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Paliperidone-induced leukopenia and neutropenia: A case report
Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 284–285
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Letter to the Editor (Case report) Paliperidone-induced leukopenia and neutropenia: A case report Sir: Paliperidone (9-hydroxyrisperidone) is the primary active metabolite of risperidone and INVEGA is an extended release formulation of paliperidone used for the acute and maintenance treatment of schizophrenia. The most commonly reported adverse events of INVEGA are insomnia, headache, akathisia and extrapyramidal symptom-related adverse events including involuntary movements, tremors and muscle stiffness (Emsley et al., 2008). Leukopenia is a decrease in the number of white blood cells (leukocytes) and is often due to neutropenia. Neutropenia can be defined as a neutrophil count of b1.50 × 109/L. Although leukopenia and neutropenia are rare while taking antipsychotic medications, they are serious and potentially life-threatening hematological side effects associated with the use of typical and atypical antipsychotic drugs, especially clozapine. To our knowledge, we report the first case in which a patient developed leukopenia and neutropenia during treatment with paliperidone. A 33-year-old female was admitted to hospital with a 1-year history of auditory and visual hallucinations, persecutory delusion, aggressive behavior, and an unstable mood. She had no significant psychiatric or medical history. She had taken no psychiatric medications. On admission, the laboratory assessment showed a white blood cell (WBC) count of 6.17 × 109/L and neutrophil count of 3.97 × 109/L. The other cell counts were also within the normal ranges, although her red blood cell (RBC) count was near the lower limit of normal (RBC count 3.49 × 106/μL, hemoglobin (Hb) 11.7 g/dL, hematocrit (Hct) 34%) and serum creatinine kinase was elevated slightly (473 IU/ L). Her serum creatinine kinase was normalized on the third day of her hospitalization. She was treated with paliperidone 6 mg/day. Her auditory and visual hallucinations disappeared gradually, although her persecutory and somatic delusions were continued. Therefore, the dose of paliperidone was increased to 9 mg/day on the ninth day without any concomitant medications. However her WBC and neutrophil counts fell abruptly to 2.96 × 109/L and 1.18 × 109/L, respectively, on day 14, and her RBC count was decreased slightly (RBC 3.23 × 106/μL, Hb 10.7 g/dL, Hct 31.5%). The cell counts continued to hover near these levels for the next few days. There were no signs or symptoms of any infection. We consulted a hematologist about her status and it was suggested that her leukopenia and neutropenia might be associated with the antipsychotic medication. Additional laboratory tests (peripheral blood smear, total iron-binding capacity, reticulocyte count, and levels of ferritin and iron) were within the normal ranges. We suspected that paliperidone had induced her leukopenia and neutropenia. The paliperdone was discontinued on day 22. Three days after discontinuing the paliperidone, her leukopenia and neutropenia had improved later (WBC count 3.42 × 109/L, neutrophil count 1.57 × 109/L). We started with olanzapine and increased it to 15 mg/ day. On day 36, her WBC and neutrophil counts had normalized (WBC 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.09.018
count 4.70 × 109/L, neutrophil count 2.77 × 109/L) and they remained normal for the remainder of her admission. The pathophysiology of medication-induced neutropenia might be related to toxic effects or immune reactions in the bone marrow or, more rarely, involve the peripheral destruction of cells (Flanagan and Dunk, 2008). Medication-induced neutropenia usually occurs after taking medications for 1 to 2 weeks, and the severity of neutropenia is associated with the dosage of medication and duration of exposure (Flanagan and Dunk, 2008). When chlorpromazine was introduced in the early 1950s, neutropenia was first observed as a side effect of psychotropic medication. In particular, clozapine appears to influence the endogenous production of hematopoietic cytokines (Esposito et al., 2003). Although clozapine is the antipsychotic drug most likely to cause leukopenia and neutropenia (Flanagan and Dunk, 2008), these side effects have been reported in patients taking antipsychotics including risperidone (Sluys et al., 2004), olanzapine (Stergiou et al., 2005) and quetiapine (Cowan and Oakley, 2007). In our case, leukopenia and neutropenia were seen after taking paliperidone for 2 weeks. After discontinuing the drug, the WBC and neutrophil counts normalized three days later. The increment in the WBC and neutrophil counts after stopping the paliperidone in this case and the normal results for other laboratory tests are highly suggestive that paliperidone was indeed the cause of the leukopenia and neutropenia. There is a report that the neutrophil count normalized 2 days after stopping risperidone (Meylan et al., 1995). There are several reports on risperidone-induced leukopenia and neutropenia (Dernovsek and Tavcar, 1997; Finkel et al., 1998; Sluys et al., 2004; Uzun et al., 2008). Paliperidone is the primary active metabolite of risperidone and has a relatively long elimination half-life (t1/2 = 20.5 h) compared to risperidone (t1/2 = 2.8 h). The psychopharmacological effect of risperidone on patients results from the combined concentrations of risperidone and its major metabolite, paliperidone. This case implies that clinicians should be aware that paliperidone, like risperidone, might induce leukopenia and neutropenia. We propose that the WBC and neutrophil counts should be monitored carefully when starting atypical antipsychotics other than clozapine.
References Cowan C, Oakley C. Leukopenia and neutropenia induced by quetiapine. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:292–4. Dernovsek Z, Tavcar R. Risperidone-induced leucopenia and neutropenia. Br J Psychiatry 1997;171:393–4. Emsley R, Berwaerts J, Eerdekens M, Kramer M, Lane R, Lim P, et al. Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies. Int Clin Psychopharmacol 2008;23:343–56. Esposito D, Aouille J, Rouillon F, Limosin F. Morning pseudoneutropenia during clozapine treatment. World J Biol Psychiatry 2003;4:192–4. Finkel B, Lerner AG, Oyffe I, Sigal M. Risperidone-associated agranulocytosis. Am J Psychiatry 1998;155:855–6. Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008;23(Suppl 1):27–41. 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 [discussion 3].
Letter to the Editor (Case report) Sluys M, Guzelcan Y, Casteelen G, de Haan L. Risperidone-induced leucopenia and neutropenia: a case report. Eur Psychiatry 2004;19:117. Stergiou V, Bozikas VP, Garyfallos G, Nikolaidis N, Lavrentiadis G, Fokas K. Olanzapineinduced leucopenia and neutropenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:992–4. Uzun S, Kozumplik O, Jakovljevic M, Folnegovic-Smalc V. Leukopenia during therapy with risperidone long-acting injectable: two case reports. J Clin Psychopharmacol 2008;28:713–4.
Jin-Nah Kim Boung-Chul Lee Ihn-Geun Choi Department of Neuropsychiatry, Hallym University, Han-Gang Sacred Heart Hospital, Seoul, Republic of Korea
285
Duk-In Jon Myung Hun Jung* Department of Neuropsychiatry, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea ⁎Corresponding author. Department of Neuropsychiatry, Hallym University Sacred Heart Hospital, 896, Pyeongchon-dong, Dongan-gu, Anyang, Gyeonggi-do 431-070, Republic of Korea. Tel.: +82 31 380 3753; fax: +82 31 381 3753. E-mail address: [email protected](M.H. Jung). 19 August 2010
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Letter to the Editor (Case report) Paliperidone-induced leukopenia and neutropenia: A case report Sir: Paliperidone (9-hydroxyrisperidone) is the primary active metabolite of risperidone and INVEGA is an extended release formulation of paliperidone used for the acute and maintenance treatment of schizophrenia. The most commonly reported adverse events of INVEGA are insomnia, headache, akathisia and extrapyramidal symptom-related adverse events including involuntary movements, tremors and muscle stiffness (Emsley et al., 2008). Leukopenia is a decrease in the number of white blood cells (leukocytes) and is often due to neutropenia. Neutropenia can be defined as a neutrophil count of b1.50 × 109/L. Although leukopenia and neutropenia are rare while taking antipsychotic medications, they are serious and potentially life-threatening hematological side effects associated with the use of typical and atypical antipsychotic drugs, especially clozapine. To our knowledge, we report the first case in which a patient developed leukopenia and neutropenia during treatment with paliperidone. A 33-year-old female was admitted to hospital with a 1-year history of auditory and visual hallucinations, persecutory delusion, aggressive behavior, and an unstable mood. She had no significant psychiatric or medical history. She had taken no psychiatric medications. On admission, the laboratory assessment showed a white blood cell (WBC) count of 6.17 × 109/L and neutrophil count of 3.97 × 109/L. The other cell counts were also within the normal ranges, although her red blood cell (RBC) count was near the lower limit of normal (RBC count 3.49 × 106/μL, hemoglobin (Hb) 11.7 g/dL, hematocrit (Hct) 34%) and serum creatinine kinase was elevated slightly (473 IU/ L). Her serum creatinine kinase was normalized on the third day of her hospitalization. She was treated with paliperidone 6 mg/day. Her auditory and visual hallucinations disappeared gradually, although her persecutory and somatic delusions were continued. Therefore, the dose of paliperidone was increased to 9 mg/day on the ninth day without any concomitant medications. However her WBC and neutrophil counts fell abruptly to 2.96 × 109/L and 1.18 × 109/L, respectively, on day 14, and her RBC count was decreased slightly (RBC 3.23 × 106/μL, Hb 10.7 g/dL, Hct 31.5%). The cell counts continued to hover near these levels for the next few days. There were no signs or symptoms of any infection. We consulted a hematologist about her status and it was suggested that her leukopenia and neutropenia might be associated with the antipsychotic medication. Additional laboratory tests (peripheral blood smear, total iron-binding capacity, reticulocyte count, and levels of ferritin and iron) were within the normal ranges. We suspected that paliperidone had induced her leukopenia and neutropenia. The paliperdone was discontinued on day 22. Three days after discontinuing the paliperidone, her leukopenia and neutropenia had improved later (WBC count 3.42 × 109/L, neutrophil count 1.57 × 109/L). We started with olanzapine and increased it to 15 mg/ day. On day 36, her WBC and neutrophil counts had normalized (WBC 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.09.018
count 4.70 × 109/L, neutrophil count 2.77 × 109/L) and they remained normal for the remainder of her admission. The pathophysiology of medication-induced neutropenia might be related to toxic effects or immune reactions in the bone marrow or, more rarely, involve the peripheral destruction of cells (Flanagan and Dunk, 2008). Medication-induced neutropenia usually occurs after taking medications for 1 to 2 weeks, and the severity of neutropenia is associated with the dosage of medication and duration of exposure (Flanagan and Dunk, 2008). When chlorpromazine was introduced in the early 1950s, neutropenia was first observed as a side effect of psychotropic medication. In particular, clozapine appears to influence the endogenous production of hematopoietic cytokines (Esposito et al., 2003). Although clozapine is the antipsychotic drug most likely to cause leukopenia and neutropenia (Flanagan and Dunk, 2008), these side effects have been reported in patients taking antipsychotics including risperidone (Sluys et al., 2004), olanzapine (Stergiou et al., 2005) and quetiapine (Cowan and Oakley, 2007). In our case, leukopenia and neutropenia were seen after taking paliperidone for 2 weeks. After discontinuing the drug, the WBC and neutrophil counts normalized three days later. The increment in the WBC and neutrophil counts after stopping the paliperidone in this case and the normal results for other laboratory tests are highly suggestive that paliperidone was indeed the cause of the leukopenia and neutropenia. There is a report that the neutrophil count normalized 2 days after stopping risperidone (Meylan et al., 1995). There are several reports on risperidone-induced leukopenia and neutropenia (Dernovsek and Tavcar, 1997; Finkel et al., 1998; Sluys et al., 2004; Uzun et al., 2008). Paliperidone is the primary active metabolite of risperidone and has a relatively long elimination half-life (t1/2 = 20.5 h) compared to risperidone (t1/2 = 2.8 h). The psychopharmacological effect of risperidone on patients results from the combined concentrations of risperidone and its major metabolite, paliperidone. This case implies that clinicians should be aware that paliperidone, like risperidone, might induce leukopenia and neutropenia. We propose that the WBC and neutrophil counts should be monitored carefully when starting atypical antipsychotics other than clozapine.
References Cowan C, Oakley C. Leukopenia and neutropenia induced by quetiapine. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:292–4. Dernovsek Z, Tavcar R. Risperidone-induced leucopenia and neutropenia. Br J Psychiatry 1997;171:393–4. Emsley R, Berwaerts J, Eerdekens M, Kramer M, Lane R, Lim P, et al. Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies. Int Clin Psychopharmacol 2008;23:343–56. Esposito D, Aouille J, Rouillon F, Limosin F. Morning pseudoneutropenia during clozapine treatment. World J Biol Psychiatry 2003;4:192–4. Finkel B, Lerner AG, Oyffe I, Sigal M. Risperidone-associated agranulocytosis. Am J Psychiatry 1998;155:855–6. Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008;23(Suppl 1):27–41. 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 [discussion 3].
Letter to the Editor (Case report) Sluys M, Guzelcan Y, Casteelen G, de Haan L. Risperidone-induced leucopenia and neutropenia: a case report. Eur Psychiatry 2004;19:117. Stergiou V, Bozikas VP, Garyfallos G, Nikolaidis N, Lavrentiadis G, Fokas K. Olanzapineinduced leucopenia and neutropenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:992–4. Uzun S, Kozumplik O, Jakovljevic M, Folnegovic-Smalc V. Leukopenia during therapy with risperidone long-acting injectable: two case reports. J Clin Psychopharmacol 2008;28:713–4.
Jin-Nah Kim Boung-Chul Lee Ihn-Geun Choi Department of Neuropsychiatry, Hallym University, Han-Gang Sacred Heart Hospital, Seoul, Republic of Korea
285
Duk-In Jon Myung Hun Jung* Department of Neuropsychiatry, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea ⁎Corresponding author. Department of Neuropsychiatry, Hallym University Sacred Heart Hospital, 896, Pyeongchon-dong, Dongan-gu, Anyang, Gyeonggi-do 431-070, Republic of Korea. Tel.: +82 31 380 3753; fax: +82 31 381 3753. E-mail address: [email protected](M.H. Jung). 19 August 2010