Agranulocitosis inducida por clozapina

Autores/as

DOI:

https://doi.org/10.24265/horizmed.2020.v20n1.10

Palabras clave:

Clozapina, Antipsicóticos, Agranulocitosis, Neutropenia, Farmacovigilancia

Resumen

Clozapina, actualmente, sigue siendo el gold standard para la esquizofrenia resistente al tratamiento, pero solo bajo un adecuado monitoreo hematológico, porque está asociado a agranulocitosis. Clozapina se metaboliza produciendo N-desmetilclozapina (farmacológicamente activa), el N-óxido de clozapina (inactivo) y especies reactivas de oxígeno (ion nitrenio). El recuento de neutrófilos <1000 células/mm3 corresponde a un estado de neutropenia. La agranulocitosis es un estado grave de neutropenia con un recuento absoluto de neutrófilos <500 células/mm3. Clozapina se asocia con la agranulocitosis en aproximadamente el 0,8 % de los pacientes, y el riesgo aumenta con la edad y en mujeres. Existen dos mecanismos que explican la agranulocitosis inducida por clozapina: inmunológico (respuesta mediada por el sistema inmunitario contra neutrófilos haptenizados) y tóxico (por acción de los metabolitos N-desmetilclozapina y ion nitrenio). La farmacogenética es una herramienta valiosa para conseguir la referida medicina personalizada, al adaptar e individualizar el tratamiento basado en los marcadores genéticos de cada paciente. Numerosos estudios han demostrado una asociación potencial de la agranulocitosis inducida por clozapina con ciertos haplotipos HLA (HLA-B38, DR4, DQw3, DQB1). Luego que un paciente ha presentado agranulocitosis, se conocen tres mecanismos de reexposición a clozapina: simple, con litio y con factores estimuladores de colonias de granulocitos. Debido al riesgo de agranulocitosis, las formulaciones de clozapina están disponibles solo a través de una distribución controlada, con un registro detallado de los pacientes y con una farmacovigilancia sistematizada y obligatoria.

Descargas

Los datos de descargas todavía no están disponibles.

Citas

Stepnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia. Molecules. 2018; 23(8).

Wiciński M, Węclewicz MM. Clozapine-induced agranulocytosis/ granulocytopenia: mechanisms and monitoring. Curr Opin Hematol. 2018; 25(1): 22-8.

Pirmohamed M, Park K. Mechanism of clozapine-induced agranulocytosis: current status of research and implications for drug development. CNS Drugs. 1997; 7(2): 139-58.

De Berardis D, Rapini G, Olivieri L, Di Nicola D, Tomasetti C, Valchera A, et al. Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine. Ther Adv Drug Saf. 2018; 9(5): 237-56.

Mehta TM, Van Lieshout RJ. A review of the safety of clozapine during pregnancy and lactation. Arch Womens Ment Health. 2017; 20(1): 1-9.

Mukku SSR, Sivakumar PT, Varghese M. Clozapine use in geriatric patients- Challenges. Asian J Psychiatry. 2018; 33: 63-7.

Bishara D, Taylor D. Adverse effects of clozapine in older patients: epidemiology, prevention and management. Drugs Aging. 2014; 31(1): 11-20.

Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics: differential risk and clinical implications. CNS Drugs. 2007; 21(11): 911-36.

Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993; 329(3): 162-7.

Dunk LR, Annan LJ, Andrews CD. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Br J Psychiatry. 2006; 188: 255-63.

Whiskey E, Taylor D. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs. 2007; 21(1): 25-35.

Zhang J-P, Malhotra AK. Pharmacogenetics of antipsychotics: recent progress and methodological issues. Expert Opin Drug Metab Toxicol. 2013; 9(2): 183-91.

Combs MD, Perry PJ, Bever KA. N-desmethylclozapine, an insensitive marker of clozapine-induced agranulocytosis and granulocytopenia. Pharmacotherapy. 1997; 17(6): 1300-4.

Wiciński M, Węclewicz MM, Miętkiewicz M, Malinowski B, Grześk E, Klonowska J. Potential mechanisms of hematological adverse drug reactions in patients receiving clozapine in combination with proton pump inhibitors. J Psychiatr Pract. 2017; 23(2): 114-20.

Regen F, Herzog I, Hahn E, Ruehl C, Le Bret N, Dettling M, et al. Clozapine-induced agranulocytosis: evidence for an immune-mediated mechanism from a patient-specific in-vitro approach. Toxicol Appl Pharmacol. 2017; 316: 10-6.

Myles N, Myles H, Xia S, Large M, Kisely S, Galletly C, et al. Metaanalysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand. 2018; 138(2): 101-9.

Inada K, Oshibuchi H, Ishigooka J, Nishimura K. Analysis of clozapine use and safety by using comprehensive national data from the japanese clozapine patient monitoring service. J Clin Psychopharmacol. 2018; 38(4): 302-6.

Steinauer LM, Leung JG, Burkey BW, McGrane IR, Letts V, Goren JL, et al. A retrospective multicenter evaluation of clozapine use in pediatric patients admitted for acute psychiatric hospitalization. J Child Adolesc Psychopharmacol. 2018; 28(9): 615-9.

Tunsirimas N, Pariwatcharakul P, Choovanichvong S, Ratta-Apha W. Clozapine-induced agranulocytosis and leukopenia: incidence, associated factors, and rate of hematologic adverse-effects monitoring in psychiatric out-patient services in Thailand. Asian J Psychiatry. 2019; 41: 13-6.

Law A, Croucher M. Prescribing trends and safety of clozapine in an older persons mental health population. Int Psychogeriatr. 2019; 1-7.

Hollingworth SA, Winckel K, Saiepour N, Wheeler AJ, Myles N, Siskind D. Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993-2014. Psychopharmacology (Berl). 2018; 235(7): 1915-21.

Li XH, Zhong XM, Lu L, Zheng W, Wang SB, Rao WW, et al. The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies. Psychol Med. 2019; 1-12.

Numata S, Umehara H, Ohmori T, Hashimoto R. Clozapine pharmacogenetic studies in schizophrenia: efficacy and agranulocytosis. Front Pharmacol. 2018; 9: 1049.

De With SAJ, Pulit SL, Staal WG, Kahn RS, Ophoff RA. More than 25 years of genetic studies of clozapine-induced agranulocytosis. Pharmacogenomics J. 2017; 17(4): 304-11.

Manu P, Lapitskaya Y, Shaikh A, Nielsen J. Clozapine rechallenge after major adverse effects: clinical guidelines based on 259 acses. Am J Ther. 2018; 25(2): e218-23.

Nielsen J, Correll CU, Manu P, Kane JM. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided?. J Clin Psychiatry. 2013; 74(6): 603-13.

Simon L, Cazard F. Clozapine rechallenge after neutropenia in resistant schizophrenia: a review. Encephale. 2016; 42(4): 346-53.

Manu P, Sarpal D, Muir O, Kane JM, Correll CU. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res. 2012; 134(2-3): 180-6.

Myles N, Myles H, Clark SR, Bird R, Siskind D. Use of granulocytecolony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: a systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry. 2017; 51(10): 980-9.

Lally J, Malik S, Krivoy A, Whiskey E, Taylor DM, Gaughran FP, et al. The use of granulocyte colony-stimulating factor in clozapine rechallenge: a systematic review. J Clin Psychopharmacol. 2017; 37(5): 600-4.

Winckel K, Siskind D. Clozapine in primary care. Aust Prescr. 2017; 40(6): 231-6.

Citrome L, McEvoy JP, Saklad SR. Guide to the management of clozapine-related tolerability and safety concerns. Clin Schizophr Relat Psychoses. 2016; 10(3): 163-77.

Inada K, Ishigooka J, Niho R. Clozapine. Jpn J Clin Med. 2013; 71(4): 678-83.

De Fazio P, Gaetano R, Caroleo M, Cerminara G, Maida F, Bruno A, et al. Rare and very rare adverse effects of clozapine. Neuropsychiatr Dis Treat. 2015; 11: 1995-2003.

##submission.downloads##

Publicado

2020-03-26

Cómo citar

1.
Luque Espino JC, Oscanoa Espinoza TJ. Agranulocitosis inducida por clozapina. Horiz Med [Internet]. 26 de marzo de 2020 [citado 26 de septiembre de 2022];20(1):69-76. Disponible en: https://www.horizontemedico.usmp.edu.pe/index.php/horizontemed/article/view/1197

Número

Sección

Artículos de revisión

Artículos más leídos del mismo autor/a