Neutropenia Following Use of Haloperidol and Paliperidone Palmitate

Neutropenia (absolute neutrophil count [ANC] <1,500/mm³) and agranulocytosis (ANC <500/µL) have been well defined in the literature as rare but serious side effects of initiating antipsychotic therapy (1, 2). The antipsychotic most known for inducing neutropenia and agranulocytosis is clozapine, with reported incidence rates of 1%–2% (3). Consequently, the current standard of care when initiating clozapine requires weekly complete blood counts (CBCs) for the first 6 months, then biweekly CBCs for the next 6 months to monitor ANC levels (4). There are reported cases of patients developing neutropenia after initiating other antipsychotics, including paliperidone palmitate extended-release injection and haloperidol, but there is no standard of care for monitoring ANC with these medications (5–8). Although the incidence of neutropenia is lower with paliperidone palmitate and haloperidol, psychiatrists should be aware of this potential side effect when initiating use of these medications with their patients.

Here, we describe the case of a patient with a diagnosis of schizophrenia who developed neutropenia first while taking paliperidone palmitate and later while taking haloperidol. He was subsequently started on lithium to correct his neutrophil count, which improved in both instances.

Case Presentation

A 24-year-old man with diagnoses of schizophrenia and severe cannabis use disorder was transitioned to long-acting injectable paliperidone palmitate because of progressive psychotic symptoms and nonadherence to previously prescribed risperidone. The patient received the first two loading doses (234 mg followed by 156 mg a week later) without any issues and planned to follow up monthly to receive paliperidone palmitate 156 mg intramuscularly. At follow-up 2 months later, the patient reported new-onset fatigue. Laboratory tests revealed neutropenia with a white blood cell (WBC) count of 2.8/mm³ and an ANC of 920/µL. His past medical history, with additional consultation and workup, revealed no additional pathophysiological causes that could predispose him to neutropenia (e.g., no clear autoimmune, infectious, or bone marrow disorder). Paliperidone palmitate was discontinued, and lithium 300 mg at bedtime was started and increased to 600 mg. Two weeks after the initial finding of neutropenia, repeat laboratory tests indicated resolving neutropenia, with the patient’s WBC count and ANC up to 4.0/mm³ and 1,850/µL, respectively.

To control psychotic symptoms, haloperidol was then started at 2.5 mg at bedtime (and slowly increased to 10 mg at bedtime), and lithium was decreased to 300 mg at bedtime. With this regimen, the patient’s psychosis improved, and his neutropenia resolved. He was lost to follow-up until 3 months later when he again presented to the emergency department with psychotic symptoms and nonadherence to the medication regimen. There was no evidence of neutropenia at the time (WBC count: 4.1/mm³; ANC: 2,440/µL), and he was admitted to inpatient psychiatry and restarted on haloperidol 5 mg two times per day, with improvement in his psychotic symptoms. Because of his history of neutropenia while taking paliperidone palmitate, repeat CBCs were drawn after 1 week, which revealed evidence of new-onset haloperidol-induced neutropenia (WBC count: 3.3/mm³; ANC: 1,400/µL).

Haloperidol was discontinued, and lithium was restarted and increased to 450 mg at bedtime. Repeat CBCs 2 weeks later revealed resolving neutropenia, with a WBC count of 4.4/mm³ and an ANC of 2,200/µL. Aripiprazole 5 mg every morning was started, with resolution of the patient’s neutropenia and with plans for him to follow up with CBCs within 4 days after discharge. However, the patient did not return for the follow-up.

Discussion

In this case, the patient developed neutropenia after initially starting paliperidone and again after starting haloperidol. Developing neutropenia after initiation of an antipsychotic is a rare side effect (9–12). According to surveillance data from 1993 to 2016, incidence of neutropenia or agranulocytosis among patients receiving antipsychotic therapy was 0.37% in a study population of 333,175 patients (2). This number reflected the incidence of neutropenia or agranulocytosis among patients taking any antipsychotic medication as well as patients receiving multiple antipsychotic medications (2). It is also rare for a patient to develop neutropenia while taking multiple antipsychotics (13, 14). In the present case report, given the patient’s lack of known medical causes of neutropenia and time course after initiation of each antipsychotic, both instances of neutropenia were likely medication-induced, although it is unclear whether the patient had an underlying predisposition that made him more susceptible to developing neutropenia with both medications.

Neutropenia is mostly known in relation to clozapine, which is the subject of strict clinical guidelines for monitoring a patient’s CBCs with differential. Risperidone and, less commonly, olanzapine and quetiapine have also been linked to neutropenia (12, 15, 16). It has been noted that paliperidone is a metabolite of risperidone, giving mechanistic probability to paliperidone-induced neutropenia (17). Although these findings and the present case indicate that antipsychotics other than clozapine can cause neutropenia, no standard clinical guidelines exist for monitoring CBCs outside of clozapine. Among patients who have taken an antipsychotic in the past and have a known history of developing neutropenia while receiving antipsychotic therapy, it may be prudent to monitor their WBC count when starting them on any new antipsychotic in case they are more susceptible to developing neutropenia again.

Lithium was used as an adjunct to help resolve our patient’s neutropenia. Previous case reports have revealed success with lithium to treat antipsychotic-induced neutropenia (6, 9). Lithium contributes to increased release of hematopoietic growth factors, leading to increased neutrophil production (18). In a previous study, receiving lithium with a rechallenge of the antipsychotic that initially caused neutropenia allowed patients to have effective treatment for their psychiatric symptoms while maintaining a stable ANC (19). In that particular study, the effect was seen only when lithium levels were maintained between 0.8 and 1.1 µg/mL, with the ANC dipping when the lithium level dropped below 0.8 µg/mL (19). Further research is needed to understand the optimal lithium level to maintain this benefit because this is case-level evidence. Given its potential to help resolve antipsychotic-induced neutropenia, further research should be done to understand whether a standard range for lithium levels can be determined. Lastly, future studies could benefit from the investigation of patients who develop neutropenia after starting multiple antipsychotics.

Key Points/Clinical Pearls