Antiepileptic drug-induced psychosis associated with MTHFR C677T: a case report

Various antiepileptic drugs can potentially cause psychiatric side effects in patients with epilepsy, but the precise mechanism of these actions remains unknown. In recent years, the common polymorphism C677T in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has attracted attention for its role in the onset of psychiatric diseases. MTHFR and several vitamins (as cofactors) are crucial for remethylation of homocysteine via folate and homocysteine metabolism. We report a case of a Japanese patient who presented with reversible schizophrenia-like symptoms during antiepileptic drug therapy.

Our patient had frontal lobe epilepsy and had been treated with several antiepileptic drugs since the age of 13 years. He developed auditory hallucinations and multiple personalities at 17 years of age, several months after the initiation of phenytoin and phenobarbital, despite these antiepileptic drugs being used within the therapeutic ranges. Genetic analysis revealed that he was homozygous for the C677T polymorphism of MTHFR. Hyperhomocysteinemia, hypomethionemia, and multiple vitamin deficiencies, including folate, riboflavin, and pyridoxal, were identified at the age of 23 years. Vitamin supplementation and alteration of the antiepileptic drugs improved his psychotic symptoms. Multiple vitamin deficiencies with homozygous MTHFR C677T should be considered in patients presenting with schizophrenia-like symptoms during antiepileptic drug therapy.

To the best of our knowledge, this is the first report of antiepileptic drug-induced psychosis associated with homozygous C677T and multiple vitamin deficiencies. Our findings will contribute to the elucidation of the pathogenesis of the psychiatric side effects of antiepileptic drugs and lead to improved medical management for patients with epilepsy.