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Insomnia conceptualization and management in 2009 Martin Reite MD Clinical Professor of Psychiatry Medical Director, Neuromagnetic Imaging Lab UCHSC

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What we are going to talk about: Neurophysiology of sleep Process S and Process C Functions of sleep Effects of sleep loss What are the insomnia disorders? How do we go about a differential diagnosis? What treatment options are available and how, when, and how long do you use them?

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Arousal control systems Saper et al. Nature 437:27, 2005 BF basal forebrain LC locus coeruleus LDT laterodorsal tegmental LHA lateral hypothalamus PPT pediculopontine TMN tuberomammillary

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Sleep control systems Saper et al. Nature 437:27, 2005 VLPO ventrolateral preoptic nucleus ORX orexin neurons

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Orexin modulated flip-flop switch Saper et al. Nature 437:27, 2005 Awake state Sleep state

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Histamine and wake/sleep regulation Histamine in CSF decreased in narcolepsy and primary hypersomnia Three receptor subtypes: 1.H1 & H2 widespread in brain as well as peripheral postsynaptic and promote excitatory neurotransmission & wakefulness antagonists promote sleep 2.H3 presynaptic in brain activation decreases histamine release and promotes sleep antagonists promote wakefulness Histaminergic neurons in tubero-mammilary nucleus (TMN) of post hypothalamus Hypocretin neurons project to and regulate TMN histamine production via hcrt-2 receptor subtype Kanbayashi et al Sleep 32:181, 2008Nishino et al Sleep 32:175. 2008

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Sleep stages and their function General purpose of sleep is maintenance of brain function. Total sleep deprivation leads to death. Non-REM slow wave sleep, especially Stage 3-4 (delta) sleep may be involved in synaptic pruning and tuning and other aspects of learning and memory REM sleep essential for the developing mammalian brain, but functions of REM sleep in adults remains uncertain

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Consquences of sleep loss in normal subjects psychomotor performance antibody performance following immunization* leptin and grehlin production** C-reactive protein*** risk for insulin resistance and type 2 diabetes Chronic insomniacs may be at increased risk for all the above *Lange et al Psychosom Med 65:831, 2003 **Spiegel et al Ann Int Med 141:846, 2005* ***Meier-Ewert et al J Am Coll Cardiol 43:678, 2004

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Insomnia the most common sleep complaint 30% of people in the general population experience symptoms consistent with insomnia Symptoms may include: Cant get to sleep, cant stay asleep, wake to early, sleep not refreshing, all of the above

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Consequences of chronic insomnia Diminished quality of life, impaired memory and concentration, ability to accomplish daily tasks, ability to enjoy interpersonal relationships risk of developing anxiety and depression* health care costs Impaired memory consolidation hippocampal volumes** (?memory?) *Neckelmann et al Sleep 30:873, 2007 **Riemannn et al Sleep 30:955, 2007

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Differential Diagnosis of a chronic insomnia complaint - a 6 step process : Step 1. Medical conditions and dementia Step 2. Psychiatric disorders Step 3. Substance misuse Step 4. Circadian rhythm disorders Step 5. Movement disorders including Restless leg syndrome (RLS) and Periodic Leg Movements in Sleep (PLMS) Step 6. The primary insomnia, conditioned insomnia and SSMP group Primary insomnia Conditioned insomnia Sleep State Misperception Syndrome (SSMS)

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*Drugs reported to cause insomnia Adrenocorticotropic hormoneDopamine agonists AlcoholGinseng Anticancer drugs -Methyldopa Anticholinergic: ipratropium bromide Monoamine oxidase inhibitors Niacin Anticonvulsants: phenytoin, topiramate, lamotrigine Oral contraceptives Phenytoin Antidepressants, particularly SSRIs Steriods Antihypertensives: alpha- agonists, beta-blockers, clonidine Statins AntimetabolitesStimulants BronchodilatorsStimulating tricyclic agents CaffeineTamoxifen Calcium channel blockersTheophylline CorticosteroidsThiazides DecongestantsThyroid preparations Note. SAM-e = S-adenosylmethionine; SSRI = selective serotonin reuptake inhibitor. Source. Pagel 2005; Walsh 2006. From Reite, Weissberg & Ruddy, Clinical Manual for the Evaluation and Treatment of Sleep Complaints APA Press, 2009

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Common circadian rhythm disorders Delayed sleep phase syndrome most common usually familial/genetic causes Onset adolescence & early adulthood Advanced sleep phase syndrome Onset late adulthood Both familial and age related causes Non-24 hour sleep wake rhythm Seen in 50% of blind persons Also seen in developmental disorders All masquerade as insomnia

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Circadian Rhythm with a 24 Hour Period 6 Hour Delay of the Circadian Rhythm phase delay Free-running Circadian Rhythm 6 AM Alterations in the Circadian Rhythm

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Diagnosis of circadian rhythm disorders History Actigraphy Polysomnography usually not helpful

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Actigraphy in DSPD

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Treatment of circadian rhythm disorders Light treatment at appropriate time Appropriately timed melatonin Strict sleep schedule Limited use of hypnotics

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The Primary Insomnia, Conditioned Insomnia, Sleep State Misperception (Paradoxical Insomnia) Group often termed psychophysiological insomnia Primary Insomnia a DSM-4 diagnosis Difficulty initiating, maintaining, or non restorative sleep >1mo Causes significant daytime functional impairment Other med, psych, circadian causes ruled out Conditioned or Learned insomnia Starts with stressful situation impairing sleep Fears going to bed because wont be able to sleep May sleep normally in other places e.g. sleep lab Sleep state misperception syndrome Unaware of being asleep May have normal PSG in lab (yet complain of not sleeping) Daytime impairment similar to primary insomnia Termed paradoxical insomnia

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Treating Insomnia Requires a Comprehensive Approach Treat Underlying Causes Modify BehaviorRelieve Symptoms Approach Pain management Psychotherapy Medical specialists Sleep specialists Review medications Patient education Reconditioning to improve sleep hygiene Pharmacotherapy Methods Primarily for short- term treatment Restore restful sleep while other modalities implemented Longer term effect Restore/establish good sleep hygiene Prevent chronic insomnia Long term goal Reduce/eliminate sleep disruption caused by other conditions Goals

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Nonpharmacologic Treatment Strategies Cognitive behavioral therapy very important Sleep education Sleep hygience education Sleep restriction Relaxation training Biofeedback may be helpful Exercise & improved aerobic fitness But pharmacoloigcal treatments will usually also be necessary

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Other sleep agents -1 Tiagabine (Gabitril) inhibits GABA reuptake, approved for seizure control only improved sleep in chronic pain (Todorov et al, 2005), increases SWS in dose dependent fashion 4-10 mg (Walsh 2006) Sodium oxybate (Xyrem) approved for narcolepsy increases Stage 3-4 sleep considerable potential risk one of the date rape drugs (GHB, flunitrazepam, ketamine) may be useful in fibromyalgia (Scharf et al 2003) Todorov et al Clin J Pain 21:358, 2005 Walsh et al J Clin Sleep Med 2:35, 2006 Scharf et al J Rheumaton 30:1070, 2003

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Other sleep agents - 2 Gaboxadol selective extrasynaptic GABAa agonist increases SWS dose dependent up to 15mg (Deacon et al 2007) Doxepin effective for primary insomnia at 3 and 5 mg (Roth et al 2007) Ramelteon (Rozerem) M1 & M2 melatonin receptor agonist - role still uncertain in insomnia but is approved for long term use probably circadian rhythm control Deacon et al Sleep 30:281, 2007 Roth et al Sleep 30:1555, 2007

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Other Sedating Antidepressants and Prescription Medications Used Off-label Sedating antidepressants Mirtazapine, doxepin and amitriptyline are used but with little supporting data except for doxepin The NIH panel raised concerns about the risk-benefit ratio due to the associated adverse effects Antipsychotics (eg, quetiapine and olanzapine) and barbiturates The NIH panel concluded that these classes lack the data for use in insomnia and were not recommended due to significant risks associated with treatment National Institutes of Health. NIH state-of-the-science conference statement: manifestations and management of chronic insomnia in adults. June 13-15, 2005. Available at http://consensus.nih.gov/ta/026/InsomniaDraftStatement061505.pdf

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Benzodiazepine Receptor Agonists NIH Panel Conclusions Benzodiazepines Estazolam, flurazepam, quazepam, temazepam, and triazolam Nonbenzodiazepines Eszopiclone, zaleplon, and zolpidem Both classes are indicated for treating insomnia, but the risk-benefit ratio for nonbenzodiazepines is superior to that of the benzodiazepines Efficacious for short term treatment Eszopiclone has been studied for 6 months and is approved for use without a specified time limit Extended release zolpidem has been studied for 3 weeks and does not have a specified limit to treatment duration 1 No evidence of tolerance or abuse during short-term treatment in adult and/or elderly patients 1 Extended release zolpidem package insert, 2005. National Institutes of Health. NIH state-of-the-science conference statement: manifestations and management of chronic insomnia in adults. June 13-15, 2005. Available at http://consensus.nih.gov/ta/026/InsomniaDraftStatement061505.pdf

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Comparison of Sleep Cycles in Young Adults and the Elderly The elderly tend to have less stage 3 and 4 sleep and develop advanced phase sleep syndrome (go to bed early, wake up early), while the young tend to have delayed phase shift syndrome (go to bed late, wake up late). Neubauer DN. Am Fam Physician. 1999;59:2551-2558. Millman RP, Working Group on Sleepiness in Adolescents/Young Adolescents. Pediatrics. 2005;115:1774-1786. Hours of Sleep Young Adults Awake REM Stage 1 Stage 2 Stage 3 Stage 4 12345678 Awake REM Stage 1 Stage 2 Stage 3 Stage 4 12345678 Hours of Sleep Elderly

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Sleep and aging Multiple med/psych/environ causes for insomnia Process S 50% loss of VLPO neurons with age Process C decreased melatonin production and decreased light sensitivity with age Does sleep loss and fragmentation in the elderly contribute to many of the symptoms attributed to normal aging e.g. cognitive difficulties, inflammation, weight/diabetes? Where do we stand with respect to long term hypnotic use to improve sleep in otherwise healthy older adults? What about hypnotic use and falls?

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Insomnia, hypnotics, and falls in the elderly In 34,163 nursing home residents in Michigan, complaints of insomnia (past month), but not hypnotic use (past week) predicted falls. Untreated insomnia, and hypnotic unresponsive insomnia, primarily responsible for falls. Avidan et al J Am Geriatr Soc 53:955, 2005

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Overall Summary Sleep complaints should be taken seriously Accurate differential diagnosis important Sleep studies usually for EDS disorders Sleep studies usually not needed for insomnia Safe and effective treatments available for most insomnias Long term treatment may be necessary for insomnia as in depression Dont neglect behavioral (eg CBT) treatments