsabola H, Bvumbwe M, Mhango J, Khosa J, Silverstein A, Nyondo-Mipando AL., Kerkhoff, A D. Factors associated with antiretroviral therapy adherence among adolescents living with HIV in the era of isoniazid preventive therapy as part of HIV care. PLOS Glob Public Health. 2022;2(6):e0000418. doi: 10.1371/journal.pgph.0000418
   PubMedGoogle Scholar
• Ye J, Zhang V, Strimenopoulou F, Zhao Y, Pan H, Shabbout M, Gamalo M. Recent use of pediatric extrapolation in pediatric drug development in US. J Biopharm Stat. 2023 Nov 2;33(6):681–695. doi: 10.1080/10543406.2023.2170407.
   PubMed Web of Science ®Google Scholar
• Ollivier C,m Thompson A, Manolis E, Blake K, Karlsson K, Knibbe CAJ, Pons G, Hemmings R. Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics. B J Clin Pharmacol. 2019;85(4):659–668
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Concept paper on extrapolation of efficacy and safety in medicine development. 19 March 2013 https://www.ema.europa.eu/en/documents/scientific-guideline/concept-paper-extrapolation-efficacy-and-safety-medicine-development_en.pdf Accessed 24 February 2024
   Google Scholar
• Kane JM, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, Nyilas M, Carson WH, Sanchez R, Eriksson H. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res 2015;164(1–3):127–135. doi: 10.1016/j.schres.2015.01.038
   PubMed Web of Science ®Google Scholar
• Fleischhacker WW, Hobart M, Ouyang J, Forbes A, Pfister S, McQuade RD, Carson WH, Sanchez R, Nyilas M, Weiller E. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with s schizophrenia: A randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol 2017;20(1):11–21. doi: 10.1093/ijnp/pyw076
   PubMed Web of Science ®Google Scholar
• Malla A, Ota A, Nagamizu K, et al. The effect of brexpiprazole in adult outpatients with early-episode schizophrenia: an exploratory study. Int Clin Psychopharmacol. 2016;31(6):307–314. doi: 10.1097/YIC.0000000000000140
   PubMed Web of Science ®Google Scholar