Because of the lack of literature regarding long-term therapy, it is recommended to consider short-term treatment with filgrastim to normalize ANC after a severe drop in a symptomatic patient. Physicians also must consider the potential barriers to filgrastim treatment including adverse effects, such as allergic reactions, bone pain, and thrombocytopenia, and high cost.
Adjunctive lithium
Lithium could cause leukocytosis, which could balance neutropenia induced by clozapine. One of the largest studies evaluating lithium therapy with clozapine-induced neutropenia and agranulocytosis studied 25 patients taking clozapine with a previous “red result” (WBC <3,000/μL, ANC <1,500/μL, or platelets <50,000/μL).3 Lithium treatment was started before or simultaneously with the reinitiation of clozapine in most patients; the remaining patients started treatment at a later date. Only 1 of 25 patients experienced a repeat “red result.” The average lithium level was 0.54 mEq/L.
It is important to remember that initiating adjunctive lithium carries risk. Adverse effects include gastrointestinal upset, tremors, polyuria, polydipsia, and nephrotoxicity.
Additionally, there is risk that lithium simply masks the preliminary states of neutropenia leading to a more severe agranulocytosis without warning.3 Again, the mechanism of action of clozapine-induced neutropenia is thought to be related to the drug’s effect on WBC precursors. The mechanism of lithium-induced leukocytosis is unknown, therefore it’s possible that lithium will not protect a patient from clozapine-induced neutropenia or agranulocytosis, and can lead to serious adverse events.
When deciding whether to rechallenge a patient on clozapine who had a prior episode of moderate or severe neutropenia or agranulocytosis, a risk vs benefit discussion is necessary. One study found that 20 of 53 patients (38%) experienced a repeat dyscrasia when rechallenged.5 Of these patients, most experienced a lower ANC that presented faster and took longer to resolve.5 If a patient has experienced true agranulocytosis, the recommendation is to not rechallenge clozapine.
Related Resources
• Clozapine REMS Program. www.clozapinerems.com.
• Newman BM, Newman WJ. Rediscovering clozapine: adverse effects develop—what should you do now? Current Psychiatry. 2016;15(8):40-46,48,49.
• Whiskey E, Taylor D. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs. 2007;21(1):25-35.
Drug Brand Names
Atorvastatin • Lipitor
Chlorpromazine • Thorazine
Clozapine • Clozaril
Fligrastim • Neupogen
Lisinopril • Prinivil
Lithium • Eskalith, Lithobid
Omeprazole • Prilosec