Effect of Gaboxadol on Sleep in Adult and Elderly Patients with Primary Insomnia: Results From Two Randomized, Placebo-Controlled, 30-Night Polysomnography Studies

GABOXADOL IS A NOVEL HYPNOTIC WITH A DISTINCT MECHANISM OF ACTION COMPARED WITH CURRENT HYPNOTICS.1,2 TRADITIONAL BENZODIAZEPINE (e.g., triazolam) and non-benzodiazepine (e.g., zolpidem) hypnotics, collectively referred to as benzodiazepine receptor agonists (BzRAs), share a similar mode of action as allosteric modulators of γ-aminobutyric acid type A (GABA-A) receptors. By contrast, gaboxadol is an agonist that acts directly on the GABA binding site of the GABA-A receptor and has no affinity for the benzodiazepine binding site. It has highest functional activity for δ-containing GABA-A receptors where it behaves as a super-agonist (i.e., more efficacious than GABA in a functional assay). δ-Containing GABA-A receptors are insensitive to BzRAs, probably exist mainly extrasynaptically, and are localized predominantly in the thalamus, dentate gyrus, cerebellum, and cortex. These characteristics have led to gaboxadol being classified as a selective extrasynaptic GABA-A agonist (SEGA).3 The functional consequences of these anatomical and pharmacological differences are yet to be understood. Both BzRAs and gaboxadol appear to have sleep maintenance properties and beneficial effects on sleep onset, although less consistently with regard to sleep onset for gaboxadol. Two previous exploratory PSG studies demonstrated that short term treatment with gaboxadol 10, 15, and 20 mg increased sleep continuity over an initial 2 nights of treatment in patients with primary insomnia.4,5 Effects on measures of sleep onset were only observed in one study with gaboxadol 15 mg.4 Effects on sleep onset, as well as maintenance, have also been observed for gaboxadol in larger studies using a model of transient insomnia.6,7 From a sleep architecture perspective, clear differences are observed between BzRAs and gaboxadol. Numerous studies have shown that classical benzodiazepines promote stage 2 NREM sleep and reduce both slow wave sleep (SWS) and REM sleep, while non-benzodiazepines may increase stage 2 sleep but have no effect on other visually scored sleep stages.8–13 Gaboxadol has shown consistent increases in SWS with no significant effect on stage 2 or REM sleep in healthy adult/elderly subjects and early phase studies in patients with primary insomnia.4–6,14–17 Clear differences in NREM EEG spectral profiles are also observed between zolpidem and gaboxadol, with the latter selectively enhancing lower frequency slow wave activity (SWA), underlining a neurochemical difference in the mechanism of action between zolpidem and gaboxadol.6 Other putative sleep agents, including the 5-HT2A/2C receptor antagonists ritanserin and seganserin and the GABA reuptake inhibitor tiagabine, as well as α2δ calcium channel modulators, also increase SWS/SWA.18–21 In terms of the functional significance of sleep there has been much interest in SWS and the development of SWS-enhancing compounds for treating insomnia. There are marked age-related changes in sleep maintenance and continuity measures, but perhaps the most striking observation is that SWS is reduced with age.22–24 SWS is a marker of homeostatic sleep drive, and it is an intriguing question whether increased sleep problems seen with age are in fact the result of changes in SWS, and whether enhancement of SWS might result in more restorative, less fragmented sleep in the elderly. The objectives of the present studies were to confirm the efficacy and SWS-enhancing properties of gaboxadol in 2 large phase 3 PSG studies, one in adult and one in elderly adult patients with primary insomnia, and to determine whether the short term efficacy (1–3 nights) on objective measures of sleep seen to date could be maintained over 30 nights. Based on previous findings suggesting greater drug exposure in elderly patients (Cmax and AUC0-inf of gaboxadol 20 mg increased by approximately 40%, t½ increased from 1.5 to 2 h),25 the maximum gaboxadol dose investigated was 10 mg in the elderly patients versus 15 mg in adult patients. To our knowledge, the elderly study constitutes the largest PSG dataset yet available in this population and is the first to evaluate the PSG effects of a SWS-enhancer in elderly patients over an extended period. Since SWS declines with age, there is interest in the potential differential effects of a SWS-enhancer in the elderly compared to adult insomniac patients. The adult study is therefore presented here in the same paper to allow an illustrative comparison of elderly and adult primary insomnia patients before and after treatment with gaboxadol in large 4-week treatment studies with identical designs and specifically identical PSG entry criteria.