Zotepine-associated vitamin B12 deficiency and pancytopenia

To the Editor

Among antipsychotic drugs, only clozapine, olanzapine and quetiapine have been associated with pancytopenia. Here, we report the first case of zotepine-associated pancytopenia.

A 46-year-old Asian male with a history of schizophrenia presented because of an exacerbation of psychotic symptoms. He had no medical or family history of note. After treatment with 250 mg/day of zotepine, the patient’s psychotic symptoms were improved, and he was transferred to our chronic ward. However, 16 months later, the complete blood count (CBC) revealed a white blood cell count of 2410 cells/mm³; neutrophils/lymphocytes, 41%/52%; haemoglobin, 8.6 g/dL; mean corpuscular volume, 108.9 fL; and platelet count, 7.1 × 10³/mm³.

The patient was transferred to the haematology unit where laboratory examinations showed serum levels of vitamin B12, 165 pg/mL; folate, 1.5 ng/mL; ferritin, 173 ng/mL; and normal coagulation tests. All other haematological examinations were normal. The patient did not show any signs of malignancy, liver cirrhosis or virus infection. There were no changes in diet, body weight or use of psychotropic drugs. Zotepine was switched to risperidone, and cobalamin and folic acid were administered for 4 weeks. Surprisingly, while the CBC returned to normal limits, the psychotic symptoms became exacerbated. Switching from risperidone back to zotepine led to the recurrence of blood dyscrasia. Therefore, zotepine was continued, and folic acid and vitamin B complex were given, causing a return to normal CBC results.

The score on the Naranjo scale was 6, and the recurrence of pancytopenia on rechallenge supports zotepine as a probable causative factor (Liang et al., 2014). Preliminary evidence suggests that second-generation antipsychotics (SGAs) might decrease the serum levels of vitamin B12 (Misiak et al., 2014) because of the potential of SGAs to increase DNA methylation of several genes, particularly those involved in metabolic homeostasis. As vitamin B12 plays an important role in haematopoiesis, zotepine might decrease the levels of vitamin B12, which in turn contributes to pancytopenia.

Clozapine-associated neutropenia and agranulocytosis might be related to the formation of a nitrenium cation catalysed by the flavin-containing monooxygenase-3 system of leukocytes (Nooijen et al., 2011). Although the mechanism of zotepine-induced pancytopenia is unclear, zotepine might cause bone marrow suppression through similar mechanisms. Moreover, the decreased levels of vitamin B12 by zotepine might further negatively affect haematopoiesis. Importantly, although the patient was still on zotepine, the supplementation of cobalamin and folic acid could normalise the blood dyscrasia. This suggests that zotepine-associated vitamin B12 deficiency and pancytopenia can be reversed by zotepine discontinuation and managed with the supplementation of cobalamin and folic acid.