Paediatric Drugs

, Volume 2, Issue 4, pp 253–262 | Cite as

Management of Schizophrenia in Children and Adolescents

The Role of Clozapine
  • Helmut Remschmidt
  • Christian Fleischhaker
  • Klaus Hennighausen
  • Eberhard Schulz
Disease Management

Abstract

Clozapine is a dibenzodiazepine derivative with established antipsychotic efficacy in adult patients with schizophrenic psychoses. There are more than 15 studies that have also demonstrated the antipsychotic efficacy of clozapine in childhood and adolescent schizophrenia.

The main advantages of clozapine treatment in this age group in comparison with typical antipsychotics are: (i) high antipsychotic efficacy during an acute schizophrenic episode; (ii) better improvement in chronic cases with a high load of negative symptoms; and (iii) markedly fewer extrapyramidal adverse effects and, therefore, fairly good tolerability.

However, because of its possible adverse effects on the haemopoetic system (granulocytopenia, agranulocytosis), clozapine should not be used as first-line antipsychotic medication. Other adverse effects are related to the cardiovascular system (hypotonia, tachycardia or arrhythmia), the central nervous system (epileptic seizures, fever) and liver function (transient increases in levels of hepatic transaminases). Two other frequent adverse effects are hypersalivation and body-weight gain, which may present a particular problem in adolescents and young adults.

Careful monitoring of haematological parameters and other adverse effects are preconditions for a successful treatment programme.

Keywords

Clozapine Negative Symptom Antipsychotic Medication Agranulocytosis Bodyweight Gain 

References

  1. 1.
    Kane JM, Honigfeld G, Singer J, et al. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 1988; 24: 62–7PubMedGoogle Scholar
  2. 2.
    Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin Psychiatry 1990; 50: 329–38Google Scholar
  3. 3.
    Naber D, Müller-Spahn F, editors. Clozapin. Pharmakologie und Klinik eines atypischen Neuroleptikums: eine kritische Bestandsaufnahme. Stuttgart: Schattauer, 1992Google Scholar
  4. 4.
    Meltzer HY. Multiple-outcome criteria in schizophrenia: an overview of outcome with clozapine. Eur Psychiatry 1995; 10: 19–25CrossRefGoogle Scholar
  5. 5.
    Angst J, Bente D, Berner P. Das klinische Wirkungsbild von Clozapin (Untersuchung mit dem AMP-System). Pharmakopsychiatrie 1971; 4: 200–11Google Scholar
  6. 6.
    Stille G, Hippius H. Kritische Stellungnahme zum Begriff der Neuroleptika (und von pharmakologischen und klinischen Befunden mit Clozapin). Pharmakopsychiatrie 1971; 4: 182–91CrossRefGoogle Scholar
  7. 7.
    Coward DM. General pharmacology of clozapine. Br J Psychiatry 1992; 160 Suppl. 17: 5–11Google Scholar
  8. 8.
    Kane JM. Clinical efficacy of clozapine in treatment-refractory schizophrenia: an overview. Br J Psychiatry 1992; 160 Suppl. 17:41–5Google Scholar
  9. 9.
    Meltzer HY. The effect of clozapine and other atypical antipsychotic drugs on negative symptoms. In: Marneros A, Andreasen NC, Tsuang MT, editors. Negative versus positive schizophrenia. New York (NY): Springer Verlag, 1991: 365–76CrossRefGoogle Scholar
  10. 10.
    Gerlach J, Koppelhus P, Helweg E, et al. Clozapine and haloperidol in a single-blind cross-over trial: therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr Scand 1974; 50: 410–24PubMedCrossRefGoogle Scholar
  11. 11.
    Honigfeld G, Patin J, Singer J. Clozapine: antipsychotic activity in treatment-resistant schizophrenics. Adv Ther 1984; 1: 77–97Google Scholar
  12. 12.
    Ekblom B, Haggstrom JE. Clozapine (Leponex) compared with chlorpromazine: a double-blind evaluation of pharmacological and clinical properties. Curr Ther Res 1974; 16: 945–57PubMedGoogle Scholar
  13. 13.
    Leon CA. Therapeutic effects of clozapine: a four-year follow-up of a controlled clinical trial. Acta Psychiatr Scand 1979; 60: 471–80CrossRefGoogle Scholar
  14. 14.
    Meltzer HY. Dimensions of outcome with clozapine. Br J Psychiatry 1992; 17: 46–53Google Scholar
  15. 15.
    Breier A, Buchanan RW, Irish D, et al. Clozapine treatment of outpatients with schizophrenia: outcome and long-term response patterns. Hosp Community Psychiatry 1993; 44: 1145–9PubMedGoogle Scholar
  16. 16.
    Siefen RG, Remschmidt H. Behandlung mit Clozapin bei schizophrenen Jugendlichen. Z Kinder Jugenpsychiatr 1986; 14: 245–57PubMedGoogle Scholar
  17. 17.
    Schmidt MH, Trott GE, Blanz B, et al. Clozapine medication in adolescents. In: Stefanis CN, Rabavilas AD, Soldatos CR, editors. Psychiatry: a world perspective. Vol. 1. Proceedings of the VIII World Congress of Psychiatry; 1989 Oct 12–19; New Jersey (NJ): Excerpta Medica, 1991: 1100–4Google Scholar
  18. 18.
    Braun-Scharm H, Martinius J. EEG-Veränderungen und Anfälle unter Clozapinmedikation bei schizophrenen Jugendlichen. Z Kinder Jugenpsychiatr 1991; 19: 164–9PubMedGoogle Scholar
  19. 19.
    Farmer AE, Blewett A. Drug treatment of resistant schizophrenia: limitations and recommendations. Drugs 1993; 45: 374–83PubMedCrossRefGoogle Scholar
  20. 20.
    Fleischhaker C. Die Bedeutung der biogenen Amine für die Pharmakotherapie schizophrener Psychosen in der Adoleszenz [dissertation]. Marburg: University of Marburg, 1996Google Scholar
  21. 21.
    Schulz E, Fleischhaker C, Clement HW, et al. Blood biogenic amines during clozapine treatment of early-onset schizophrenia. J Neural Transm 1997; 104: 1077–89PubMedCrossRefGoogle Scholar
  22. 22.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-III-R), 3rd ed. Washington, DC: American Psychiatric Association, 1987Google Scholar
  23. 23.
    Birmaher B, Baker R, Kapur S, et al. Clozapine for the treatment of adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 1992; 31: 160–4PubMedCrossRefGoogle Scholar
  24. 24.
    Boxer G, Davidson J. More on clozapine [letter]. J Am Acad Child Adolesc Psychiatry 1992; 31: 993PubMedCrossRefGoogle Scholar
  25. 25.
    Blanz B, Schmidt MH. Clozapine for schizophrenia [letter]. J Am Acad Child Adolesc Psychiatry 1993; 32: 223–4PubMedCrossRefGoogle Scholar
  26. 26.
    Mandoki M. Clozapine for adolescents with psychosis: literature review and two case reports. J Child Adolesc Psychopharmacol 1993; 3: 213–21CrossRefGoogle Scholar
  27. 27.
    Mozes T, Toren P, Chernauzan N, et al. Clozapine treatment in very early onset schizophrenia. J Am Acad Child Adolesc Psychiatry 1994; 33: 65–70PubMedCrossRefGoogle Scholar
  28. 28.
    Jacobsen LK, Walker MC, Edwards JE, et al. Clozapine in the treatment of a young adolescent with schizophrenia. J Am Acad Child Adolesc Psychiatry 1994; 33: 645–50PubMedCrossRefGoogle Scholar
  29. 29.
    Levkovitch Y, Kaysar N, Kronnenberg Y, et al. Clozapine for schizophrenia [letter]. J Am Acad Child Adolesc Psychiatry 1994; 33: 431PubMedCrossRefGoogle Scholar
  30. 30.
    Towbin KE, Dykens EM, Pugliese RG. Clozapine for early developmental delays with childhood-onset schizophrenia: protocol and 15-month outcome. J Am Acad Child Adolesc Psychiatry 1994; 33: 651–7PubMedCrossRefGoogle Scholar
  31. 31.
    Frazier JA, Gordon CT, McKenna K, et al. An open trial of clozapine in 11 adolescents with childhood onset schizophrenia. J Am Acad Child Adolesc Psychiatry 1994; 33: 658–63PubMedCrossRefGoogle Scholar
  32. 32.
    Mandoki M. Anti-aggressive effects of clozapine in children and adolescents [abstract]. In: Proceedings of the Annual Meeting, Society for Biological Psychiatry; 1994 May; Philadelphia. Biol Psychiatry 1994; 35 Suppl.: 469Google Scholar
  33. 33.
    Remschmidt H, Schulz E, Martin M. An open trial of clozapine in thirty-six adolescents with schizophrenia. J Child Adolesc Psychopharmacol 1994; 4: 31–41CrossRefGoogle Scholar
  34. 34.
    Kumra S, Frazier JA, Jacobsen LK, et al. Childhood-onset schizophrenia: a double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry 1996; 53: 1090–7PubMedCrossRefGoogle Scholar
  35. 35.
    Bleeham T. Leponex® — Clozaril® (clozapine) literature review Data on file, Sandoz Pharma Ltd, 1993Google Scholar
  36. 36.
    Elliger T, Englert E, Freisleder FJ, et al. Zur Behandlung schizophrener Psychosen des Kindes- und Jugendalters mit Clozapin (Leponex). Konsensuskonferenz vom 4. März 1994. Z Kinder Jugenpsychiatr 1994; 22: 325–27Google Scholar
  37. 37.
    Fulton B, Goa KL. Olanzapine: a review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs 1997; 53: 281–98PubMedCrossRefGoogle Scholar
  38. 38.
    Schulz E, Fleischhaker C, Remschmidt H. 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: 119–31PubMedCrossRefGoogle Scholar
  39. 39.
    Perry PJ, Miller DD, Arndt SV, et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991; 148: 231–5PubMedGoogle Scholar
  40. 40.
    Miller DD, Fleming F, Holman TL, et al. Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiatry 1994; 55 Suppl. B: 117–21PubMedGoogle Scholar
  41. 41.
    Potkin SG, Bera R, Gulasekaram B, et al. Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 1994; 55 Suppl. B: 133–6PubMedGoogle Scholar
  42. 42.
    Kronig MH, Munne RA, Szymanski S, et al. Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 1995;152: 179–82PubMedGoogle Scholar
  43. 43.
    Piscitelli SC, Frazier JA, McKenna K, et al. Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. J Clin Psychiatry 1994; 55 Suppl. B: 94–7PubMedGoogle Scholar
  44. 44.
    Olesen OV Therapeutic drug monitoring of clozapine treatment. Therapeutic threshold value for serum clozapine concentrations. Clin Pharmacokinet 1998; 34: 497–502PubMedCrossRefGoogle Scholar
  45. 45.
    Lindenmayer JP, Apergi FS. The relationship between clozapine plasma levels and clinical response. Psychiatr Ann 1996; 26: 406–12Google Scholar
  46. 46.
    Hummer M, Kurz M, Kurzthaler I, et al. Clozapine-induced transient white blood count disorders. J Clin Psychiatry 1994; 55: 429–32PubMedGoogle Scholar
  47. 47.
    Dev VJ, Krupp P. Adverse event profile and safety of clozapine. Rev Contemp Pharmacother 1995; 6: 197–208Google Scholar
  48. 48.
    Krupp P, Barnes P. Clozapine-associated agranulocytosis: risk and aetiology. Br J Psychiatry 1992; 160: 38–40Google Scholar
  49. 49.
    Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis: incidence and risk factors in the United States. N Engl J Med 1993; 329: 162–7PubMedCrossRefGoogle Scholar
  50. 50.
    Naber D, Hippius H. The European experience with the use of clozapine. Hosp Community Psychiatry 1990; 41: 886–90PubMedGoogle Scholar
  51. 51.
    Pacia SV, Devinsky O. Clozapine-related seizures: experience with 5,629 patients. Neurology 1994; 44: 2247–9PubMedCrossRefGoogle Scholar
  52. 52.
    National Institute of Mental Health (NIMH). DOTES-dosage record and treatment emergent symptom scale. In: Guy W, editor. ECDU Assessment Manual for Psychopharmacology. Rockville (MD): National Institute of Mental Health, US Department of Health, Education and Welfare, 1976: 223–44Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Helmut Remschmidt
    • 1
  • Christian Fleischhaker
    • 2
  • Klaus Hennighausen
    • 1
  • Eberhard Schulz
    • 2
  1. 1.Department of Child and Adolescent PsychiatryPhilipps-UniversityMarburgGermany
  2. 2.Department of Child and Adolescent PsychiatryAlbert-Ludwigs-UniversityFreiburgGermany

Personalised recommendations