Enhancement of Slow Wave Sleep: Implications for Insomnia

Abstract

Slow wave sleep (SWS) is defined as the sum of stage 3 and stage 4 sleep and is characterized by high-voltage, synchronized electroencephalographic (EEG) waveforms, often measured as slow wave activity (SWA). SWS has been widely hypothesized to be a time of relatively heightened neurophysiologic restoration or recuperation.1,2 This viewpoint is prompted by a number of observations including: (1) enhanced SWA following sleep deprivation in proportion to the duration of prior wakefulness3; (2) reduced SWA during nocturnal sleep following afternoon/evening naps4; (3) a gradual decline in SWA across a night of sleep5; and (4) increased SWS following nights of fragmented sleep.6 Within the two-process model of sleep regulation, heightened SWS/SWA has been viewed as reflecting Process S, the homeostatic component.7 Other authors have proposed that increased SWS/SWA represents ongoing cortical recovery from activities during prior wakefulness.8 A number of agents have been found to increase the time spent in SWS (Table 1). Interestingly, despite the common observation of enhanced SWS, these drugs have several different mechanisms of action. For example, tiagabine is an inhibitor of GAT-1, one of four transporter proteins that promote the reuptake of γ-aminobutyric acid (GABA) into presynaptic terminals and surrounding glial cells. GAT-1 inhibition results in increased synaptic levels of GABA9 and heightened inhibitory activity. In contrast, gaboxadol is an extrasynaptic GABAA receptor agonist that is selective for δ receptors.10 When activated, α4-δ receptors produce a tonic inhibitory conductance, which is thought to result in a more stable inhibitory pattern compared with phasic synaptic inhibition.11 Other drugs have no direct GABAergic effects yet also increase SWS. Examples include α2-δ calcium channel ligands (e.g., gabapentin and pregabalin), serotonin (5HT)2A receptor antagonists (e.g., eplivanserin and ritanserin), and drugs that are active at multiple receptors (e.g., mirtazapine, trazodone, and olanzapine). Table 1 Drugs Known to Increase Slow Wave Sleep The availability of drugs that increase SWS has led to research on the behavioral and phenomenologic correlates of pharmacologic SWS enhancement. This article examines the pharmacologic enhancement of SWS with emphasis on two studies12,13 designed to determine whether increasing SWS (with either tiagabine or gaboxadol) reduces the established neurobehavioral and physiologic deficits associated with sleep restriction. In addition, the potential role of SWS enhancement as a novel approach to the treatment of insomnia is considered.