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Leukopenia and neutropenia induced by quetiapine
Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 292 – 294 www.elsevier.com/locate/pnpbp
Case report
Leukopenia and neutropenia induced by quetiapine Colin Cowan ⁎, Clare Oakley Hallam Street Hospital, UK Received 22 March 2006; received in revised form 17 June 2006; accepted 17 July 2006 Available online 22 August 2006
Abstract Leukopenia and neutropenia are recognised as side effects of antipsychotic medication, notably clozapine. A case is presented in which a female Caucasian patient who had previously developed these side effects with clozapine also developed them with quetiapine in conjunction with semisodium valproate. There was no such reaction to zuclopenthixol, sulpiride, olanzapine and aripiprazole. It is concluded that caution should be exercised when treating with quetiapine especially where there has been neutropenia with a previous antipsychotic agent. © 2006 Elsevier Inc. All rights reserved. Keywords: Antipsychotic agents; Leukopenia; Neutropenia; Quetiapine; Valproic acid
1. Introduction Leukopenia and neutropenia can be caused by a range of antipsychotics and mood stabilisers, most notably as a result of treatment with clozapine (Copolov et al., 1998). Although clozapine has the greatest potential for this, the same side effects have been described with risperidone (Dernovsek and Tavcar, 1997; Sluys et al., 2004), olanzapine (Buchman et al., 2001; Stergiou et al., 2005) and quetiapine (Croarkin and Rayner, 2001; Jackson, 2001). Leukopenia is listed in the summary of product characteristics as a common side effect of quetiapine, but neutropenia as a very rare side effect (< 0.01%) (Seroquel SPC, 2005). Thus leukopenia with neutropenia is a much rarer finding than leukopenia alone. Case reports have described leukopenia developing when quetiapine is added to valproate (Clark et al., 2001) and when the doses of both long-term quetiapine and valproate were increased (Nair and Lippmann, 2005), as well as dose-related leukopenia with quetiapine (Ojuboka et al., 2003). Severe neutropenia has also been described in association with valproic acid (Vesta and Medina, 2003) but in the case of semisodium valproate only leukopenia is listed as a rare adverse effect of which resolves when the drug is discontinued (Depakote SPC, 2004). Semisodium valproate is identical to divalproex sodium and is composed of equimolar sodium valproate and valproic acid. ⁎ Corresponding author. E-mail address: [email protected] (C. Cowan). 0278-5846/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.07.003
A case is described here of reversible neutropenia and leukopenia developing with quetiapine in conjunction with semisodium valproate, which did not occur with other antipsychotic medications, in a patient who previously had the same adverse effects with clozapine. 2. Case report A 36-year-old Caucasian female with treatment resistant schizophrenia had a relapse of psychosis resulting in admission to a psychiatric ward. Prior to this admission treatment with clozapine had been problematic due to prolonged leukopenia and neutropenia, with the white cell count dropping to 3.3 × 109/ L and the neutrophil count to 1.4 × 109/L. Following admission she was treated with olanzapine 40 mg daily for 3 months in view of the previous difficulties with clozapine but she did not respond to this, or to aripiprazole 15 mg daily for 3 weeks. Both of these antipsychotics were combined with semisodium valproate 1250 mg daily due to the elation and grandiose delusions which accompanied her hallucinations but with no improvement. This was associated with a valproate plasma level of 75 mg/L. No leukopenia or neutropenia occurred during this period of treatment. It was then decided to recommence clozapine, despite the previous haematological difficulties, as this drug had previously led to an improvement in her mental state. However, preliminary blood test results were below the drug company's required threshold for initiation of clozapine, with a white cell count of 4.4 × 109/L and a neutrophil count of
C. Cowan, C. Oakley / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 292–294
2.1 × 109/L. Other haematological markers were normal with a platelet count of 221 × 109/L, mean corpuscular volume of 89 fL and haemoglobin of 12.5 g/dL. Because of these blood results the plan to treat with clozapine was abandoned and 2 days later quetiapine at doses increasing to 600 mg daily was added to semisodium valproate. At this point she had been receiving semisodium valproate for 12 weeks. About 14 days later she had developed neutropenia and leukopenia, with a white cell count of 2.9 × 109/L and a neutrophil count of 1.0 × 109/L. Liver function and renal function were both within normal limits at this point. Quetiapine was discontinued because of this and by 3 days later the blood results had returned to a normal level (white cell count 4.0 × 109/ L, neutrophil count 2.2 × 109/L). Semisodium valproate was then discontinued to be replaced by lithium carbonate 400 mg daily alone, and by 13 days later the white cell count had increased to 6.1 × 109/L and the neutrophil count was 4.0 × 109/ L. Her clinical condition once more deteriorated, lithium was discontinued and 1 week later treatment with zuclopenthixol depot 800 mg every 2 weeks was introduced. No leukopenia or neutropenia was found over the following 3 months. Lithium carbonate 800 mg daily was later added to zuclopenthixol over a 5-week period but with no clinical benefit. No increase in the neutrophil count was associated with lithium treatment on this occasion. Sulpiride 800 mg daily was later added to zuclopenthixol without any haematological abnormality over a 6week period. Her clinical condition continued to deteriorate so clozapine was commenced again but this led to a rapid recurrence of leukopenia and neutropenia, the white cell count dropping to 3.6 × 109/L and the neutrophil count to 1.4 × 109/L. Following withdrawal of clozapine the blood results returned to normal. All blood tests referred to in this report were based on samples which had been taken in the morning. 3. Discussion Our case demonstrates that a patient who had previously experienced neutropenia and leukopenia with clozapine also experienced this with quetiapine in conjunction with semisodium valproate. While the association of leukopenia with quetiapine is common, neutropenia is a much rarer finding. It is of particular significance as it did not occur with other antipsychotics which included olanzapine, amisulpride, sulpiride and zuclopenthixol. However, in view of the reports of neutropenia and leukopenia associated with olanzapine and risperidone, it cannot be concluded from this case that quetiapine is qualitatively different to other antipsychotics in this area. Although there are two other case reports of neutropenia in association with quetiapine (Croarkin and Rayner, 2001; Jackson, 2001) these reports have to be considered alongside the findings of Yatham et al. (2004) that no abnormal laboratory test results occurred in 196 patients taking quetiapine with either divalproex or lithium. A larger study would be required to evaluate the true incidence of leukopenia and neutropenia with quetiapine.
293
The possibility of semisodium valproate being the causative agent in the combination with quetiapine has to be considered, given the existence of a case report demonstrating severe neutropenia caused by valproic acid (Vesta and Medina, 2003). In our case semisodium valproate was unlikely to be the causative agent in combination with quetiapine as neutropenia and leukopenia did not occur when semisodium valproate was combined with olanzapine or amisulpride. The possibility of semisodium valproate being a contributory factor specific to quetiapine alone and not to any other antipsychotics cannot be ruled out, although it would seem unlikely. Valproate has been associated with increases of 77% in quetiapine plasma levels (Aichhorn et al., 2006) and so there is a possibility that in this case quetiapine levels were unexpectedly high, but there was no evidence of other adverse effects of quetiapine. Given the case reports cited above suggesting that quetiapine-related leukopenia can be dose-related, the possibility that high quetiapine levels might have produced neutropenia that would not have occurred at lower levels cannot be excluded. Another possible confounding factor is the “morning pseudoneutropenia” observed with clozapine and risperidone whereby absolute neutrophil count can more than double in the space of 6 h between morning and afternoon sampling, possibly on account of amplification of natural circadian variation by antipsychotics (Esposito et al., 2003, 2005). In our case there would have been little opportunity for a circadian effect between neutrophil counts as all samples were taken in the morning with only, but the possibility that afternoon sampling would have yielded normal results cannot be discounted. It is of interest that the reported increase in neutrophil count associated with lithium due to increased granulopoiesis (Paton and Esop, 2005) was observed with lithium alone but not when given in association with an antipsychotic. Possibly this reflects a general tendency in this patient for antipsychotic medication to suppress granulopoiesis which prevents lithium from having any positive effect on neutrophil count. 4. Conclusion Quetiapine shares a propensity for causing neutropenia and leukopenia with other atypical antipsychotics, and possibly an increased risk when prescribed with other drugs which also have potential to lower the white cell count. This is a particular concern as such side effects are more likely to be missed when there is no mandatory white cell count monitoring as there is with clozapine. Careful monitoring is advisable when commencing quetiapine in patients who have previously had leukopenia or neutropenia with other antipsychotic treatment, particularly clozapine. References Aichhorn W, Marksteiner J, Walch T, Zernig G, Saria A, Kemler G. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006;21(2):81–5.
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C. Cowan, C. Oakley / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 292–294
Buchman N, Strous RD, Ulman AM, Lerner M, Kotler M. Olanzapine-induced leukopenia with human leukocyte antigen profiling. Int Clin Psychopharmacol 2001;16(1):55–7. Clark N, Weissberg E, Noel J. Quetiapine and leukopenia. Am J Psychiatry 2001;158:817–8. Copolov DL, Bell WR, Benson WJ, Keks NA, Strazzeri DC, Johnson GF. Clozapine treatment in Australia: a review of haematological monitoring. Med J Aust 1998;168:495–7. Croarkin P, Rayner T. Acute neutropenia in a patient treated with quetiapine. Psychosomatics 2001;41(4):368. Depakote SPC, (Date of revision May 2004) electronic Medicines Compendium (eMC). http://emc.medicines.org.uk (accessed 13 March 2006). Dernovsek Z, Tavcar R. Risperidone-induced leucopenia and neutropenia. Br J Psychiatry 1997;171:393–4. Esposito D, Aouille J, Rouillon F, Limosin F. Morning pseudoneutropenia during clozapine treatment. World J Biol Psychiatry 2003;4(4):192–4. Esposito D, Corruble E, Hardy P, Chouinard G. Risperidone-induced morning pseudoneutropenia. Am J Psychiatry 2005;162:397. Jackson RS. Continuing treatment with novel antipsychotic drugs despite leukopenia or thrombocytopenia. Arch Gen Psychiatry 2001;58:706–7.
Nair P, Lippmann S. Is leukopenia associated with divalproex and/or quetiapine? Psychosomatics 2005;46:188–9. Ojuboka O, Haslam D, Lam T, Bown-Demarco D. Quetiapine-induced leucopenia: possible dosage-related phenomenon. Can J Psychiatry 2003; 48(1):65–6. Paton C, Esop R. Managing clozapine-induced neutropenia with lithium. Psychiatr Bull 2005;29(5):186–8. Seroquel SPC, (Date of revision 23rd June 2005) electronic Medicines Compendium (eMC). http://emc.medicines.org.uk (accessed 13 March 2006). Sluys M, Güzelcan Y, Casteelen G, de Haan L. Risperidone-induced leucopenia and neutropenia: a case report. Eur Psychiatr 2004;19(2):17. Stergiou V, Bozikas VP, Garyfallos G, Nikolaidis N, Lavrentiadis G, Fokas K. Olanzapine-induced leucopenia and neutropenia. Prog Neuro-psychopharmacol Biol Psychiatry 2005;29:992–4. Vesta KS, Medina PJ. Valproic acid-induced neutropenia. Ann Pharmacother 2003;37(6):819–21. Yatham LN, Paulsson B, Mullen J, Vågerö M. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol 2004;24(6):599–606.
Case report
Leukopenia and neutropenia induced by quetiapine Colin Cowan ⁎, Clare Oakley Hallam Street Hospital, UK Received 22 March 2006; received in revised form 17 June 2006; accepted 17 July 2006 Available online 22 August 2006
Abstract Leukopenia and neutropenia are recognised as side effects of antipsychotic medication, notably clozapine. A case is presented in which a female Caucasian patient who had previously developed these side effects with clozapine also developed them with quetiapine in conjunction with semisodium valproate. There was no such reaction to zuclopenthixol, sulpiride, olanzapine and aripiprazole. It is concluded that caution should be exercised when treating with quetiapine especially where there has been neutropenia with a previous antipsychotic agent. © 2006 Elsevier Inc. All rights reserved. Keywords: Antipsychotic agents; Leukopenia; Neutropenia; Quetiapine; Valproic acid
1. Introduction Leukopenia and neutropenia can be caused by a range of antipsychotics and mood stabilisers, most notably as a result of treatment with clozapine (Copolov et al., 1998). Although clozapine has the greatest potential for this, the same side effects have been described with risperidone (Dernovsek and Tavcar, 1997; Sluys et al., 2004), olanzapine (Buchman et al., 2001; Stergiou et al., 2005) and quetiapine (Croarkin and Rayner, 2001; Jackson, 2001). Leukopenia is listed in the summary of product characteristics as a common side effect of quetiapine, but neutropenia as a very rare side effect (< 0.01%) (Seroquel SPC, 2005). Thus leukopenia with neutropenia is a much rarer finding than leukopenia alone. Case reports have described leukopenia developing when quetiapine is added to valproate (Clark et al., 2001) and when the doses of both long-term quetiapine and valproate were increased (Nair and Lippmann, 2005), as well as dose-related leukopenia with quetiapine (Ojuboka et al., 2003). Severe neutropenia has also been described in association with valproic acid (Vesta and Medina, 2003) but in the case of semisodium valproate only leukopenia is listed as a rare adverse effect of which resolves when the drug is discontinued (Depakote SPC, 2004). Semisodium valproate is identical to divalproex sodium and is composed of equimolar sodium valproate and valproic acid. ⁎ Corresponding author. E-mail address: [email protected] (C. Cowan). 0278-5846/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.07.003
A case is described here of reversible neutropenia and leukopenia developing with quetiapine in conjunction with semisodium valproate, which did not occur with other antipsychotic medications, in a patient who previously had the same adverse effects with clozapine. 2. Case report A 36-year-old Caucasian female with treatment resistant schizophrenia had a relapse of psychosis resulting in admission to a psychiatric ward. Prior to this admission treatment with clozapine had been problematic due to prolonged leukopenia and neutropenia, with the white cell count dropping to 3.3 × 109/ L and the neutrophil count to 1.4 × 109/L. Following admission she was treated with olanzapine 40 mg daily for 3 months in view of the previous difficulties with clozapine but she did not respond to this, or to aripiprazole 15 mg daily for 3 weeks. Both of these antipsychotics were combined with semisodium valproate 1250 mg daily due to the elation and grandiose delusions which accompanied her hallucinations but with no improvement. This was associated with a valproate plasma level of 75 mg/L. No leukopenia or neutropenia occurred during this period of treatment. It was then decided to recommence clozapine, despite the previous haematological difficulties, as this drug had previously led to an improvement in her mental state. However, preliminary blood test results were below the drug company's required threshold for initiation of clozapine, with a white cell count of 4.4 × 109/L and a neutrophil count of
C. Cowan, C. Oakley / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 292–294
2.1 × 109/L. Other haematological markers were normal with a platelet count of 221 × 109/L, mean corpuscular volume of 89 fL and haemoglobin of 12.5 g/dL. Because of these blood results the plan to treat with clozapine was abandoned and 2 days later quetiapine at doses increasing to 600 mg daily was added to semisodium valproate. At this point she had been receiving semisodium valproate for 12 weeks. About 14 days later she had developed neutropenia and leukopenia, with a white cell count of 2.9 × 109/L and a neutrophil count of 1.0 × 109/L. Liver function and renal function were both within normal limits at this point. Quetiapine was discontinued because of this and by 3 days later the blood results had returned to a normal level (white cell count 4.0 × 109/ L, neutrophil count 2.2 × 109/L). Semisodium valproate was then discontinued to be replaced by lithium carbonate 400 mg daily alone, and by 13 days later the white cell count had increased to 6.1 × 109/L and the neutrophil count was 4.0 × 109/ L. Her clinical condition once more deteriorated, lithium was discontinued and 1 week later treatment with zuclopenthixol depot 800 mg every 2 weeks was introduced. No leukopenia or neutropenia was found over the following 3 months. Lithium carbonate 800 mg daily was later added to zuclopenthixol over a 5-week period but with no clinical benefit. No increase in the neutrophil count was associated with lithium treatment on this occasion. Sulpiride 800 mg daily was later added to zuclopenthixol without any haematological abnormality over a 6week period. Her clinical condition continued to deteriorate so clozapine was commenced again but this led to a rapid recurrence of leukopenia and neutropenia, the white cell count dropping to 3.6 × 109/L and the neutrophil count to 1.4 × 109/L. Following withdrawal of clozapine the blood results returned to normal. All blood tests referred to in this report were based on samples which had been taken in the morning. 3. Discussion Our case demonstrates that a patient who had previously experienced neutropenia and leukopenia with clozapine also experienced this with quetiapine in conjunction with semisodium valproate. While the association of leukopenia with quetiapine is common, neutropenia is a much rarer finding. It is of particular significance as it did not occur with other antipsychotics which included olanzapine, amisulpride, sulpiride and zuclopenthixol. However, in view of the reports of neutropenia and leukopenia associated with olanzapine and risperidone, it cannot be concluded from this case that quetiapine is qualitatively different to other antipsychotics in this area. Although there are two other case reports of neutropenia in association with quetiapine (Croarkin and Rayner, 2001; Jackson, 2001) these reports have to be considered alongside the findings of Yatham et al. (2004) that no abnormal laboratory test results occurred in 196 patients taking quetiapine with either divalproex or lithium. A larger study would be required to evaluate the true incidence of leukopenia and neutropenia with quetiapine.
293
The possibility of semisodium valproate being the causative agent in the combination with quetiapine has to be considered, given the existence of a case report demonstrating severe neutropenia caused by valproic acid (Vesta and Medina, 2003). In our case semisodium valproate was unlikely to be the causative agent in combination with quetiapine as neutropenia and leukopenia did not occur when semisodium valproate was combined with olanzapine or amisulpride. The possibility of semisodium valproate being a contributory factor specific to quetiapine alone and not to any other antipsychotics cannot be ruled out, although it would seem unlikely. Valproate has been associated with increases of 77% in quetiapine plasma levels (Aichhorn et al., 2006) and so there is a possibility that in this case quetiapine levels were unexpectedly high, but there was no evidence of other adverse effects of quetiapine. Given the case reports cited above suggesting that quetiapine-related leukopenia can be dose-related, the possibility that high quetiapine levels might have produced neutropenia that would not have occurred at lower levels cannot be excluded. Another possible confounding factor is the “morning pseudoneutropenia” observed with clozapine and risperidone whereby absolute neutrophil count can more than double in the space of 6 h between morning and afternoon sampling, possibly on account of amplification of natural circadian variation by antipsychotics (Esposito et al., 2003, 2005). In our case there would have been little opportunity for a circadian effect between neutrophil counts as all samples were taken in the morning with only, but the possibility that afternoon sampling would have yielded normal results cannot be discounted. It is of interest that the reported increase in neutrophil count associated with lithium due to increased granulopoiesis (Paton and Esop, 2005) was observed with lithium alone but not when given in association with an antipsychotic. Possibly this reflects a general tendency in this patient for antipsychotic medication to suppress granulopoiesis which prevents lithium from having any positive effect on neutrophil count. 4. Conclusion Quetiapine shares a propensity for causing neutropenia and leukopenia with other atypical antipsychotics, and possibly an increased risk when prescribed with other drugs which also have potential to lower the white cell count. This is a particular concern as such side effects are more likely to be missed when there is no mandatory white cell count monitoring as there is with clozapine. Careful monitoring is advisable when commencing quetiapine in patients who have previously had leukopenia or neutropenia with other antipsychotic treatment, particularly clozapine. References Aichhorn W, Marksteiner J, Walch T, Zernig G, Saria A, Kemler G. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006;21(2):81–5.
294
C. Cowan, C. Oakley / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 292–294
Buchman N, Strous RD, Ulman AM, Lerner M, Kotler M. Olanzapine-induced leukopenia with human leukocyte antigen profiling. Int Clin Psychopharmacol 2001;16(1):55–7. Clark N, Weissberg E, Noel J. Quetiapine and leukopenia. Am J Psychiatry 2001;158:817–8. Copolov DL, Bell WR, Benson WJ, Keks NA, Strazzeri DC, Johnson GF. Clozapine treatment in Australia: a review of haematological monitoring. Med J Aust 1998;168:495–7. Croarkin P, Rayner T. Acute neutropenia in a patient treated with quetiapine. Psychosomatics 2001;41(4):368. Depakote SPC, (Date of revision May 2004) electronic Medicines Compendium (eMC). http://emc.medicines.org.uk (accessed 13 March 2006). Dernovsek Z, Tavcar R. Risperidone-induced leucopenia and neutropenia. Br J Psychiatry 1997;171:393–4. Esposito D, Aouille J, Rouillon F, Limosin F. Morning pseudoneutropenia during clozapine treatment. World J Biol Psychiatry 2003;4(4):192–4. Esposito D, Corruble E, Hardy P, Chouinard G. Risperidone-induced morning pseudoneutropenia. Am J Psychiatry 2005;162:397. Jackson RS. Continuing treatment with novel antipsychotic drugs despite leukopenia or thrombocytopenia. Arch Gen Psychiatry 2001;58:706–7.
Nair P, Lippmann S. Is leukopenia associated with divalproex and/or quetiapine? Psychosomatics 2005;46:188–9. Ojuboka O, Haslam D, Lam T, Bown-Demarco D. Quetiapine-induced leucopenia: possible dosage-related phenomenon. Can J Psychiatry 2003; 48(1):65–6. Paton C, Esop R. Managing clozapine-induced neutropenia with lithium. Psychiatr Bull 2005;29(5):186–8. Seroquel SPC, (Date of revision 23rd June 2005) electronic Medicines Compendium (eMC). http://emc.medicines.org.uk (accessed 13 March 2006). Sluys M, Güzelcan Y, Casteelen G, de Haan L. Risperidone-induced leucopenia and neutropenia: a case report. Eur Psychiatr 2004;19(2):17. Stergiou V, Bozikas VP, Garyfallos G, Nikolaidis N, Lavrentiadis G, Fokas K. Olanzapine-induced leucopenia and neutropenia. Prog Neuro-psychopharmacol Biol Psychiatry 2005;29:992–4. Vesta KS, Medina PJ. Valproic acid-induced neutropenia. Ann Pharmacother 2003;37(6):819–21. Yatham LN, Paulsson B, Mullen J, Vågerö M. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol 2004;24(6):599–606.