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 Ginseng
Anticancer drugs a-Methyldopa
Anticholinergic: ipratropium Monoamine oxidase inhibitors
bromide Niacin
Anticonvulsants: phenytoin, Oral contraceptives
topiramate, lamotrigine Phenytoin
Antidepressants, particularly Steriods
SSRIs
Antihypertensives: alpha- Statins
agonists,
beta-blockers, clonidine

Antimetabolites Stimulants
Bronchodilators Stimulating tricyclic agents
Caffeine Tamoxifen
Calcium channel blockers Theophylline
Corticosteroids Thiazides
Decongestants 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

TCAs
Amitriptyline (Elavil)    
Doxepin (Sinequan)    
Imipramine (Tofranil)    
Nortriptyline (Pamelor)    
Desipramine (Norpramin)    
Clomipramine (Anafranil)    

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

SSRIs

Fluoxetine (Prozac)    
Paroxetine*(Paxil)    
Sertraline (Zoloft)    
Citalopram (Celexa)    ND

Fluvoxamine (Luvox)    ND

Others

Bupropion (Wellbutrin)    
Venlafaxine (Effexor)    
Trazodone (Desyrel)    
Mirtazapine (Remeron)    
Nefazodone (Serzone)    
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
Treat Underlying
Relieve Symptoms Modify Behavior Causes

Methods
• Pharmacotherapy • Patient education • Pain management
• Reconditioning to • Psychotherapy
improve sleep hygiene • Medical specialists
• Sleep specialists
• Review medications

Goals
• Primarily for short- • Longer term effect • Long term goal
term treatment • Restore/establish • Reduce/eliminate
• Restore restful sleep good sleep hygiene sleep disruption
while other modalities • Prevent chronic caused by other
implemented insomnia 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 6 7 8
Hours of Sleep
Awake
REM
Stage 1
Stage 2
Stage 3
Stage 4 Elderly

1 2 3 4 5 6 7 8
Hours of Sleep
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