Antiepileptic drugs reduce vitamin B₁₂ and folate levels

Commonly used antiepileptic drugs (AEDs) can cause vitamin B₁₂ or folate deficiency, which is, in turn, associated with hyperhomocysteinemia, new research published in Annals of Neurology has found. “Most AEDs, including the newer ones, were associated with reduced blood levels of folate and vitamin B₁₂,” says Michael Linnebank from University Hospital Zurich, Switzerland. “Only levetiracetam and benzodiazepines were without any association with folate or vitamin B₁₂ parameters.”

AEDs are used to control epileptic seizures, as well as some psychiatric disorders and pain syndromes. The drugs are associated with a number of adverse effects. Previous studies have suggested that reductions in serum levels of folate and vitamin B₁₂—cofactors that are crucial in the biochemical conversion of the neurotoxic amino acid homocysteine—are a result of AED therapy and could mediate these negative effects.

Linnebank and colleagues analyzed routine laboratory results from 2,900 patients with epilepsy (2,730 treated with one or more of a wide range of AEDs, including valproate, gabapentin and phenytoin, and 170 not treated with AEDs) at the University Hospital Bonn in Germany, and compared them with 200 healthy individuals as controls. Of the patients who were treated with AEDs, 958 received AED monotherapy and 1,772 were treated with two or more AEDs in combination.

Overall, the AED group had a higher frequency of subnormal serum folate levels than untreated patients or controls. Although the frequency of subnormal vitamin B₁₂ levels did not differ between the study groups, treatment with phenobarbital, pregabalin, primidone and topiramate led to reduced serum levels of vitamin B₁₂. Subnormal folate and vitamin B₁₂ levels were associated with increased plasma levels of homocysteine, as well as increased mean corpuscular volume. Moreover, oral vitamin B₁₂ and folate supplementation normalized vitamin and homocysteine plasma levels and restored the mean corpuscular volume.

Linnebank recommends that patients treated with AEDs should have their serum levels of folate and vitamin B₁₂ closely monitored, or should receive prophylactic vitamin supplementation while receiving AED therapy. AED use during pregnancy is a particular concern for Linnebank, and he indicates that folate prophylaxis and sufficient vitamin B₁₂ intake seems especially important in women of child-bearing age who are taking AEDs. The study authors now plan to investigate the genetic and nutritional factors that underlie folate and vitamin B₁₂ deficiency in patients treated with AEDs. “We will also analyze to what extent folate, vitamin B₁₂ and homocysteine levels influence neuropsychological performance and seizure frequency of patients,” Linnebank explains.