Introduction

One need not specialize in hematology to prescribe clozapine, but the concern about neutropenia compels all clinicians to develop expertise with concepts such as benign ethnic neutropenia (BEN), and the dose-dependent impact of divalproex/valproate on neutrophil counts and neutropenia risk. The mandatory monitoring has also revealed a propensity for clozapine to induce other hematological abnormalities including eosinophilia, neutrophilia, abnormal platelet counts, and anemia. This spectrum of hematologic abnormalities is not unique to clozapine, but an analysis of 285 antipsychotic-treated patients found that persistent anemia, neutrophilia and eosinophilia occurred at significantly higher rates compared to other antipsychotics during the first 18 weeks of therapy [ 1 ]. A retrospective Canadian study of 1-year hematologic outcomes among 101 new clozapine starts found a cumulative incidence of 48.9% for neutrophilia (> 7500/mm ³ ), 5.9% for eosinophilia (> 1500/mm ³ ), and 3% each for thrombocytosis (> 500,000/mm ³ ) and thrombocytopenia (< 100,000/mm ³ ) [ 2 ]. An Italian study of 2404 patients reported a leukocytosis rate of 7.7% using the total WBC threshold of 15,000/mm ³ [ 3 ]. Most of the aberrations were self-limited and did not necessitate treatment interruption. Anemia may have multiple causes, and one study of 96 new clozapine starts found that 24.5% developed anemia during the first 2 years of treatment, but it was not a cause of treatment discontinuation [ 4 ].

Principles

• Eosinophilia without evidence of organ involvement is not a reason to permanently discontinue clozapine. When there is no evidence of organ involvement or other systemic reaction to clozapine eosinophilia is self-limited and resolves without need for treatment interruption, unless dictated by local prescribing guidelines.

• Exposure to divalproex/ valproate is associated with neutropenia (see Chapters 6 and 10 ), but also thrombocytopenia and rarely anemia. Use of alternate agents is necessary to determine whether clozapine (or another etiology) is the offending medication.

• Thrombocytopenia (not due to other causes) and thrombocytosis each occur at rates no higher than 3%. These are usually self-limited processes that resolve without need for treatment interruption unless dictated by local prescribing guidelines. Extremely low (< 50,000/mm ³ ) or high (> 750,000/mm ³ ) platelet counts pose risk for bleeding or thrombosis and will necessitate treatment interruption.

• Anemia can be associated with clozapine treatment (once other causes have been ruled out), but is not a reason for treatment discontinuation.

• Moderate elevations of transaminases (ALT, AST) >  2 times the upper limit of normal (ULN) not part of a systemic reaction do occur early in clozapine treatment in over 30%. When presenting after longer periods (e.g. months or years), nonalcoholic steatohepatitis due to insulin resistance is the likely etiology.

• Patients have been successfully rechallenged after manifesting ALT or AST levels exceeding 3 times ULN but who had no prior evidence of fever or other systemic reaction.

While clozapine is prone to a host of unusual adverse effects, in certain instances the problem relates not to clozapine but to other medical conditions, or to the concurrent use of medications, especially divalproex/ valproate. Thrombocytopenia rates during the first 24 weeks of divalproex are 18% when defined as a platelet count < 100,000/mm ³ , with a significant negative correlation found between valproate levels and platelet counts [ 5 ]. Divalproex has direct effects on hematopoiesis and is not uncommonly associated with macrocytosis, but anemia and pure red cell aplasia have also been reported [ 6 , 7 ]. The overarching principle is that for each cell line abnormality there are a small number of considerations to evaluate before hematology or other expertise is required. Moreover, these problems typically develop insidiously and do not require urgent action, permitting time for any necessary work-up or concurrent medication changes. Having a comfort level with the expected rates and course of these hematological abnormalities will allow clinicians to focus their energies on more daunting and persistent problems such as weight gain, sialorrhea, and constipation. Eosinophilia and leukocytosis should not be reasons for discontinuing clozapine treatment. Thrombocytosis and thrombocytopenia may necessitate temporary cessation, but are only rarely grounds for permanently stopping clozapine therapy [ 8 ].

Abnormalities of hepatic function tests present another source of worry for many clinicians, and may be a more prevalent problem for clozapine compared to other antipsychotics. An early prospective trial found that 37.3% of clozapine-treated patients had alanine aminotransferase (ALT) levels more than 2 times the upper limit of normal (ULN) during the first 18 weeks of treatment compared to 16.6% for a haloperidol-treated cohort [ 9 ]. As with certain hematological issues this is typically a transient phenomenon: 61% of patients who exhibited an ALT > 2 times ULN at any point in weeks 1–6 of the 18 week study had ALT levels≤ 2 times ULN during weeks 13–18 [ 9 ]. In a manner analogous to the anemia work-up, the time course and severity will help guide appropriate diagnostic testing to evaluate nonmedication-related reasons for changes in liver function tests. Early increases in ALT or aspartate aminotransferase (AST) beyond 3 times ULN may require a pause in clozapine treatment, but in the absence of systemic illness (e.g. drug reaction with eosinophilia and systemic symptoms syndrome [DRESS]), rechallenge with adjusted titration and careful monitoring often allows patients to be successfully resumed on clozapine [ 10 ].