Clozapine for severe ("kraepelinian") schizophrenia: Sustained improvement over 5 years

Clozapina para esquizofrenia ("kraepeliniana") grave

Abstract

Clozapine has become a keystone in the treatment of schizophrenia because of its efficacy as an antipsychotic with negligible neuroleptic effects. The long-term stability of its effects, however, is poorly understood, because most studies have probed the usefulness of clozapine over a period of weeks to several months at the most. Knowing whether clozapine's benefits are sustained over the very long-term, i.e., more than 5 years, may be critical for cost-benefit analyses. Objective: To report the results of an open study on the efficacy of clozapine over the very long-term. Methods: Thirty-three adults (26 men) with severe (kraepelinian) schizophrenia were assessed at regular intervals using a brief neuropsychiatric battery over a 5-year period. Results: A significant improvement was observed between the pre-clozapine and the first "on-clozapine" evaluation. This improvement was paralleled by a remarkable conversion of schizophrenia from "active" (mostly paranoid) into "residual" in 70% of all patients. Eight patients became functionally productive to the point of being capable of living an independent life. Roughly one-third of our cases showed no improvement. Conclusions: Clozapine is a safe and effective drug for patients with severe schizophrenia who have failed to improve on other antipsychotic drugs. Clozapine's maximal benefit is established by the end of the first year of treatment and continues unabated for many years thereafter. Clozapine-resistant patients remain a major challenge calling for the discovery of new treatments for schizophrenia.

Key words:
clozapine; antipsychotic; neuroleptic; kraepelinian; schizophrenia

Resumo

A clozapina revolucionou o tratamento da esquizofrenia em virtude de sua comprovada eficácia como antipsicótico dotado de efeitos neuroléticos mínimos. A estabilidade de seu benefício terapêutico de longo-prazo, todavia, ainda é pouco conhecida, uma vez que a maioria dos estudos comprovou sua utilidade por períodos de semanas a meses. Caso os benefícios da clozapina se sustentem por prazos maiores, i.e., por mais de 5 anos, esta informação será relevante para análises de custo-benefício. Objetivo: Relatar a eficácia da clozapina por prazos maiores em estudo aberto. Métodos: Trinta e três pacientes (26 homens) com esquizofrenia grave ("kraepeliniana") foram examinados a intervalos regulares com uma bateria psiquiátrica breve por mais de 5 anos. Resultados: Melhora significativa foi observada entre a avaliação pré-clozapina e a primeira avaliação com clozapina, o que se acompanhou de uma notável conversão da esquizofrenia de "ativa" (constituída, na maioria, do subtipo paranóide) em "residual" em 70% dos pacientes. Oito pacientes se tornaram funcionalmente produtivos a ponto de levarem vidas independentes. Cerca de um terço dos nossos casos não melhoraram. Conclusões: A clozapina é segura e eficaz para pacientes com esquizofrenia grave que não responderam a outros antipsicóticos. Naqueles que responderam, seu benefício máximo se estabelece ao longo do primeiro ano de tratamento e assim permanece pelos anos subseqüentes. Pacientes resistentes a clozapina constituem grande incentivo para a descoberta de novos tratamentos para a esquizofrenia.

Palavras-chave:
clozapina; antipsicótico; neuroléptico; esquizofrenia; kraepeliniana

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Acknowledgements

The authors are indebted to Professor Omar da Rosa Santos (Head of Internal Medicine Service of Gaffrée e Guinle Hospital) and to Mr. José Ricardo Pinheiro (Oswaldo Cruz Library).

References

• ¹
  Tuunainen A, Wahlbeck K, Gilbody S. Newer atypical antipsychotic medication in comparison to clozapine: a systematic review of randomized trials. Schizophr Res 2002;56:1-10.
• ²
  Rosenheck R, Cramer J, Xu W, Thomas J, et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Eng J Med 1997;337:809-815.
• ³
  Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001;158:518-526.
• ⁴
  Oliveira-Souza R, Marrocos RP, Figueiredo WM. Sustained long-term improvement with clozapine in schizophrenia. Arq Neuropsiquiatr 1999;57:18-22.
• ⁵
  Conley RR, Carpenter WT, Tamminga CA. Time to clozapine response in a standardized trial. Am J Psychiatry 1997; 154:1243-1247.
• ⁶
  Rosenheck R, Evans D, Herz L, et al. How long to wait for a response to clozapine: a comparison of time course of response to clozapine and conventional antipsychotic medication in refractory schizophrenia. Schizophr Bull 1999;25:709-719.
• ⁷
  Andreasen NC, Carpenter WT, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: Proposed criteria and rationale for consensus. Am J Psychiatry 2005;162:441-449.
• ⁸
  Kraepelin E. Dementia Præcox and Paraphrenia (Originally published in 1919). Translated by RM Barclay. Huntington, NY: Robert E. Krieger Publishing Co., 1971.
• ⁹
  Keefe RSE, Frescka E, Apter SH, et al. Clinical characteristics of kraepelinian schizophrenia: Replication and extension of previous findings. Am J Psychiatry 1996;153:806-811.
• ¹⁰
  American Psychiatric Association. Diagnostic and Statistic Manual of Mental Disorders, 4th ed. (DSM-IV). Washington, DC: American Psychiatric Association; 1994.
• ¹¹
  Woerner MG, Mannuzza S, Kane JM. Anchoring the BPRS: An aid to improved reliability. Psychopharmacol Bull 1988;24:112-117.
• ¹²
  Brucki S, Nitrini R, Caramelli P, Bertolucci PHF, Okamoto IH. Sugestões para o uso do Mini-Exame do Estado Mental no Brasil. Arq Neuropsiquiatr 2003;61:777-781.
• ¹³
  Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004;24:192-208.
• ¹⁴
  van Putten T. Why do schizophrenic patients refuse to take their drugs? Arch Gen Psychiatry 1974;31:67-72.
• ¹⁵
  Kozuki Y, Froelicher ES. Lack of awareness and nonadherence in schizophrenia. West J Nurs Res 2003;25:57-74.
• ¹⁶
  Motulsky H. Intuitive Biostatistics. New York: Oxford University Press, 1995.
• ¹⁷
  Cohen J. A power primer. Psychol Bull 1992;112:155-159.
• ¹⁸
  Stern RG, Kahn RS, Davidson M, Nora RM, Davis KL. Early response to clozapine in schizophrenia. Am J Psychiatry 1994;151:1817-1818.
• ¹⁹
  Silva CER, Pereira BB, Rozenthal M, Elkis H. Clozapine pilot study in a public hospital: one-year follow-up results (in Portuguese). Rev Bras Psiquiatr 2001;23:180-187.
• ²⁰
  Haase HJ. Extrapyramidal modification of fine movements - a "conditio sine qua non" of the fundamental therapeutic action of neuroleptic drugs. Rev Can Biol 1961;20:425-449.
• ²¹
  Johnstone EC, Crow TJ, Frith CD, Carney MW, Price JS. Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet 1978;1:848-851.
• ²²
  Delay J, Deniker P. Drug-induced extrapyramidal syndromes. In: Handbook of Clinical Neurology, volume 6, chapter 10. PJ Vinken, GW Bruyn, eds. Amsterdam: North Holland Publishing Co., 1968:248-266.
• ²³
  Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev 1966;18:925-964.
• ²⁴
  Seeman P. Dopamine receptors and psychosis. Sci Am Sci Med 1995;2:28-37.
• ²⁵
  Westen D, Weinberger J. When clinical description becomes statistical prediction. Am Psychol 2004;59:595-613.

Publication Dates

• Publication in this collection
  Jan-Mar 2008

History

• Received
  04 Feb 2008
• Reviewed
  17 Feb 2008
• Accepted
  04 Mar 2008