Factors to Consider Before Restarting a Patient on Clozapine

Clozapine is a proven therapy for patients with treatment-resistant schizophrenia. In rare cases, clozapine can cause neutropenia, which is defined as an absolute neutrophil count (ANC) below 1,500 cells/mm³. Neutrophils are a critical part of the immune system and neutropenia increases the risk of infection. A recent meta-analysis calculated the incidence of clozapine-induced neutropenia at 3.8 per 100 person-years of exposure and the incidence of severe neutropenia, or agranulocytosis (ANC below 500 cells/mm³) at 0.9 percent per 100 person-years of exposure ⁽¹⁾.

The development of neutropenia can be anxiety provoking for all involved. What steps should physicians take to resolve this issue? Since clozapine is underutilized for people with schizophrenia in the United States ⁽²⁾, and neutropenia is a rare adverse effect, there are limited outcomes data to help guide clinical decision making.

Per the clozapine REMS guidelines, if an individual develops mild neutropenia (ANC = 1,000 to 1,499 cells/mm³), clozapine can be continued, but thrice-weekly monitoring is required until the ANC ≥1,500 cells/mm³. If a patient develops moderate neutropenia (ANC = 500 to 999 cells/mm³), it is recommended that the patient is taken off clozapine, and ANC are monitored daily until the count is ≥ 1,000 cells/mm³. If a patient develops severe neutropenia, a hematology consultation is recommended in addition to discontinuation of clozapine and daily monitoring of ANC counts until the count is ≥ 1,000 cells/mm³.

A physician who is treating a patient who has clozapine therapy interrupted due to moderate or severe neutropenia must consider the possibility of a rebound of the patient's psychotic symptoms and should consider a new antipsychotic for the patient. This can be problematic since patients have often failed multiple antipsychotics prior to clozapine. Reports suggest that most patients who are taken off clozapine and prescribed a different antipsychotic will experience symptom relapse ⁽³⁾.

The alternative to switching antipsychotics is to restart, or rechallenge, the patient on clozapine. A rechallenge can pose significant risks, as patients may reexperience neutropenia, which is often more rapid and longer-lasting the second time around (4). A recurrence of neutropenia has been shown to occur in somewhere between 30 percent to 40 percent of rechallenged patients ^{(4, 5)}, with older patients and patients who experienced neutropenia early in the course of the initial clozapine treatment more likely to have an unsuccessful rechallenge ⁽⁶⁾.

Before restarting a patient on clozapine, there are several questions about the patient a physician ought to consider:

• Were there other factors that could have caused neutropenia in the patient, such as an infection, chemotherapy, or other medications such as lamotrigine or penicillin G?

• Did the patient experience a benefit from the clozapine before the onset of neutropenia?

• Does the patient and (if applicable) the patient’s support system feel that the benefits greatly outweigh the risks of rechallenge?

While clozapine can be reintroduced by itself after neutropenia resolves, augmentation of clozapine with lithium is a strategy that has been attempted with some success. A meta-analysis of case reports identified a 94 percent success rate when patients with a history of neutropenia were rechallenged with clozapine plus lithium ⁽⁷⁾. It should be noted that lithium is not entirely protective against agranulocytosis, as there have been several failed cases reported in the literature ⁽⁵⁾.

Once a patient is successfully reintroduced and stabilized on clozapine, a physician must consider whether to discontinue the lithium—which also has its own renal, thyroid, and neurological side effects. Lithium combined with clozapine likely does not offer any additional benefits in terms of symptom reduction for people with treatment-resistant schizophrenia ⁽⁸⁾. Nonetheless, a literature analysis I recently conducted with colleagues suggests that lithium discontinuation in rechallenged patients should be avoided ⁽⁹⁾.

We identified limited reports of lithium discontinuation, but among all cases, stopping lithium resulted in the development of neutropenia or agranulocytosis within 35 days on average. Several of the instances were severe, including one patient who died due to complications from infection. The quick time to neutropenia relapse points to a possible masking effect for lithium—that is, the drug is increasing the ANC through demargination (inducing existing white blood cells attached to blood vessels to re-enter circulation) and not stopping the myelosuppressive effect of clozapine.

Given the limited reports on this topic, I believe we need more prescribers to provide reports on their clozapine rechallenge experiences, either successful or unsuccessful. There also needs to be more research to better understand the hematological effects of both lithium and clozapine, so we may better understand the safest strategies for rechallenging clozapine after neutropenia. ■