Clozapine neutropenia

Lithium can be used in combination with clozapine, and in these patients the possibility of inducing leukocytosis and increasing the total leukocyte count and the granulocyte count has been considered (SEDA-20, 50). Lithium has even been used to prevent clozapine-induced neutropenia (SEDA-22, 59) (162). It has also been used in a patient with clozapine-induced neutropenia and in another with complete agranulocytosis in both cases lithium increased the neutrophil count to within the reference range within 6 days (163). In the patient who had neutropenia, clozapine was restarted in the presence of lithium and the neutrophil count did not fall thereafter. Five other patients who took combined clozapine and lithium had a significant improvement with this... 

Agranulocytosis A severe form of neutropenia where the number of neutrophils (the major type of leucocyte or white blood cell) is very low, so reducing an individual s ability to fight infection. It is a potentially serious side effect of the atypical antipsychotic clozapine. 

Hematological Agranulocytosis, leukopenia, neutropenia N/A Complete blood count with differential at baseline and if symptoms of infection, pallor, or bruising develop shortly after treatment initiation White blood counts weekly for 6 months, then every other week thereafter if treated with clozapine... 

Clozapine and SSRIs are often used together, because depressive syndromes are common in patients with schizophrenia. Clozapine carries a relatively high risk of agranulocytosis, but this adverse effect is very rarely seen with SSRIs, although a case of possible fluoxetine-induced neutropenia has been described (SEDA-22, 15). Two cases in which the addition of paroxetine to clozapine was associated with neutropenia have been reported (11). The patients had been taking stable doses of clozapine for 6-12 months and had previously tolerated other SSRIs without adverse hematological consequences. In both cases the white cell count recovered when clozapine was withdrawn, although paroxetine was continued. 

Lithium has beneficial granulocytopoietic effects (35-37). For example, lithium carbonate (800-900 mg/day) effectively corrected neutropenia due to chemotherapy or radiotherapy in over 85% of 100 cancer patients (38). The potential benefit and possible risks of using lithium to treat clozapine-induced neutropenia/agranulocytosis have been reviewed (39). 

The potential of lithium to prevent or treat clozapine-induced granulocytopenia has been reviewed (39). In a study of 38 patients on clozapine for schizophrenia or schizoaffective disorder, the addition of lithium increased the leukocyte count (42). A 20-year-old man with olanzapine-induced neutropenia 5 mg/day was able to tolerate 20 mg/day while taking lithium (43). 

Of 39 patients taking lithium, 18% had neutrophilia and 15% had raised activity of polymorphonuclear elas-tase (a marker of granulocyte activation) (345). In keeping with these observations, a chart review of 38 patients taking clozapine showed an increase in leukocyte count when lithium was added (42). A man with olanzapine-induced neutropenia (with a prior history of risperidone-induced neutropenia), which normalized with drug withdrawal, had no difficulty when the drug was reintroduced after the patient had been treated with lithium (43). 

Blier P, Slater S, Measham T, Koch M, Wiviott G. Lithium and clozapine-induced neutropenia/agranulocytosis. Int Clin Psychopharmacol 1998 13(3) 137-40. 

Silverstone PH. Prevention of clozapine-induced neutropenia by pretreatment with lithium. J Clin Psychopharmacol 1998 18(l) 86-8. 

Patients with aggressive schizophrenia (n = 29) improved when treated with clozapine one was withdrawn after the development of leukopenia. In 10 mentally retarded patients taking clozapine for 15 days to 46 months improvement was observed. Half of the patients developed sedation and hypersalivation, and one discontinued the drug after 2 weeks because of neutropenia. The putative neurotoxicity of clozapine in moderately to... 

The efficacy and safety of treatment with clozapine in patients with Parkinson s disease have been discussed (SEDA-22, 57), and a multicenter retrospective review of the effects of clozapine in 172 patients with Parkinson s disease has been published (78). The mean duration of clozapine treatment was 17 (range 1-76) months. Low-dose clozapine improved the symptoms of psychosis, anxiety, depression, hypersexuality, sleep disturbances, and akathisia. Of the 40 patients, 24% withdrew as a result of adverse events, mostly sedation (n = 19). Sedation was reported in 46%, sialorrhea in 11%, and postural hypotension in 9.9%. Neutropenia was detected in four patients (2.3%). 

Immune-mediated mechanisms of clozapine-induced agranulocytosis have been reviewed in the context of agranulocytosis in a 46-year-old woman (140). Immune and toxic mechanisms have also been explored in patients taking clozapine, three who developed agranulocytosis, seven who developed neutropenia, and five who were asymptomatic. There was no evidence of antineutrophil antibodies in the blood of patients shortly after an episode of clozapine-induced agranulocytosis, and an antibody mechanism... 

Circadian variation in white cell count, with a dip in the morning, has been misdiagnosed as clozapine-induced neutropenia (148). 

A 17-year-old boy with severe clozapine-induced neutropenia had a negative rechallenge because he had had an unsatisfactory response to traditional neuroleptic drugs, clozapine was continued despite a fall in white blood cell count, since concomitant treatment with granulocyte colony-stimulating factor was followed by rapid normalization of the white blood cell count (152). 

A 45-year-old woman developed neutropenia after taking clozapine 500 mg/day for 6 years combined with other agents (olanzapine 10 mg/day, benzopril hydrochloride 20 mg/day, and haloperidol 150 mg/ day) (154). Clozapine was withdrawn immediately and the granulocytes recovered within a few days. However, 10 weeks later clozapine was restarted and there was no recurrence over more than 3 years. 

In a cohort study, based on a prospective drug exposure database, the effectiveness of centralized routine monitoring of blood counts was evaluated in 1500 patients taking clozapine between March 2001 and December 2001 (157). Seven patients developed severe neutropenia while taking clozapine (neutrophil counts below 1.5 x 109/ 1). The mean time to withdrawal of therapy was 1.6 days (maximum 6 days), and neutrophil counts recovered to normal in all cases after 6.4 days (maximum 13 days). Based on an estimate of 500 patient-years of exposure, the frequency of severe neutropenia was one case per 71 patient-years of therapy or 1.4% per annum. 

According to the recommended guidelines by Novartis, neutropenia (a white blood cell count below 3.0 x 109/1 or an absolute neutrophil count below 1.5 x 109/1) during clozapine treatment is classified as being in the red-alert zone immediate withdrawal of clozapine is recommended and reinstitution prohibited. However, in some patients, this is not feasible, because of lack of effective alternatives to clozapine. In five patients who were maintained on clozapine despite red-alert zone neutropenia and two control patients who discontinued clozapine because of neutropenia, hematological and clinical progress was followed for more than 600 days (158). In all five patients, there were no additional episodes of neutropenia despite continued clozapine treatment. 

Treatment with granulocyte colony-stimulating factor and granulocyte macrophage colony stimulating factors was helpful in a case of sepsis and neutropenia induced by clozapine (160) and in a case of agranulocytosis in a 45-year-old man (161). 

Clozapine-induced eosinophilia and subsequent neutropenia has been reported (165). As the patient had a high IgE concentration, an allergic cause was proposed. In a previous study in 70 patients there was no predictive value of eosinophilia for clozapine-induced neutropenia (166). Eosinophilia associated with clozapine treatment has been reported in 13% of treated patients in a study in Australia (38). 

A 46-year-old woman with schizophrenia who was taking clozapine 700 mg/day developed breast cancer and underwent segmental mastectomy she developed neutropenia, which persisted for more than 6 months after her last radiation treatment (225). 

There is a potentially dangerous interaction with cancer treatment in patients with schizophrenia taking clozapine, because of the unpredictable risk of myelotoxicity. However, a 37-year-old patient taking clozapine for schizophrenia was given full-dose cisplatin and concomitant radiotherapy for an undifferentiated nasopharyngeal carcinoma, without significant neutropenia (250). 

In a case of neutropenia the authors suggested that an interaction of clozapine with erythromycin had been the... 

Jauss M, Pantel J, Werle E, Schroder J. G-CSF plasma levels in clozapine-induced neutropenia. Biol Psychiatry 2000 48(ll) 1113-5. 

Sperner-Unterweger B, Czeipek I, Gaggl S, Geissler D, Spiel G, Fleischhacker WW. Treatment of severe clozapine-induced neutropenia with granulocyte colony-stimulating factor (G-CSF). Remission despite continuous treatment with clozapine. Br J Psychiatry 1998 172 82 1. 

Small JG, Weber MC, Klapper MH, Kellams JJ. Rechallenge of late-onset neutropenia with clozapine. J Clin Psychopharmacol 2005 25 185-6. 

Pascoe ST. The adjunctive use of a centralised database in the monitoring of clozapine-related neutropenia. Pharmacoepidemiol Drug Saf 2003 12 395-8. 

Ahn YM, Jeong SH, Jang HS, Koo YJ, Kang UG, Lee KY, Kim YS. Experience of maintaining clozapine medication in patients with red-alert zone neutropenia long-term follow-up results. Int Clin Psychopharmacol 2004 19 97-101. 

Melzer M, Hassanyeh FK, Snow MH, Ong EL. Sepsis and neutropenia induced by clozapine. Clin Microbiol Infect 1998 4(10) 604-5. 

Lucht MJ, Rietschel M. Clozapine-induced eosinophilia subsequent neutropenia and corresponding allergic mechanisms. J Clin Psychiatry 1998 59(4) 195-7. 

Ames D, Wirshing WC, Baker RW, Umbricht DS, Sun AB, Carter J, Schooler NR, Kane JM, Marder SR. Predictive value of eosinophilia for neutropenia during clozapine treatment. J Clin Psychiatry 1996 57(12) 579-81. 

Usiskin SI, Nicolson R, Lenane M, Rapoport JL. Retreatment with clozapine after erythromycin-induced neutropenia. Am J Psychiatry 2000 157(6) 1021. 

In a 46-year-old man taking olanzapine 10 mg/day, leukopenia and neutropenia were associated with HLA types A1 24, B7, B35, DRB1 15, DRB1 11, DRB3 01-03, DRB5 01-02, a haplotype distinct from that previously observed in clozapine-induced hemo-toxicity (213). 

In a 31-year-old woman clozapine monotherapy 75 mg/day caused neutropenia (neutrophil count 1.1 x 109/1) 5 days after clozapine withdrawal the neutrophil count normalized (2.6 x 109/1). Olanzapine was then introduced at 5 mg/day and the next day increased to 10 mg/day. After a week the neutrophil count fell to 0.9 x 109/1 and olanzapine was withdrawn. The neutrophil count was normal 4 weeks after olanzapine withdrawal. 

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