Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep.

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Bodenmann S, Xu S, Luhmann UF, Arand M, Berger W, Jung HH, Landolt HP

Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep.

Clin Pharmacol Ther. 2009 Mar;85(3):296-304. doi: 10.1038/clpt.2008.222. Epub 2008 Nov 26.

PubMed ID

19037200 [ View in PubMed

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Abstract

Sleep loss impairs waking functions and is homeostatically compensated in recovery sleep. The mechanisms underlying the consequences of prolonged wakefulness are unknown. The stimulant modafinil may promote primarily dopaminergic neurotransmission. Catechol-O-methyltransferase (COMT) catalyzes the breakdown of cerebral dopamine. A functional Val158Met polymorphism reduces COMT activity, and Val/Val homozygous individuals presumably have lower dopaminergic signaling in the prefrontal cortex than do Met/Met homozygotes. We quantified the contribution of this polymorphism to the effects of sleep deprivation and modafinil on subjective state, cognitive performance, and recovery sleep in healthy volunteers. Two-time 100 mg modafinil potently improved vigor and well-being, and maintained baseline performance with respect to executive functioning and vigilant attention throughout sleep deprivation in Val/Val genotype subjects but was hardly effective in subjects with the Met/Met genotype. Neither modafinil nor the Val158Met polymorphism affected distinct markers of sleep homeostasis in recovery sleep. In conclusion, dopaminergic mechanisms contribute to impaired waking functions after sleep loss.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Modafinil	Catechol O-methyltransferase Gene symbol: COMT UniProt: P21964	---	(A;A)	AA allele (rs4680)	Effect Directly Studied	Patients with this genotype have reduced improvement in vigor and well-being with modafinil.	Details
Modafinil	Catechol O-methyltransferase Gene symbol: COMT UniProt: P21964	---	(G;G)	GG allele (rs4680)	Effect Directly Studied	Patients with this genotype have increased improvement in vigor and well-being with modafinil.	Details