Human Sleep. Research and Clinical Care

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1 Human Sleep Research and Clinical Care

2 The Doc/or, by Luke Fildes, 1891, is a vivid portrayal of a physician studying his sleeping patient.

3 Human Sleep Research and Clinical Care Wallace B. Mendelson, M.D. Director of Sleep- Wake Study Program State University of New York at Stony Brook Stony Brook, New York PLENUM MEDICAL BOOK COMPANY NEW YORK AND LONDON

4 Mendelson, Wallace B. Human sleep. Library of Congress Cataloging in Publication Data Includes bibliographies and index. 1. Sleep disorders. 2. Sleep-Physiological aspects. 3. Hypnotics. I. Title. [DNLM: 1. Sleep-drug effects. 2. Sleep-physiology. 3. Sleep Disorders. WL 108 M537h] RC547.M ' lsbn-13: e-1sbn-13: : / First Printing-December 1987 Second Printing-June 1989 The author has written this book as a private individual. The views expressed here do not necessarily reflect those of the State University of New York Plenum Publishing Corporation Softcover reprint of the hardcover 1st edition Spring Street, New York, N.Y Plenum Medical Book Company is an imprint of Plenum Publishing Corporation All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

5 For Nina

6 Preface Sleep plays an important role in the history of the neurosciences. On Easter Monday in 1920, Otto Loewi was awakened in the night by a dream in which he conceived of neurotransmitters communicating across the synapse. He quickly made notes, but in the morning he could not understand his scribbles. The following night, the dream came again. He wrote down his thoughts more carefully and, the next day, conducted the crucial experiment that launched modern neurophysiology (Koelle, 1986). Since the beginning of the modern era of sleep research in the 1950s, we have used the principles of neurotransmission to explore the regulation of sleep. Without resorting excessively to comments on blind men and elephants, however, it is fair to say that the phenomena of sleep and waking can be approached from many perspectives. Among other things, sleep is a process that can be described electrically, an experience that so far defies physiological measurements, and a social behavior. In this book, I have tried to describe the physiology and pharmacology of sleep (Part I) and to relate them to clinical sleep disorders (Part II). Having neither the skill nor the grandiosity of Rousseau, I have made no attempt to write an encyclopedia of all that is known on the subject. Rather, I think of this book as more of a snapshot, giving a picture of where we are, and it is hoped, a history of how we got here. Renoir, who knew a few things about making pictures, also made a comment that seems relevant to this endeavor. It was his belief that before painting a bowl of flowers, one should arrange them carefully; the next step was to turn them around and paint them from the other vii

7 viii PREFACE side. He meant that sometimes the effort to impose a certain order on observations can cause one to miss the inherent meaning. After some years of observing the processes of sleep, I can understand this. It is a common experience for most of us to think that we have finally found a pleasing pattern in the data; then a new observation is made and we find ourselves looking at it all from a new, unexplained perspective. A number of times in this book we will see how, despite our best efforts, the flowers have managed to rearrange themselves. One of the special qualities of sleep research is that it covers such a wide range of human experience. Consequently, there is a tremendous amount of anecdotal material available, and one of the hardest parts of writing a textbook is resisting the temptation to include the colorful stories that might appear in my lectures. I have found, for instance, that I never really understood the power of circadian rhythms until a trip to Florida. There I saw fishermen wading in a lake among sedentary alligators, who spend their daytime digesting and resting. In the folk culture of the area, it was known that one may walk among the alligators during the day-but never at night. So, if in the midst of a discussion of sleep apnea I reveal yet another story about a Western gunslinger who was chased by Wild Bill Hickock because he shot a man for snoring too loudly, I hope I will be forgiven. / I am indebted to Miodrag Radulovacki, Laurence S. Jacobs, Dennis L. Murphy, Gary Miller, Phil Skolnick, Judith L. Rapoport, Joseph V. Martin, and Steven P. James for their helpful suggestions on various chapters. I have certainly learned from discussions with Richard R. Bootzin. My wife, Nina Crimm Mendelson, photographed the illustrations of "Flaming June," "The Sentinel," and "The Doctor." Stony Brook, New York Wallace B. Mendelson

8 Contents I Physiology and Pharmacology of Sleep 1 An Introduction to Sleep Studies... 3 Techniques of Human Sleep Studies Polysomnography Stages of Sleep... 6 Waking... 6 Non-REM Sleep REM Sleep The REM-Non-REM Cycle Sleep Stages and Age Effects of Temporal Variables on Sleep Physiological Variables in Sleep Stages Sleep Deprivation Total Sleep Deprivation Selective Sleep Stage Deprivation Natural Long, Short, and Variable Sleepers Regulation of Sleep Passive versus Active Regulation Neurotransmitters Models of Sleep Regulation Circulating Humors and Sleep Hypnotics Summary ix

9 x CONTENTS 2 Pharmacology and Neurotransmitters in Sleep Serotonin and Sleep L-Tryptophan Hydroxytryptophan Parachlorophenylalanine Methysergide Lysergic Acid Diethylamide Fluoxetine Quipazine and Fenfluramine Ritanserin Ventricular Fluid 5-HIAA Dopamine L-Dihydroxyphenylalanine (L-DOPA) Dopamine Receptor Agonists and Antagonists Pimozide Other Studies of Dopamine and Sleep Norepinephrine Alpha-Methyl-Paratyrosine (AMPT) Alpha-Methyldopa Adrenergic Receptor Blockers Other Drugs Influencing Amines Reserpine Amphetamines Chlorpromazine Tricyclic Antidepressants Monoamine Oxidase Inhibitors Endogenous MAO and Biogenic Amines The Cholinergic System Muscarinic Nicotinic Agonists Gamma-Aminobutyric Acid Adenosine Circulating Sleep Factors Arginine Vasotocin (AVT) Delta Sleep-Inducing Peptide (DSIP) Muramyl Dipeptide (MDP) Steroids Cholecystokinin (CCK) Discussion Serotonin Dopamine... 75

10 CONTENTS xi Norepinephrine... "... " Acetylcholine Circulating Sleep Factors Gamma-Aminobutyric Acid Interaction between Transmitters Pharmacological Treatment of Insomnia Aspects of Insomnia Pharmacology of Hypnotics Barbiturates Benzodiazepines Nonbarbiturate, Nonbenzodiazepine Hypnotics Efficacy Studies of Hypnotics Flurazepam Temazepam Triazolam Residual Daytime Effects General Issues Data on Performance and Wakefulness The Elderly Benzodiazepines and Respiration Reliance and Dependence Hypnotics and Alcohol Hypnotics and Acute Time Shifts Clinical Recommendations Conclusions The Benzodiazepine Receptor and Sleep Pharmacological Probes of the BZ Recognition Site Studies with Beta-Carbolines The BlO Enantiomers Do Alterations in Calcium Flux Mediate Some Pharmacological Effects of BZs? Dihydropyridines and Diazepam-Stimulated Calcium Uptake into Synaptosomes

11 xii CONTENTS Nifedipine Blocks Sleep Induction by Flurazepam BAY K 8644 Enhances Hypnotic Effect of Flurazepam The Relation of Barbiturates and Ethanol to the BZ Receptor Complex Effects of PB and Ethanol on Ion Channels... _ 119 Chloride Channel Function: Ethanol and PB Toxicity Relation of PB to BZ Recognition Site Function: Hypnotic, Anticonvulsant, and Anxiolytic Properties Heterogeneity of BZ Receptors Issues for the Future Endogenous Compounds Separation of Pharmacological Properties Summary \ 5 Neuroendocrinology and Sleep Basic Concepts in Neuroendocrinology Growth Hormone Secretion in Sleep and Waking Effect of Alterations in Neurotransmitter Function on GH Secretion Locus of Drug Effect Somatostatin Secretion of GH in Psychiatric Patients Secretion of GH in Disease Aging and GH Effects of GH Administration The Pituitary-Adrenal Axis Relation to the Sleep-Waking Cycle Sleep-Related Cortisol Secretion in Disease Effects of Cortisol and ACTH on Sleep Prolactin Relation of PRL to Other Hormones Drugs and Sleep-Related PRL Secretion Sleep-Related PRL Secretion in Disease Follicle-Stimulating Hormone and Luteinizing Hormone Relation of LH and FSH Secretion to Sleep Relation of Testosterone Secretion to Sleep Effects of Sex Hormones on Sleep

12 CONTENTS xiii Sleep-Related FSH and LH Secretion in Disease Thyroid-Stimulating Hormone TSH Secretion and Sleep Sleep in Hyperthyroidism and Hypothyroidism Central Nervous System Actions of TRH Antidiuretic Hormone and Renin ADH and Renin Secretion during Sleep Effects of ADH on Sleep Melatonin Summary II Pathology of Sleep 6 Sleep-Related Breathing Disorders Introduction Snoring Incidence of Sleep Apnea Syndromes Regulation of Respiration in Sleep Methods of Recording and Measuring Sleep-Related Respiration 189 Clinical Syndromes Obstructive Sleep Apnea Central Sleep Apnea Mixed Apneas Hypoventilation Syndromes Treatment... ~ Obstructive Sleep Apnea Central Sleep Apnea Adjunctive Treatment and Precautions... : Questions for the Future Summary Narcolepsy and Disorders of Excessive Sleepiness Definition Excessive Daytime Sleepiness and Sleep Attacks Cataplexy

13 xiv CONTENTS Sleep Paralysis Hypnogogic and Hypnopompic Hallucinations Disordered Nocturnal Sleep Automatic Behavior Psychosocial Consequences Performance Deficits Disordered Physiology Natural History Epidemiology and Genetics Etiology Animal Models of Narcolepsy Diagnosis Sleep Laboratory Findings Narcolepsy with Other Sleep Disorders Clinical Evaluation Other Disorders of Excessive Daytime Sleepiness Idiopathic Central Nervous System Hypersomnolence Sleep Drunkenness Insufficient Sleep Syndrome Hypersomnolence Associated with Medical or Toxic Conditions 240 "Secondary Narcolepsy" Excessive Sleepiness in Depression Pharmacotherapy of Narcolepsy Stimulants Antidepressants Monoamine Oxidase Inhibitors Serotonin Antagonists and Agonists Gamma-Hydroxybutyrate Propranolol Opiates Other Treatments Summary Alcohol, Alcoholism, and the Problem of Dependence Animal Studies Ethanol and the Sleep EEG Effects of Prior Exposure to Ethanol Behavioral Measures of Sleep in Long- and Short-Sleeping Mice

14 CONTENTS xv Ethanol and Neurotransmitters Ethanol in Normal Human Subjects Effects of Ethanol in Chronic Alcoholics Sleep in "Dry" Alcoholics Response to Ethanol Sleep during Acute Withdrawal REM Sleep Rebound Experimental Approaches to Ethanol Toxicity and Withdrawal Ethanol and Hypnotics Ethanol and Sleep Apnea Summary Affective Disorders Observations of Patients Symptomatic Depressed Patients Compared to Controls Longitudinal Studies Sleep and the Switch Process in Bipolar Patients Theories of Sleep in Depression REM Deprivation Extended Sleep and Sleep Satiety Circadian View of Depression Implications of the Two-Process Model Reciprocal Interaction Model Pharmacological Models Manipulations of Sleep as Treatments for Depression REM Sleep Deprivation Total Sleep Deprivation Partial Sleep Deprivation Advance of the Sleep-Wake Cycle Summary Circadian Rhythms and Sleep Background Models of Sleep-Wake Regulation Disorders of the Sleep-Wake Schedule

15 xvi CONTENTS Transient Disturbance Persistent Distu{bance Pharmacology Use of Hypnotics in Acute Phase Shifts Circadian Rhythm Alteration by Drugs Summary n Nocturnal Myoclonus and the Restless Legs Syndrome Nocturnal Myoclonus Prevalence Relation to Sleep Disturbance Drugs Associated with Myoclonus Differential Diagnosis Tr~atment Restless Legs Syndrome Clinical Features Treatment Summary U Chronic Insomnia Persistent Psychophysiological DIMS Subjective DIMS without Objective Findings Other Forms of Chronic Insomnia Qualities Associated with Insomnia Daytime Sleepiness Daytime Performance Sleep Studies of Insomniacs The Subjective Experience of Insomniacs Is Poor Sleep the Same as "Light" Sleep? Insomniacs' Perception of Habitual Sleep Treatment of Insomnia Nonpharmacological Techniques Sleep Hygiene

16 CONTENTS xvii A Program for Patients Summary Bibliography Index

17 Commonly Used Abbreviations ACTH AMPT AOAA ASDC AVT BZ cps DBE DIMS DOES DSIP DST EEG EMG EOG FSH GABA GH 5-HTP L-DOPA LH MAO MOP MMPI Adrenocorticotropic hormone Alpha-methyl-paratyrosine Aminooxyacetic acid Association of Sleep Disorder Centers Arginine vasotocin Benzodiazepine Cycles per second (also Hertz or Hz) Disordered breathing event Disorder of initiating and maintaining sleep Disorder of excessive sleepiness Delta sleep-inducing peptide Dexamethasone suppression test Electroencephalogram Electromyogram Electrooculogram Follicle-stimulating hormone Gamma-aminobutryic acid Growth hormone 5-Hydroxytryptophan L-Dihydroxyphenylalanine Luteinizing hormone Monoamine oxidase Muramyl dipeptide Minnesota Multiphasic Personality Inventory xix

18 xx MSLT MWT NE PB PCPA PGO PLM PRC PRL REM ROE RTSW SCN TRH TSH Multiple sleep latency test Maintenance of wakefulness test Norepinephrine Pentobarbital Parachlorophenylalanine Pontine-geniculate-occipital Periodic leg movement Phase response curve Prolactin Rapid eye movement Range of entrainment Repeated test of sustained wakefulness Suprachiasmatic nucleus Thyrotropin-stimulating hormone Thyroid-stimulating hormone ABBREVIATIONS

The Use and Misuse of. Sleeping Pills. -A Clinical Guide-

The Use and Misuse of. Sleeping Pills. -A Clinical Guide- The Use and Misuse of Sleeping Pills -A Clinical Guide- Head of Hypnos (Photograph courtesy of the British Museum) The Use and Misuse of Sleeping Pills --A Clinical Guide-- Wallace B. Mendelson, M. D.