Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy.

BACKGROUND: The neuropeptides hypocretin-1 and -2 (hcrt-1 and -2, also known as orexin A and B) are crucially involved in the regulation of sleep/wake states. On the one hand, the sleep-wake disorder narcolepsy can be caused by an hcrt-1 deficiency. On the other, intracerebral administration of hcrt-1 produces an increase in wakefulness at the expense of REM sleep in normal and narcoleptic animals. In humans intranasal administration has been shown to effectively deliver neuropeptides directly to the central nervous system. We hypothesised that the intranasal application of hcrt-1 increases wakefulness and reduces REM sleep in the natural human hcrt-1 deficiency narcolepsy with cataplexy. METHODS: In this double-blind, random-order crossover, placebo-controlled, within-subject design study we administered human recombinant hcrt-1 (435 nmol) intranasally to eight subjects with narcolepsy with cataplexy before night sleep, followed by standard polysomnography. RESULTS: Although intranasal administration of hcrt-1 had no statistically significant effect on nocturnal wakefulness, we found that it reduced REM sleep quantity, particularly during the second half of the recording. Furthermore, intranasal hcrt-1 had a clear REM sleep stabilising effect and led to significantly reduced direct wake to REM transitions. CONCLUSION: In this pilot study we found, first, evidence that the intranasal administration of hcrt-1 has functional effects on sleep in narcolepsy with cataplexy. Our results may encourage the use of the intranasal approach in further studies on hypocretinergic sleep regulation and might also contribute to the future development of a causal treatment for narcolepsy with cataplexy.

Effects of olanzapine on slow wave sleep, sleep spindles and sleep-related memory consolidation in schizophrenia.

INTRODUCTION: Memory deficits and sleep disturbances are common clinical features of schizophrenia. Sleep is supposed to promote memory consolidation and the antipsychotic olanzapine is suggested to improve both sleep and memory functions. Therefore we performed a study to analyse the acute effects of olanzapine on distinct sleep parameters and sleep-related memory consolidation in parallel. METHODS: We studied 26 patients with schizophrenia on stable antipsychotic medication with amisulpride (age range 19-44 years). Immediately before polysomnography and the morning after we performed neuropsychological tasks. Before the third night in the sleep laboratory, patients received either olanzapine or a placebo. RESULTS: We found a significant positive association for slow wave sleep and declarative memory performance in schizophrenia at baseline. Additionally, Stage 2 sleep spindle density was positively related to overnight memory consolidation. Olanzapine caused a significant increase in the amount of slow wave sleep in accordance with recent studies, but led also to a significant decrease in sleep spindle density, which had not been described before. Memory performance the next morning was not different between the two groups. DISCUSSION: Since not only slow wave sleep but also sleep spindles are supposed to promote sleep-related memory consolidation, we suggest that a putative positive effect on memory performance by slow wave sleep augmentation is neutralised by the decrease in sleep spindles due to olanzapine.