Insomnia – conceptualization
and management in 2009
Martin Reite MD
Clinical Professor of Psychiatry
Medical Director, Neuromagnetic Imaging Lab
UCHSC
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?
Arousal control systems
BF basal forebrain
LC
locus coeruleus
LDT laterodorsal tegmental
LHA lateral hypothalamus
PPT pediculopontine
TMN tuberomammillary
Saper et al. Nature 437:27, 2005
Sleep control systems
VLPO ventrolateral preoptic
nucleus
ORX orexin neurons
Saper et al. Nature 437:27, 2005
Orexin modulated flip-flop switch
Awake state
Sleep state
Saper et al. Nature 437:27, 2005
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, 2008
Nishino et al Sleep 32:175. 2008
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
Process S & Process C
Process S: Homeostatic Sleep Drive
Non-REM sleep (especially Stage 3-4) – the process by which the brain reverses the
neurometabolic effects of waking brain activity.
• Increases with increased time and intensity of preceding wakefulness
• Neurons in the VLPO serve to initiate and maintain sleep
• Purine nucleotide adenosine might serves as a “final common factor”
• Associated with synaptic “pruning and tuning” previous days learning
Process C: Circadian Wakefulness Drive
The circadian tendency to maintain alertness• maximally expressed in the late afternoon and early evening, and minimally
expressed in the morning hours (e.g., 3:00-4:00 am) – closely related to body
temperature rhythm.
•Controlled by light from retina to SCN via retino-hypothalamic tract
• mediated by melatonin and orexin/hypocretin
REM cycle – q90min/24hours a day
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
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
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
Three Questions to Screen for
Sleep Disorders
• Are you content with your sleep? (picks up the insomnias)
• Are you excessively sleepy during the day? (Picks up the
EDS disorders like narcolepsy, primary hypersomnia and and obstructive
apnea )
• Does your bedpartner (or parent) complain about your
sleep? (picks up the parasomnias)
These questions will take about 20 seconds, and pick up
90% of serious sleep problems
If you get the “wrong” answer to any question consider
taking a sleep history
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)
From Reite, Weissberg & Ruddy, Clinical Manual for the Evaluation and Treatment of Sleep Complaints APA Press, 2009
* Drugs reported to cause insomnia
Adrenocorticotropic hormone Dopamine agonists
Alcohol
Anticancer drugs
Anticholinergic: ipratropium
bromide
Ginseng
a-Methyldopa
Monoamine oxidase inhibitors
Niacin
Anticonvulsants: phenytoin,
topiramate, lamotrigine
Oral contraceptives
Phenytoin
Antidepressants, particularly Steriods
SSRIs
Antihypertensives: alphaagonists,
beta-blockers, clonidine
Statins
Antimetabolites
Bronchodilators
Caffeine
Calcium channel blockers
Corticosteroids
Decongestants
Stimulants
Stimulating tricyclic agents
Tamoxifen
Theophylline
Thiazides
Thyroid preparations
Note. SAM-e = S-adenosylmethionine; SSRI = selective serotonin reuptake inhibitor.
Source. Pagel 2005; Walsh 2006.
Overview of the Effects of Antidepressants on Sleep
EEG sleep effects
Drug
Continuity
SWS
REM
Sedation
Amitriptyline (Elavil)
Doxepin (Sinequan)








Imipramine (Tofranil)
Nortriptyline (Pamelor)
Desipramine (Norpramin)












Clomipramine (Anafranil)












TCAs
MAOIs
Phenelzine (Nardil)
Tranylcypromine (Parnate)
From:Reite, Nagel & Ruddy, A Concise Guide to the Evaluation and Treatment of Sleep Disorders, 3rd Ed. APA Press, in press.
EEG sleep effects
Drug
Continuity
SWS
REM
Sedation
Fluoxetine (Prozac)




Paroxetine*(Paxil)




Sertraline (Zoloft)




Citalopram (Celexa)



ND
Fluvoxamine (Luvox)



ND




Venlafaxine (Effexor)




Trazodone (Desyrel)




Mirtazapine (Remeron)




Nefazodone (Serzone)




SSRIs
Others
Bupropion (Wellbutrin)
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”
Alterations in the Circadian Rhythm
Circadian Rhythm
with a 24 Hour
Period
6 Hour Delay of
the Circadian
Rhythm – phase
delay
Free-running
Circadian Rhythm
6 AM
6 AM
6 AM
6 AM
6 AM
Diagnosis of circadian
rhythm disorders
• History
• Actigraphy
• Polysomnography usually not helpful
Actigraphy in DSPD
Treatment of
circadian rhythm disorders
• Light treatment at appropriate time
• Appropriately timed melatonin
• Strict sleep schedule
• Limited use of hypnotics
Other Sleep Disorders
Associated With Insomnia
• Sleep apnea
– 10-second reduction or cessation of breathing occurring >30 times
nightly during sleep
• Restless legs syndrome (RLS)
– Sensorimotor disorder associated with creeping sensation
(dysesthesia) in feet or calves causing irresistible urge to
move limb
– Interferes with ability to fall asleep
• Periodic limb movement disorder
– Regular, jerky, unilateral or bilateral movements characterized
by involuntary repetitive extensions of the great toe during
NREM sleep
• Often accompanied by flexion of hips, knees, and/or ankles
• In some cases, arms are also affected
Czeisler CA et al. In: Braunwald E et al, eds. Harrison’s Principles of Internal Medicine.
15th ed. 2001:155-163.
Please see important safety information on accompanying slides and full prescribing information.
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”
Treating Insomnia Requires a
Comprehensive Approach
Approach
Relieve Symptoms
Treat Underlying
Causes
Modify Behavior
Methods
• Pharmacotherapy
• Patient education
• Reconditioning to
improve sleep hygiene
•
•
•
•
•
Pain management
Psychotherapy
Medical specialists
Sleep specialists
Review medications
Goals
• Primarily for shortterm 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
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
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
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
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
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 duration1
• No evidence of tolerance or abuse during short-term treatment in adult
and/or elderly patients
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
1Extended
release zolpidem package insert, 2005.
Comparison of Sleep Cycles in
Young Adults and the Elderly
Awake
REM
Stage 1
Stage 2
Stage 3
Stage 4
Young Adults
1
2
3
4
5
Hours of Sleep
Awake
REM
Stage 1
Stage 2
Stage 3
Stage 4
6
7
8
7
8
Elderly
1
2
3
4
5
Hours of Sleep
6
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.
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?
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
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
• Don’t neglect behavioral (eg CBT) treatments