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Sleep: Considerations
in the Patient With
Psychiatric Disorders
Rafael Pelayo, MD
Topics
• Definition of insomnia
• Epidemiology of insomnia with psychiatric disorders
• Specific features of sleep and sleep disturbances
in psychiatric disorders
• Diagnostic evaluation of insomnia/sleep problems
in psychiatric disorders
• Causes/etiologies of sleep problems in specific
psychiatric disorders
• Behavioral treatment
• Medication treatment
Respondents (%)
Sleep in America:
2005 National Sleep Foundation Poll
60
Weekdays
Weekends
49%
50
31%
40
30
24%
16%
20
24%
26%
15%
10%
10
0
<6
6 to 6.9
7 to 7.9
8
Hours of Sleep/Night
N=1,506 adults
Mean=6.8 hours on weekdays; 7.4 hours on weekends
National Sleep Foundation. 2005 Sleep in America Poll: Summary of findings. Available at:
http://www.kintera.org/atf/cf/{F6BF2668-A1B4-4FE8-8D1A-A5D39340D9CB}/2005_summary_of_findings.pdf.
Accessed January 23, 2008.
Sleep in America:
Frequency of “A Good Night’s Sleep”
Every night/Almost every night
49%
A few nights per week
24%
A few nights per month
13%
Rarely
26%
10%
N=1,506 adults
Never
3%
0%
10%
20%
30%
40%
50%
60%
• Of the adults getting “a good night’s sleep,” only 26% get a few
nights per month or less
National Sleep Foundation. 2005 Sleep in America Poll: Summary of findings. Available at:
http://www.kintera.org/atf/cf/{F6BF2668-A1B4-4FE8-8D1A-A5D39340D9CB}/2005_summary_of_findings.pdf.
Accessed January 23, 2008.
Insomnia: Definition
• Complaint of inadequate sleep despite sufficient
opportunity
• Typically complains of trouble falling asleep
and/or staying asleep
• Results in daytime impairment
• Insomnia is a 24-hour condition
National Institutes of Health State of the
Science Conference Statement
•
•
•
•
•
Manifestations and Management Of Chronic Insomnia in Adults
Chronic insomnia is a major public health problem affecting millions of individuals,
along with their families and communities
Little is known about the mechanisms, causes, clinical course, comorbidities, and
consequences of chronic insomnia
Evidence supports the efficacy of cognitive-behavioral therapy and benzodiazepine
receptor agonists in the treatment of this disorder
Very little evidence supports the efficacy of other treatments, despite their
widespread use
–
–
•
Even treatments that have been systematically evaluated, the panel is concerned about the
mismatch between the potential lifelong nature of this illness and the longest clinical trials,
which have lasted 1 year or less
A substantial public and private research effort is warranted, including the development of
research tools and the conduct of longitudinal studies and randomized clinical trials
There is a major need for educational programs directed at physicians, healthcare
providers, and the public
National Institutes of Health. Sleep. 2005;28:1049-1057.
National Institutes of Health State of the
Science Conference Statement (cont’d)
• Manifestations and management of chronic
insomnia in adults
– Primary insomnia
• Implies no other cause of sleep disturbance
– Comorbid insomnia
• Formerly known as secondary insomnia
• Limited understanding of pathophysiology and direction of
causality
• Use of term “secondary” leads to undertreatment
National Institutes of Health. Sleep. 2005;28:1049-1057.
National Institutes of Health State of the
Science Conference Statement (cont’d)
• Manifestations and management of chronic
insomnia in adults
– Some evidence suggests high healthcare utilization
– Direct and indirect costs of chronic insomnia
estimated as tens of billions of dollars annually
– Difficulty separating economic effects of insomnia
from comorbid conditions
National Institutes of Health. Sleep. 2005;28:1049-1057.
Comorbid Insomnia
Psychiatric disorders
• Depression
• Anxiety
Medical conditions
• Cardiopulmonary
• Musculoskeletal
Comorbid insomnia
Sleep disorders
• Obstructive sleep apnea
• Restless legs syndrome
• Circadian rhythm
Pharmacological agents
• Prescription/OTC
medications
• Nicotine
• Substance abuse
Impairments Associated With Insomnia
• Impaired cognitive functioning
• Negative quality-of-life measures
• Increased incidence of bodily pain,
poor general health
• Increased future risk of psychiatric disorders
• Decreased job performance, increased
absenteeism
• Increased risk of accidents
• Increased healthcare costs
Model of Chronic Insomnia
Predisposing Factors
Precipitating Factors
Perpetuating Factors
• Biological traits
• Psychological traits
• Social factors
• Medical illness
• Psychiatric illness
• Stressful life events
• Excessive time in bed
• Napping
• Conditioning
Insomnia
Threshold
Preclinical
Adapted from: Spielman et al
Onset
Short-term
Chronic
Insomnia
Depression
• 40%-60% of outpatients and up to 90% of
inpatients with a major depressive episode
experience sleep problems
Sleep in Depressed Patients
• Patients experience:
–
–
–
–
Difficulty falling asleep
Frequent awakenings
Waking too early in the morning (terminal insomnia)
Fatigue when awake
Place of Chronic Insomnia in the Course
of Depressive and Anxiety Disorders
9.0
7.8
8.0
7.0
Rate (%)
6.0
5.0
5.0
4.0
3.1
3.0
1.6
2.0
1.0
0.9
0.6
0.0
1 month
1-6 months
6-12 months
1-5 years
Insomnia duration
Ohayon MM, Roth T. J Psychiatr Res. 2003;37:9-15.
5-10 years
10 years
Sleep Timing
• Sleep timing is influenced by
homeostatic and circadian factors
• The less we sleep, the more sleep we
need and vice versa
• Twice a day our alertness level peaks
• Twice a day our sleepiness peaks
Sleep Stages
Electroencephalography
Recordings
Typical Nighttime Sleep Pattern
in a Young Adult
Awake
Awake
Stage 1
and REMa
Stage 1
Stage 2
Stage 2
Stage 3
Stage 3
Stage 4
Delta 4
1
2
3
4
5
Time (hours)
aRapid
eye movement
6
7
Key Polysomnographic Terms
•
•
•
•
•
•
•
Sleep latency
REM latency
Sleep efficiency
Wake after sleep onset (WASO)
Percent REM sleep
Percent slow-wave sleep (SWS)
Percent stage 1
Polysomnographic Changes in
Depression
• Prolonged sleep latency
• Increased WASO
• Decreased SWS
Polysomnographic Changes in
Depression (cont’d)
• Reduced REM latency
• Prolonged first REM period
• Density of the rapid eye movements during REM
is more variable in depressed subjects, with
periods when the eye movements are very
sparse and periods when there are eye
movement storms
• Patients in remission from depression show a
reduction in eye movement density, but reduced
REM latency remains
Comorbid Psychiatric Conditions:
Major Depressive Disorder
• Sleep-wake disturbances are experienced by
40% to 60% of outpatients with major depressive
disorder (MDD)1
• 29% of patients with excessive sleepiness were
diagnosed with MDD2
• 16% to 20% of patients with MDD and 36% of patients
with atypical MDD report excessive sleepiness3,4
• Most common residual symptoms in outpatients with full
response to fluoxetine were sleep-wake disturbances
and fatigue5
1. Armitage R. Can J Psychiatry. 2000;45:803-809.
2. Roberts RE, Shema SJ, Kaplan GA, Strawbridge WJ. Am J Psychiatry. 2000;157:81-88.
3. Posternak MA, Zimmerman M. Arch Gen Psychiatry. 2002;59:70-76.
4. Horwath E, Johnson J, Weissman MM, Hornig C. J Affect Disord. 1992;26:117-125.
5. Nierenberg AA, Keefe BR, Leslie VC, et al. J Clin Psychiatry. 1999;60:221-225.
Sleep Loss and Health:
Physiologic Studies1-4
• In the laboratory setting, short-term sleep restriction leads to a
variety of adverse physiologic sequelae, including:
–
–
–
–
–
–
–
Impaired glucose control
Increased cortisol
Increased blood pressure
Sympathetic activation
Increased appetite
Increased C-reactive protein
Immune function
• These data suggest that sleep restriction may have health
consequences (obesity, diabetes, cardiovascular disease)
1. Spiegel K, Tasali E, Penev P, Van Cauter E. Ann Intern Med. 2004;141:846-850.
2. Meier-Ewert HK, Ridker PM, Rifai N, et al. J Am Coll Cardiol. 2004;43:678-683.
3. Spiegel K, Leproult R, L'hermite-Balériaux M, Copinschi G, Penev PD, Van Cauter E. J Clin Endocrinol Metab.
2004;89:5762-5771.
4. Spiegel K, Sheridan JF, Van Cauter E. JAMA. 2002;288:1471-1472.
Insomnia By Age Group
30
25
20
%
15
10
5
0
18-34
35-49
50-64
Age Group
Mellinger GD, Balter MB, Uhlenhuth EH. Arch Gen Psychiatry. 1985;42:225-232.
65-79
Insomnia and Depression
• Striking association between insomnia
and depression
• Insomnia early marker for onset of depression
• May be linked by common pathophysiology1
• Need to treat both insomnia and depression
1. Benca RM. Mood disorders. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine.
Philadelphia, PA: Elsevier/Saunders; 2005:1311-1326.
Impact of Insomnia on Quality of Life
Insomnia is associated with
reduced mental health, vitality, and social functions
Deviation From Reference Group
Impact on SF-36 HRQOL Domainsa (N=3,445)
5
Physical
Function
Role,
Physical
Pain
Health
Perception
Vitality
Social
Role,
Emotional
0
-5
-10
-15
-20
-25
-30
-35
Mild insomnia
Severe insomnia
Congestive heart failure
Clinical depression
except congestive heart failure association with pain, emotional role, and mental health
Graph adapted from: Katz DA, McHorney CA. J Fam Pract. 2002;51:229-235.
Taylor DJ, Lichstein KL, Durrence HH, Reidel BW, Bush AJ. Sleep. 2005;28:1457-1464.
aP≤0.001
Mental
Health
Dreaming and Mood Regulation
• Why do we feel better after a good night
of sleep?
• What is it about sleep that restores us both
physiologically and psychologically?
Dreaming and Mood Regulation (cont’d)
• Dreaming has been hypothesized to have an
active self-regulatory role in emotional
modulation, and that role can be disrupted due
to various trait and state variables and their
interactions
Dreaming and Mood Regulation (cont’d)
• Dreams that are spontaneously remembered
are often accompanied by anxiety or other
negative feelings
– Dream content analysis of 250 healthy adults showed
unpleasant effects predominating at a ratio of 2:1,
with fear, anxiety, and anger as the most commonly
identified1
• Patients suffering from an episode of major
depression typically have reduced recall of
dreams and absence of dream affect
1. Snyder, F. The phenomenology of dreaming. In: Madow L, Snow L, eds. The psychodynamic implications of the
physiological studies on dreams. Springfield, IL: C.C. Thomas; 1970:124-151.
Relation of Dreams to Waking Concerns
•
•
•
•
To test that dreams are influenced by the presleep waking emotional
concerns of the sleeper and have an effect on waking adaptation, 20
depressed and 10 control subjects, who were all going through a divorce,
were enrolled in a repeated measures study lasting 5 months
A Current Concerns test was administered on 3 occasions before nights
when every REM period was interrupted to record recalled mental content
The degree of waking concern about the ex-spouse correlated
significantly with the number of dreams in which the former partner
appeared as a dream character
Those who were in remission at the follow-up evaluation had a higher
percentage of well-developed dreams than those who remained depressed
– Dreams of the former spouse reported by those in remission differed from those who
remained depressed in the expression of dream affect and in the within-dream
linkage among units of associated memory material
– Dreams of the former spouse that are reported by those who are not in remission
lack affect and connection to other memories
Cartwright R, Agargun MY, Kirkby J, Friedman JK. Psychiatry Res. 2006;141:261-270.
REM Sleep Reduction, Mood Regulation,
and Remission in Untreated Depression
•
•
•
The contribution of ↑REM pressure through repeated, mild, reduction
of REM sleep to remission from untreated depression was studied
over a 5-month period in 20 depressed and 10 control volunteers
60% of the depressed were in remission at the end of the study
64% of the variance in remission could be accounted for by 4
variables:
– The initial level of self-reported symptoms
– The reported diurnal variability in mood
– The degree of overnight reduction in depressed mood following interruptions
of REM sleep
– The quality of dream reports from these awakenings
– Increased REM pressure is beneficial for those who are able to construct
well-organized dreams
•
Increased REM pressure is beneficial for those who are able to construct
well-organized dreams
Cartwright R, Agargun MY, Kirkby J, Friedman JK. Psychiatry Res. 2006;141:261-270.
Diagnosis and
Treatment of Insomnia in
Patients With
Psychiatric Disorders
Ruth M. Benca, MD, PhD
University of Wisconsin-Madison
Evaluation of Insomnia Relies on a
Subjective Report1,2
• Based primarily on subjective report of patient
and/or family
• Medical history, physical examination, and
laboratory testing to assess comorbid conditions
• Sleep diaries and questionnaires useful for
diagnosis and to assess treatment response
• Actigraphy
• Polysomnography not usually indicated
1.
2.
National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:1049-1057.
Chesson A Jr, Hartse K, Anderson WM, et al. Sleep. 2000;23(2):237-241.
Sleep Problems Are Often Multifactorial
•
•
•
•
Psychiatric illness-specific factors
Medications
Primary sleep disorders
Behavioral factors
Psychiatric Illness-specific Factors
• Mood disorders
– Diurnal mood variation
– Rapid cycling
– Seasonal and circadian rhythm abnormalities
• Anxiety disorders
– Nocturnal panic attacks
– Posttraumatic stress disorder and anxiety dreams
• Schizophrenia
– Exacerbation of psychosis at night
Psychiatric Disorders Associated With
Objective Changes in Sleep Architecture
TSTa
SEb
SLc
SWSd
REM Le
Mood
Alcoholism
Anxiety
disorders
Schizophrenia
Insomnia
• Comparison of sleep EEGf in groups of patients with psychiatric
disorders or insomnia to age-matched normal controls
aTotal
sleep time; bsleep efficiency; csleep latency ; dslow-wave sleep; erapid eye movement latency; felectroencephalograph
Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Arch Gen Psych. 1992;49:651-668.
Effects of Psycopharmacologic Agents
on Sleep
• Psychopharmacologic agents act on
neurotransmitter systems involved in sleeping
and waking
– 5-hydroxytryptamine, acetylcholine, dopamine,
histamine, norepinephrine
• They can have clinically significant effects on
sleep, which may enhance therapeutic effects
(eg, treat insomnia) or result in side effects (eg,
insomnia or daytime sleepiness)
DeMartinis NA and Winokur A. CNS Neurol Disord Drug Targets. 2007;6:17-29.
Effects of Psychopharmacologic Agents
on Sleep (continued)
• Antidepressants
• Antipsychotics
• Stimulants
Antidepressants and Their Effect on
Sleep
• Most antidepressants disrupt sleep, although a
minority of patients may report sedation
–
–
–
–
SSRIsa (fluoxetine, sertraline, paroxetine, citalopram)
Dual reuptake inhibitors (venlafaxine, duloxetine)
Bupropion
Monoamine oxidase inhibitors
• Sedating antidepressants frequently used to
treat insomnia associated with depressionb
.
– Trazodone
– Tricyclics (amitriptyline, doxepin)
– Mirtazapine
aSelective
serotonin reuptake inhibitors
use by the US Food and Drug Administration (FDA)
Peterson MJ, Benca RM. Psychiatr Clin North Am. 2006;29:1009-1032;
bUnapproved
Antidepressant and Their Effects on
Sleep
• The following drugs decrease sleep continuity
–
–
–
–
SSRIs – also suppress REMa sleep
Bupropion – has inconsistent effects on REM and SWSb
Venlafaxine – can also suppress REM sleep
MAOIsc – have a tendency to suppress REM and impair sleep
continuity and decrease sleep time
• The following drugs increase sleep continuity
– Trazodone – can have sedating effects and suppress REM sleep
– Mirtazapine – has prominent sedating effects
– TCAsd – tend to result in sedation and REM suppression
aRapid
eye movement; bslow-wave sleep; cmonoamine oxidase inhibitors; dtricyclic antidepressants
Mayers AG and Baldwin DS. Hum Psychopharmacol Clin Exp. 2005;20:533-559;
Argyropoulos SV and Wilson SJ. Int Rev Psychiatry. 2005;17:237-245.
Antipsychotics and Their Effect on Sleep
• Typical agents include:
– Thorazine
– Haloperidol
• Newer atypical agents include:
– Clozapine: tends to enhance sleep continuity1,2
– Olanzapine: tends to enhance sleep continuity1,3
– Quetiapine: decreases sleep latency and wake time, increases
sleep time and no changes in SWS, REM L, or REM density
were noted4
– Risperidone: decreases awakenings, improves sleep quality, and
increases SWS in patients with schizophrenia1,3
1 DeMartinis NA and Winokur A. CNS Neurol Disord Drug Targets. 2007;6:17-29; 2. Armitage R, Cole D, Suppes T,
Ozcan ME. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:1065-1070; 3. Giménez S, Clos S, Romero S, Grasa
E, Morte A, Barbanoj MJ. Psychopharmacology (Berl). 2007;190:507-516. Epub 2007 Jan 5; 4. Keshavan MS, Prasad
KM, Montrose DM, Miewald JM, Kupfer DJ. J Clin Psychopharmacol. 2007;27:703-705.
Stimulants and Their Effect on Sleep
• Increasingly used for attention deficit disorder/
attention deficit hyperactivity disorder,
depression, fatigue
– Methylphenidate
– Amphetamine
– Modafinil
• Effects include:
– Decreased TST
– Increased arousals
– Suppressed REM sleep
Mendelson WB, Caruso C. Pharmacology in sleep medicine. In: Poceta JS, Mitler MM, eds. Sleep
Disorders: Diagnosis and Treatment. Totowa, NJ: Humana Press Inc.; 1998:137-160.
Primary Sleep Disorders and
Psychiatric Illnesses
• Obstructive sleep apnea
• Restless legs/periodic limb movements
• Narcolepsy
Obstructive Sleep Apnea
• High rates of comorbidity with depression
– For patients with either disorder, there is a 1 in 5 risk
of having both disorders1
• Overlapping symptoms between apnea and
depression, particularly:
– Fatigue, decreased attention/concentration, lack of
motivation, decreased enjoyment
1. Ohayon MM. J Clin Psychiatry. 2003;4:1195-1200.
Psychiatric Medications May Exacerbate
Sleep Apnea Through:
• Weight gain
– Atypical antipsychotics
– Antidepressants
– Mood stabilizers
• Muscle relaxation
– Benzodiazepines
– Barbiturates
• Decreased arousal threshold
Sleep-related Movement Disorders
• Many psychiatric medications can increase PLMSa that
lead to arousals and sleep fragmentations
– SSRIs, serotonin-norepinephrine reuptake
inhibitors
– Antipsychotics (typical and atypical)
• Bupropion less likely to exacerbate restless leg
syndrome/PLMS
• Pharmacologic mechanisms thought to be associated
with PLMS:
– Reuptake inhibition of 5-hydroxytryptamine
– Dopamine antagonism
aPeriodic
leg movements in sleep
Yang C, White DP, Winkelman JW. Biol Psychiatry. 2005;58:510-514. Epub 2005 Jul 7;
Nofzinger EA, Fasiczka A, Berman S, Thase ME. J Clin Psychiatry. 2000;61:858-862.
Narcolepsy and Schizophrenia
• The onset of both diseases occurs in the teenage years
and 20s1
• It is unknown whether one disorder presents a greater
risk for the other1
• Narcolepsy incidence is drastically lower than that of
schizophrenia1
• Due to an overlap in symptoms, they are both commonly
misdiagnosed1
– Hypnagogic/hypnopompic hallucinations associated with
psychotic disorders2
• Patterns usually differ3
– Auditory hallucinations more common in schizophrenia
– Visual or kinetic hallucinations more common in narcolepsy
1. Kishi Y, Konishi S, Koizumi S, Kudo Y, Kurosawa H, Kathol RG. Psychiatry Clin Neurosci. 2004;58:117-124;
2. Ohayon MM, Priest RG, Caulet M, Guilleminault C. Br J Psychiatry. 1996;169:459-467;
3. Dahmen N, Kasten M, Mittag K, Müller MJ. Eur J Health Econ. 2002;3(suppl 2):S94-S98.
Narcolepsy and Schizophrenia (continued)
• Psychotic form of narcolepsy vs stimulant-induced
psychotic disorder?1,2
– Stimulants may lead to psychotic symptoms in narcoleptics
• Misdiagnosis may lead to inappropriate treatment2
– Reports of treatment-refractive schizophrenia that turns out to be
stimulant-responsive narcolepsy
• Comorbid disorders can create treatment dilemmas2
– Stimulants often exacerbate psychotic symptoms
– Antipsychotics may exacerbate sleepiness
1. Dahmen N, Kasten M, Mittag K, Müller MJ. Eur J Health Econ. 2002;3(suppl 2):S94-S98;
• Benca RM. J Clin Psychiatry. 2007;68 (suppl 13):5-8.
Behavioral Factors Contributing to Sleep
Problems in Psychiatric Patients
• Lack of daily structure
• Irregular sleep patterns/napping
• Psychosocial stressors
Relationship Between Sleep and
Psychiatric Disorders
• Symptom overlap of insomnia and psychiatric
disorders, particularly depression
– Creates diagnostic issues
• Psychological disorders are associated with
sleep disturbance
– Insomnia may be a risk factor in psychological
disorders
– Psychological medications may affect sleep
1. Wilson S, Argyropoulos S. Drugs. 2005;65:927-947.
Treatment of Insomnia
•
•
•
•
Optimize treatment of psychiatric disorder
Promote good sleep hygiene
Consider cognitive behavior therapy
Consider medications to improve sleep
Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346.
Practicing Good Sleep Hygiene
•
•
•
•
Increase exposure to bright light during the day1
Time regular exercise for the morning and/or afternoon2,3
Enhance sleep environment: dark, quiet, cool temperature2,3
Avoid:
–
–
–
–
“Watching the clock”
Use of stimulants, eg, caffeine, nicotine, particularly near bedtime2,3
Heavy meals or drinking alcohol within 3 hours of bed2
Exposure to bright light during the night2,3
• Practice a relaxing routine around bedtime1-3
• Reduce time in bed; regular sleep/wake cycle1-3
1. Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346;
2. NHLBI Working Group on Insomnia. 1998. NIH Publication. 98-4088;
3. Lippmann S, Mazour I, Shahab H. South Med J. 2001;94:866-873.
Cognitive Behavioral Therapy for Sleep
• Change maladaptive sleep habits
• Decrease autonomic and cognitive arousal
• Modify dysfunctional beliefs and attitudes
about sleep
Morin CM, Hauri PJ, Espie CA, Spielman AJ, Buysse DJ, Bootzin RR. Sleep. 1999;22:1134-1156.
Behavioral Techniques
1. Stimulus control therapy: positive association
made between the bed and bedroom1
2. Sleep restriction: limit time in bed to increase
homeostatic sleep drive1
3. Relaxation training: decrease arousal and
anxiety1
4. Circadian rhythm entrainment: reinforce or
reset biological rhythm using light and/or
chronotherapy1,2
1. Morin CM, Bootzin RR, Buysse DJ, Edinger JD, Espie CA, Lichstein KL. Sleep. 2006;29:1398-1414;
2. Barion A, Zee PC. Sleep Med. 2007;8:566-577. Epub 2007 Mar 28.
Studies Show Effectiveness of Behavioral
Interventions in Insomnia
Meta-analysis of 59 Trials (N=2,102)
Sleep-onset Latency P<0.001
Pretreatment
Time Awake After Sleep Onset P<0.001
Posttreatment
Pretreatment
70
80
60
70
60
Minutes
50
Minutes
Posttreatment
40
30
50
40
30
20
20
10
10
0
0
Control
Conditions
Behavioral
Treatments
Morin CM, Culbert JP, Schwartz SM. Am J Psychiatry. 1994;151:1172-1180.
Control
Conditions
Behavioral
Treatments
Pharmacologic Treatment
• Over-the-counter (OTC) agentsa
– Antihistamines1
– Herbs2
– Melatonin3
• 23% Of patients with insomnia use OTC remedies to self-medicate4
• 28% Of patients with insomnia use alcohol to self-medicate4
• Prescription agents
–
–
–
–
–
aUnapproved
Benzodiazepine receptor agonists1
Melatonin receptor agonists
Antidepressants, sedatinga,1
Anticonvulsantsa,3
Atypical antipsychoticsa,2
use by the US Food and Drug Administration (FDA)
1. Mendelson WB, Caruso C. Pharmacology in sleep medicine. In: Poceta JS, Mitler MM, eds. Sleep Disorders: Diagnosis and
Treatment. Totowa, NJ: Humana Press Inc.; 1998:137-160; 2. National Institutes of Health State of the Science Conference
Statement. Sleep. 2005;28:1049-1057; 3. Lippmann S, Mazour I, Shahab H. South Med J. 2001;94:866-873; 4. Smith MT, Perlis
ML, Park A, et al. Am J Psychiatry. 2002;159:5-11.
Benzodiazepine Receptor Agonists
• Allosteric modulators of γ-aminobutyric acidA
(GABA)-receptor complex
• Increased influx of Cl- into neurons, leading to
hyperpolarization
• GABA receptors found in sleep-promoting
pathways, including cerebral cortex, thalamus,
hypothalamus
Benzodiazepine Hypnotics
(FDA Approved)
• Effective in promoting sleep1
– All benzodiazepine hypnotics reduce sleep latency
• Longer-acting agents maintain sleep1
– May decrease wakefulness during sleep
– Increase total sleep time
• Agents
–
–
–
–
–
Triazolam: dose, 0.125-0.25 mg ; t1/2 2-4 hours2
Temazepam: dose 15-30 mg; t1/2 8-20 hours3
Estazolam: dose 1-2 mg; t1/2 10-24 hours4
Flurazepam: dose 15-30 mg; t1/2 24-100 hours5
Quazepam: dose 7.5-15 mg; t1/2 25-41 hours6
1. Charney DS, Mihic SJ, Harris RA. In: Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. New York: McGraw-Hill; 2001:399-427; 2. Pfizer Inc. Available at: http://www.pfizer.com/files/products/
uspi_halcion.pdf. Accessed June 4, 2008; 3. Mallinckrodt Pharmaceuticals. Available at: http://www.restoril.com. Accessed June
4, 2008 ; 4. Abbott. Available at: http://www.rxabbott.com/pdf/prosom.pdf. Accessed June 4, 2008; 5. West-ward Pharmaceutical
Corp Available at: http://www.rxlist.com/cgi/generic/fluraz_cp.htm. Accessed June 4, 2008; 6. Questcor Pharmaceuticals.
Available at: http://www.doralforsleep.com/PDF/Doral_PI.pdf. Accessed June 4, 2008.
Limitations to Benzodiazepine Use
• Potential adverse effects
– Residual sedation
• Related to dose and elimination half-life
• Potential impairment of psychomotor skills
– Tolerance
• May require larger doses Risk of symptoms on withdrawal
– Potential for abuse
• Especially in those with history of drug abuse
Charney DS, Mihic SJ, Harris RA. In: Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. New York: McGraw-Hill; 2001:399-427.
Benzodiazepines and Sleep
Electroencephalogram
• Tend to suppress REM sleep and SWS
• Diazepam effects on GABAA leads to
suppression of delta waves1
1. Kopp C, Rudolph U, Löw K, Tobler I. Proc Natl Acad Sci U S A. 2004;101:3674-3679.
Newer Agents:
Benzodiazepine Receptor Agonists
• May have adverse events similar to
benzodiazepines
– Headache, drowsiness, dizziness, nausea, amnesia
• Dose reduction needed in elderly
• Potential for dependence in vulnerable
populations
• Agents
–
–
–
–
Zaleplon: dose, 5-20 mg; t1/2 1 hour1,2
Zolpidem: dose, 5-15 mg; t1/2 2.5 hours3
Zolpidem MR: dose 6.25-12.5 mg, t1/2 2.8 hours4
Eszopiclone: dose, 1-3 mg; t1/2 ~6 hours1,5
1. Benca RM. Psychiatr Serv. 2005;56:332-343; 2. King Pharmaceuticals. Available at: http://www.kingpharm.com/kingpharm/
uploads/pdf_inserts/Sonata_PI_and_MedGuide.pdf. Accessed June 4, 2008; 3. Sanofi-Aventis Corporation. Available at:
http://products.sanofi-aventis.us/ambien/ambien.pdf; Accessed June 4, 2008; 4. Sanofi-Aventis Corporation. Available at:
http://products.sanofi-aventis.us/ambien_cr/ambienCR.pdf. Accessed June 4, 2008; 5. Sepracor. Available at:
http://www.lunesta.com/PostedApprovedLabelingText.pdf. Accessed June 4, 2008.
Potential Differences Between Newer
Benzodiazepine Receptor Agonists vs
Benzodiazepines
• Receptor selectivity and/or shorter half-life
may lead to:
– Reduced side effects
– Reduced withdrawal symptoms
– Preserved sleep architecture at therapeutic doses
• Rapid onset of action
– Increased risk for amnesia?
• Indication for newer agents (eszopiclone,
zolpidem MR) does not limit length of use
Melatonin-receptor Agonist: Ramelteon
• Selective agonist of MT1, MT2 receptors1
– Melatonin receptors associated with regulation of sleepiness and
circadian rhythms1
– No affinity for other receptors involved in sleep and wakefulness
(eg, GABA, norepinephrine, serotonin, dopamine, acetylcholine)2
• t1/2=1-2.6 hours; major metabolite also acts as MT1 and
MT2 receptors (t1/2=2-5 hours) 2
• Indication does not limit duration of use2
• Primarily useful for sleep onset2
• No WASO effect2
1. Kato K, Hirai K, Nishiyama K, et al. Neuropharmacology. 2005;48:301-310;
2. Borja NL, Daniel KL. Clin Ther. 2006;28:1540-1555.
US Food and Drug Administration Request for
Label Change to Sedative-hypnotic Agents
• Revision of product labeling to include potential adverse events1
– Severe allergic reactions (anaphylaxis)
– Complex sleep-related behaviors (sleep-driving, sleep-eating)
• Health care providers received letters of notification regarding
labeling changes
• Patient Medication Guides will be given to patients, families, and
caregivers when a product is dispensed to provide
recommendations on proper use
– Avoid alcohol and/or other central nervous system depressants
– Consult health care provider prior to discontinuation
• Recommendation for additional clinical studies investigating the
occurrence of complex sleep-related behaviors associated with
specific agents
1. FDA requests label change for all sleep disorder drug products [press release]. Bethesda, MD: US Food and Drug
Administration; March 14, 2007.
Use of Other Psychotropic Drugs for Sleep
• Use drugs to treat comorbid illnesses and sleep related illnesses
• Antidepressantsa: mirtazapine, trazodone, nefazodone,amitriptyline,
doxepin, trimipramine1-13
– Pros: Low abuse potential1
– Cons: daytime sedation, weight gain, anticholinergic effects,
cardiotoxicity1 and in a patient with bipolar disorder, it can trigger a
switch into mania13
• Atypical Antipsychoticsa: olanzapine, quetiapine, risperidone,
ziprasidone
– Pros: anxiolytic, mood stabilizing in bipolar disorder, has low abuse
potential14
– Cons: daytime sedation, weight gain, risks of extrapyramidal effects,
metabolic abnormalities (glucose, lipid)14
• Anticonvulsantsa: gabapentin, tiagabine15,16
– Pros: SWS may be enhanced and has low abuse potential16
– Cons: cognitive impairment and daytime sedation16
aUnapproved
use by the FDA; 1. Lippmann S, Mazour I, Shahab H. South Med J. 2001;94:866-873; 2. Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346; 3. Warren M, Bick PA. Am J
Psychiatry. 1985;141(9):11-3-1104. 4. Knobler HY, Itzchaky S, Emanuel D, Mester R, Maizel S. Br J Psychiatry. 1986;149:787-789. 5. Lennhoff M. J Clin Psychiatry. 1987;48(10):423-424. 6.
Zmitek A. Br J Psychiatry. 1987;151:274-275. 7. Dubin H, Spier S, Giannandrea P. Am J Psychiatry. 1997;154(4)578-579. 8. Zaphiris HA, Blaidsdell GD, Jermain DM. Ann Clin Psychiatry.
1996;8(4)207-210. 9. Liu CC, Liang KY, Liao SC. J Psychopharmacol. 2008[Epub ahead of print]. 10. Bhanji NH, Margolese HC, Saint-Laurent M, Chouinard G. Int Clin Psychopharmacol.
2002;17(6)319-322. 11. Chengappa KN, Suppes T. Berk M. Expert Rev Neurother. 2004;4(6 suppl 2):S17-S25. 12. Bowden CL. J Clin Psychiatry. 2005;66(supple 3):12-19. 13. Post RM,
Altshuler LL, Leverich GS, et al. Br J Psychiatry. 2006;189:124-131; 14. Sharpley AL, Vassallo CM, Cowen PS. Biol Psychiatry. 2000;47:468-470; 15. Steiger A. J Psychiatr Res.
2007;41(7):537-552. 16. Karam-Hage M, Brower KJ. Psychiatry Clin Neurosci. 2000;57:542-544.
Summary
• Cognitive behavior therapy is effective, unlikely to have
adverse effects, and may provide long-lasting benefits
– More practitioners need to provide this therapy
– Treatment should begin with behavioral therapy before turning to
pharmacotherapy
• Pharmacotherapy is effective in treating insomnia related
to psychiatric illness
– Many medications approved for insomnia have not been
evaluated for long-term use
– Newer benzodiazepine receptor agonists appear to have fewer
side effects and less severe reactions than benzodiazepines
• Some studies suggest that treating insomnia in patients
with psychiatric disorders may improve the response to
treatment for depression
National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:1049-1057.