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Optimal drug dose for treating narcolepsy depends on one gene


Researchers have found that men and women with narcolepsy have different responses to the drug modafinil. This may be due to an underlying genetic difference: Men and women tend to have different forms of a gene called COMT, which plays a role in regulating the brain chemical dopamine. Modafinil is a stimulant that modifies dopamine levels in the brain.

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Mehdi Tafti, of Université de Genève, Switzerland, and colleagues analyzed the response of 84 narcoleptic patients to modafinil as a function of their COMT genes. The optimal dose of modafinil was approximately 100 mg lower in women and lower in all patients with the ‘L’ form of COMT (catechol-O-methyltransferase) compared to others in the study.

The gene, which encodes an enzyme, comes in two forms—‘L’ for low enzyme activity and ‘H’ for high enzyme activity. Last year, Tafti and colleagues reported that women tend to have two copies of the L form, while males tend to have the H form. That observation was supported by the new study. Modafinil appears to be more efficient at modifying dopamine levels when the enzyme is less active, according to the researchers.

“The findings of this study constitute the first report of the use of pharmacogenetics in sleep disorders. The differences in daily dose between gender and COMT genotypes may help individualization of modafinil treatment and highlight the importance of understanding the genetic basis of variability in drug response,” the researchers write.

In the previous study, Tafti‘s group found that the severity of symptoms in narcolepsy was associated with the particular form of COMT a person had. During a sleep study, women narcoleptics with the HH genotype fell asleep twice as fast as those with the LL genotype while the opposite was true for men. The researchers concluded that the results “strongly suggested a genetic link between narcolepsy and the dopaminergic/noradrenergic systems.”

Modafinil has been used in narcolepsy treatment for over a decade in France and has recently been introduced in other countries as a means of treating pathological sleepiness. How modafinil works in the brain is not fully understood, but the drug can treat excessive daytime sleepiness without the risks of addiction and abuse that come with other stimulants.

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Dauvilliers, Y. et al. Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. Pharmacogenomics J 2, 65-68 (2002).
Dauvilliers, Y. et al. MAO-A and COMT polymorphisms and gene effects in narcolepsy. Mol Psychiatry 6, 367-372 (July 2001).

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