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New Variant of Serotonin Transporter Gene Said To Improve Prediction of Resistance to Antiepileptics

HURLEY, DAN

doi: 10.1097/01.NT.0000326102.62964.25
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ARTICLE IN BRIEF

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A variant of the serotonin transporter gene nearly triples the risk of drug resistance among patients with mesial temporal lobe epilepsy with hippocampal sclerosis. But experts say the results need to be replicated in other studies.

CHICAGO—A variant of the serotonin transporter gene nearly triples the risk of drug resistance among patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTE-HS), according to findings of a study described here at the AAN meeting in April.

But amid growing concern by epilepsy researchers that other initially promising gene findings have not been confirmed by subsequent studies, even the author of the new study emphasized the need for replication of his results.

“A lot of studies that initially were positive couldn't be duplicated,” said Marcelo Kauffman, MD, a consultant in neurogenetics at the Epilepsy Center of Hospital Ramos Mejía in Buenos Aires, Argentina. “Every positive finding has to be replicated in different populations and by other research teams.”

So concerned are epilepsy researchers about the growing number of genetic association studies reaching discordant conclusions that a Web site has been started with links to all related papers, so that clinicians and academics alike can begin to make sense of them all.

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Findings Difficult to Replicate

“The trouble with these genetic association studies is the replication rate is pretty dismal, with only about one in six getting positively confirmed,” said Nigel C.K. Tan, MRCP, a researcher at the National Neuroscience Institute in Singapore and co-founder of the Epilepsy Genetic Association Database (epiGAD), at epilepsygenes.org.

“So many studies come out contradicting each other,” he said. “We're trying to collect all the studies so anyone interested can look at them all.”

Dr. Tan and his collaborator on his epiGAD site, Samuel F. Berkovic, MD, of the Epilepsy Research Centre at the University of Melbourne in Australia, previously co-authored one of the first major papers failing to confirm a previously reported association. After a study was published to great fanfare in the New England Journal of Medicine in 2003 suggesting that a polymorphism in the drug transporter gene ABCB1 was associated with multidrug resistance in epilepsy, Dr. Tan and Dr. Berkovic reported the next year in Neurology that they could not confirm the association, and suggested that the original findings may have been due to chance.

“Even general neurologists will find they get deluged with papers saying this or that gene is associated with a particular kind of epilepsy,” Dr. Tan said. “They might not be aware of what else is out there. They can get a really skewed view. Now they can visit the Web site, look at the study in the context of the greater whole, and then make up their mind.”

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The Serotonin Transporter Gene

In the current study, Dr. Kauffman sought to follow up on evidence supporting the role of serotonin neurotransmission in epilepsy. Because the serotonin transporter gene could play a biological role in both epileptogenesis and in pharmacoresistance, he decided to test for it in 111 MTE-HS patients stratified according to individual response to antiepileptic drugs.

Homozygous carriers of the polymorphism for the serotonin transporter gene were nearly three times more likely to be refractory than were non-carriers (p=0.0143). Only 29.5 percent of subjects responding to antiepileptic drugs had two copies of the polymorphism, compared to 53.7 percent for those who were refractory. Dr. Kauffman's team estimated that having knowledge of the patient's genotype at the time of diagnosis would improve the accuracy of predicting drug responsiveness from 33 percent to 82 percent.

Given that a number of small studies have suggested that selective serotonin reuptake inhibitors (SSRIs) might reduce the frequency of epileptic seizures, Dr. Kauffman said larger trials should be considered if his genetic association results are confirmed.

Asked whether clinicians might consider prescribing a drug such as fluoxetine in the meanwhile to their drug-resistant epilepsy patients, Dr. Kauffman replied: “Considering that it's an approved drug and is without a high risk for serious adverse events, you could consider it. But in order to know the real effect of this class of drugs, clinical trials are needed.”

Dr. Tan pointed out, however, that not all studies have found a link between serotonin levels and epilepsy. Even so, he said Dr. Kauffman's study is encouraging. “His data are tantalizing. But it would nice to see a second and a third that reproduce it. Then we could say if the association is real.”

Ruth Ottman, PhD, professor of epidemiology in the neurology department and the Sergievsky Center at Columbia University, commented: “Knowing that a patient is going to be resistant to epilepsy medications would be very important.” But, she added: “You have to take each study with a grain of salt and wait until you see a replication until you take it too seriously.”

She urged AAN members to consider reviewing the epiGAD site before allowing themselves to be swayed by any genetic association study. “People have such trouble staying on top of all the allele association studies,” she said.

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REFERENCES

•Kauffman M, Consalvo D, Moron DG, et al. Serotonin transporter gene Variation and prediction of pharmacoresistance in mesial temporal lobe epilepsy with hippocampal sclerosis. Abstract IN4-1.001. AAN 2008.
    •Siddiqui A, Kerb R, Weale ME, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. New Engl J Med 2003;348:1442–1448.
      •Tan NCK, Heron SE, Scheffer IE. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology 2004;63:1090–1092.
        •Theodore WH, Hasler G, Giovacchini G, et al. Reduced hippocampal 5HT1A PET receptor binding and depression in temporal lobe epilepsy. Epilepsia 2007;48:1526–1530.
          •Mainardi P, Leonardi A, Albano C. Potentiation of brain serotonin activity may inhibit seizures, especially in drug-resistant epilepsy. Med Hypotheses 2008;70:876–879.
            •Albano C, Cupello A, Mainardi P, et al. Succesful treatment of epilepsy with serotonin reuptake inhibitors: proposed mechanism. Neurochem Res 2006;31:509–514.
              ©2008 American Academy of Neurology