Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT

Abstract

Study objectives: Modafinil may promote wakefulness by increasing cerebral dopaminergic neurotransmission, which importantly depends on activity of catechol-O-methyltransferase (COMT) in prefrontal cortex. The effects of modafinil on sleep homeostasis in humans are unknown. Employing a novel sleep-pharmacogenetic approach, we investigated the interaction of modafinil with sleep deprivation to study dopaminergic mechanisms of sleep homeostasis.

Design: Placebo-controlled, double-blind, randomized crossover study.

Setting: Sleep laboratory in temporal isolation unit.

Participants: 22 healthy young men (23.4 +/- 0.5 years) prospectively enrolled based on genotype of the functional Val158Met polymorphism of COMT(10 Val/Val and 12 Met/Met homozygotes).

Interventions: 2 x 100 mg modafinil and placebo administered at 11 and 23 hours during 40 hours prolonged wakefulness.

Measurements and results: Subjective sleepiness and EEG markers of sleep homeostasis in wakefulness and sleep were equally affected by sleep deprivation in Val/Val and Met/Met allele carriers (placebo condition). Modafinil attenuated the evolution of sleepiness and EEG 5-8 Hz activity during sleep deprivation in both genotypes. In contrast to caffeine, modafinil did not reduce EEG slow wave activity (0.75-4.5 Hz) in recovery sleep, yet specifically increased 3.0-6.75 Hz and > 16.75 Hz activity in NREM sleep in the Val/Val genotype of COMT.

Conclusions: The Val158Met polymorphism of COMT modulates the effects of modafinil on the NREM sleep EEG in recovery sleep after prolonged wakefulness. The sleep EEG changes induced by modafinil markedly differ from those of caffeine, showing that pharmacological interference with dopaminergic and adenosinergic neurotransmission during sleep deprivation differently affects sleep homeostasis.

Figure 1

In contrast to sustained vigilant attention, modafinil attenuates the evolution of subjective sleepiness and theta activity in the waking EEG (C3A2 derivation, power within 5-8 Hz) during sleep deprivation independently of Val158Met polymorphism of COMT. (A) Median reaction times (RT), expressed as speed (1/RT) on the psychomotor vigilance task (PVT); (B) mean scores on the Stanford Sleepiness Scale (SSS); and (C) EEG theta activity are plotted for consecutive 3-h intervals. EEG power in placebo and modafinil conditions was expressed as a percentage of mean theta activity in the waking EEG recordings at 11:00, 14:00, and 17:00 on day 1 of prolonged wakefulness. Error bars represent SEM. Tick marks on the x-axes are rounded up to the nearest hour. Modafinil (100 mg) was administered at 11 and 23 h waking (vertical dashed lines). Black symbols: Val/Val genotype (open circles: placebo; closed circles: modafinil). Gray symbols: Met/Met genotype (open circles: placebo; closed circles: modafinil). Asterisks indicate the time intervals with significant differences between modafinil and placebo (P < 0.05, paired 2-tailed t-tests).

Figure 2

Sleep deprivation affects EEG similarly in Val/Val (n = 10, black lines) and Met/Met (n = 12, gray lines) homozygotes of the Val158Met polymorphism of COMT. EEG power density (C3A2 derivation) in (A) wakefulness, (B) NREM sleep (stages 2-4), and (C) REM sleep in the placebo condition. Absolute power values in each frequency bin after sleep deprivation were expressed as percentage of the corresponding value in baseline (horizontal dashed line at 100%). To quantify the effects on the waking EEG, power values in the recording sessions at 11:00, 14:00, and 17:00 on day 2 of sleep deprivation were expressed as a percentage of the corresponding values of day 1. Means ± SEM are plotted for each 0.5 Hz bin in waking and for each 0.25 Hz bin in NREM and REM sleep. Black and gray triangles denote significant differences from baseline in Val/Val and Met/Met genotypes, respectively (P < 0.05, paired 2-tailed t-tests).

Figure 3

Intake of 2 x 100 mg modafinil does not affect the rebound of EEG slow wave activity (C3A2 derivation, power within 0.75-4.5 Hz) in NREM sleep (stages 2-4) after sleep deprivation in either Val/Val or Met/Met genotype of COMT. Mean slow wave activity in NREM sleep episodes 1-4 in baseline (mean of 2 nights) and recovery nights was expressed as a percentage of the mean all-night values in baseline (dashed vertical lines). Val/Val genotype: black symbols (dots: mean baseline; open triangles: placebo recovery; filled triangles: modafinil recovery). Met/Met genotype: gray symbols (dots: mean baseline; open triangles: placebo recovery; filled triangles: modafinil recovery). Means ± SEM are plotted. *P < 0.01 (placebo-recovery vs. mean baseline; paired, 2-tailed t-tests) +P < 0.03 (modafinil-recovery vs. mean baseline; paired, 2-tailed t-tests)

Figure 4

Modafinil increases EEG 3.0-6.75 and 16.75-20.0 Hz activity in NREM sleep (stages 2-4) in Val/Val genotype but has no effect in Met/Met genotype. Top panel: In each frequency bin between 0.0-20.0 Hz, EEG power (C3A2 derivation) after modafinil was expressed as a percentage of the corresponding values after placebo (horizontal dashed line at 100%). Val/Val genotype: black line (n = 10); Met/Met genotype: gray line (n = 12). Means ± SEM are plotted for each 0.25 Hz bin. Black triangles indicate frequency bins which differed in the Val/Val genotype between modafinil and placebo (P < 0.05, paired 2-tailed t-tests). No significant differences were observed in the Met/Met genotype. Bottom panel: Significant (P < 0.05, black) and non-significant (P > 0.05, white) F-values of genotype × treatment interaction in 3-way mixed-model ANOVA with between-subjects factor genotype (Val/Val, Met/Met) and within-subjects factors condition (baseline, sleep deprivation) and treatment (placebo, modafinil).