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Clinical Case Conference   |    
White Blood Cell Monitoring During Long-Term Clozapine Treatment
Dan Cohen, M.D., Ph.D.; Marcel Monden, M.D.
Am J Psychiatry 2013;170:366-369. doi:10.1176/appi.ajp.2012.12081036
View Author and Article Information

Dr. Cohen has served as an advisory board member for, received speaking fees from, and received an unrestricted grant from AstraZeneca. Dr. Monden has received speaking fees from Lundbeck.

From the Department of Severe Mental Illness, Mental Health Care North-Holland North, Heerhugowaard, Netherlands; and the Department of Clinical Epidemiology, University Medical Center Groningen, Groningen, Netherlands.

Address correspondence to Dr. Cohen (d.cohen@ggz-nhn.nl).

Copyright © 2013 by the American Psychiatric Association

Received August 06, 2012; Revised October 29, 2012; Accepted December 17, 2012.

Abstract

Late-onset agranulocytosis is rare during treatment with clozapine, especially in monotherapy. The authors describe a case of agranulocytosis that emerged after 19 years of continuous clozapine monotherapy. The discovery of the agranulocytosis was due to the lifelong white blood cell counts that are now required for clozapine treatment. Despite the fact that this requirement probably saved the life of this patient, this monitoring is not evidence-based because the incidence of agranulocytosis does not exceed that of conventional antipsychotic drugs, for which no such requirement exists. For mentally competent and adequately informed patients, the Netherlands Clozapine Collaboration Group now permits quarterly monitoring after the first 6 months of clozapine treatment.

Abstract Teaser
Figures in this Article

“Mr. L,” a white male, was first seen in 1990 when he was 23 years old. He was dependent on several substances, mainly heroin, which he used intravenously. He was acutely psychotic with paranoid delusions that made him threaten and attack passers-by. After he set fire to his house, he was involuntarily admitted to the acute ward of a psychiatric hospital.

Mr. L was diagnosed with paranoid schizophrenia and opium abuse according to DSM-IV criteria. He was started on clozapine in April 1990, after a trial of depot flupentixol (50 mg every 2 weeks) proved ineffective for his delusional thinking and aggressive behavior. A satisfactory therapeutic response was achieved with a dosage of 250 mg/day (plasma level, 160 μg/L), resulting in complete remission of his psychosis and opioid addiction. This beneficial response was maintained for 19 years with the same dosage of clozapine. Lorazepam (2.5 mg) was used occasionally for the treatment of anxiety.

Before the initiation of clozapine, Mr. L’s WBC count was 4.2×109/L, and it remained above 4.0×109/L during clozapine treatment until February 2007, when it decreased to 3.7×109/L with a neutrophil count of 1.9×109/L; there were no changes in other leukocytes. In February 2009, the patient’s WBC count suddenly decreased to 2.5×109/L with a neutrophil count of 1.3×109/L, and in April 2009 it decreased further to 1.9×109/L with a neutrophil count of 1.0×109/L, a lymphocyte count of 0.6×109/L, a monocyte count of 0.3×109/L, an eosinophil count of 0.0×109/L, and a basophil count of 0.0×109/L. In the same week, the patient developed laryngitis with a temperature of 40.2°C and was admitted to the hospital. The patient was treated with phenethicillin (500 mg daily), and the consultant hematologist advised immediate discontinuation of clozapine. After 2 days, the fever abated and the patient was discharged. The consultant hematologist advised a drug-free period, during which the patient was seen twice a week by a psychiatrist (M.M.). A week after the discontinuation of clozapine, the patient’s WBC count increased to 3.5×109/L, and 3 weeks later to 4.7×109/L. Treatment was started with aripiprazole (45 mg/day) and lorazepam (5 mg/day). Since then, the patient has remained in full remission without relapse of the psychosis or substance abuse. His WBC count was 5.9×109/L in May 2011.

Eight fatal cases of agranulocytosis in Finland (1) prompted the worldwide ban of clozapine. The drug was subsequently reintroduced for the treatment of refractory schizophrenia (2) with the stipulation that WBC and absolute neutrophil counts should be performed regularly to enable the early detection of treatment-emergent leukopenia and agranulocytosis. Since the incidence of leukopenia is highest in the first year of treatment, and especially in the first 6 months, regulatory authorities have made WBC and neutrophil counts mandatory. In Europe, WBC and neutrophil counts must be performed weekly during the first 18 weeks and at least every 4 weeks thereafter through treatment (3). In the United States, weekly WBC and neutrophil counts are required during the first 26 weeks and biweekly counts during the second 26 weeks and every 4 weeks thereafter through treatment (4). The detection of late-onset leukopenia or agranulocytosis constitutes the main argument in favor of lifelong WBC monitoring, but the validity of this argument has been questioned (5).

We searched PubMed for studies published between January 1980 and September 2012, using the following terms: clozapine, late onset, agranulocytosis. To date, 16 patients have been reported to have developed agranulocytosis after the early high-risk period, with incidences from 17 months to 11 years. To our knowledge, our patient, with an apparent onset after 19 years of treatment, is the latest onset. This is only the sixth case of late-onset agranulocytosis during clozapine monotherapy reported (Table 1). After withdrawal of clozapine, our patient’s WBC count increased within 7 weeks to 5.9×109/L and his neutrophil count to 3.9×109/L, and both have remained stable since then (>3 years). The stable but low total WBC and neutrophil counts during clozapine therapy can, with hindsight, be explained as being due to a constant but mild clozapine-induced suppression of WBCs during the 19 years of clozapine treatment.

 
Anchor for Jump
TABLE 1.Reports of Late-Onset Neutropenia or Agranulocytosis
Table Footer Note

a The two periods of neutropenia occurred in the same patient.

Although the majority of the reported cases, both early and late onset, involved cotreatment with somatic or psychiatric medications (2224), it remains extremely difficult to prove that a given drug increases the risk of neutropenia or agranulocytosis in clozapine treatment when used as comedication. For example, although valproate was used as comedication in two cases of early-onset (23, 24) and four of 10 cases of late-onset polypharmacy-induced neutropenia or agranulocytosis, no such cases were reported in 34 patients treated for at least 4 weeks with a combination of clozapine and valproate (25). In some cases, however, the relation between comedication and onset of agranulocytosis seems clear-cut. For instance, in one case, agranulocytosis developed after addition of risperidone after 22 months of uncomplicated clozapine monotherapy (12).

We found only five cases of late-onset neutropenia that developed after a maximum of 11 years of clozapine monotherapy. Our patient developed agranulocytosis after 19 years of clozapine monotherapy; no concomitant medication was involved, and after discontinuation of clozapine, the patient’s WBC count recovered within a week.

Prolonged (>6 months) treatment with clozapine has not been found to carry a greater risk of neutropenia than does treatment with conventional antipsychotics (5). Two recent studies have also addressed this issue. One study (26) addressed the question of whether clozapine use is associated with an increased incidence of neutropenia. Ninety-five new clozapine users (86.6% with diagnoses of schizophrenia, schizoaffective disorder, or bipolar disorder) were compared with 884 non-clozapine users (65% with diagnoses of other disorders, treated with first-generation antipsychotics for schizophrenia, selective serotonin reuptake inhibitors for major depression, and benzodiazepines for anxiety disorder). The 24-month incidence of neutropenia was 6.3% (95% CI=2.3–11.7) in the clozapine group and 5.9% (95% CI=4.4–7.5) in the non-clozapine group. In the clozapine group, all cases occurred within the first year of treatment (range, 37–338 days) and in the non-clozapine group during the 2 years (range, 2–711 days) of treatment. In the second study, by Kang et al. (27), during 11 years of follow-up, 54 cases of agranulocytosis occurred among 6,782 clozapine users, with 29 cases (53%) occurring within the first 18 weeks and 40 (74%) within the first year of treatment. The 14 remaining cases occurred during the 13,594 years of cumulative exposure, corresponding to an incidence of 1.03 per 1,000 patient-years (Table 2). Although the incidence of agranulocytosis during long-term clozapine treatment (1 per 1,000 patient-years) reported by Kang et al. is twice as high as that reported in other countries (Table 2), it is comparable to the incidence of 0.1–1.4 reported for conventional antipsychotics (5). This suggests that the risk of agranulocytosis during long-term treatment with clozapine is similar to that with other antipsychotic drugs.

 
Anchor for Jump
TABLE 2.Incidence of Clozapine-Associated Agranulocytosis per 1,000 Patient-Yearsa
Table Footer Note

a Some of the data presented in this table first appeared in Schulte (5).

We thus have a paradox: timely detection of agranulocytosis, the result of the requirement for lifelong WBC counts in clozapine therapy, probably saved this patient’s life. However, WBC monitoring after the first 6 months of clozapine treatment is not evidence-based because the incidence of agranulocytosis does not exceed that of conventional antipsychotics, for which no such requirement exists. For mentally competent and adequately informed patients who request it, the Netherlands Clozapine Collaboration Group (29) permits lowering the frequency of blood tests to four times a year, which may be a reasonable compromise.

Idänpään-Heikkilä  J;  Alhava  E;  Olkinuora  M;  Palva  I:  Letter: Clozapine and agranulocytosis.  Lancet 1975; 2:611
[CrossRef]
 
Kane  JM;  Honigfeld  G;  Singer  J;  Meltzer  HY:  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine.  Arch Gen Psychiatry 1988; 45:789–796
[CrossRef] | [PubMed]
 
European Agency for the Evaluation of Medicinal Products, Committed for Proprietary Medicinal Properties (CPMP): Summary information on referral opinion following arbitration pursuant to Article 30 of Council Directive 2001/83/EC for Leponex and associated names (international non-proprietary name (INN): clozapine): Background information and Annex III. London, Nov 12, 2002 (http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Leponex_30/WC500010966.pdf)
 
Novartis: Package insert for Clozaril. East Hanover, NJ, Nov 2004. (http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019758s054lbl.pdf)
 
Schulte  PFJ:  Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring.  Ann Pharmacother 2006; 40:683–688
[CrossRef] | [PubMed]
 
Tamam  L;  Kulan  E;  Ozpoyraz  N:  Late onset neutropenia during clozapine treatment.  Psychiatry Clin Neurosci 2001; 55:547–548
[CrossRef] | [PubMed]
 
Latif  Z;  Malik  MA;  Jabbar  F;  Ahmed  Y;  McDonough  C:  Clozapine-induced late leukopenia.  Ir J Med Sci 2012; 181:139–141
[CrossRef] | [PubMed]
 
Raja  M;  Azzoni  A;  Maisto  G:  Late onset neutropenia associated with clozapine.  J Clin Psychopharmacol 2011; 31:780–781
[CrossRef] | [PubMed]
 
Sedky  K;  Shaughnessy  R;  Hughes  T;  Lippmann  S:  Clozapine-induced agranulocytosis after 11 years of treatment.  Am J Psychiatry 2005; 162:814
[CrossRef] | [PubMed]
 
Nongpiur  A;  Praharaj  SK;  Sarkar  S;  Das  B:  Delayed onset of clozapine-induced leucopenia.  Am J Ther 2012; 19:e118–e119
[CrossRef] | [PubMed]
 
Bhanji  NH;  Margolese  HC;  Chouinard  G;  Turnier  L:  Late-onset agranulocytosis in a patient with schizophrenia after 17 months of clozapine treatment.  J Clin Psychopharmacol 2003; 23:522–523
[CrossRef] | [PubMed]
 
Godleski  LS;  Sernyak  MJ:  Agranulocytosis after addition of risperidone to clozapine treatment.  Am J Psychiatry 1996; 153:735–736
[PubMed]
 
Raveendranathan  D;  Sharma  E;  Venkatasubramanian  G;  Rao  MG;  Varambally  S;  Gangadhar  BN: Late-onset clozapine-induced agranulocytosis in a patient with comorbid multiple sclerosis. Gen Hosp Psychiatry (Epub ahead of print, Aug 15, 2012)
 
Thompson  A;  Girishchandra  B;  Castle  D;  Orr  K:  Late onset neutropenia with clozapine.  Can J Psychiatry 2004; 49:647–648
[PubMed]
 
Peacock  L;  Gerlach  J:  Clozapine treatment in Denmark: concomitant psychotropic medication and hematologic monitoring in a system with liberal usage practices.  J Clin Psychiatry 1994; 55:44–49
[PubMed]
 
Small  JG;  Weber  MC;  Klapper  MH;  Kellams  JJ:  Rechallenge of late-onset neutropenia with clozapine.  J Clin Psychopharmacol 2005; 25:185–186
[CrossRef] | [PubMed]
 
Sénéchal  A;  Landry  P;  Deschamps  R;  Lessard  M:  [Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs].  Encephale 2002; 28:567–569 (French)
[PubMed]
 
Patel  NC;  Dorson  PG;  Bettinger  TL:  Sudden late onset of clozapine-induced agranulocytosis.  Ann Pharmacother 2002; 36:1012–1015
[CrossRef] | [PubMed]
 
Panesar  N;  Pai  N;  Valachova  I:  Late onset neutropenia with clozapine.  Aust N Z J Psychiatry 2011; 45:684
[CrossRef] | [PubMed]
 
Tourian  L;  Margolese  HC:  Late-onset agranulocytosis in a patient treated with clozapine and lamotrigine.  J Clin Psychopharmacol 2011; 31:665–667
[CrossRef] | [PubMed]
 
Kutscher  EC;  Robbins  GP;  Kennedy  WK;  Zebb  K;  Stanley  M;  Carnahan  RM:  Clozapine-induced leukopenia successfully treated with lithium.  Am J Health Syst Pharm 2007; 64:2027–2031
[CrossRef] | [PubMed]
 
Manfredi  R;  Sabbatani  S:  Clozapine-related agranulocytosis associated with fever of unknown origin, protective hospitalisation, and multiple adverse events related to the administration of empiric antimicrobial treatment.  Pharmacoepidemiol Drug Saf 2007; 16:1285–1289
[CrossRef] | [PubMed]
 
Madeb  R;  Hirschmann  S;  Kurs  R;  Turkie  A;  Modai  I:  Combined clozapine and valproic acid treatment-induced agranulocytosis.  Eur Psychiatry 2002; 17:238–239
[CrossRef] | [PubMed]
 
Pantelis  C;  Adesanya  A:  Increased risk of neutropaenia and agranulocytosis with sodium valproate used adjunctively with clozapine.  Aust N Z J Psychiatry 2001; 35:544–545
[CrossRef] | [PubMed]
 
Kando  JC;  Tohen  M;  Castillo  J;  Centorrino  F:  Concurrent use of clozapine and valproate in affective and psychotic disorders.  J Clin Psychiatry 1994; 55:255–257
[PubMed]
 
Ratanajamit  C;  Musakopas  C;  Vasiknanonte  S;  Reanmongkol  W:  Incidence and risk for neutropenia/agranulocytosis among clozapine users: a retrospective study.  Int J Psychiatry Clin Pract 2010; 14:109–115
[CrossRef]
 
Kang  BJ;  Cho  MJ;  Oh  JT;  Lee  Y;  Chae  BJ;  Ko  J:  Long-term patient monitoring for clozapine-induced agranulocytosis and neutropenia in Korea: when is it safe to discontinue CPMS? Hum Psychopharmacol 2006; 21:387–391
[CrossRef] | [PubMed]
 
Kumar  V: Clozaril Monitoring Systems, Registry Data and Analyses (United States, United Kingdom, and Australia). www.fda.gov/ohrms/dockets/ac/03/slides/3959S1_02_C-Novartis-Kumar.ppt
 
Schulte  PF;  Cohen  D;  Bogers  JPAM;  van Dijk  D;  Bakker  B:  A Dutch guideline for the use of clozapine.  Aust N Z J Psychiatry 2010; 44:1055–1056
[PubMed]
 
References Container
Anchor for Jump
TABLE 1.Reports of Late-Onset Neutropenia or Agranulocytosis
Table Footer Note

a The two periods of neutropenia occurred in the same patient.

Anchor for Jump
TABLE 2.Incidence of Clozapine-Associated Agranulocytosis per 1,000 Patient-Yearsa
Table Footer Note

a Some of the data presented in this table first appeared in Schulte (5).

+

References

Idänpään-Heikkilä  J;  Alhava  E;  Olkinuora  M;  Palva  I:  Letter: Clozapine and agranulocytosis.  Lancet 1975; 2:611
[CrossRef]
 
Kane  JM;  Honigfeld  G;  Singer  J;  Meltzer  HY:  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine.  Arch Gen Psychiatry 1988; 45:789–796
[CrossRef] | [PubMed]
 
European Agency for the Evaluation of Medicinal Products, Committed for Proprietary Medicinal Properties (CPMP): Summary information on referral opinion following arbitration pursuant to Article 30 of Council Directive 2001/83/EC for Leponex and associated names (international non-proprietary name (INN): clozapine): Background information and Annex III. London, Nov 12, 2002 (http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Leponex_30/WC500010966.pdf)
 
Novartis: Package insert for Clozaril. East Hanover, NJ, Nov 2004. (http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019758s054lbl.pdf)
 
Schulte  PFJ:  Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring.  Ann Pharmacother 2006; 40:683–688
[CrossRef] | [PubMed]
 
Tamam  L;  Kulan  E;  Ozpoyraz  N:  Late onset neutropenia during clozapine treatment.  Psychiatry Clin Neurosci 2001; 55:547–548
[CrossRef] | [PubMed]
 
Latif  Z;  Malik  MA;  Jabbar  F;  Ahmed  Y;  McDonough  C:  Clozapine-induced late leukopenia.  Ir J Med Sci 2012; 181:139–141
[CrossRef] | [PubMed]
 
Raja  M;  Azzoni  A;  Maisto  G:  Late onset neutropenia associated with clozapine.  J Clin Psychopharmacol 2011; 31:780–781
[CrossRef] | [PubMed]
 
Sedky  K;  Shaughnessy  R;  Hughes  T;  Lippmann  S:  Clozapine-induced agranulocytosis after 11 years of treatment.  Am J Psychiatry 2005; 162:814
[CrossRef] | [PubMed]
 
Nongpiur  A;  Praharaj  SK;  Sarkar  S;  Das  B:  Delayed onset of clozapine-induced leucopenia.  Am J Ther 2012; 19:e118–e119
[CrossRef] | [PubMed]
 
Bhanji  NH;  Margolese  HC;  Chouinard  G;  Turnier  L:  Late-onset agranulocytosis in a patient with schizophrenia after 17 months of clozapine treatment.  J Clin Psychopharmacol 2003; 23:522–523
[CrossRef] | [PubMed]
 
Godleski  LS;  Sernyak  MJ:  Agranulocytosis after addition of risperidone to clozapine treatment.  Am J Psychiatry 1996; 153:735–736
[PubMed]
 
Raveendranathan  D;  Sharma  E;  Venkatasubramanian  G;  Rao  MG;  Varambally  S;  Gangadhar  BN: Late-onset clozapine-induced agranulocytosis in a patient with comorbid multiple sclerosis. Gen Hosp Psychiatry (Epub ahead of print, Aug 15, 2012)
 
Thompson  A;  Girishchandra  B;  Castle  D;  Orr  K:  Late onset neutropenia with clozapine.  Can J Psychiatry 2004; 49:647–648
[PubMed]
 
Peacock  L;  Gerlach  J:  Clozapine treatment in Denmark: concomitant psychotropic medication and hematologic monitoring in a system with liberal usage practices.  J Clin Psychiatry 1994; 55:44–49
[PubMed]
 
Small  JG;  Weber  MC;  Klapper  MH;  Kellams  JJ:  Rechallenge of late-onset neutropenia with clozapine.  J Clin Psychopharmacol 2005; 25:185–186
[CrossRef] | [PubMed]
 
Sénéchal  A;  Landry  P;  Deschamps  R;  Lessard  M:  [Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs].  Encephale 2002; 28:567–569 (French)
[PubMed]
 
Patel  NC;  Dorson  PG;  Bettinger  TL:  Sudden late onset of clozapine-induced agranulocytosis.  Ann Pharmacother 2002; 36:1012–1015
[CrossRef] | [PubMed]
 
Panesar  N;  Pai  N;  Valachova  I:  Late onset neutropenia with clozapine.  Aust N Z J Psychiatry 2011; 45:684
[CrossRef] | [PubMed]
 
Tourian  L;  Margolese  HC:  Late-onset agranulocytosis in a patient treated with clozapine and lamotrigine.  J Clin Psychopharmacol 2011; 31:665–667
[CrossRef] | [PubMed]
 
Kutscher  EC;  Robbins  GP;  Kennedy  WK;  Zebb  K;  Stanley  M;  Carnahan  RM:  Clozapine-induced leukopenia successfully treated with lithium.  Am J Health Syst Pharm 2007; 64:2027–2031
[CrossRef] | [PubMed]
 
Manfredi  R;  Sabbatani  S:  Clozapine-related agranulocytosis associated with fever of unknown origin, protective hospitalisation, and multiple adverse events related to the administration of empiric antimicrobial treatment.  Pharmacoepidemiol Drug Saf 2007; 16:1285–1289
[CrossRef] | [PubMed]
 
Madeb  R;  Hirschmann  S;  Kurs  R;  Turkie  A;  Modai  I:  Combined clozapine and valproic acid treatment-induced agranulocytosis.  Eur Psychiatry 2002; 17:238–239
[CrossRef] | [PubMed]
 
Pantelis  C;  Adesanya  A:  Increased risk of neutropaenia and agranulocytosis with sodium valproate used adjunctively with clozapine.  Aust N Z J Psychiatry 2001; 35:544–545
[CrossRef] | [PubMed]
 
Kando  JC;  Tohen  M;  Castillo  J;  Centorrino  F:  Concurrent use of clozapine and valproate in affective and psychotic disorders.  J Clin Psychiatry 1994; 55:255–257
[PubMed]
 
Ratanajamit  C;  Musakopas  C;  Vasiknanonte  S;  Reanmongkol  W:  Incidence and risk for neutropenia/agranulocytosis among clozapine users: a retrospective study.  Int J Psychiatry Clin Pract 2010; 14:109–115
[CrossRef]
 
Kang  BJ;  Cho  MJ;  Oh  JT;  Lee  Y;  Chae  BJ;  Ko  J:  Long-term patient monitoring for clozapine-induced agranulocytosis and neutropenia in Korea: when is it safe to discontinue CPMS? Hum Psychopharmacol 2006; 21:387–391
[CrossRef] | [PubMed]
 
Kumar  V: Clozaril Monitoring Systems, Registry Data and Analyses (United States, United Kingdom, and Australia). www.fda.gov/ohrms/dockets/ac/03/slides/3959S1_02_C-Novartis-Kumar.ppt
 
Schulte  PF;  Cohen  D;  Bogers  JPAM;  van Dijk  D;  Bakker  B:  A Dutch guideline for the use of clozapine.  Aust N Z J Psychiatry 2010; 44:1055–1056
[PubMed]
 
References Container
+
+

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