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Systematic review of the efficacy and tolerability of Clozapine in the treatment of youth with early onset schizophrenia

Published online by Cambridge University Press:  15 April 2020

C. Schneider ,
R. Corrigall ,
D. Hayes ,
M. Kyriakopoulos  and
S. Frangou
C. Schneider
Affiliation:
Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK
R. Corrigall
Affiliation:
Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK
D. Hayes
Affiliation:
Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK
M. Kyriakopoulos
Affiliation:
Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK
S. Frangou*
Affiliation:
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, Box 1230, 1425, Madison Avenue, New York, NY10029, USA
*
*Corresponding author. E-mail address:[email protected] (S. Frangou).
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Abstract

Background

The use of clozapine (CLZ) for treatment-resistant schizophrenia is well established in adults. However, it is seldom used in youth with early onset schizophrenia (EOS) largely because of lack of clarity about its risk benefit ratio. This review synthesises and evaluates available evidence regarding the efficacy and tolerability of CLZ in EOS with the aim to assist clinical decision-making.

Methods

We conducted a systematic review of the primary literature on the clinical efficacy and adverse drug reactions (ADRs) observed during CLZ treatment in EOS. We also identified relevant practice guidelines and summarised current guidance.

Results

CLZ showed superior efficacy than other antipsychotics in treating refractory EOS patients; short-term clinical trials suggest an average improvement of 69% on the Brief Psychiatric Rating Scale that was sustained during long-term follow-up (up to 9 years). No fatalities linked to CLZ treatment were reported. Sedation and hypersalivation were the most common complaints, reported by over 90% of patients. Other common ADRs (reported in 10-60% of patients) were enuresis, constipation, weight gain, and non-specific EEG changes. Less common ADRs (reported in 10-30% of patients) were akathisia, tachycardia and changes in blood pressure. Neutropenia was reported in 6–15% of cases but was usually transient while agranulocytosis was rare (< 0.1%). Seizures were also uncommon (< 3%). Metabolic changes were relatively common (8–22%) but emergent diabetes was not frequently observed (< 6%). Overall the rate of discontinuation was low (3–6%). Current guidelines recommend the use of CLZ in EOS patients who have failed to respond to two adequate trials with different antipsychotics and provide detailed schedules of assessments to evaluate and assess potential ADRs both prior to initiation and throughout CLZ treatment.

Conclusion

Available data although limited in terms of number of studies are consistent in demonstrating that CLZ is effective and generally safe in the treatment of refractory EOS provided patients are regularly monitored

Keywords

SchizophreniaEarly onsetPaediatricEfficacyTolerabilityClozapine
Type
Review
Information
European Psychiatry , Volume 29 , Issue 1 , January 2014 , pp. 1 - 10
Copyright
Copyright © 2013 Elsevier Masson SAS

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References

Alfaro, C.L.Wudarsky, M.Nicolson, R.Gochman, P.Sporn, A.Lenane, M.et al.Correlation of antipsychotic and prolactin concentrations in children and adolescents acutely treated with haloperidol, clozapine, or olanzapine. J Child Adolesc Psychopharmacol 2002;12:83–91.CrossRefGoogle ScholarPubMed
American Academy of Child Adolescent Psychiatry Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 2001;40(7 Suppl.):4–23.CrossRefGoogle Scholar
Armenteros, J.L.Davies, M.Antipsychotics in early onset schizophrenia: systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2006;15:141–148.CrossRefGoogle ScholarPubMed
Cannon, M.Jones, P.Huttunen, M.O.Tanskanen, A.Huttunen, T.Rabe-Hesketh, S.et al.School performance in Finnish children and later development of schizophrenia: a population-based longitudinal study. Arch Gen Psychiatry 1999;5:457–463.CrossRefGoogle Scholar
Cannon, T.D.Rosso, I.M.Bearden, C.E.Sanchez, L.E.Hadley, T.A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia. Dev Psychopathol 1999;11:467–485.CrossRefGoogle ScholarPubMed
Cirulli, G.Clozapine prescribing in adolescent psychiatry: survey of prescribing practice in in-patient units. Psychiatr Bull 2005;29:377–380.CrossRefGoogle Scholar
Citrome, L.A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia. Expert Opin Pharmacother 2012;13:1545–1573.CrossRefGoogle ScholarPubMed
Couchman, L.Bowskill, S.V.Handley, S.Patel, M.X.Flanagan, R.J.Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged < 18 years: data from a therapeutic drug monitoring service, 1994–2010. Early Interv Psychiatry 2013;7:122–130.CrossRefGoogle ScholarPubMed
De Hert, M.Dobbelaere, M.Sheridan, E.M.Cohen, D.Correll, C.U.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;26:144–158.CrossRefGoogle Scholar
De Hert, M.Hudyana, H.Dockx, L.Bernagie, C.Sweers, K.Tack, J.et al.Second-generation antipsychotics and constipation: a review of the literature. Eur Psychiatry 2011;26:34–44.CrossRefGoogle ScholarPubMed
Eggers, C.Bunk, D.The long-term course of childhood-onset schizophrenia: a 42-year follow-up. Schizophr Bull 1997;23:105–117.CrossRefGoogle Scholar
Fitton, A.Heel, R.C.Clozapine: a review of its pharmacological properties, and therapeutic use in schizophrenia. Drugs 1990;40:722–747.CrossRefGoogle Scholar
Fleischhaker, C.Heiser, P.Hennighausen, K.Herpertz-Dahlmann, B.Holtkamp, K.Mehler-Wex, C.et al.Clinical drug monitoring in child and adolescent psychiatry: side effects of atypical neuroleptics. J Child Adolesc Psychopharmacol 2006;16:308–316.CrossRefGoogle ScholarPubMed
Fleischhaker, C.Heiser, P.Hennighausen, K.Herpertz-Dahlmann, B.Holtkamp, K.Mehler-Wex, C.et al.Weight gain in children and adolescents during 45 weeks treatment with clozapine, olanzapine and risperidone. J Neural Transm 2008;115:1599–1608.CrossRefGoogle ScholarPubMed
Fraguas, D.Merchán-Naranjo, J.Laita, P.Parellada, M.Moreno, D.Ruiz-Sancho, A.et al.Metabolic and hormonal side effects in children and adolescents treated with second-generation antipsychotics. J Clin Psychiatry 2008;69:1166–1175.CrossRefGoogle ScholarPubMed
Frazier, J.A.Gordon, C.T.McKenna, K.Lenane, M.C.Jih, D.Rapoport, J.L.An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 1994;33:658–663.CrossRefGoogle ScholarPubMed
Freedman, J.E.Wirshing, W.C.Russel, A.T.Palmer Bray, M.Jergen, U.Absence status seizures after successful long-term clozapine treatment of an adolescent with schizophrenia. J Child Adolesc Psychopharmacol 1994;4:53–62.CrossRefGoogle Scholar
Gerbino-Rosen, G.Roofeh, D.Tompkins, D.A.Feryo, D.Nusser, L.Kranzler, H.et al.Hematological adverse events in clozapine-treated children and adolescents. J Am Acad Child Adolesc Psychiatry 2005;44:1024–1031.CrossRefGoogle ScholarPubMed
Gochman, P.Miller, R.Rapoport, J.L.Childhood-onset schizophrenia: the challenge of diagnosis. Curr Psychiatry Rep 2011;13:321–322.CrossRefGoogle ScholarPubMed
Haas, S.J.Hill, R.Krum, H.Liew, D.Tonkin, A.Demos, L.et al.Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993–2003. Drug Saf 2007;30:47–57.CrossRefGoogle ScholarPubMed
Hafner, H.Nowotny, B.Epidemiology of early-onset schizophrenia. Eur Arch Psychiatry Clin Nerurosci 1995;245:80–92.CrossRefGoogle ScholarPubMed
Hrdlicka, M.Zedkova, I.Blatny, M.Urbanek, T.Weight gain associated with atypical and typical antipsychotics during treatment of adolescent schizophrenic psychoses: a retrospective study. Neuro Endocrinol Lett 2009;30:256–261.Google ScholarPubMed
Hummer, M.Kurz, M.Barnas, C.Saria, A.Fleischhacker, W.W.Clozapine-induced transient white blood count disorders. J Clin Psychiatry 1994;55:429–432.Google ScholarPubMed
Kim, Y.Kim, B.N.Cho, S.C.Kim, J.W.Shin, M.S.Long-term sustained benefits of clozapine treatment in refractory early onset schizophrenia: a retrospective study in Korean children and adolescents. Hum Psychopharmacol 2008;23:715–722.CrossRefGoogle ScholarPubMed
Koller, E.Malozowski, S.Doraiswamy, P.M.Atypical antipsychotic drugs and hyperglycemia in adolescents. JAMA 2001;286:2547–2548.CrossRefGoogle ScholarPubMed
Kumra, S.Frazier, J.A.Jacobsen, L.K.McKenna, K.Gordon, C.T.Lenane, M.C.et al.Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry 1996;53:1090–1097.CrossRefGoogle ScholarPubMed
Kumra, S.Kranzler, H.Gerbino-Rosen, G.Kester, H.M.DeThomas, C.Cullen, K.et al.Clozapine versus “high-dose” olanzapine in refractory early-onset schizophrenia: an open-label extension study. J Child Adolesc Psychopharmacol 2008;18:307–316.CrossRefGoogle ScholarPubMed
Lamberti, J.S.Olson, D.Crilly, J.F.Olivares, T.Williams, G.C.Tu, X.et al.Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 2006;163:1273–1276.CrossRefGoogle ScholarPubMed
Lay, B.Blanz, B.Hartmann, M.Schmidt, M.H.The psychosocial outcome of adolescent onset schizophrenia: a 12-year follow-up. Schizophr Bull 2000;26:801–816.CrossRefGoogle Scholar
Maziade, M.Bouchard, S.Gingras, N.Charron, L.Cardinal, A.Roy, M.-A.et al.Long-term stability of diagnosis and symptom dimensions in a systematic sample of patients with onset of schizophrenia in childhood and early adolescence. II: positive/negative distinction and childhood predictors of adult outcome. Br J Psychiatry 1996;169:371–378.CrossRefGoogle Scholar
Merrill, D.B.Dec, G.W.Goff, D.C.Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol 2005;25:32–41.CrossRefGoogle ScholarPubMed
Mukhopadhaya, K.Krishnaiah, R.Taye, T.Nigam, A.Bailey, A.J.Sivakumaran, T.et al.Obsessive-compulsive disorder in UK clozapine- treated schizophrenia and schizoaffective disorder: a cause for clinical concern. J Psychopharmacol 2009;23:6–13.CrossRefGoogle ScholarPubMed
Munro, J.O'Sullivan, D.Andrews, C.Arana, A.Mortimer, A.Kerwin, R.Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance. Br J Psychiatry 1999;175:576–580.CrossRefGoogle ScholarPubMed
National Institute for Health and Clinical Excellence. Psychosis and schizophrenia in children and young people, recognition and management, 2013. (http://www.nice.org.uk/nicemedia/live/12951/60475/60475.pdf).Google Scholar
Newcome, J.W.Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005;19(Suppl. 1):1–93.Google Scholar
Palmer, S.E.McLean, R.M.Ellis, P.M.Harrison-Woolrych, M.Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. Clin Psychiatry 2008;69:759–768.CrossRefGoogle ScholarPubMed
Peyrière, H.Roux, C.Ferard, C.Deleau, N.Kreft-Jais, C.Hillaire-Buys, D.et al.Antipsychotics-induced ischaemic colitis and gastrointestinal necrosis: a review of the French pharmacovigilance database. Pharmacoepidemiol Drug Saf 2009;18:948–955.CrossRefGoogle ScholarPubMed
Praharaj, S.K.Arora, M.Gandotra, S.Clozapine-induced sialorrhea: pathophysiology and management strategies. Psychopharmacology (Berl) 2006;185:265–273.CrossRefGoogle ScholarPubMed
Röpcke, B.Eggers, C.Early-onset schizophrenia: a 15-year follow-up. Eur Child Adolesc Psychiatry 2005;14:341–350.CrossRefGoogle ScholarPubMed
Schulz, E.Fleischhaker, C.Remschmidt, H.E.Correlated changes in symptoms and neurotransmitter indices during maintenance treatment with clozapine or conventional neuroleptics in adolescents and young adults with schizophrenia. J Child Adolesc Psychopharmacol 1996;6:119–131.CrossRefGoogle ScholarPubMed
Shaw, P.Sporn, A.Gogtay, N.Overman, G.Greenstein, D.Gochman, P.et al.Childhood-onset schizophrenia. A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 2006;63:721–730.CrossRefGoogle ScholarPubMed
Sikich, L.Frazier, J.A.McClellan, J.Findling, R.L.Vitiello, B.Ritz, L.et al.Double-blind comparison of first and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008;165:1420–1431.CrossRefGoogle ScholarPubMed
Sporn, A.L.Vermani, A.Greenstein, D.K.Bobb, A.J.Spencer, E.P.Clasen, L.S.et al.Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry 2007;46:1349–1356.CrossRefGoogle ScholarPubMed
Turetz, M.Mozes, T.Toren, P.Chernauzan, N.Yoran-Hegesh, R.Mester, R.et al.An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia. Br J Psychiatry 1997;170:507–510.CrossRefGoogle ScholarPubMed
Vyas, N.S.Hadjulis, M.Vourdas, A.Byrne, P.Frangou, S.The Maudsley early onset schizophrenia study. Predictors of psychosocial outcome at 4-year follow-up. Eur Child Adolesc Psychiatry 2007;16:465–470.CrossRefGoogle ScholarPubMed
Wehmeier, P.M.Schuler-Springorum, M.Heiser, P.Remschmidt, H.Chart review for potential features of myocarditis, pericarditis, and cardiomyopathy in children and adolescents treated with clozapine. J Child Adolesc Psychopharmacol 2004;14:267–271.CrossRefGoogle ScholarPubMed
Wudarsky, M.Nicolson, R.Hamburger, S.D.Spechler, L.Gochman, P.Bedwell, J.et al.Elevated prolactin in pediatric patients on typical and atypical antipsychotics. J Child Adolesc Psychopharmacol 1999;9:239–245.CrossRefGoogle ScholarPubMed
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