Aripiprazole is a third-generation atypical antipsychotic medication that was first approved by the U.S. Food and Drug Administration (FDA) in 2002 for the treatment of acute episodes and maintenance of schizophrenia in adults (Squibb, 2012). Subsequently, approvals have expanded to include pediatric and adolescent indications, and it is widely used in adults, children, and adolescents due to the efficacy and tolerability in these populations (Pae, 2009). Nevertheless, side effects must be considered when aripiprazole is prescribed.
Aripiprazole is indicated for the long- and short-term treatment of schizophrenia and schizoaffective disorder (Otsuka America Pharmaceutical, Inc., 2014; Pae, 2009). It has also been reported as an adjunct medication or monotherapy for acute manic episode and maintenance treatment of bipolar disorder in adults (Pae, 2009). Aripiprazole is used for agitation associated with bipolar disorder and schizophrenia, and can be used for augmentation purposes in the treatment of major depressive disorder (Pae, 2009). The FDA has approved aripiprazole for treating irritability in children 6 years and older and adolescents with autism spectrum disorder (Penfold et al., 2013). In addition, it has been approved for adolescents ages 13 to 17 with schizophrenia and children ages 10 to 17 with bipolar disorder (Penfold et al., 2013). Aripiprazole is frequently used off-label to treat aggressive and self-injurious behaviors in children and adolescents, especially in those with developmental disabilities (Penfold et al., 2013). It is also used off-label for treatment of attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, Tourette's disorder, conduct disorder, and posttraumatic stress disorder (Penfold et al., 2013).
Mechanism of Action
Aripiprazole has a unique psychopharmacological profile with an intrinsic high receptor affinity for dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A receptors (Pae, 2009). It acts as a partial agonist at pre- and post-synaptic D2 receptors and serotonin 5-HT1A receptors (Elbe, Bezchlibnyk-Butler, Virani, & Procyshyn, 2015). The net effect of dopamine partial agonism depends on the hypo- or hyperdopaminergic state in the brain (Elbe et al., 2015). In the area of decreased dopaminergic activity, the net effect results in enhancing the overall dopaminergic activity and maintaining the chemical balance; conversely, it leads to a net decrease in dopaminergic activity in areas of the hyperdopaminergic state (Elbe et al., 2015). This partial agonism at D2 receptors and antagonism of 5HT2A receptors in the tuberoinfundibular pathway explain the lack of significant hyperprolactinemia (Elbe et al., 2015). In addition, aripiprazole has a moderate affinity for histamine H1 receptors and alpha-1 adrenergic receptors, resulting in somnolence, postural hypotension, and reflex tachycardia (Elbe et al., 2015). Aripiprazole also has a moderate affinity for 5HT2C receptors as a partial agonist, resulting in a lesser risk of weight gain, and it does not affect the muscarinic receptors (Elbe et al., 2015).
The most common adverse effects of aripiprazole include headache, insomnia, agitation, nervousness, light-headedness, dizziness, somnolence, and akathisia (Marder et al., 2003). These side effects are usually transient and gradually improve during the first week of treatment (Marder et al., 2003), which enhances the importance of psychoeducation for aripiprazole-induced side effects. Weight gain is less frequent than other second-generation antipsychotic medications (Elbe et al., 2015). Rarely, aripiprazole has been reported to cause neutropenia (Marder et al., 2003). Leukopenia and neutropenia are associated with a range of antipsychotic, mood stabilizer, and selective serotonin reuptake inhibitor medications (Elbe et al., 2015). Previous reports have described clozapine carrying the highest risk of neutropenia (3%) among adults in Western countries (Copolov et al., 1998; Marder et al., 2003). Several case reports have been published regarding neutropenia associated with risperidone (Sluys, Güzelcan, Casteelen, & de Haan, 2004), olanzapine (Gajwani & Tesar, 2000; Kodesh, Finkel, Lerner, Kretzmer, & Sigal, 2001), quetiapine (Cowan & Oakley, 2007), and ziprasidone (Montgomery, 2006), but sufficient data regarding the association of neutropenia with aripiprazole are still lacking. In a review article by Sagreiya et al. (2017), neutropenia was not reported among the most common side effects observed with aripiprazole. A case of neutropenia associated with the use of aripiprazole in a 10-year-old African American boy is presented.
A 10-year-old African American boy with aripiprazole-induced neutropenia was admitted to the inpatient psychiatric hospital for worsening of physical aggression at school and home, property destruction, and suicidal and homicidal threats. The patient had a long-standing history of irritability, physical aggression, and property destruction. He would make suicidal and homicidal threats during these anger outbursts. Before hospitalization, he eloped from school twice, requiring intervention by law enforcement officials. Without medication, inattentive, hyperactive, and impulsive behaviors were also reported. He has required multiple psychiatric hospitalizations and one intensive outpatient admission for his behaviors. The patient was diagnosed with ADHD and oppositional defiant disorder at admission. His home medications included guanfacine extended release (ER) 2 mg twice per day and aripiprazole 2 mg in the morning, with partial benefit. He was taking these medications approximately 1 year prior to admission.
After obtaining collateral information, aripiprazole was titrated to 5 mg to target aggression and irritability. Aggression improved with an increase in aripiprazole, and the patient denied any adverse effect from this medication titration. His complete blood cell (CBC) count revealed a white blood cell (WBC) count of 3,300 cells/µL and low absolute neutrophil count (ANC) of 1,092 cells/µL. A repeat CBC revealed similar findings, with a WBC count of 3,400 cells/µL and low ANC of 1,034 cells/µL. Physical examination at admission and the rest of the laboratory workup were unremarkable for any underlying illnesses. The patient's guardian was advised at discharge to follow up with the outpatient psychiatrist and pediatrician regarding possible drug-induced neutropenia.
The outpatient psychiatrist decided to taper aripiprazole due to concerns regarding drug-induced neutropenia and weight gain. The dose of aripiprazole was decreased to 3 mg per day, resulting in worsening physical aggression, property destruction, and suicidal comments, and led to readmission to the inpatient psychiatric facility. On admission, the patient was taking aripiprazole 3 mg and guanfacine hydrochloride ER 2 mg twice per day. Admission CBC revealed an ANC within normal limits and a slightly low WBC count of 4,200 cells/µL on lower doses of aripiprazole. Aripiprazole was discontinued, and lurasidone hydrochloride 20 mg in the evening with 350 calories (i.e., taken with food) was initiated. The patient tolerated this medication change without any side effects. Unfortunately, no baseline WBC values were available.
There is a paucity of evidence for aripiprazole-induced neutropenia in the published literature and by the drug manufacturer, suggesting this is a rare adverse drug reaction. The decrease in WBC count and ANC with the increase in dose and improvement with discontinuation suggest a possible temporal and causal relationship. The exact pathophysiology of antipsychotic drug-induced neutropenia is still unclear, but some of the implicated mechanisms can include direct toxic effect, immune reactions, and peripheral destruction of cells (Flanagan & Dunk, 2008).
Existing Literature for Aripiprazole-Induced Neutropenia
Kimura et al. (2015) used the FDA Adverse Event Reporting System (FAERS) database to assess serious side effects caused by antipsychotic medications in children. The signal scores for antipsychotic-induced neutropenia were higher for quetiapine, clozapine, and risperidone; the association between aripiprazole and neutropenia was insignificant, but two occurrences of neutropenia in patients taking aripiprazole were reported (Kimura et al., 2015). A study by Tomita et al. (2017) evaluated the effect of chlorpromazine equivalent (CPZe) doses on WBC count, concluding that the combination of aripiprazole and quetiapine with CPZe >1,000 mg has a higher risk of neutropenia. The association between aripiprazole and neutropenia was insignificant, but the authors reported two occurrences of neutropenia in patients taking aripiprazole (Tomita et al., 2017).
A literature search revealed three case reports of adults and one case of a child describing the association of neutropenia with the use of aripiprazole. The first case was reported in a 50-year-old Caucasian woman who developed neutropenia after taking aripiprazole 15 mg per day for 5 days (Lander & Bastiampillai, 2011). The neutropenia was monitored for the next 4 days without any improvement. Ultimately, aripiprazole was discontinued, resulting in the normalization of WBC count and ANC. Antipsychotic-induced neutropenia was also observed in this patient with risperidone, quetiapine, and olanzapine (Lander & Bastiampillai, 2011).
In a 21-year-old Asian man, the drop in WBC and ANC was observed after he was taken off lithium and aripiprazole was continued (Lim, Park, & Park, 2013). The values for WBC and ANC returned to normal after the discontinuation of aripiprazole. Similar results were reported in a 32-year African American man who was started on aripiprazole to treat schizophrenia, and the discontinuation of aripiprazole resulted in the normalization of WBC count and ANC (Qureshi & Rubin, 2008). Majeed and Ali (2017) published the first case study to report neutropenia with aripiprazole use in an African American 7-year-old boy. Notably, the case report by Majeed and Ali (2017) and the current case report had African American pediatric patients, making the race an important confounder. It has been suggested that African American individuals have lower WBC counts due to increased margination (Gajwani & Tesar, 2000), potentially contributing to blood dyscrasia is this race.
Conclusion and Future Lessons
The current case study warrants further investigation into the risk of blood dyscrasia related to aripiprazole therapy. This risk might be due to some genetic vulnerability among African American individuals or cross-reactivity between certain second-generation antipsychotic medications with respect to blood dyscrasias. The potential for neutropenia has been observed in patients treated with clozapine, olanzapine, and quetiapine (Lander & Bastiampillai, 2011). These medications may share a similar mechanism considering their structural similarities (Lander & Bastiampillai, 2011); however, aripiprazole has a different chemical structure, implicating other factors in the development of this pathology (Lander & Bastiampillai, 2011).
Although it is a rare side effect, clinicians should be aware of the potentially life-threatening effects of neutropenia, requiring the cautious monitoring of WBC count in children and adolescents taking antipsychotic medications such as aripiprazole. Monitoring the WBC count is especially important if the patient has a history of leukopenia and/or neutropenia associated with antipsychotic medication use.
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