Effects of hypnotics on the sleep EEG of healthy young adults: new data and psychopharmacologic implications

Abstract

Benzodiazepine hypnotics increase NREM sleep and alter its EEG by reducing delta (0.3–3 Hz) and increasing sigma (12–15 Hz) and beta (15–23 Hz) activity. We tested whether the nonbenzodiazepine hypnotic, zolpidem (10 mg), produced the same pattern of sleep and EEG changes as two “classical” benzodiazepines, triazolam (0.25 mg) and temazepam (30 mg). Sleep EEG of 16 subjects was analyzed with period amplitude analysis for 3 nights during drug administration or placebo. The effects of zolpidem were in the same direction but generally of smaller magnitude than those of the classical benzodiazepines. These differences are more likely the result of non-equivalent dosages than different pharmacologic actions. Period amplitude analysis showed that the decreased delta activity resulted mainly from a decrease in wave amplitude. In contrast, the increased sigma and beta activity were produced by increased wave incidence. Delta suppression increased with repeated drug administration but sigma and beta stimulation did not. While these findings have little relevance for the clinical choice of hypnotics they may hold important implications for the brain mechanisms involved in hypnotic tolerance and withdrawal delirium.

Introduction

Both period-amplitude analysis (PAA) and power spectral analysis have shown that classical benzodiazepine (BZ) hypnotics strongly affect the EEG of non-rapid eye movement (NREM) sleep in three frequency bands. BZs reduce delta (0.3–3 Hz) but increase spindle (12–15 Hz) and beta (15–23 Hz) activity (Gaillard et al., 1973, Johnson et al., 1976, Johnson et al., 1979, Feinberg et al., 1978, Feinberg et al., 1979, Borbely et al., 1985; and many subsequent reports). Interestingly, these three bands show strong and interrelated oscillations across sleep. Sigma and delta oscillate inversely in NREM but both decline to their lowest levels in REM (Uchida et al., 1991); beta and delta oscillate inversely across both NREM and REM sleep (Uchida et al., 1992).

This study compared the effects of zolpidem, triazolam and temazepam on visually scored sleep stages and computer-measured NREM EEG. Although the functional significance of hypnotic-induced changes in sleep architecture and EEG is unknown, these changes are of considerable biological interest. This is particularly the case for the delta frequencies, which are thought to be correlates of the homeostatic (restorative) processes of sleep (Feinberg et al., 1974, Borbely 1982). While there is no general agreement on the functional significance of spindle and beta frequencies, their oscillatory relationships with delta make them of interest. An important additional source of interest in the pharmacology of spindle and delta EEG is the strong effect of human brain maturation and aging on these frequencies. The goals of the present studies were (1) to determine whether the non-benzodiazepine GABAergic hypnotic zolpidem produces the same changes in NREM delta, sigma and beta as those induced by two “classical” benzodiazepines, triazolam and temazepam; and (2) to explore with period amplitude analysis the effects of these drugs on the amplitude, incidence and across-night trends of the waves in these three frequencies. Spectral power, and its period-amplitude equivalent, integrated amplitude, are composite measures that reflect the number and amplitude of the waves in an EEG frequency band. Period-amplitude analysis, but not spectral analysis, can determine the separate contributions of wave amplitude and incidence. While there have been several studies (Trachsel et al., 1990, Brunner et al., 1991) of the effects of recently developed non-benzodiazepine GABAergic hypnotics on spectral power, no previous study compared the effects of zolpidem and classical GABAergic hypnotics on the amplitude and incidence of waves in NREM delta, sigma and beta frequencies.