Morning pseudoneutropenia during risperidone treatment

Abstract

Risperidone, an atypical antipsychotic drug, is associated with neutropenia in some individuals. When the absolute neutrophil count falls below 1.8×10⁹/l clinicians may consider switching the drug. We report the case of a young man who developed neutropenia while on risperidone and also showed a pronounced diurnal variation, with normal neutrophil counts later in the day. Hence neutrophil counts should be measured in the afternoon sample before making modifications to the therapeutic agent based only on a early morning sample.

BACKGROUND

Antipsychotic medication came to be the mainstay of controlling symptoms and improving quality of life in patients suffering from schizophrenia.¹ These agents are associated with side effects, commonly tolerable if not entirely benign, but significant enough at times with severe and even life threatening consequences. It is often a clinical dilemma when a particular medication helps control schizophrenia but causes troublesome side effects.

Among the many side effects potentially caused by antipsychotics, haematological side effects are one of the most worrying, often persuading the clinician to discontinue the offending medication and frequently leading to avoidance of the same agent in that particular patient.

Besides transient and persistent side effects, an entity called “morning pseudoneutropenia” exists.² This refers to a decrease in absolute neutrophil count in the mornings and an increase in neutrophil counts later in the same day. Although the reasons for such a change in neutrophil count within 1 day are not entirely clear, it is thought to be due to the effect of circadian rhythm.

Circulating blood cells show circadian rhythm even in healthy people.³ As in the diurnal variations of cortisol production, granulocyte colony stimulating factor (GCSF) is also known to display a clear pattern. Concentrations of GCSF increase continuously from their low at 08.00 h to their peak at 10.00 h, with individual differences between highest level and lowest level averaging 54%.⁴ Risperidone, an atypical antipsychotic, is associated with neutropenia.^2,5 Neutropenia is empirically defined as an absolute neutrophil count of <1.5×10⁹/l. Levels below this are regarded as abnormal irrespective of age or ethnicity.⁶

Neutropenia may range from a transient phenomenon, which may dissipate without necessitating any changes to medication or doses, to an impending agranulocytosis. It is of clinical importance to be able to differentiate between these two scenarios in order to be able to decide whether to continue treatment with the current medication.

CASE PRESENTATION

A 25-year-old man of mixed Asian and African origin was admitted to hospital with a diagnosis of paranoid schizophrenia and depression. He was started on olanzapine in July 2007 and as there was no improvement of symptoms after a full therapeutic trial, his medication was changed to risperidone in November 2007. Due to the severity of his symptoms and poor response at low dosage, risperidone was gradually built up to 8 mg twice daily. As there was not much improvement in his symptoms despite a 3 month trial, it was decided to start him on clozapine.

A pre-clozapine check up, including blood test, electrocardiogram and physical examination, was undertaken in April 2008. He was on risperidone 8 mg twice daily at the time of the pre-clozapine check up. His blood test from a sample taken at 09.00 h showed a white cell count (WCC) of 2.8 5×10⁹/l and a neutrophil count of 1.6×10⁹/l. Due to the marginal count of neutrophils the blood test was repeated in 4 days; it happened to be an afternoon sample which showed a WCC of 3.6×10⁹/l and neutrophil count of 2.1×10⁹/l.

Due to the pronounced variation in the neutrophil counts and considering the timing of the previous samples, blood tests were repeated both at 09:00 h and 15:00 h, both on the same day and on different days, a total of seven times over a 4 week period. The patient was continued on risperidone during this 4 week period. His neutrophil counts were consistently between 1.3–1.8×10⁹/l in the morning sample and between 1.7–2.2×10⁹/l in the afternoon sample. Respective ranges for the WCC were between 2.8–3.4×10⁹/ in the morning and 3.0–3.6×10⁹/l in the afternoon, suggesting morning pseudoneutropenia.

Apart from risperidone, the patient was also on fluoxetine, senna, buscopan, procyclidine and peppermint oil. Physical examination, medical history, and baseline laboratory investigations did not show any other cause for the pseudoneutropenia, and he did not have any symptoms due to the low neutrophil count. A blood test (morning sample) done 12 months before starting him on risperidone showed a normal WCC of 4.3 ×10⁹/L and a neutrophil count of 2.84×10⁹/l.

OUTCOME AND FOLLOW-UP

The risperidone dose was gradually reduced and subsequently stopped. Repeat full blood counts after stopping risperidone showed a neutrophil count within normal range.

DISCUSSION

Good practice suggests that patients receiving antipsychotic medication are monitored on a regular basis in order to identify possible harmful side effects early on. This provides an opportunity to discuss modifications to the therapeutic regimen. The prevalence of pseudoneutropenia is high in some ethnic groups.⁶ Monitoring of the haematopoietic system is important due to the seriousness of rare but potentially fatal agranulocytosis or neutropenia. However, in our opinion it is also important to be aware of diurnal variations in absolute neutrophil count and the ethnic origin of the patient so as not to deny clinical benefit.

LEARNING POINTS

• Patients on antipsychotic medication should be monitored on a regular basis for side effects.

• The patient’s ethnicity should be considered while interpreting results for neutropenia.

• Diurnal variations in neutrophil count should be ruled out before making a diagnosis of neutropenia.