CNS Drugs 2007; 21 (1): 25-35 1172-7047/07/0001-0025/$44.95/0

THERAPY IN PRACTICE

© 2007 Adis Data Information BV. All rights reserved.

Restarting Clozapine after Neutropenia Evaluating the Possibilities and Practicalities Eromona Whiskey and David Taylor Pharmacy Department, Maudsley Hospital, South London and Maudsley NHS Trust, London, UK

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 1. Mechanisms of Clozapine-Induced Blood Neutropenia and Agranulocytosis . . . . . . . . . . . . . . . . . . . . 27 2. Risk Factors for Neutropenia and Agranulocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 3. Should Clozapine Be Restarted After Neutropenia? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3.1 Possible Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3.2 Medical Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3.3 Benign Ethnic Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4. Managing Benign Ethnic Neutropenia Using Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5. Managing Clozapine-Associated Neutropenia Using Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 6. Restarting Clozapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Abstract

Clozapine remains the antipsychotic of choice for refractory schizophrenia despite its propensity for serious blood disorders. When neutropenia or agranulocytosis occur in people taking clozapine, cessation of treatment is mandated and relapse often results. Because such patients are usually unresponsive to other antipsychotics, many clinicians consider restarting clozapine, despite the risks involved. However, the risks of clozapine rechallenge vary according to the cause and nature of the blood dyscrasia. Neutropenia can arise because of factors unrelated or indirectly related to clozapine treatment. These include benign ethnic neutropenia, concomitant drug therapy, co-existing medical conditions and drug interactions. In such cases, clozapine may be restarted if non-clozapine causes of neutropenia are identified and eliminated, although concurrent treatment with lithium (to induce leukocytosis) is sometimes necessary. Close monitoring of the patient is essential because it is rarely possible to completely rule out the contribution of clozapine to the blood dyscrasia and because lithium does not protect against clozapine-related agranulocytosis. In cases of clozapine-induced neutropenia (as distinct from agranulocytosis, which may have a different pathology) rechallenge may also be considered and, again, lithium co-therapy may be required. Where clozapine is clearly the cause of agranulocytosis, rechallenge should not be considered or undertaken unless there are very exceptional circumstances (severe and prolonged relapse following clozapine discontinuation). In these

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cases, re-exposure to clozapine may rarely be attempted where there are facilities for very close and frequent monitoring. Granulocyte colony-stimulating factor is likely to be required as co-therapy, given the very high likelihood of recurrence. Uncertainty over the likely cause of blood dyscrasia in people taking clozapine, coupled with uncertainty over the mechanism by which clozapine causes both neutropenia and agranulocytosis, makes any attempt to restart clozapine a high-risk venture requiring the utmost caution.

More than 30 years ago clozapine was the first ‘atypical’ antipsychotic drug introduced into clinical use. This drug has since proved itself unique in many respects. A very large meta-analysis of the efficacy of second-generation antipsychotics showed that the effect size of clozapine over conventional antipsychotics was greater than for all other atypical antipsychotics.[1] Also, there is ample evidence to suggest that it is more effective than other atypical antipsychotics in refractory schizophrenia.[2] Most schizophrenia guidelines now recommend that clozapine is prescribed after patients’ symptoms fail to respond to adequate trials with two antipsychotics[3] (although it has been shown that there is a delay of 5 years before initiating clozapine therapy[4]). Associated with the sometimes dramatic improvements in psychopathology is the impact of clozapine on suicidality in schizophrenia and other psychotic disorders. Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide over the course of their lifetime and approximately 10% die as a result of suicide.[5] InterSePT (The International Suicide Prevention Trial)[6] provided evidence for the efficacy of clozapine in reducing recurrent suicidal behaviour in patients with schizophrenia or schizoaffective disorder who are judged to be at high risk of committing suicide. Clozapine is also perhaps uniquely toxic. Soon after it was first introduced into clinical use in Europe in the late 1960s and early 1970s, the haematological adverse profile of clozapine became apparent. In Finland in 1974, eight deaths resulted from agranulocytosis in patients taking clozapine. This observation led to its withdrawal in those coun© 2007 Adis Data Information BV. All rights reserved.

tries where it was already marketed. Pressure from many psychiatrists followed and clozapine was reintroduced in a few countries, with very close haematological scrutiny. In 1988, following the landmark trial by Kane and coworkers,[7] the place of clozapine in the treatment of refractory schizophrenia was firmly established. Thereafter, clozapine was licensed in many countries, with strict haematological monitoring. This close monitoring has dramatically reduced mortality associated with clozapine-induced blood dyscrasias; reduction in mortality has been estimated at approximately 92%.[8] Clozapine is associated with various haematological adverse effects, including leukopenia, neutropenia, agranulocytosis, leukocytosis, anaemia, eosinophilia, thrombocytopenia and thrombocythaemia, with the most clinically significant being agranulocytosis and neutropenia.[9] With active monitoring, the cumulative incidence of agranulocytosis, defined as a white blood cell (WBC) count of <1.0 × 109/L or an absolute neutrophil count (ANC) of <0.5 × 109/L, in patients treated with clozapine is approximately 0.8% after 1 year and 0.91% after 1.5 years.[10] The cumulative annual incidence of neutropenia, defined as an ANC of between 0.5 × 109/L and 1.5 × 109/L, is 2.7%.[11,12] Treatment with clozapine is almost always terminated in patients who develop neutropenia or agranulocytosis. It is widely recommended that patients in whom clozapine had been discontinued because of neutropenia or agranulocytosis should not be reexposed to the drug. These precautions have clear logic and effectively serve to protect the patient. Aside from haematological adverse effects, clozapine is also associated with other serious adCNS Drugs 2007; 21 (1)

Restarting Clozapine after Neutropenia

verse effects such as thromboembolism,[13] myocarditis, cardiomyopathy,[14] diabetes mellitus,[15] weight gain[16] and seizures.[9] Less serious adverse effects that commonly occur include sedation, drowsiness, tachycardia, constipation and hypersalivation. However, despite the seemingly heavy burden of adverse effects, many patients experience a marked increase in their subjective wellbeing[17] and report improvements in their level of satisfaction, quality of life, compliance with treatment, thinking, mood and alertness.[18] In a large survey of clozapine users, the overwhelming majority (almost 90%) preferred to remain taking clozapine than change to another drug.[19] This favourable experience with clozapine is further demonstrated in studies investigating the longterm continuation of treatment with clozapine. For example, in a study comparing clozapine with haloperidol, continuation of treatment was significantly greater with clozapine.[20] Another study conducted over 48 months demonstrated that 46% of patients were still receiving clozapine after 4 years.[21] This attrition rate is substantially lower than that seen with other antipsychotics. In the recent highly influential CATIE study (Clinical Antipsychotic Trials of Intervention Effectiveness) that compared the atypical antipsychotics with a firstgeneration antipsychotic, 74% of all patients had discontinued treatment at 18 months.[22] In an extension of this study, persistence with clozapine treatment was significantly and substantially longer than treatment with olanzapine, risperidone or quetiapine.[23] Thus, clozapine is unique in its pharmacology, actions and toxicity. Many patients experience unnecessary delays before initiation of therapy, but soon after commencement of treatment the majority of patients experience substantial symptom improvement. Thereafter, most patients would prefer to remain taking clozapine than return to previous antipsychotic treatment and persistence with treatment is better than with other antipsychotics. Therefore, the decision to stop clozapine as a result of haematological adverse effects is a frustrating one for the clinician, and is frequently disastrous for the © 2007 Adis Data Information BV. All rights reserved.

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patient. As a consequence, the possibility of rechallenge is a rather tempting proposition even though it is contrary to the manufacturers’ advice and carries the inherent risk to the patient of re-exposure to a potentially fatally toxic drug. In this review we examine the background to clozapine-related blood disorders and discuss restarting clozapine in the context of possible precipitants and clinical risk. 1. Mechanisms of Clozapine-Induced Blood Neutropenia and Agranulocytosis Although several mechanisms have been suggested, the exact mechanism of clozapine-induced haematological disorders is not known.[24] It appears possible that distinct mechanisms underlie the development of the more severe, potentially lethal agranulocytosis (ANC <0.5 × 109/L) and the mild to moderate neutropenia (ANC between 0.5 × 109/L and 1.5 × 109/L) observed with clozapine.[25] With regard to agranulocytosis, the cells affected are neutrophil precursors together with mature peripheral neutrophils,[23,26] whereas the cells affected in neutropenia appear to be only the peripheral neutrophils.[24] Agranulocytosis induced by clozapine is thought to be mediated either through a direct toxic effect or an immune-mediated reaction. Evidence that clozapine-induced agranulocytosis is immune-mediated comes from several sources. For example, in cases of clozapine rechallenge after neutropenia or agranulocytosis, where there was recurrence of toxicity on re-exposure, the effect on white cells occurred more quickly than when clozapine was first used. In a report by Safferman et al.,[27] mean time to occurrence was reduced from 24 to 14 weeks on reexposure. In a more recent report, Dunk et al.[28] observed a much quicker recurrence of blood dyscrasia, occurring after a median of 5.5 weeks as opposed to 44 weeks in the first instance. An immunogenic reaction has also been postulated as the basis of clozapine-induced agranulocytosis based on the observation that when polymorphonuclear neutrophils are exposed to serum from patients who developed agranulocytosis through complement activation, cell lysis results.[29] CNS Drugs 2007; 21 (1)

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In apparent contrast, there are several studies that postulate the direct cytotoxic effect of clozapine. For example, Gerson and Meltzer[30] showed that the metabolite N-desmethyl clozapine is more toxic to myeloid precursor cells than clozapine or its other metabolites at concentrations 3- to 5-fold higher than those normally seen in patients taking clozapine. They postulate that this metabolite may accumulate in some patients, giving rise to neutropenia and agranulocytosis. In addition, there is evidence that clozapine is bioactivated to a chemically reactive nitrenium ion that is toxic to neutrophils.[31-33] Individuals who develop agranulocytosis may be more sensitive to these clozapine reactive metabolites.[34] The reactive nitrenium ion has been demonstrated in vitro to accelerate neutrophil apoptosis,[24] possibly as a result of increased expression of pro-apoptotic proteins.[35] Clearly, the exact mechanism by which clozapine induces neutropenia and agranulocytosis is still uncertain. Even considering just two discreet options – a direct toxic effect of clozapine metabolites or an immune-mediated response – may be too simplistic as it is also possible that both might co-exist or that several other different mechanisms might also be involved. An elucidation of the nature of clozapineinduced blood dyscrasias would allow for the distinction of a more benign neutropenia as against a potentially fatal agranulocytosis. Benign neutropenia occurs more frequently than agranulocytosis. In fact, transient neutropenia, in which the neutrophil count drops below a defined value but returns to normal values with continued clozapine treatment, occurs frequently. For example, in a sample of 68 patients receiving clozapine, transient neutropenia was found in 22% of the patients when neutropenia was defined as a count of <2 × 109/L, and 12.2% when neutropenia was defined as <1.5 × 109/L.[36] The transient nature of some of these neutropenic episodes during clozapine therapy is also demonstrated in some case reports.[37,38] In two separate papers,[36,39] patients displayed a diurnal variation in the number of circu© 2007 Adis Data Information BV. All rights reserved.

Whiskey & Taylor

lating neutrophils, such that a morning pseudo-neutropenia was normalised in the afternoon. The clinical challenge is to distinguish benign or transient neutropenia from the malignant form that progresses to or is associated with agranulocytosis. One method that has been proposed is the use of a hydrocortisone test.[40] This test is based on evaluating bone marrow granulocyte reserves or the marrow storage pool. The magnitude of increase in the peripheral ANC after hydrocortisone injection is said to reflect the state of marrow reserves. An absolute increase of 2 × 109/L after a 200mg injection of hydrocortisone was considered to be a normal response. This test has not seen wide clinical use. Monitoring of endogenous granulocyte colonystimulating factor (G-CSF) levels, together with WBC counts during clozapine-induced neutropenia, has also been said to distinguish between benign and malignant neutropenia.[41] 2. Risk Factors for Neutropenia and Agranulocytosis The period of greatest risk of haematological disorders with clozapine is during the first 18 weeks of treatment. Data from the UK and Ireland indicate that 76% of cases of clozapine-induced neutropenia occur in the first year of treatment.[12] After this first year, the incidence of agranulocytosis significantly decreased to the order noted with some phenothiazines.[11] There have been suggestions that clozapine monitoring could even be discontinued after 1 year of treatment.[42] Although the risk of haematological adverse effects with clozapine diminishes with time, it is not eliminated altogether; there have been several case reports of late-occurring blood dyscrasias. A case of agranulocytosis after 11 years of treatment with clozapine was recently reported.[43] Another case in which clozapine was used nearly continuously for over 7 years before the patient developed agranulocytosis has also been published.[44] Certain risk factors for clozapine-associated blood dyscrasias have been identified. Increasing age appears to be a consistent finding as a risk factor CNS Drugs 2007; 21 (1)

Restarting Clozapine after Neutropenia

for agranulocytosis, but not neutropenia.[10-12] Women also appear to have an increased susceptibility to develop agranulocytosis and onset may be earlier than with men.[45] Two related factors that increase the risk of neutropenia are low baseline WBC counts and ethnicity. Black patients are significantly more likely to have low baseline WBC counts, and any patient, regardless of race, with a pretreatment low WBC count appears significantly more likely to develop neutropenia.[11,12] Several studies show that specific human leukocyte antigens (HLAs) play a role in iatrogenic agranulocytosis; however, there is conflicting evidence regarding genetic susceptibility to clozapineinduced agranulocytosis. Ashkenazi Jews appear to have a higher prevalence of clozapine-induced agranulocytosis, and HLA typing indicated that the HLA-B38, DR4, DQw3 haplotype may confer this increased susceptibility.[46] Other studies investigating HLA-encoded genetic susceptibility to clozapine-induced agranulocytosis, both in Jewish and non-Jewish patients, have also found associations.[47-49] In contrast, one study found no significant association between HLA system and susceptibility to clozapine-induced agranulocytosis.[50] 3. Should Clozapine Be Restarted After Neutropenia? The decision regarding whether or not to restart clozapine after neutropenia should be based on careful evaluation of the circumstances surrounding the index neutropenic episode. The aim of this evaluation is to identify those patients who have unequivocally experienced a clozapine-related, potentially serious neutropenia or agranulocytosis so that consideration of re-exposure can be abandoned for all but the most exceptional circumstances. 3.1 Possible Drug Interactions

Clozapine should not normally be used in combination with drugs known to have a substantial potential to depress bone marrow function. The concurrent use of clozapine and drugs such as carbamazepine, chloramphenicol, sulfonamides, penicillamine and cytotoxic agents is contraindicated. The © 2007 Adis Data Information BV. All rights reserved.

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assumption here is that the combination poses a greater risk than any of these drugs used alone. For example, it has been demonstrated that the combination of N-methyl clozapine (a major metabolite of clozapine) and carbamazepine was more toxic to bone marrow than either drug alone and the effect may possibly be additive.[28] However, several drugs that are not known to have a substantial risk of neutropenia have been implicated in association with clozapine. For example, valproic acid (sodium valproate) can rarely cause neutropenia; it was one of the drugs reported in the literature to cause neutropenia when used in combination with clozapine.[51,52] However, a review of 55 cases of combined use of valproic acid and clozapine did not observe an increase in risk for developing neutropenia compared with clozapine monotherapy.[53] Other drugs that have been reported to cause neutropenia when used adjunctively with clozapine include risperidone,[54] quetiapine,[55] ranitidine,[49] interferon-α,[56] erythromycin[57] and haloperidol.[58] In clinical situations where there is a high probability that the neutropenia is a result of the introduction of another agent, rechallenge may be considered. In addition, in such cases adjunctive medications should be avoided as far as is practicable. 3.2 Medical Complications

Concurrent co-morbid medical conditions may complicate the appearance of neutropenia in patients treated with clozapine. For example, a clinical dilemma arises when patients stabilised on clozapine require radiation and/or cancer chemotherapy. These therapeutic agents are well known to cause myelosuppression and there are limited data on the safety of concurrent drug therapy including clozapine, as well as very little guidance in the management of these patients. There have been reports of the concurrent use of clozapine with chemotherapy in which patients have continued clozapine with very close supervision despite the onset of neutropenia.[59-61] Decreased circulating neutrophils are found in bacterial and viral infections, including HIV. ChronCNS Drugs 2007; 21 (1)

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ic neutropenia often accompanies HIV infection and results from impaired production and accelerated destruction of neutrophils. In addition, antiretroviral treatment carries a further risk of bone marrow suppression. There are only a few published reports of the successful use of clozapine in HIV patients.[62,63] 3.3 Benign Ethnic Neutropenia

When neutropenia (defined by normative data in White populations) occurs in individuals of other ethnic groups who are otherwise healthy and who do not have repeated or severe infections, the condition may be referred to as benign ethnic neutropenia.[64] Approximately 25–50% of people of African descent and some ethnic groups in the Middle East have benign ethnic neutropenia.[62] Although the need for separate WBC and ANC reference values for people of African descent has long been advocated, it was not until recently that the Clozaril Patient Monitoring Service in the UK and Ireland recognised and allowed the use of clozapine in patients with benign ethnic neutropenia. The risk of clozapine-associated neutropenia is 77% higher in Black African Caribbean patients than in Caucasians.[12] This increased risk results from the observation that the baseline WBC in African Caribbean patients was significantly lower than for all other racial groups. Indeed, this group of patients were 140-fold more likely than any other racial group to have pretreatment neutropenia.[11] The importance of recognition of benign ethnic neutropenia in the context of clozapine treatment was recently highlighted in an editorial by Rajagopal.[65] The diagnosis of benign ethnic neutropenia should not be difficult in a person whose race is known to be affected, is physically healthy and lacks a history of susceptibility to infection.[62] Although extensive or invasive testing is not required, it is important where possible to confirm the pattern of neutropenia by repeating blood sampling every month for 3 consecutive months and to establish that morphological characteristics of the blood cells are normal.[62,66] © 2007 Adis Data Information BV. All rights reserved.

African Caribbean patients with a low pretreatment WBC count who develop neutropenia while taking clozapine constitute a therapeutic dilemma. If benign ethnic neutropenia is established then any lowering of WBC counts during clozapine treatment may be coincidental. Restarting clozapine may therefore be considered, perhaps after allowing or provoking WBC counts to return to normal. 4. Managing Benign Ethnic Neutropenia Using Lithium It has long been recognised that lithium treatment causes an increase in WBC counts. The exact mechanism by which lithium does this is not completely understood; however, it seems to result from an increase in granulocyte production rather than from a redistribution of marginated granulocytes.[67-70] It has also been suggested that increased WBC production could be a result of its effect on enhanced cortisol secretion.[71] WBC elevations occur in almost all haematologically normal patients who have been prescribed lithium for between 1 and 4 weeks. There is no correlation between increases in WBC counts and lithium dose or serum concentrations, age, gender or bodyweight,[66,67] although lithium concentrations of at least 0.4 mmol/L may be required. The usual magnitude of elevation of the WBC count seen in patients treated with lithium is approximately 2.0 × 109/L, or between 30% and 45% greater than pretreatment levels.[66,72] The increase in WBC counts with lithium is reversible upon discontinuation, but persists with long-term treatment,[67] although one study suggested that after 6 months of treatment, WBC counts were not different to those taken at baseline.[69] Historically, lithium has been employed clinically to increase WBC counts in neutropenia of various aetiologies. For example, it has been used in patients with chemotherapy-induced neutropenia,[73,74] Felty’s syndrome[75] and in some cases of druginduced neutropenia such as with carbamazepine[76] and zidovudine.[77] The use of lithium to prevent clozapine-associated neutropenia, or, more precisely, neutropenia coincident with clozapine treatment, was first reported CNS Drugs 2007; 21 (1)

Restarting Clozapine after Neutropenia

in 1995.[78] Since then, there have been several more cases published in the literature.[79-83] Most of these reports describe positive outcomes with the combination – patients continued receiving clozapine without any obvious toxic effects. The combination has also been used successfully in children taking clozapine; one report involved two children aged 7 and 12 years in which this strategy was successfully used.[81] In the largest and most recent series reported (a retrospective chart review of 25 patients undergoing clozapine rechallenge using lithium pretreatment) there was only one case of a second episode of neutropenia.[84] Nevertheless, the use of a lithium-clozapine combination is not without risk. There is concern that the use of lithium may mask impending agranulocytosis;[76] there has been one fatality reported possibly as a result of this combination[85] (although this case was complicated by the concurrent use of carbamazepine, clonazepam and benztropine, and by the withdrawal of lithium). In another report, a patient developed agranulocytosis during treatment with the combination of lithium and clozapine, and treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) was ineffective.[80] This is particularly disturbing since it suggests the possibility that prior and concomitant use of lithium somehow rendered GM-CSF ineffective. Neurological adverse effects, including tremors, involuntary jerking, stumbling gait and seizures, have also been reported with the lithium-clozapine combination, although these reports seem to be associated with high doses of clozapine.[86,87] It is worth noting that (reversible) neurotoxic effects may be observed, even at normal lithium concentrations[88] when lithium is used alongside antipsychotics. On a more positive note, one double-blind, placebo-controlled crossover study[70] and one retrospective chart review[89] evaluated the safety and efficacy of the lithium-clozapine combination and each concluded that it was well tolerated. Any adverse events that were observed had well known associations with either clozapine or lithium monotherapy and occurred in frequencies expected in monotherapy. A few patients developed transient, © 2007 Adis Data Information BV. All rights reserved.

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reversible neurological adverse effects, as noted earlier. 5. Managing Clozapine-Associated Neutropenia Using Cytokines Many clinicians sensibly fear the onset of neutropenia, particularly agranulocytosis, because of the potential for fatality and because there are few effective remedial treatments. Nonetheless, several reports have described the successful use of the cytokines, G-CSF and GM-CSF to shorten the duration of clozapine-induced agranulocytosis.[90-93] On average, agranulocytosis caused by clozapine lasts for between 12 and 20 days.[43] Treatment with GCSF or GM-CSF stimulates the proliferation and differentiation of myeloid precursor cells and appears to speed the recovery process and shorten this period by approximately one-half. These agents are usually discontinued after recovery of WBC counts and once signs of infection have resolved.[91] As mentioned previously, continued treatment with clozapine is highly desirable in many instances despite the toxic effects of this drug. The long-term, concurrent use of clozapine and G-CSF is a contentious treatment option for such patients, although there are a few published cases of this approach.[90,94,95] The cost of long-term treatment with these agents is very prohibitive, and safety and efficacy still remain to be determined. 6. Restarting Clozapine The decision to restart clozapine should be taken on a case-by-case basis and should take into account the likely risks and benefits of restarting. There are few situations where clozapine should not be restarted and, similarly, few situations where rechallenge should always be undertaken. The risks involved in rechallenge are but one aspect of the decisionmaking process; the individual’s prior response to clozapine and the magnitude of their deterioration on stopping treatment are also important factors to take into consideration. As previously indicated, the first step in determining whether or not to restart clozapine is to attempt to gain some certainty over the cause of the CNS Drugs 2007; 21 (1)

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Table I. Practical measures when restarting clozapine after neutropenia Before rechallenge

Immediately after rechallenge (0–6mo)

Long-term (6mo plus)

• Perform full blood counts twice-weekly • Perform tests for other parameters weekly • Consider admission to hospital for 2–4wk

• Perform full blood counts weekly • Perform tests for other parameters monthly

• Where possible, measure temperature, pulse and blood pressure daily • Monitor for concurrent physical illness

• Monitor weekly for concurrent physical illness

Tests and procedures • Establish pattern of ‘normal’ white blood cell counts over a period of at least 2wk, preferably longer. Consider sampling at different times of the day to establish any diurnal variation • Establish lithium therapy, where appropriate • Perform full work-up, including blood urea nitrogen, electrolytes, liver function tests, lipids, blood glucose • Involve clozapine manufacturer in the clinical decision-making process Physical monitoring • Monitor temperature, pulse and blood pressure weekly • Monitor for concurrent physical illness Other considerations • Where possible, gain informed consent for rechallenge from patient and primary carer • Where possible, withdraw all other medication, especially drugs known to be associated with neutropenia • Consider referral to, or shared care with, haematology specialist

• Ask patient to report any physical changes, • Ask patient to report any physical particularly fever, sore throat, or other changes, particularly fever, sore signs or symptoms of infection throat, or other signs or symptoms • Where possible, avoid concomitant drug of infection therapy

episode of neutropenia or agranulocytosis. This is not always possible, particularly when patients have sparse records of blood count results before starting clozapine. Where there has been a clear clozapinerelated episode of agranulocytosis, rechallenge is not normally considered. In very exceptional circumstances, restarting clozapine may be contemplated, but extra precautions must be observed (table I) and G-CSF may be needed, given the high probability of reoccurrence. The use of lithium is not recommended in these patients. In confirmed or suspected cases of benign ethnic neutropenia, where there is no evidence of agranulocytosis, restarting clozapine is often considered and is usually appropriate. Co-therapy with lithium is sometimes needed to maintain blood counts in the normal range. Caution is required because clozapine-related bone marrow toxicity can occur in the context of benign ethnic neutropenia and lithium probably offers no protection against this. Where neutropenia is thought to be linked to coadministered drugs or to medical co-morbidity, removal of the suspect drug or resolution of the medical condition is a prerequisite of restarting © 2007 Adis Data Information BV. All rights reserved.

clozapine. Again, caution is required because clozapine toxicity may be the prime cause of neutropenia in such cases. Overall, in considering restarting clozapine, it is important to recognise our uncertainty over many aspects of reduced WBC counts occurring in people receiving clozapine and the risk this uncertainty engenders. We do not know the mechanisms by which clozapine causes neutropenia or agranulocytosis and extraneous factors make it difficult, in many individual patients, to be sure about the exact cause or likely pathology of any observed reduced neutrophil counts. Studious caution and close monitoring are required in all cases of rechallenge. All decisions to restart clozapine should involve consultation with the manufacturer, referral to a haematology specialist, where necessary, and thorough education of the patient as to the warning signs and symptoms of blood dyscrasia. Acknowledgements Eromona Whiskey has no conflicts of interest that are directly relevant to the content of this review. David Taylor has received grants from Bristol-Myers Squibb and Novartis,

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honoraria from Bristol-Myers Squibb, Novartis and Genthon, and acted as a consultant for Bristol-Myers Squibb, SanofiSynthelabo and AstraZeneca. No sources of funding were used to assist in the preparation of this review.

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Correspondence and offprints: Dr David Taylor, Pharmacy Department, Maudsley Hospital, South London and Maudsley NHS Trust, Denmark Hill, London, SE5 8AZ, UK. E-mail: [email protected]

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