Hemolytic anemia potentially associated with aripiprazole

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We report a case of a female patient, aged 48 years, medicated for depressive features with clomipramine 75 mg once/day and bromazepam 6 mg three times/day, with the recent addition (8 weeks at admission time) of aripiprazole 10 mg once/day. She started experiencing fatigue, tachycardia, and paleness (symptoms suggestive of anemia) as well as weight loss and dark-colored urine. She presented with macrocytic anemia (hemoglobin 7.7 g/dL, mean corpuscular volume 108.1 fL), leukocytosis (17.160/L), thrombocytosis (612 x 109/L), and hyperbilirubinemia (total 1.86 mg/dL, direct 0.46 mg/dL). All causes of macrocytic anemia were excluded as well as most common causes for hemolytic anemia: The patient did not present any medical risk factors, rheumatologic, or neoplastic causes; and common drugs were excluded. Aripiprazole was appointed as the most probable cause after a literature search, with the hypothesis of warm-bodies autoimmune reaction-induced hemolytic anemia. Aripiprazole was discontinued (maintaining clomipramine and bromazepam) and a prednisolone cycle (2 mg/kg/day) was initiated with complete remission. Adverse events due to psychiatric drugs are rare but possibly severe (significant cases incidence 1–2/100 000, mortality rate 8–17%). These usually occur during initial stages of treatment and most commonly disappear with discontinuation, and are due to bone marrow direct toxicity, antibody formation aimed at hematopoietic precursors, or peripheral cell destruction.1 The most common events are neutropenia, eosinophilia, and thrombocytopenia (usually of low severity and easily resolved). Less commonly, but more severely, agranulocytosis or aplastic anemia might also occur.1 In regards to the pharmacological class, antipsychotics and carbamazepine are mostly associated with agranulocytosis (<0.1%; higher risk with phenothiazines and clozapine); SSRI have been linked to platelet dysfunction and augmented bleeding risk.1-3 Aripiprazole is the first third-generation atypical antipsychotic and therefore has a better adverse events profile; it is theoretically associated with less extrapyramidal effects, hyperprolactinemia, sedation, and propensity for weight gain, with hematological reactions occurring at an unknown frequency.1, 2 Literature research shows very few cases of autoimmune hemolytic anemia linked to antidepressants or antipsychotics. The US Food and Drug Administration (FDA) labeled leukopenia, neutropenia, and agranulocytosis, and the European Medicines Agency lists leukopenia, neutropenia, and thrombocytopenia as adverse effects associated with aripiprazole. In a 2008 FDA review of aripiprazole's safety profile, three unique cases of hemolytic anemia associated with aripiprazole were identified. There was no recommendation to label this supposed adverse reaction.3 Regarding our case, an apparently under-described and possibly severe reaction, we present the pros and cons of our hypothesis: It may be supported as there are previous reports to the FDA, and there may be an under-notification of this adverse reaction. On the other hand, the notified cases did not establish with certainty this association (one case did not provide enough information and the others might be confounded by the concomitant use of antibiotics and omeprazole in which hemolytic anemia is labeled as an adverse reaction).3 Although currently hemolytic anemia is not an established adverse reaction associated with aripiprazole, to our knowledge, this is the first description of a suspicious case. We believe that this association should be considered, hopefully leading to future notification and search of evidence. This case also reveals how the linkage between different medical specialties is essential and liaison psychiatry is a privileged context for it. The patient has been informed about the importance of reporting this adverse reaction as well as the pertinence of this submission, giving us her consent. The FDA was also contacted and allowed us to use this information. The authors have nothing to disclose; there is no conflict of interest.

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