Sleep Neurobiology and Insomnia.pptx

Sleep Neurobiology and Insomnia.pptx

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  Sleep Neurobiology and Insomnia Dr.Pramod Krishnan, M.D, D.M Consultant Neurologist and Epileptologist, Sleep Medicine Specialist, HOD Neurology Manipal Hospital, Bengaluru
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  Introduction • All organismsfrom virus to complex mammals have periods of activity and inactivity. • Such a pervasive finding suggests that sleep is basic to life. What is sleep? • Sleep is defined behaviorally as a reversible state of perceptual disengagement from and unresponsiveness to the environment. • Sleep is physiologic, necessary, temporary, reversible, and cyclic.
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  • A rolefor the brain in sleep-wake behavior was first indicated in 1916, when Baron Constantine von Economo studied encephalitis lethargica. • Lesions at the junction of the midbrain and posterior hypothalamus (diagonal hatching) caused hypersomnolence. • Lesions of the basal forebrain and anterior hypothalamus (horizontal hatching) produced profound insomnia. • Lesions between these two sites (arrow), which included the lateral hypothalamic area, caused narcolepsy. O, optic nerve; VE, third ventricle; Hy, hypothalamus; Th, thalamus; V4, fourth ventricle; Aq, cerebral aqueduct; K, oculomet, oculomotor nerve.
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  Hypothalamus Wakefulness is maintainedby the combined excitatory influence of forebrain-projecting noradrenergic (locus coeruleus), histaminergic (tuberomammillary nucleus), serotoninergic (dorsal raphe), and cholinergic (not shown) cell groups located at or near the mesopontine junction. The cerebral cortex and medullary brainstem also contain subpopulations of GABA-ergic sleep-active neurons. The pineal gland, located in the epithalamus, produces melatonin, a hormone thought to function as a hypnotic signal.
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  Sleep is initiatedand maintained by neurons in the median preoptic (MnPO) and ventrolateral preoptic (VLPO) nuclei. Hypocretin (orexin) neurons located in the lateral hypothalamus reinforce activity in the brainstem arousal pathways and also stabilize both sleep and wakefulness. The suprachiasmatic nuclei (SCN) determine the timing of the sleep-wake cycle and help to “consolidate” these behavioral states.
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  Wakefulness “Waking is inducedand maintained by multiple redundant neuronal systems localized from the medulla oblongata to the forebrain”.
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  Ascending arousal systemconsists of: 1. Noradrenergic (NE) neurons of the ventrolateral medulla and locus coeruleus. 2. Cholinergic neurons (ACh) in the pedunculopontine tegmental/laterodorsal tegmental (PPT/LDT) nuclei. 3. Serotonergic (5-HT) neurons in the dorsal raphe nucleus. 4. Dopaminergic neurons (DA) of the ventral PAG. 5. Histaminergic neurons (His) of the tuberomammillary nucleus (TMN). 6. Glutamatergic neurons of the parabrachial nucleus. These systems produce cortical arousal via two pathways: 1. Dorsal route through the thalamus 2. Ventral route through hypothalamus and BF. • The latter pathway receives contributions from the hypocretin (ORX) and melanin-concentrating hormone (MCH) neurons of the lateral hypothalamic area (LHA) as well as GABA-ergic or cholinergic neurons of the BF.
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  NREM Sleep “NREM sleepis induced and maintained by GABAergic neurons of the VLPO system by inhibitory projections to the different populations of waking neurons”.
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  • The medianpreoptic nucleus and ventrolateral preoptic nucleus (VLPO) contain sleep-active cells, which contains the inhibitory neurotransmitters GABA and galanin (Gal). • The VLPO projects to all the main components of the ascending arousal system. • Inhibition of the arousal system by the VLPO during sleep is critical for the maintenance and consolidation of sleep. • There is a node of GABAergic neurons in the parafacial zone of the rostral medulla that are also sleep active. BF, basal forebrain; LC, locus coeruleus; LDT, laterodorsal tegmental nuclei; PPT, pedunculopontine; SN, substantia nigra; TMN, tuberomammillary nucleus; VTA, ventral tegmental area.
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  REM Sleep “REM sleepis generated by neurons located in the brainstem’. However, recent studies suggest that hypothalamic neurons control REM sleep by descending projections.
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  • GABA-ergic ventrolateralPAG (vlPAG) neurons fire during NREM states to inhibit entry into REM sleep. • During REM sleep these neurons are inhibited by a population of GABAergic REM sleep–active neurons in the sublaterodorsal region (SLD) and pre coeruleus (PC). • This mutually inhibitory relationship produces a REM-NREM flip switch, promoting rapid and complete transitions between these states. • The core REM sleep switch is, in turn, modulated by other neurotransmitter systems.
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  Noradrenergic neurons inthe locus coeruleus (LC) and serotonergic neurons in the dorsal raphe (DR) inhibit REM sleep by exciting REM-off neurons and inhibiting REM-on neurons. During REM sleep, they are silent. Cholinergic neurons (blue) promote REM sleep by having opposite actions on the same two neuronal populations. The orexin neurons inhibit entry into REM sleep by exciting neurons in the REM-off population, whereas the VLPO neurons promote entry into REM sleep by inhibiting this same target. - - - - + +
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  • During REMsleep, glutamatergic neurons in the SLD (red) activates a series of inhibitory interneurons in the medulla and spinal cord, which inhibit motor neurons and produce the atonia of REM sleep. • Withdrawal of tonic excitatory input from the REM-off regions may also contribute to atonia. • Ascending projections from glutamatergic neurons in the parabrachial (PB) nucleus and pre- coeruleus (PC) area activate forebrain pathways that drive EEG desynchronization and hippocampal theta rhythms (typical of REM sleep). + + + + - - -
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  Hypocretin/ Orexin system
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  • Orexin Aand Orexin B are cleaved from prepro-orexin1 • Orexin A binds OX1R and OX2R1 • Orexin B binds OX2R1 only • Activation of OX1R/OX2R is responsible for the transition of respective sleep states to a state of wakefulness1-3 Promotes wakefulness OX1R OX2R Promotes wakefulness Orexin A Orexin B Pro-hormone Peptide Prepro-orexin N C GKR GRR Via regulation of neurons involved in REM sleep Via regulation of neurons involved in REM + NREM sleep Fundamental role of orexin in sleep-wake regulation NREM=non-rapid eye movement; OX1R=orexin receptor type-1; OX2R=orexin receptor type-2; REM=rapid eye movement 1. Equihua AC et al. Front Pharmacol. 2013;4:163. 2. Beuckmann CT et al. J Pharm Mol Ther. 2017;362(2):287-295. 3. Willie JT et al. Neuron. 2003;38(5):715-730
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  The first glimpseof Orexin. An in situ hybridization autoradiography showing Orexin expression in the hypothalamic region of the rat brain.
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  Fundamental Role ofOrexin in Sleep-Wake Regulation Firing rate of orexin neurons across sleep-wake states Firing rate (a.u.) 100 50 0 aW qW tSWS SWS tPS PS • Preclinical studies have demonstrated the fundamental role of orexins in gating and sustaining wakefulness. • Orexin neuronal activity is highest during active wakefulness and lowest during sleep. • This diurnal pattern of orexin activity regulates the sleep-wake cycle and normal sleep architecture. a.u.=arbitrary units; aW=active wakefulness; PS=paradoxical sleep; qW=quiet wakefulness; SWS=slow-wave sleep; tPS=transition to paradoxical sleep; tSWS=transition to slow-wave sleep Azzez IA, et al. Front Pharmacol. 2018;9:1061
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  Hypocretin neurons inthe lateral hypothalamic area innervate all the ascending arousal systems as well as the cerebral cortex, and are excitatory. BF, basal forebrain; LC, locus coeruleus; LDT, laterodorsal tegmental nuclei; PPT, pedunculopontine; SN, substantia nigra; TMN, tuberomammillary nucleus; VTA, ventral tegmental area.
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  Sleep homeostasis • Thenetworks for wake, NREM and REM sleep are well known. • However, the mechanisms at the origin of the switch between states remains to be fully understood.
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  • VLPO andMnPO inhibit the components of the ascending arousal pathways in both the hypothalamus and the brainstem. • This interaction between the VLPO and MnPO and components of the arousal system is, mutually inhibitory and analogous to an electronic “flip” switch/circuit. • The lateral hypothalamic orexin neurons likely play a stabilizing role for the switch and reduce transitions during both sleep and wakefulness. VLPOex, extended ventrolateral preoptic nucleus; VLPOc, core ventrolateral preoptic nucleus.
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  CIRCADIAN RHYTHM “The Suprachiasmaticnucleus in the anterior hypothalamus is an endogenous clock entrained by excitatory projections arising from specialized light-sensitive neurons of the retina”.
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  Photic information reachesthe suprachiasmatic nucleus (SCN) from the retina via the retinohypothalamic tract (RHT). Melatonin is released from the pineal gland at night, and its output is regulated by the SCN via the superior cervical ganglion (SCG). In addition to its ability to synchronize circadian rhythms, melatonin can also promote sleep. Integrated timing information from the SCN is transmitted to sleep-wake centers.
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  Two-process model: theSCN promotes wakefulness by stimulating arousal networks. SCN activity appears to oppose the homeostatic sleep drive. The propensity to be awake or asleep at any time is related to the homeostatic sleep drive and the opposing SCN alerting signal. At normal bedtime, both the alerting drive and the sleep drive are at their highest level. The SCN has at least two types of melatonin receptors, MT1 and MT2, involved in the regulation of sleep. Stimulation of MT1 receptors is believed to decrease the alerting signal from the SCN, whereas MT2 stimulation is thought to be involved in synchronizing the circadian system.
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  The Two-Process Modelof Sleep-Wake Regulation: Working in Unison
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  The Two-Process Modelof Sleep-Wake Regulation: The Homeostatic Process (Process S) A homeostatic process is represented by the buildup of sleep pressure and consists of a rising phase during wake and a declining phase during sleep.1,2 EEG=electroencephalograph; REM=rapid eye movement 1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Borbély AA et al. J Sleep Res. 2016;25(2):131-143.
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  The Two-Process Modelof Sleep-Wake Regulation: Adenosine Levels Correlate With the Buildup of Sleep Pressure • Adenosine levels increase over duration of wake-time activity during the day, correlating with a buildup of sleep pressure.1,2 • Adenosine levels gradually increase in arousal-promoting areas such as the reticular activating system of the brain stem; with higher concentrations, adenosine inhibits arousal and induces sleepiness.2 1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Bjorness TE, Greene RW. Curr Neuropharmacol. 2009;7:238-245
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  The Two-Process Modelof Sleep-Wake Regulation: The Circadian Process (Process C) The dimming of environmental light at dusk triggers the release of melatonin by the pineal gland via input from the suprachiasmatic nucleus (circadian pacemaker), promoting the onset of sleep.2 1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Arendt J. J Biol. Rhythms. 2005;20(4):291-303.
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  The Two-Process Modelof Sleep-Wake Regulation: Melatonin Induces Release of Preoptic GABA Signaling at Night • The rise in melatonin production coincides with increased GABA signaling from the ventrolateral preoptic area, and induces onset of sleep.1,2 • Preoptic GABA activity is elevated during sleep and inhibited during daytime wake behavior.1 GABA=gamma aminobutyric acid; SCN=suprachiasmatic nucleus 1. Kryger MH et al. Principles and Practice of Sleep Medicine. 6th ed. Philadelphia, PA: Elsevier; 2017. 2. Arendt J. J Biol. Rhythms. 2005;20(4):291-303
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  Fundamental Role ofOrexin in Sleep-Wake Regulation GABA=gamma aminobutyric acid; NREM=non-rapid eye movement; REM=rapid eye movement 1. Equihua AC et al. Front Pharmacol. 2013;4:163. 2. Azzez IA, et al. Front Pharmacol. 2018;9:1061 Preclinical studies have shown that orexin neuronal activity follows a diurnal fluctuation pattern – highest during active wake behavior, decreases during non-active wake and sleep behaviors, and lowest during NREM Stage 3 sleep.1,2
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  Summary of Sleepand Wakefulness
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  EEG, EOG, EMGand neurotransmitter dominance in wakefulness, NREM and REM sleep: Neuromodulator activity is primarily cholinergic during wake and REM sleep. Wake is supported by activity of monoamines, histamine and hypocretin/ orexin. In sleep, monoaminergic systems, including norepinephrine and serotonin are attenuated, and are silent in REM sleep. Dopamine levels do not change dramatically across the sleep wake cycle. Awake NREM Sleep REM sleep
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  Retinal inputs Suprachiasmatic nucleus Adenosine buildup during wake period VLPO Multiple waking systems NREM sleep Sublaterodorsal tegmental nucleus REM sleep + + + - - Tonic, NE and ACh GABA Via A2A receptors - via A1 receptors vlPAG, LPT + - GABA - GABA Lateral hypothalamus Orexin + Pineal gland Melatonin LDT/ PPT Glutamate ACh
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  Normal sleep andits functions
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  Sleep-Wake Changes WithAge NEWBORNS • Sleep is intermittently distributed across the day and night • Infants sleep ~16 to 18 hours within a 24-hr period • Greater than 50% of sleep is spent in REM sleep • The transition between sleep and wake is achieved through REM sleep during the first year of life Sleep-wake cycles and sleep architecture show distinctive changes with age. CHILDREN • Children between the ages 3 and 5: • Total sleep time decreases to 10-12 hours/day • Sleep is composed predominantly of SWS ADOLESCENTS: • Require 8 to 10 hours of sleep per night • SWS duration decreases by ~40% ADULTS • Sleep duration is ~8 hours per night • Those with normal sleep enter sleep through NREM sleep and transition to REM sleep within ~90 min • NREM and REM sleep then alternate throughout the night in ~90-min epochs • Sleep efficiency decreases with age LATE LIFE • Sleep efficiency and total sleep time diminish • Sleep is broken up, lighter, and associated with many nighttime arousals • Deep sleep diminishes
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  Proportion of thenight spent in the various sleep stages in adults. Wakefulness in sleep usually makes up less than 5% of the night. Stage N1 sleep generally makes up 2% to 5% of sleep; stage N2, 45% to 55%; and stage N3, 3% to 15%. Non–rapid eye movement sleep is therefore usually 75% to 80% of sleep. Stage R sleep is usually 20% to 25% of sleep and occurs in three to six discrete episodes.
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  Sleep Architecture
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  Age-related changes insleep stages in healthy men.
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  Sleep Is Essential Chronicsleep loss is linked to: Depression Anxiety Compromised immune system function High blood pressure Cardiovascular disease Diabetes Obesity Lack of sleep is associated with: Memory impairments Reductions in cognitive abilities Mood lability Suggested physiological roles for sleep: • Replenish energy reserves • Modulate metabolism and body temperature • Facilitate learning and memory • Removal of metabolic waste products Sleep is essential for daily function and survival
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  INSOMNIA
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  Insomnia Can Manifestat Different Times of the Sleep Cycle and Cause Daytime Impairments 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association; 2013. 2. Misra AK et al. J Assoc Physicians India. 2017;65(4):43-47 The goal of insomnia therapy is to allow patients to fall asleep, stay asleep, wake, and function well Timing of Insomnia Symptoms Daytime Impairments (Wake Behavior): • Fatigue • Daytime sleepiness • Impairment in cognitive performance • Mood disturbances • Depressive or anxiety symptoms Get in bed / Lights off 24-hour Sleep/Wake Behavior Get out of bed / Lights on Waking too early Problems staying asleep Problems falling asleep
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  Epidemiology: Prevalence of adultsexperience symptoms of insomnia 33% ~ Population-based studies Insomnia is one of the most prevalent sleep disorders
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  Epidemiology: Socio-demographics Insomnia disorderaffects people of all ages and backgrounds, but certain populations tend to have a higher rate. S O C I O D E M O G R A P H I C FA C T O R S A F F E C T I N G T H E P R E VA L E N C E O F I N S O M N I A D I S O R D E R Gender Diagnosis more common in women Shift hours Patients with irregular shifts at work are more likely to report symptoms of insomnia Disability Higher odds of diagnosis in patients who report having a disability Race Increased risk in racial minorities. Age Greater risk in older patients Socioeconomic status Greater risk in patients with a lower socioeconomic status Comorbidities Increased risk in patients with concurrent medical and/or mental disorders
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  Risk factors forinsomnia disorder are multifaceted, as the development of this condition can involve an interplay among a variety of factors. Insomnia Risk Factors and Potential Causes Environmental Behavioral Physiological Pharmacological o Temperature o Amount of light in the bedroom o Level of noise in the bedroom o Mattress state o Alone/bedpartner o TV on/off o Excessive worry about sleep o Diet/exercise o Daytime activities (e.g., napping) o Pre-bedtime activities (e.g., computer use, exercise) o Increases in basal heart rate and metabolism o Irregular brain metabolism o Age-related changes in brain function o Antidepressants o Sedatives o Antihypertensives o Steroids o Decongestants o Antihistamines o Adrenergic agonists
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  Approximate distribution oftypes of insomnia. Those with primary insomnia make up only a small portion of the population of people with insomnia.
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  Spielman’s 3-P modelfor insomnia. Insomnia develops and is a function of predisposing and precipitating factors and is sustained over time by perpetuating factors.
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  Steps in theevolution of Insomnia
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  Models for InsomniaDisorder A number of models have been proposed to explain the etiology and underlying pathophysiology of insomnia disorder. Behavioral Models: Insomnia disorder is due to behaviors that preclude sleep (e.g., spending too much time in bed) Cognitive Models: Thoughts, feelings, and beliefs underlie insomnia disorder (e.g., excessive worrying) Physiological Models: Insomnia disorder is due to aberrant physiological processes (e.g., dysfunctional sleep-wake regions in brain)
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  Symptoms must havelasted for ≥3 months at a frequency of ≥3 times per week despite adequate opportunity and circumstances to sleep. Dissatisfaction with sleep quantity or quality with one or more of the following: • Difficulty initiating sleep. • Difficulty maintaining sleep, characterized by frequent awakenings. • Early morning awakening with inability to return to sleep. Not better explained by/occur solely during the course of another sleep-wake disorder. The sleep disturbance causes clinically significant distress or impairment in daytime functioning, as evidenced by one of the following: o Fatigue or low energy o Daytime sleepiness o Impaired attention, concentration or memory o Mood disturbances o Behavioural difficulties o Impaired occupational or academic function o Impaired interpersonal or social function o Negative effect on caregiver or family functioning DSM-5 Definition of Insomnia Disorder
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  ICSD 3 criteriafor chronic insomnia disorder Criteria A to F must be met A. The patient reports, or the patients parent or caregiver observes one or more of the following: Difficulty initiating sleep. Difficulty maintaining sleep. Waking up earlier than desired. Resistance to going to bed or appropriate schedule. Difficulty sleeping without parent or caregiver intervention. B. The patient reports, or the patients parent or caregiver observes one or more of the following: Fatigue/ malaise Attention, concentration or memory impairment Impaired social, family, occupational or academic performance. Mood disturbance/ irritability. Daytime sleepiness. Behavioural problems (eg. Hyperactivity, impulsivity, aggression) Reduced motivation/ energy/ initiative. Proneness for errors/ accidents. Concerns about or dissatisfaction with sleep. C. The reported sleep/ wake complaints cannot be explained purely by inadequate opportunity or inadequate circumstances for sleep. D. The sleep disturbance and associated daytime symptoms occur at least 3 times/week. E. The sleep disturbance and associated daytime symptoms have been present for at least 3 months. F. The sleep/ wake difficulty is not explained more clearly by another sleep disorder.
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  Insomnia Disorder: MoreThan Just Insomnia Symptoms (1)Inclusion of 3-month duration criterion, with 3 times per week as the minimum frequency. (2)Elimination of the distinction between “primary” and “secondary” insomnia diagnoses, recognizing that it is often impossible to reliably determine directionality or causality between insomnia and comorbid conditions. (3)ICSD-3 collapses “primary insomnia” subtypes into a single diagnosis, given poor reliability and discriminant validity of these subtypes. Key Revisions From Earlier Criteria Diagnostic Criteria for Insomnia (DSM-5/ICSD-3a) Symptoms Impairment Chronicity + +
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  Clinical Evaluation The AmericanAcademy of Sleep Medicine (AASM) published a guideline for the evaluation and management of chronic insomnia disorder. The AASM recommends that the diagnosis of insomnia disorder rely primarily on a clinical evaluation. What are key components of a clinical evaluation for insomnia disorder? Sleep history. Other history: (e.g., medical and psychiatric history, medication use, family/social/occupational history). Physical and mental health status.
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  Examples of Testsand Tools That Aid in the Diagnosis of Insomnia Disorder T E S T O R T O O L D E S C R I P T I O N A A S M R E C O M M E N DA T I O N Sleep-wake diaries Daily records in which the patient tracks bedtime, length of time to fall asleep, length of sleep, number of nighttime awakenings, length of nighttime sleeplessness, and quality of sleep. Consensus-based Insomnia questionnaires Self-report surveys that assess either sleep quality, sleepiness, psychological issues, or quality of life. Consensus-based Actigraphy Noninvasive method using a portable device worn on the wrist that monitors physical activity to gauge rest and activity cycles. Optional Polysomnography A test involving an overnight stay at a sleep center that is used to identify medical causes of insomnia (e.g., sleep apnea, restless legs syndrome) Only when indicated. Multiple Sleep Latency Test Used to identify suspected hypersomnolence disorders or narcolepsy that may present with symptoms of insomnia. Only when indicated.
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  Management of insomnia •Hypnotic medications used judiciously is the mainstay of treatment. • For few nights to a maximum of 4 weeks. • Most commonly used are BZD receptor agonists. • Melatonin and melatonin receptor agonists for sleep onset insomnia. • Cognitive behavioural therapy, sleep hygiene. • Judicious use of hypnotics. Acute, transient, short term insomnia Chronic insomnia
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  Different Approaches toInsomnia Management CNS=central nervous system; GABA=gamma aminobutyric acid; OTC=over-the-counter 1. Morin CM et al. Sleep. 1999.;22(8):1134-56. 2. Atkin T et al. Pharmacol Rev. 2018;70(2):197-245
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  Technique Involves Addresses Sleephygiene education Review of diet, exercise, alcohol, and environmental factors that may help or interfere with sleep; importance of regular bedtime and set time and the negative effects of long naps. Lifestyle and behaviors that are hurdles to good quality sleep. Stimulus control Teach patient to go to bed only when sleepy; get out of bed when unable to sleep; and when sleepy, stop all sleep-incompatible activities (e.g., television viewing while in bed, using electronic devices before bedtime). The learned associations of the bed with wakefulness. Sleep restriction Emphasize the importance of reducing time in bed to actual sleep time. Disrupted and fragmented sleep related to too much time in bed. Relaxation Teach patient to reduce muscle tension with relaxation techniques and to reduce thoughts that will not shut off by using imagery training and meditation. Increased hyperarousal (physiologic, cognitive, emotional). Cognitive Correct inaccurate beliefs and attitudes about insomnia. Incorrect information and misconceptions that are perpetuating the problem. Components of Cognitive Behavioural Therapy in Insomnia
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  Cognitive behavioural therapyfor insomnia (CBTI) produces durable improvements in sleep-onset latency, wake after sleep onset, and total sleep time 6 months after treatment is discontinued.
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  GABA-A Agonists Drugs GenerationRepresentative Issues Barbiturates 1900 GABAA receptor positive allosteric modulator barbital pentobarbital breathing depression, memory deficits, motor deficits, dependency, tolerance Benzodiazepines 1960 GABAA receptor positive allosteric modulator temazepam triazolam flurazepam memory deficits, motor deficits, dependency, tolerance, rebound insomnia Non-Benzodiazepines 1985 GABAA receptor positive allosteric modulator zolpidem zaleplon zopiclone memory deficits, motor deficits, dependency, tolerance, rebound insomnia (in general, side effects are milder)
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  Effects of theapproved treatment options on Sleep Architecture • Majority of available sleep medications are associated with suppression of REM sleep 1. MacFarlane, J. (2019). The Effects of Psychotropic and Neurotropic Medications on Sleep. Sleep Review Mag. 2. Rosenberg R, et al. (2005). An Assessment of the Efficacy and Safety of Eszopiclone in the Treatment of Transient Insomnia in Healthy Adults. Sleep Med. 2005;6:15-22. 3. Moline, M. et al. Effect of Lemborexant on Sleep Architecture in Older Adults with Insomnia Disorder. Poster presented at 33rd Annual Meeting of the APSS; June 8-12; San Antonio, TX 4. Data on File Eisai Limited. % SWS % REM Sleep Benzodiazepines (BZDs) ↓↓ ↔↓ Non-BZD Receptor Agonists ↔↑ ↔ Tricyclic Antidepressants (TCAs) ↔↑ ↓ ↓ : REM Suppressant ↔: REM Neutral
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  American Academy ofSleep Medicine Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults aAASM guideline suggested use of medication by clinicians for treatment of sleep onset and/or sleep maintenance insomnia versus no treatment. All recommendation categories in gray [including Direction (“For” / “Against”), Quality of Evidence (Very low, Low, Moderate, High, and Very High), and Strength (“Strong” / “Weak”)] based on GRADE approach; for GRADE approach details, refer to Morgenthaler et al. J Clin Sleep Med. 2016; bThese uses may be different than FDA-approved indication; cFDA-approved for treatment of insomnia . AASM=American Academy of Sleep Medicine; FDA=Food and Drug Administration Adapted from Sateia MJ et al. J Clin Sleep Med. 2017;13(2):307-349
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  Unmet Needs inInsomnia Treatment Availability of Additional New Drugs: Lack of additional new drugs in the market which are of good quality and address both sleep onset and sleep maintenance. Long-Term Efficacy: Drugs which can be used for long periods without concerns of dependency or side effects. Fewer Side Effects: Current drugs are addictive or cause dependence. Need drugs which could lower cognitive impairment. Next-Morning Impact: Limited or absence of next-morning impact or behavioral concern.
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  THANK YOU