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