To the Editor: Amisulpride, an atypical antipsychotic used in treatment of both positive and negative symptoms of schizophrenia, has a benign adverse-effect profile.¹ Commonly reported adverse effects include dose-related extrapyramidal syndromes, gastrointestinal, and sexual problems.² A summary of product characteristics³ for amisulpride does not report any hematological toxicity. A PubMed search did not reveal any such association. We report a case of macrocytic anemia induced by amisulpride that reversed after discontinuation of the drug.

The patient, a 29-year-old man, diagnosed with paranoid schizophrenia 10 years ago, presented with wandering behavior, suspiciousness, and unprovoked violence. Mental status revealed guarded attitude and constricted affect with grandiose and persecutory delusions. His mother had paranoid schizophrenia. His baseline investigations including complete hemogram; liver and renal function tests were normal. The patient responded to a combination of depot zuclopenthixol injection 200 mg every 3 weeks and olanzapine 7.5 mg/day without any emergent adverse effect. However, because of prominent negative symptoms, olanzapine was discontinued and tablet amisulpride 100 mg/day was added. After 2 months, he reported fatigability and, on examination, pallor was noted. Complete hemogram revealed macrocytic anemia (Hb 4.6 gm/dl; PCV 14.9%; MCV 119.2 fl; MCH 39.2 pg; MCHC 32.9%). There was no history of alcohol abuse, and nutritional status was adequate. His liver and renal function tests were within normal range. A possibility of amisulpride-induced macrocytic anemia was considered and the drug was discontinued, after which the affected hematological parameters normalized. A Naranjo ADR probability scale score of 4 suggested a possible association.⁴

In our case, macrocytic anemia appeared within a few weeks of exposure to amisulpride, which improved after discontinuation of the suspected offending agent. Before initiation of amisulpride, baseline hematological indices were normal. There was no change in dietary intake during this period. Also, no folate or vitamin supplement was prescribed. Therefore, it is possible that amisulpride was the offending agent in our case.

Macrocytic anemia is commonly associated with folate and vitamin B₁₂ deficiency, among others. Besides alcohol, drug-induced causes of macrocytic anemia include sulphasalazine, methotrexate, hydantoins, valproate, and oral contraceptives.^5–8 Although the exact mechanism is not known, folate deficiency, either by inhibition of absorption or interference with metabolism, has been commonly hypothesized.⁸ A similar mechanism is likely to have caused macrocytic anemia in our case.

The recent edition of Meyler’s Side Effects of Psychiatric Drugs⁹ does not list any hematological adverse effects with amisulpride. Thus, our case study exemplifies that rare adverse effects, not previously reported in pre-marketing trials or post-marketing efficacy and safety studies, may occur during clinical use.