Hematological Side Effects of Atypical Antipsychotic Drugs

Yıl 2009, Cilt: 1 Sayı: 3, 255 - 279, 01.09.2009

Serap Erdoğan

Öz

Atypical antipsychotics cause less frequently extrapyramidal system symptoms, neuroleptic malignant syndrome and hyperprolactinemia than typical antipsychotics. However hematological side effects such as leukopenia and neutropenia could occur during treatment with atypical antipsychotics. These side effects could lead to life threatening situations and the mortality rate due to drug related agranulocytosis is about 5-10%. There are several hypothesis describing the mechanisms underlying drug induced leukopenia and/or neutropenia such as direct toxic effects of these drugs upon the bone marrow or myeloid precursors, immunologic destruction of the granulocytes or supression of the granulopoiesis. Clozapine is the antipsychotic agent which has been most commonly associated with agranulocytosis. A nitrenium ion which is formed by the bioactivation of clozapine is thought to have an important role in the pathophysiogy of this adverse effect. Aside from clozapine, there are several case reports reporting an association between olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole and leukopenia. We did not find any study or case report presenting amisulpride or sulpride related hematological side effects in our literature search. Patients who had hematological side effects during their previous antipsychotic drug treatments and who had lower baseline blood leukocyte counts, have higher risk to develop leukopenia or neutropenia during their current antipsychotic treatment. Once leukopenia and neutropenia develops, drugs thought to be responsible for this side effect should be discontinued or dosages should be lowered. In some cases iniatition of lithium or G-CSF (granulocyte colony-stimulating factor) therapy may be helpful in normalizing blood cell counts. Clinicans should avoid any combination of drugs known to cause hematological side effects. Besides during antipsychotic treatment, infection symptoms such as fever, cough, sore throat or fatigue should be evaluated closely and routinely. In this review, all up to date studies including case reports presenting or searching for atypical antipsychotic drugs related hematological side effects have been reviewed and possible mechanisms leading to these adverse effects and suggested treatment modalities have been discussed..

Anahtar Kelimeler

Atypical antipsychotics, hematological side effects, leukopenia

Atipik Antipsikotik İlaçların Hematolojik Yan Etkileri

Öz

Atipik antipsikotikler ekstrapiramidal sistem yan etkilerine, nöroleptik malign sendroma ve hiperprolaktinemiye tipik antipsikotiklere göre daha az sıklıkla yol açmaktadır. Bununla birlikte atipik antipsikotiklerle lökopeni ve nötropeni gibi hematolojik yan etkiler ortaya çıkabilmektedir. Bunlar yaşamı tehdit edici durumlara yol açabilmektedir ve ilaçlara bağlı olarak gelişen agranülositozdan kaynaklanan ölüm oranı %5-10'dur. İlaçlara bağlı lökopeni ve/veya nötropeni gelişiminin altında kemik iliği ya da myeloid öncüllere doğrudan toksik etki, granülositlerin immunolojik yıkımı ya da granülopoezin baskılanması gibi çeşitli mekanizmalar yatmaktadır. Literatürde agranülositozla en çok ilişkilendirilen antipsikotik ilaç klozapindir ve ilacın biyoaktivasyonu ile oluşan bir nitrenyum iyonunun bu yan etki gelişiminde önemli bir role sahip olduğu düşünülmektedir. Klozapinden başka olanzapin, ketiyapin ve risperidonla ilişkili lökopeni olgu bildimleri de bulunmaktadır. Ziprasidon ve aripiprazol lökopeniye nadiren yol açmakta ve literatürde amisülprid ve sülpridle ilişkili hematolojik yan etkilere dair olgu bildirimi bulunmamaktadır. Önceki antipsikotik tedavileri sırasında hematolojik değişiklikler yaşayan ve tedavi başlangıcındaki beyaz küre sayıları normal sınırların altında olan hastalar lökopeni ve nötropeni gelişimine karşı yüksek risk altındadırlar. Lökopeni ve nötropeni ortaya çıktığında kullanılmakta olan ilaç kesilebilmekte ya da doz azaltılabilmektedir. Kimi zaman lityum ve G-CSF tedavileri kan hücrelerinin sayısını normale döndürmede faydalı olabilmektedir. Klinisyenler hematolojik yan etkilere yol açtığı bilinen ilaçları birlikte kullanmaktan kaçınmalı ve antipsikotik tedavisi sırasında vücut ısısında yükselme, öksürük, boğaz ağrısı ve yorgunluk gibi enfeksiyon belirtileri düzenli olarak kontrol edilmelidir. Bu gözden geçirme yazısında klozapin, olanzapin, ketiyapin, risperidon, aripiprazol ve ziprasidonla ilişkili hematolojik yan etkilerle ilgili olgu bildirimleri özetlenecek ve bu hematolojik yan etkilere yol açan olası mekanizmalar ve tedavi yaklaşımları tartışılacaktır.

Anahtar Kelimeler

Atipik antipsikotikler, hematolojik yan etki, lökopeni

Kaynakça

• Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23(Suppl 1):27-41.
• Kodesh A, Finkel B, Lerner AG, Kretzmer G, Sigal M. Dose-dependent olanzapine-associated leukopenia: three case reports. Int Clin Psychopharmacol 2001; 16:117-119.
• Croarkin P, Rayner T. Acute neutropenia in a patient treated with quetiapine. Psychosomatics 2001; 42:368.
• Uetrecht JP. Reactive metabolites and agranulocytosis. Eur J Haematol Suppl 1996; 60:83-88.
• Stübner S, Grohmann R, Engel R, Bandelow B, Ludwig WD, Wagner G et al. Blood dyscrasias induced by psychotropic drugs. Pharmacopsychiatry 2004; 37(Suppl 1):70-78.
• Delieu JM, Horobin RW, Duguid JK. Formation of immature neutrophil leucocytes in schizophrenic patients treated with various antipsychotic drugs: Comparisons and predictions. J Psychopharmacol 2006; 20:824-828.
• Delieu JM, Horobin RW, Duguid JK. Exploring the relationship of drug-induced neutrophil immaturity & haematological toxicity to drug chemistry using quantitative structure-activity models. Med Chem 2009; 5:7-14.
• Marder SR, Wirshing DA. Clozapine. In: Nemeroff CB, Schatzberg AF. Textbook of Psychopharmacology. 3rd ed., Arlington, American Psychiatric Publishing. 2004; pp.443-456.
• Williams DP, Pirmohamed M, Naisbitt DJ, Uetrecht JP, Park BK. Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. Mol Pharmacol 2000; 58:207-216.
• Uetrecht JP. Metabolism of clozapine by neutrophils. Possible implications for clozapine-induced agranulocytosis. Drug Saf 1992; 7(Suppl 1):51-56.
• Pereira A, Dean BClozapine bioactivation induces dose-dependent, drug- specific toxicity of human bone marrow stromal cells: A potential in vitro system for the study of agranulocytosis Biochem Pharmacol 2006; 72:783-793.
• Schuld A, Kraus T, Hinze-Selch D, Haack M, PollmaÈcher T. Granulocyte colony- stimulating factor plasma levels during clozapine- and olanzapine-induced granulocytopenia. Acta Psychiatr Scand 2000; 102:153-155.
• Opgen-Rhein C, Dettling M. Clozapine-induced agranulocytosis and its genetic determinants. Pharmacogenomics 2008; 9:1101-1111.
• Whiskey E, Taylor D. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs 2007; 21:25-35.
• Silvestrini C, Arcangeli T, Biondi M, Pancheri P. A second trial of clozapine in a case of granulocytopenia. Hum Psychopharmacol 2000; 15:275–279.
• Dunk LR, Annan LJ, Andrews CD. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Br J Psychiatry 2006; 188:255-263.
• Esposito D, Rouillon F, Limosin F. Continuing clozapine treatment despite neutropenia. Eur J Clin Pharmacol 2005; 60:759-764.
• Papetti F, Darcourt G, Giordana JY, Spreux A, Thauby S, Feral F et al. Treatment of clozapine-induced granulocytopenia with lithium (two observations). Encephale 2004; 30:578-582.
• Eymin G, Andresen M, Godoy J, Rada G. Malignant neuroleptic syndrome and polyserositis associated to clozapine use: report of one case. Rev Med Chil 2005; 133:1225-1228.
• Chin-Yee I, Bezchlibnyk-Butler K, Wong L. Use of cytokines in clozapine- induced agranulocytosis. Can J Psychiatry 1996; 41:280-284.
• Zipris P, Melamed Y, Weizman A, Bleich A. Clozapine-induced eosinophilia and switch to quetiapine in a patient with chronic schizophrenia with suicidal tendencies. Isr J Psychiatry Relat Sci 2007; 44:54-56.
• Ziegenbein M, Steinbrecher A, Garlipp P. Clozapine-induced aplastic anemia in a patient with Parkinson's disease. Can J Psychiatry 2003; 48:352.
• Gonzales MF, Elmore J, Luebbert C.Evidence for immune etiology in clozapine- induced thrombocytopenia of 40 months' duration: a case report. CNS Spectr 2000; 5:17-18.
• Schulz SC, Olson S, Kotlyar M. Olanzapine. In: Nemeroff CB, Schatzberg AF. Textbook of Psychopharmacology. 3rd ed., Arlington, American Psychiatric Publishing. 2004; 457-472.
• Oyewumi LK, Al-Semaan Y. Olanzapine: safe during clozapine-induced agranulocytosis. J Clin Psychopharmacol 2000; 20:279-281.
• Vilella CT, Ripoll AR, Mari-Alfonso B, Naval-Sendra E. Olanzapine-induced agranulocytosis A case report and review of the literature. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26:411-414.
• Dernovsek MZ, Tavcar R. Olanzapine appears haematologically safe in patients who developed blood dyscrasia on clozapine and risperidone. Int Clin Psychopharmacol 2000; 15:237-238.
• Gardner I, Zahid N, MacCrimmon D, Uetrecht JP. A Comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes. Mol Pharmacol 1998; 53:991-998.
• Buchman N, Strous RD, Ulman AM, Lerner M, Kotler M. Olanzapine-induced leukopenia with human leukocyte antigen profiling. Int Clin Psychopharmacol 2001; 16:55-57.
• Kodesh A, Finkel B, Lerner AG, Kretzmer G, Sigal M. Dose-dependent olanzapine-associated leukopenia: three case reports. Int Clin Psychopharmacol 2001; 16:117-119.
• Abdullah N, Voronovitch L, Taylor S, Lippmann S. Olanzapine and haloperidol: potential for neutropenia? Psychosomatics 2003; 44:83.
• Jagadheesan K, Mehrtens JProlongation of clozapine-induced neutropenia with olanzapine. Aust N Z J Psychiatry 2007; 41:192.
• Sayın A, Coșar B. Prolongation of clozapine-induced leukopenia with olanzapine treatment. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:958-959.
• Duggal HS, Gates C, Pathak PC. Olanzapine-induced neutropenia: Mechanism and Treatment. J ClinPsychopharmacol 2004; 24:234-235.
• Naumann R, Felber W, Heilemann H, Reuster T. Olanzapine-induced agranulocytosis. The Lancet 1999; 354:566.
• Schuld A, Kraus T, Hinze-Selch D, Haack M, PollmaÈcher T. Granulocyte colony- stimulating factor plasma levels during clozapine- and olanzapine-induced granulocytopenia. Acta Psychiatr Scand 2000; 102:153-155.
• Gajwani P, Tesar GE. Olanzapine-induced neutropenia. Psychosomatics 2000; 41:150-151.
• Bachmann S, Schröder J, Pantel J, Mundt C, Zorn M, Witzens M et al. Olanzapine-induced thrombocytopenia in association with idiopathic thrombocytopenic purpura. Br J Psychiatry 1998; 173:352.
• Carrillo JA, González JA, Gervasini G, López R, Fernández MA, Nşñez GM. Thrombocytopenia and fatality associated with olanzapine. Eur J Clin Pharmacol 2004; 60:295-296.
• Norgard NB, Stark JE. Olanzapine-associated neuroleptic malignant syndrome. Pharmacotherapy 2006; 26:1180-1182.
• Lieberman JA. Quetiapine. In: Nemeroff CB, Schatzberg AF. Textbook of Psychopharmacology. 3rd ed., Arlington, American Psychiatric Publishing. 2004; pp.473-486.
• Ruhé HG, Becker HE, Jessurun P, Marees CH, Heeringa M, Vermeulen HD. Agranulocytosis and granulocytopenia associated with quetiapine. Acta Psychiatr Scand 2001; 104:311-313.
• Oluboka O, Haslam D, Lam T, Bown-Demarco D. Quetiapine-induced leucopenia: possible dosage-related phenomenon. Can J Psychiatry 2003; 48:65-66.
• Cowan C, Oakley C. Leukopenia and neutropenia induced by quetiapine. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:292-294.
• Lobato MI, Crestana T, Onsten TG. Sustained leukopenia probably related to quetiapine. Psychosomatics 2005; 46:188-189.
• Penninga EI, Dalhoff KP, Lykkegaard SE. Quetiapine-induced leucopenia. Ugeskr Laeger 2008; 170:2892.
• Shankar BR. Quetiapine-induced leucopenia and thrombocytopenia. Psychosomatics 2007; 48:530-531.
• Nair P, Lippmann S. Is leukopenia associated with divalproex and/or quetiapine? Can J Psychiatry 2003; 48:65-66.
• Clark N, Weissberg E, Noel J. Quetiapine and leukopenia. Am J Psychiatry 2001; 158:817-818.
• Rahman A, Mican LM, Fischer C, Campbell AH. Evaluating the incidence of leukopenia and neutropenia with valproate, quetiapine, or the combination in children and adolescents. Ann Pharmacother 2009; 43:822-830.
• Diaz P, Hogan TP. Granulocytopenia with clozapine and quetiapine. Am J Psychiatry 2001; 158:651.
• Goff DC. Risperidone. In: Nemeroff CB, Schatzberg AF. Textbook of Psychopharmacology. 3rd ed., Arlington, American Psychiatric Publishing. 2004; 495-505.
• Uzun S, Kozumplik O, Jakovljevic M, Folnegovic-Smalc V. Leukopenia during therapy with risperidone long-acting injectable: Two case reports. J Clin Psychopharmacol 2008; 28:713-714.
• Sluys M, Güzelcan Y, Casteelen G, de Haan L. Risperidone-induced leucopenia and neutropenia: A case report. Eur Psychiatry 2004; 19:117.
• Finkel B, Lerner AG, Oyffe I, Sigal M. Risperidone-associated agranulocytosis. Am J Psychiatry 1998; 155:855-856.
• Esposito D, Corruble E, Hardy P, Chouinard G. Risperidone-induced morning pseudoneutropenia. Am J Psychiatry 2005; 162:397.
• Etain B, Roubaud L, Le Heuzey MF, Mouren Simeoni MC. A case of leukopenia in treatment with risperidone in an adolescent. Encephale 2000; 26:81-84.
• Edleman RJJ. Risperidone side effects. J Am Acad Child Adolesc Psychiatry 1996; 35:4-5.
• Bondolfi G, Morena P, Dascal DR, Bertschy G. Risperidone and reversible neutropenia: a negative rechallenge. Eur Neuropsychopharmacol 1996; 6:257.
• Meylan C, Bondolfi G, Aubert AC, Baumann P. Reversible neutropenia during a cold: possible involvement of risperidone? A case report. Eur Neuropsychopharmacol 1995; 5:1-2.
• Godleski LS, Sernyak MJ. Agranulocytosis after addition of risperidone to clozapine treatment. Am J Psychiatry 1996; 153:735-736.
• Assion HJ, Kolbinger HM, Rao ML, Laux G. Lymphocytopenia and thrombocytopenia during treatment with risperidone or clozapine. Pharmacopsychiatry 1996; 29:227-228.
• Lieberman JA. Aripiprazole. In: Nemeroff CB, Schatzberg AF. Textbook of Psychopharmacology. 3rd ed., Arlington, American Psychiatric Publishing. 2004; pp.487-494.
• Mendhekar D, Duggal H, Andrade C Leukopenia and thrombocytopenia on adding aripiprazole to phenytoin. World J Biol Psychiatry 2008; 7:1-2.
• Qureshi SU, Rubin E. Risperidone and aripiprazole induced leukopenia: A case report. Prim Care Companion J Clin Psychiatry 2008; 10:482-483.
• Yalcin DO, Goka E, Aydemir MC, Kisa C. Is aripiprazole the only choice of treatment of the patients who developed anti-psychotic agents-induced leucopenia and neutropenia? A case report. J Psychopharmacol 2008; 22:333- 335.
• Daniel DG, Copeland. LF, Tamminga C. Ziprasidone. In: Nemeroff CB, Schatzberg AF. Textbook of Psychopharmacology. 3rd ed., Arlington, American Psychiatric Publishing. 2004; pp. 507-519.
• Montgomery J. Ziprasidone-related agranulocytosis following olanzapine- induced neutropenia. Gen Hosp Psychiatry 2006; 28:83-85.
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