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Leukopenia Induced by Quetiapine in a Patient with History of Clozapine-Induced Leukopenia

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Leukopenia Induced by Quetiapine in a Patient with History of Clozapine-Induced Leukopenia Case Report Taiwanese Journal of Psychiatry (Taipei) Vol. 25 No. 3 2011 • 191 • Leukopenia Induced by Quetiapine in a Patient with History of Clozapine-induced Leukopenia Chih-Jen Wang, M.D.1, Cheng-Chen Chang, M.D.1, Si-Sheng Huang, M.D.1,2,3,4 Objective: Many antipsychotic medications can cause hematological abnor- malities. Quetiapine is a dibenzothiazepine derivative similar to clozapine, an an- tipsychotic agent which has the highest risk of causing blood dyscrasias. A case of quetiapine-induced leukopenia is described here in a patient who had a previous history of leukopenia induced by clozapine. Case Report: A 34-year-old Taiwan- ese woman patient with schizophrenia had a history of clozapine-induced leukope- nia. She developed leukopenia again after her receiving quetiapine treatment. Af- ter quetiapine was discontinued, her white blood count was increased to a normal range. Conclusion: Physicians should be cautious of having potential hematologi- cal abnormalities before prescribing leukopenia-causing drugs, especially in pa- tients with a history of drug-induced leukopenia. Key words: clozapine, quetiapine, leukopenia, blood dyscrasia (Taiwanese Journal of Psychiatry [Taipei] 2011; 25: 191-4) acterized by high 5-HT2 related to DA2 receptor Introduction affi nity. In this case report, a patient with a previ- ous history of clozapine-induced leukopenia is Many antipsychotic medications can cause presented with quetiapine-induced leukopenia. hematological abnormalities such as eosinophilia, leukopenia, leukocytosis, and agranulocytosis. Case Report Among all antipsychotic medications, clozapine is the most well-known drug of causing hemato- A 34-year-old Taiwanese female patient fi rst logic abnormalities. Clozapine has the highest diagnosed with schizophrenia at age 29 years, had leukopenia risk, which has also been observed in received haloperidol, amisulpride, risperidone and risperidone, olanzapine, and quetiapine. Similar fl upentixol injection for the fi rst few years after to clozapine, quetiapine is a dibenzothiazepine de- the diagnosis. Due to poor drug compliance, she rivative in chemical structure. Quetiapine is char- was admitted to the psychiatric ward several times 1 Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan 2 Department of Psychiatry, Lu-Tung Branch of Chan- ghua Christian Hospital, Changhua, Taiwan 3 Center of General Education, Central Taiwan University of Science and Technology, Taichung, Taiwan 4 Department of Psychiatry, Yun-Lin Branch of Changhua Christian Hospital, Yunlin, Taiwan Received: October 26, 2010; revised: December 6, 2010; accepted: December 6, 2010 Address correspondence to: Dr. Si-Sheng Huang, Lu-Tung Branch of Department of Psychiatry, Changhua Christian Hospital, No. 888, Section 2, Ludong Road, Lugang, Changhua County 50550, Taiwan • 192 • Leukopenia Associated with Quetiapine for the treatment of acute exacerbations of psy- received trihexyphenidyl hydrochloride 10 mg chotic symptoms including persecutory delusions, BID, and fl unitrazepam 3 mg HS for extrapyrami- auditory hallucinations as well as self-harming dal side effects and insomnia, respectively. On and destructive behavior. Her white blood counts day 13 of admission, we rechecked her white were ranged from 3,490 cells/μL to 6,900 cells/μL blood count because of poor wound healing; her during those hospitalizations. Two years before white blood cell count was 3,400 cells/μL. On day this admission, she received clozapine. Her drug 20 of admission, her Parkinsonian symptoms, compliance was improved and white blood counts psychotic symptoms, and wound healing were im- were checked regularly. After her psychotic symp- proved, and she was discharged with a white blood toms were stabilized, the patient had received the count of 2,900 cells/μL. Quetiapine was discon- maintenance clozapine dosage at 300 mg HS for tinued, and her antipsychotic agent was switched about one year. She developed side effects of hy- to ziprasidone 120 mg/day. The hematologist also persalivation and sedation during the fi rst few suspected that leukopenia was caused by quetiap- months of clozapine use. About six months ago, ine, and suggested further observation. her white blood count was dropped to 2,330 cells/ Our patient was suggested for outpatient fol- μL. Although she did not show clinical symptoms low up because of the absence of infection. But of leukopenia except for a low white blood count, she continued to have poor insight and returned to patient’s clozapine was discontinued immediately our clinic only once. She had poor drug compli- and switched to olanzapine. She did not show up ance and also had irregular outpatient follow-ups for the follow up clinic appointments after her at the clinic at other hospitals. Her ziprasidone medication change. was switched to olanzapine 20 mg/day during out- Two weeks before her appointment, the pa- patient clinic follow ups at another hospital. Two tient was admitted to our hospital, because she months after discharge, her white blood count was was found to have locked herself up in her room increased to 3,900 cells/μL. Four months later, and cut her wrists in response to auditory halluci- she was readmitted to a psychiatric ward because nations and persecutory delusions. But she was of recurrent psychotic symptoms after her having admitted to a psychiatric ward of another hospital. been free from any antipsychotic drug. Her white On the day of admission, her white blood count blood count was 6,900 cells/μL which was within was 7,600 cells/μL. She was then treated with normal range. quetiapine 200 mg/day and haloperidol 5 mg/day. But the drug response was poor and she experi- Discussion enced severe Parkinsonian symptoms including hand tremors, bradykinesia and rigidity. She was In this case report, we have shown that a pa- later referred to our inpatient service by her fami- tient with a history of leukopenia induced by clo- ly. On the day of admission to our hospital, the re- zapine, also experienced the same side effect with sults of her physical examination and laboratories quetiapine. Her other medications included tri- were normal except for bilateral wounds of her hexyphenidyl hydrochloride and fl unitrazepam. A wrists and a white blood count being 8,200 cells/ chronologic relationship existed between leuko- μL. We discontinued haloperidol and titrated que- penia development and increased dose of quetiap- tiapine to 200 mg BID. After her admission, she ine. Leukopenia only appeared when she was tak- Wang CJ, Chang CC, Huang SS • 193 • ing quetiapine, and her white blood cell count was high 5HT2-receptor affi nity related to DA2 recep- normalized after its discontinuation. Thus, we be- tors; quetiapine and clozapine, or their metabo- lieved no other medications besides quetiapine lites, may also cause blood dyscrasias. could have caused leukopenia. Clozapine is a second-generation (atypical) Leukopenia is defi ned as a white blood count antipsychotic drug which is effective in the treat- below 3,000 cells/μL. Severe leukopenia is a pre- ment-refractory schizophrenia. Its use is limited in disposing factor for infections, and its symptoms some patients due to its side effects of blood dys- can include headache, malaise, and fever. crasias (eosinophilia, neutropenia, leukopenia, Leukopenia may result from associated physical leukocytosis, agranulocytosis) and seizure. The and emotional stimuli, infections, tumors as well incidences of leukopenia and agranulocytosis in- as metabolic, endocrinological, hematological, duced by clozapine are 3% and 1%, respectively. and congenital disorders. In addition, many medi- The mechanisms how clozapine causes blood dys- cations such as antipsychotic agents, antibiotics, crasia are still unknown. anticonvulsants, antidepressants and immunosup- The hypotheses of leukopenia include bone pressive agents can also decrease the number of marrow suppression and/or peripheral destruction white blood cells. The rates of quetiapine-induced of the white blood cells. Clozapine is metabolized blood dyscrasias including leukopenia and agran- through the mediation of cytochrome P450 1A2 ulocytosis are 1% and < 1%, respectively. (CYP1A2) mainly into norclozapine, which is be- The literature focusing on quetiapine-in- lieved to be the primary cause of blood dyscrasia duced blood dyscrasia mechanisms is scarce. A [6]. A dose-dependent toxicity exists for blood PubMed search yielded only fi ve other case re- dyscrasia; the higher medication dosage may have ports of quetiapine-induced leukopenia. The dos- higher risks for causing blood dyscrasia [1]. ages of quetiapine for those cases were at least Besides drug-induced blood dyscrasia, there may 600 mg/day. There may be in vivo or in vitro dos- be dose-independent hypersensitivity. Certain age-related blood dyscrasia phenomenon which haplotypes of human leukocyte antigen genes [7], was induced by quetiapine [1]. Four of the dyscra- such as tumor necrosis factor microsatellites d3, sia cases included individuals taking quetiapine b4 [8], variant genes of HSP 70 (heat-shock pro- and valproate [2-5]. The leukopenia incidence tein), and dihydronicotinamide riboside (NRH). caused by valproate itself is about 0.5%. Valproate Quinone oxidoreductase gene (NQO2) polymor- acid can increase quetiapine plasma levels up to phisms may be also associated with clozapine-in- 77%. Thus, the causes of leukopenia in the above duced agranulocytosis [9]. Our patient had leuko- cases might be related to the increased quetiapine penia
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