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Optimizing outcomes in clozapine rechallenge following neutropenia using human leukocyte antigen typing: A case report

2017; Wiley; Volume: 71; Issue: 4 Linguagem: Inglês

10.1111/pcn.12505

1440-1819

Naruhisa Yamaki, Akitoyo Hishimoto, Ikuo Otsuka, Toru Sasada, Shuken Boku, Takeo Saito, Yuka Yasuda, Hidenaga Yamamori, Masashi Ikeda, Manabu Ikeda, Ichiro Sora, Nakao Iwata, Ryota Hashimoto,

Immunodeficiency and Autoimmune Disorders

Clozapine stands alone as a highly effective antipsychotic agent in the treatment of refractory schizophrenia. Despite its effectiveness, its clinical use has been strictly limited because of its potential adverse effects. In particular, clozapine-induced agranulocytosis and clozapine-induced granulocytopenia, which occur in 2.6% and 7.79% of clozapine-treated patients in Japan, respectively, can both be fatal if not detected early.1 Once a clozapine treatment is discontinued following an adverse drug reaction, patients typically have limited future treatment options. Although some studies have shown that regions of the major histocompatibility complex are associated with clozapine-induced agranulocytosis/granulocytopenia (CIAG), there have been few reports in Asian patient populations. A recent study showed that human leukocyte antigen (HLA)-B*59:01 was a risk factor for CIAG in a Japanese population.2 We present a case of a successful rechallenge with clozapine following neutropenia in which we then confirmed that the patient had a low risk of CIAG using HLA typing. This report was approved by the Ethical Committee for Genetic Studies of Kobe University Graduate School of Medicine. The subject gave informed consent and anonymity has been preserved. The patient was a 38-year-old woman with a 20-year history of paranoid schizophrenia. After clozapine was initiated and its dose was titrated up to 450 mg/day, her psychotic condition, auditory hallucinations, and delusions improved. Her white blood cell (WBC) counts ranged between 9000 and 12 000/mm3 while she received a daily dosage of clozapine. No specific reason for an increasing WBC count could be identified after consultation with the hematologic department. Four years after initiating clozapine, her WBC count declined abruptly to 4200/mm3 (absolute neutrophil count, 1350). She was subsequently hospitalized and her clozapine treatment was stopped. Although WBC counts increased rapidly after discontinuing clozapine, her psychotic symptoms worsened and she required a physical restraint due to her delusions and aggression. The patient was treated with quetiapine (1100 mg/day) and blonanserin (28 mg/day), but her psychotic symptoms persisted. Five months after clozapine discontinuation, we considered a rechallenge and discussed this possibility with the hematologic consultation service. We decided to initiate clozapine again with the approval of the Clozaril Patient Monitoring Service; the dose was gradually increased from 12.5 to 450 mg/day. Furthermore, we added lithium carbonate (Li) to augment the leukocyte count. During the second clozapine regimen, the patient did not develop neutropenia and her psychiatric symptoms gradually improved. We examined HLA typing of the patient to assess the risk of CIAG. HLA-B*52:01/52:01 was found, which supported the fact that the patient was not at high risk of CIAG. At the end of week 51 of her hospitalization, she was discharged home on clozapine (450 mg/day) and Li (600 mg/day). In Japan, the use of clozapine is restricted because of severe adverse effects, such as CIAG. Consequently, clozapine rechallenge is rare. With a prior risk assessment, including HLA typing and careful monitoring during treatment, a clozapine rechallenge is possible and safe. Dr Hishimoto reports grants from Japan Agency for Medical Research and Development (AMED) and JSPS KAKENHI during the conduct of the study; grants and personal fees from GlaxoSmithKline, Otsuka, Dainippon Sumitomo, and Mochid outside the submitted work; and personal fees from Eli Lilly, Shionogi, Janssen Pharmaceutical K.K., Nipponshinyaku, and MSD outside the submitted work. Dr Saito reports grants from AMED and JSPS KAKENHI during the conduct of the study. Dr Masashi Ikeda reports grants from AMED, SENSHIN Medical Research Foundation, and JSPS KAKENHI during the conduct of the study; and grants from Janssen Pharmaceutical K.K. outside the submitted work. Dr Manabu Ikeda reports personal fees from Dainippon Sumitomo Pharma, Co., Ltd., Novartis Pharma K.K., Pfizer Inc., Yoshitomiyakuhin Corporation, Eisai, Co., Ltd., Janssen Pharmaceutical K.K., Otsuka Pharmaceutical, Co., Ltd., Astellas Pharma Inc., Meiji Seika Pharma, Co., Ltd., Daiichi Sankyo, Co., Ltd., Eli Lilly Japan K.K., and Nihon Medi-Physics, Co., Ltd. outside the submitted work. Dr Sora reports grants from GlaxoSmithKline; grants and personal fees from Otsuka Pharmaceutical; and personal fees from Tsumura, Meiji Seika Pharma, Shionogi, MSD, and Pfizer outside the submitted work. Dr Iwata reports grants from AMED, SENSHIN Medical Research Foundation, and JSPS KAKENHI during the conduct of the study; grants and personal fees from GlaxoSmithKline, Eli Lilly, Otsuka, and Dainippon Sumitomo outside the submitted work; grants from Daiichi-Sankyo outside the submitted work; and personal fees from Janssen Pharmaceutical K.K., Shionogi, and Tanabe Mitsubishi outside the submitted work. Dr Hashimoto reports grants from Dainippon Sumitomo Pharma, Co., Ltd.; and personal fees from Dainippon Sumitomo Pharma, Co., Ltd., Novartis Pharma K.K., Pfizer Inc., Yoshitomiyakuhin Corporation, Hisamitsu Pharmaceutical, Co., Inc., Janssen Pharmaceutical K.K., Otsuka Pharmaceutical, Co., Ltd., Astellas Pharma Inc., Meiji Seika Pharma, Co., Ltd., Mochida Pharmaceutical, Co., Ltd., Eli Lilly Japan K.K., and Shionogi & Co., Ltd. outside the submitted work. All other authors declare that they have no conflicts of interest.