Clozapine therapy, what to do when an "absolute indication" is coupled with a strong "contraindication"?

An interesting case study published in Hindawi journal by Neill et al. showcases a rare case of late-onset neutropenia (after 14 years) in a clozapine user, that was managed by filgrastim. The challenging aspects were that no other antipsychotic could manage her refractory schizophrenia besides clozapine, but neutropenia occurred every time a clozapine challenge was tried.

Treatment-resistant schizophrenia is an enduring and challenging illness which affects about one-third of the patients with schizophrenia (SCZ). Clozapine has become the gold standard in patients with treatment-resistant schizophrenia.

Clozapine's ability to work on various molecular targets, (which includes acting on 5HT2A, a1-adrenergic, muscarinic, D1, and D2 receptors), has the advantage of improving efficacy and reliability in treating psychosis when compared with more classic treatments. But it is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures.

Neutropenia is the most common life threatening side effect of clozapine use, and an absolute neutrophil count (ANC) of less than 1500/mm can result in increased chances of infection. Such side effects necessitate close monitoring of blood results. The incidence of agranulocytosis and neutropenia is the highest within the first 6-18 weeks of commencing clozapine. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine etc. Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine induced neutropenia. Filgrastim works most effectively when prescribed prophylactically, and there is limited data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia.

The index patient here was diagnosed with SCZ at the age of 26 years. She was started on clozapine in that same year following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes.

At 41-year of age with she was admitted to an acute mental health unit due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia with an ANC of less than 0:5 × 10^9 /L. Deterioration in her mental state began to manifest from day 5 post clozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep.

All the other investigations including blood picture, urine samples, full viral and autoimmune work-up revealed no abnormalities. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained  which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.

Patient remained neutropenic for many weeks. To correct her white blood cell (WBC) count filgrastim, G-CSF (Neupogen) 30MU was prescribed. This resulted in a WBC which increased from 3:4 × 10 9 /L to 6:5 × 10 9 /L and ANC which increased from 1:78 × 10 9 /L to 4:8 × 10 9 /L one day later. One month post treatment with Neupogen, the patient's white cells fell once again to 2.4 with ANC of 1:64 × 10 9 /L which required a further dose of filgrastim.

Lithium 800mg once daily, was started a month later, that seemed to result in an improvement in patient's leukocyte count averaging between 3:3 × 10 9 /L and 4:4 × 10 9 /L. Initially, clozapine rechallenge was avoided but combination antipsychotic treatment proved to be ineffective, and the patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while patient remained an in-patient. The patient responded well to clozapine rechallenge. Unfortunately, clozapine use continued to cause recurrent neutropenic results. Discontinuation of clozapine consequently led to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.

A filgrastim treatment protocol was created for the patient as part of a multidisciplinary approach. A biweekly prophylactic use of filgrastim was initiated. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment could be achieved.

Currently, patient is on biweekly filgrastim prophylactically in combination with lithium and is maintaining well with white cell and neutrophil count in an acceptable range and has thus far facilitated continuous use of clozapine over the past 6-months approximately. With sustained and uninterrupted clozapine treatment, the patient's mental state has stabilized with mild residual symptoms.

Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count.

Source: Hindawi Case reports: Eimear O' Neill, Deirdre Carolan, Sarah Kennedy, Sandra Barry, "Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF", Case Reports in Psychiatry, vol. 2021, Article ID 6640681, 5 pages, 2021. https://doi.org/10.1155/2021/6640681