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Understanding the Sleep-Wake Cycle: Sleep, Insomnia, and the Orexin System Andrew D Academic Proceedings Understanding the Sleep-Wake Cycle: Sleep, Insomnia, and the Orexin System Andrew D. Krystal, MD, MS; Ruth M. Benca, MD, PhD; and Thomas S. Kilduff, PhD nsomnia is a common, chronic, and pervasive sleep disorder in which people regularly have difficulty falling asleep and/or staying asleep This Academic Proceedings Supplement I despite an adequate opportunity to sleep. According to the International to The Journal of Clinical Psychiatry presents 1 the highlights of the planning roundtable Classification of Sleep Disorders, insomnia is defined as not getting enough teleconference “Understanding the Sleep-Wake sleep or not feeling rested after sleep and is associated with daytime Cycle: Sleep, Insomnia, and the Orexin System,” impairments such as diminished quality of life, fatigue, restlessness, which was held on May 24, 2013. This report was irritability, anxiety, or tiredness. People who have insomnia often experience prepared and independently developed by the physical and emotional problems, an increased occurrence of accidents CME Institute of Physicians Postgraduate Press, and comorbid psychiatric disorders, a loss of work productivity due to Inc., and was supported by an educational grant absenteeism, and difficulty performing work duties.2 from Merck & Co., Inc. Although insomnia is a prevalent and serious problem, it is The teleconference was chaired by Andrew D. underdiagnosed and undertreated.3 Recent research into the sleep-wake Krystal, MD, MS, Insomnia and Sleep Research cycle and how disruptions to that cycle can cause sleep disorders may Program, Department of Psychiatry and Behavioral provide some promise for new insomnia treatments. Andrew D. Krystal, Sciences, Duke University School of Medicine, MD, MS, gathered a panel of experts in the area of the sleep-wake cycle Durham, North Carolina. The faculty were Ruth M. and insomnia to review recent research and advances in understanding, Benca, MD, PhD, Center for Sleep Medicine current treatments for insomnia, and how those new advances might be and Sleep Research, Department of Psychiatry, University of Wisconsin, Madison; and Thomas S. translated into new, more effective treatments. Kilduff, PhD, Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California. THE Sleep-WAKE CYCLE AND THE ROLES OF Financial disclosure: Dr Krystal is a consultant GABA AND OREXIN IN SLEEP AND INSOMNIA for Attentiv, Merck, Novartis, Jazz, Takeda, Sanofi-Aventis, Eisai, Purdue, and Transcept; Dr Krystal began by defining sleep as a state of decreased responsivity has received grant/research support from the to environmental stimuli that occurs on a regular basis. He explained that National Institutes of Health, Teva, Sunovion, different animals assume different postures during sleep and that different Brainsway, Neosync, Janssen, Takeda, Astellas, and species have specific characteristic electroencephalographic (EEG) features ANS St Jude; and has been an expert witness for during sleep as well. Sleep is a reversible state, and, unlike hibernation and Somaxon. Dr Benca is a consultant for Merck, torpor, it is not dependent on the availability of food, water, or environmental and has received grant support from the National temperature. Dr Krystal then went on to explore the biological mechanisms Institutes of Health and the Agency for Healthcare that regulate the sleep-wake cycle, both the homeostatic and circadian Research & Quality. Dr Kilduff has received grant/ processes and the neurobiological systems involved. research support from the National Institutes of Health/National Institute of Neurological Disorders The Homeostatic and Circadian Processes and Stroke, F. Hoffman-LaRoche, CHDI Foundation, and Inscopix, Inc, and has received honoraria from The sleep-wake cycle, according to Dr Krystal, is a highly regulated the National Institutes of Health. system that has long been believed to be driven by 2 underlying processes: the homeostatic (which regulates the amount of sleep) and the circadian The opinions expressed herein are those of (which regulates the timing of sleep).4 The interplay between the 2 processes the faculty and do not necessarily reflect the opinions of the CME provider and publisher determines when people sleep and when they are awake. or the commercial supporter. Dr Krystal summed up the sleep-wake homeostatic process, which is sometimes referred to as “Process S,” simply—the longer one is awake, the J Clin Psychiatry 2013;74(suppl 1):3–20 stronger the drive is for sleep. Often measured by analyzing slow-wave (doi:10.4088/JCP.13011su1c) activity during sleep via EEG, homeostatic drive builds across waking © Copyright 2013 Physicians Postgraduate Press, Inc. episodes and dissipates with sleep.4 In other words, as one goes through a normal day, Process S increases in intensity, and any time that sleep occurs, it is reduced. A daytime nap, for example, causes an exponential decline in Process S to the degree that it may interfere with sleep initiation at the usual bedtime. If one is sleep-deprived, however, the homeostatic sleep drive increases to the point where it becomes overwhelming. J© Clin 20 Psychiatry13 COPYR I2013;74GHT PH Y(supplSICIA N1)S POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPO S E S 3. Krystal et al promoting systems inhibit the wake-promoting systems. That ■ The sleep-wake cycle is regulated by homeostatic and is, if there is greater activity in the wake-promoting systems, circadian processes and competing neurobiological structures then the sleep-promoting systems are inhibited and one is that tip the balance from sleep to wake. awake. Conversely, if there is greater activity in the sleep- promoting systems, then the wake-promoting systems are ■ Possible mechanisms of insomnia are diminished GABA and elevated orexin levels; more research is needed to clarify these inhibited and one is asleep. The orexin system has a special relationships. role in this relationship, because it appears to regulate other Clinical Points wake-promoting systems and prevent sudden, unwanted changeover into sleep such as occurs in narcolepsy.5 The circadian process, Dr Krystal explained, is different. He then went into more detail about the neurobiology of This process is an entrained and synchronized cycle of both the GABA and orexin systems (Figure 1). He explained physiologic systems. He mentioned that the longer that that GABA is the primary inhibitory neurotransmitter in the the circadian process, or Process C, has been researched, human brain. In most areas of the brain, GABA is involved in the clearer it has become that circadian variation occurs local inhibitory circuits. The ventrolateral preoptic nucleus in essentially all of the body’s systems. This process (VLPO), a hypothalamic nucleus involved in the promotion influences the timing of sleepiness based on the endogenous of sleep, uses GABA as its main neurotransmitter and projects circadian clock, the suprachiasmatic nucleus (SCN) of the to several sleep active targets. Thus, increased activity of hypothalamus, primarily by activation and deactivation the VLPO during sleep will inhibit the wake-promoting of systems that promote waking. Process C facilitates the histamines in the tuberomammillary nucleus (TMN), the rhythmic cycle of sleep at the same approximate nighttime orexinergic perifornical area (PeF), the serotoninergic hours each day, reinforced by the light input to the retina neurons in the raphe nuclei, the cholinergic laterodorsal during the day and the release of melatonin from the pineal tegmentum/pedunculopontine tegmentum (LDT/PPT), gland during the dark hours of night.5 In fact, Dr Krystal dopaminergic cells in the ventral periaqueductal gray pointed out that light is the strongest driver of the circadian (vPAG), and the noradrenergic locus ceruleus (LC), which process as it is currently understood. He also emphasized in turn will tilt the seesaw toward sleep.5,6 Conversely, the that it is important to appreciate that the circadian process VLPO itself can be inhibited by these wake-promoting is not just a driver of sleep-wake processes—it also drives systems, tilting the seesaw toward wakefulness instead of hormone release, body temperature changes, and essentially sleep. all regulated physiologic systems. The circadian process has Orexin, as recent research indicates, is implicated in been observed in nearly all species. the stimulation of the wake-promoting systems and the These 2 systems—the homeostatic and the circadian— stabilization of the sleep-wake cycle. Dr Krystal explained compete against each other, according to Dr Krystal, with the that orexin is a peptide produced by neurons in the lateral “winner” determining whether one is awake or asleep. During hypothalamus and that it projects widely to both cortical and the day, the circadian process opposes the homeostatic drive. subcortical targets, including the same targets that GABA The homeostatic drive activates sleep-promoting systems inhibits and additional targets in the cortex.7 Its activation and inhibits wake-promoting systems to a greater degree also leads to diminished activity in sleep-promoting areas, the longer one is awake and pushes one toward sleep, and thereby tilting the balance toward wakefulness, and is the circadian process drives the tendency to stay awake at theorized to be involved in consolidation of wakefulness particular times of the day. The relationship and give-and- and associated functions into a sustained episode.6
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