Abstract
To the Editor:
It is not clear whether patients who are susceptible to developing blood dyscrasias with certain atypical antipsychotics will develop this adverse effect from all of the atypical antipsychotics. There are many case reports of drug-induced neutropenia from atypical antipsychotics in which human leucocyte antigen (HLA) testing was performed (Whalen et al. 2011). The results found variations in HLA typing among patients taking the same drug. However, there were no trends to determine a common variable among the different atypical antipsychotics to warrant HLA typing (Buchman et al. 2001).
Genetic testing to determine which patients may be more susceptible to clozapine-induced agranulocytosis is progressing, but is still not available in a clinical setting (Chowdhury 2011). Athanasiou et al. (2011) found a sequence variant (6672G>C) in HLA-DQB1 that is associated with an increased risk for clozapine-induced agranulocytosis.
Among the atypical antipsychotics, there are different structural classes. Clozapine (Clozaril), quetiapine (Seroquel), olanzapine (Zyprexa) and the newer asenapine (Saphris), are in the same chemical class, dibenzo-oxepino pyrrole (Hussar and Abbas 2010). Aripiprazole (Abilify) is in its own class, dihydroquinolinone. The third chemical class is the benzisoxazoles, including risperidone (Risperdal), ziprasidone (Geodon), paliperidone (Invega, active isomer of risperidone), and iloperidone (Fanapt) (Hussar and Abbas 2010). Patients who experience blood dyscrasias from an antipsychotic are more likely to experience a blood dyscrasia from another antipsychotic in the same chemical class.
Case Report
The patient is a 12-year-old with paranoid schizophrenia and a probable case of congenital rubella syndrome (CRS), marked by rubella retinopathy; mild hearing deficits; and diffuse damage to both parietal, temporal, and frontal lobes; as well as mildly enlarged ventricles. Approximately 50% of those with CRS develop schizophrenia, and many are psychotic in early childhood (Vernon 1969; Chess et al. 1971; Brown and Susser 2002). The patient also has bilateral vitiligo, an autoimmune disorder of the melanocytes.
The patient is an intelligent child, and when not tortured with hallucinations, is very verbal and pleasant. She has had atypical behaviors, including an exaggerated startle response and fits of screaming, from birth. As a toddler, her odd behaviors continued and she developed multiple imaginary friends and frequently told her parents that they were not her parents, the neighbors were. She has had an individualized education plan (IEP) since preschool for vision, motor, and social difficulties. She was placed on home instruction in the middle of her fifth-grade year when she heard voices commanding her to get on the wrong bus and insisted her schoolmates were taunting her over the loudspeakers in the lunch room and in person, among other hallucinations. She was placed on aripiprazole. She was hospitalized when she saw and heard her bus driver commanding her to kill herself, before the bus driver killed her, and indeed thought the bus driver had already run over her and other children with the bus many times. When not well controlled with antipsychotics, she hears voices that tell her to hurl herself into traffic, and has attempted to do so twice.
She was placed on a series of antipsychotics (aripiprazole, perphenazine, risperidone, thorazine) all of which were either eventually ineffective or caused undesirable side effects such as oral-mandibular/buccal-lingual syndrome. She was subsequently placed on clozapine, and experienced good control of her symptoms and an increase in positive affect. Prior to the clozapine she had been receiving 300 mg of chlorpromazine, 5 mg of escitalopram, and 200 mg of bupropion. The escitalopram and bupropion remained constant throughout the trials of antipsychotics described in this case report.
She developed what was thought to be clozapine-induced neutropenia and leucopenia, and clozapine was discontinued in accordance with the label. A re-challenge with clozapine ended with the same result, and she was placed back on chlorpromazine and then switched to olanzapine, as she had a history of trying to bolt into traffic while on chlorpromazine. Her white blood cell (WBC) counts and absolute neutrophil counts (ANC) were within the normal range when clozapine was begun and slowly increased until the 8th week of dosing, when her WBC and ANC abruptly decreased (Fig. 1).
Absolute neutrophil count (ANC) versus time and antipsychotic. The white blood cell (WBC) count followed the same pattern.
Olanzapine was thought to have the closest efficacy to that of clozapine, but without the risk of agranulocytosis. Therefore, the patient was started on olanzapine after clozapine was discontinued. However, she also developed neutropenia and leucopenia on olanzapine: therefore, olanzpine treatment was discontinued. She was then started on quetiapine. Quetiapine had to be discontinued when she once again developed leucopenia, and she was placed on ziprasidone.
While taking ziprasidone, her WBC and ANC stayed within acceptable ranges. During the 4th and 5th weeks on ziprasidone, however, her WBC and ANC continued to decrease, and the hematology department was consulted. At first, the hematologist thought that the patient's decreased WBC and ANC was drug induced (Thome and Kopf 2005; Montgomery 2006). After further study over several months, the hematologist concluded that the patient's decreased WBC and ANC was most likely an autoimmune response, possibly unrelated to the antipsychotics, and perhaps related to her history of vitiligo, a known autoimmune disorder. The hematologist was comfortable restarting the patient on quetiapine, which had proven to work well for her. The patient's schizophrenia improved over the following several months while she was taking quetiapine, but was still not well controlled.
After 1 year of observations, the hematologist was confident that the patient's periodic decreases in WBC and ANC neutrophils-μL were not related to any of the medications she was taking. More than 1 year after her last clozapine trial, the patient restarted clozapine under the care of both her psychiatrist and the hematologist. Over the 6 month period of the patient's third trial on clozapine, her WBC and ANC have ranged from 1500 to 5600. The decreases in WBC and ANC occurred at random. An increase in patient's ANC>3000 was related to a cold or sinus infection, indicating that her immune system was responding appropriately.
Discussion
Although a diurnal variation in WBC and ANC has been reported (Ahokas and Elonen 1999), attributing a patient's sudden decrease in WBC and ANC solely to a diurnal variation is not supported by the data. This patient experienced some high results in the mornings and low results in the afternoons, indicating that the sudden decrease in WBC and ANC were not solely caused by diurnal variation. Another possible cause of neutropenia is benign ethnic neutropenia, which is common in those of African descent and is one of the major reasons clozapine is discontinued unnecessarily in this population (Kreyenbuhl 2007). Benign ethnic neutropenia tends to be less recognized in the United States than in other countries.
At first, this patient's WBC and ANC decreases appeared to be induced first by clozapine and then by subsequent atypical antipsychotics. The data in Figure 1 clearly show a decrease in WBC and ANC over the short term (≤6 weeks). However, study over a much longer period of time (≥12 months), demonstrated that the patient's ANC fluctuated from 1500 to 3000 when she was well and from 3000 to 5600 when she was unwell. The hematologist determined that the patient's neutropenia was most likely related to immune dysregulation secondary to congenital rubella.
Conclusions
The authors conclude that any child who demonstrates a decrease in WBC and ANC while being prescribed an atypical antipsychotic should be monitored for a prolonged period of time to see if there is a relationship with any of the medications the child is taking to control the psychotic illness. It would also be beneficial, if possible, to collect weekly baseline WBC and ANC over 4–6 weeks to document the child's natural WBC and ANC fluctuations. This approach, combined with a hematology consultation if warranted, might prevent having to abruptly discontinue an antipsychotic that is helping a child. In addition, the reluctance to administer clozapine to children, even when there is limited or no response to other antipsychotics, is perhaps unwarranted, as the risk of agranulocytosis is no higher than the rate seen in adults (Gerbino-Rosen et al., 2005). Physicians of congenital rubella patients should be alerted to the possibility of immune dysregulation as a cause of their patient's neutropenia.
Clinical Significance
The depression of the child's WBC and ANC in conjunction with antipsychotic use was noticed only because of the ongoing monitoring required by the clozapine registry. A depression in WBC and ANC may have many different causes and may not lead to agranulocytosis.
Footnotes
Acknowledgments
We thank Dr. Cheryl Pikora for her assistance with the literature search and Dr. Punam Malik for her hematology consultations.
Disclosures
Neither Dr. Wilson nor Dr. Offenberger had any financial support of any kind or any affiliation with any pharmaceutical company. This work consists of a case report of one patient, who is the daughter of Dr. Wilson. The work consists of an analysis of hematology data in relationship to antipsychotics administered to treat the child's paranoid schizophrenia.