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Title: Sleep:%20Considerations%20in%20the%20Patient%20With%20Psychiatric%20Disorders


1
Sleep Considerations in the Patient With
Psychiatric Disorders
  • Rafael Pelayo, MD

2
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

3
Sleep in America2005 National Sleep Foundation
Poll
60
Weekdays
Weekends
49
50
31
40
Respondents ()
26
24
24
30
16
15
10
20
10
0
lt6
6 to 6.9
7 to 7.9
8
Hours of Sleep/Night
N1,506 adults
Mean6.8 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.
4
Sleep in AmericaFrequency of A Good Nights
Sleep
49
24
13
26
10
N1,506 adults
3
  • Of the adults getting a good nights 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.
5
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

6
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.
2005281049-1057.
7
National Institutes of Health State of the
Science Conference Statement (contd)
  • 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.
2005281049-1057.
8
National Institutes of Health State of the
Science Conference Statement (contd)
  • 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.
2005281049-1057.
9
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

10
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

11
Model of Chronic Insomnia
  • Predisposing Factors

Precipitating Factors
Perpetuating Factors
  • Excessive time in bed
  • Napping
  • Conditioning
  • Medical illness
  • Psychiatric illness
  • Stressful life events
  • Biological traits
  • Psychological traits
  • Social factors

Adapted from Spielman et al
12
  • 40-60 of outpatients and up to 90 of
    inpatients with a major depressive episode
    experience sleep problems

13
Sleep in Depressed Patients
  • Patients experience
  • Difficulty falling asleep
  • Frequent awakenings
  • Waking too early in the morning (terminal
    insomnia)
  • Fatigue when awake

14
Place of Chronic Insomnia in the Course of
Depressive and Anxiety Disorders
Ohayon MM, Roth T. J Psychiatr Res. 2003379-15.
15
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

16
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
6
7
Time (hours)
aRapid eye movement
17
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

18
Polysomnographic Changes in Depression
  • Prolonged sleep latency
  • Increased WASO
  • Decreased SWS

19
Polysomnographic Changes in Depression (contd)
  • 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

20
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.
200045803-809. 2. Roberts RE, Shema SJ, Kaplan
GA, Strawbridge WJ. Am J Psychiatry.
200015781-88. 3. Posternak MA, Zimmerman M.
Arch Gen Psychiatry. 20025970-76. 4. Horwath E,
Johnson J, Weissman MM, Hornig C. J Affect
Disord. 199226117-125. 5. Nierenberg AA, Keefe
BR, Leslie VC, et al. J Clin Psychiatry.
199960221-225.
21
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. 2004141846-850. 2. Meier-Ewert
HK, Ridker PM, Rifai N, et al. J Am Coll Cardiol.
200443678-683. 3. Spiegel K, Leproult R,
L'hermite-Balériaux M, Copinschi G, Penev PD, Van
Cauter E. J Clin Endocrinol Metab. 2004895762-5
771. 4. Spiegel K, Sheridan JF, Van Cauter E.
JAMA. 20022881471-1472.
22
Insomnia By Age Group

Age Group
Mellinger GD, Balter MB, Uhlenhuth EH. Arch Gen
Psychiatry. 198542225-232.
23
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 20051311-1326.
24
Impact of Insomnia on Quality of Life
Insomnia is associated with reduced mental
health, vitality, and social functions
Impact on SF-36 HRQOL Domainsa (N3,445)
5
0
-5
-10
Deviation From Reference Group
-15
-20
-25
Mild insomnia
Severe insomnia
-30
Congestive heart failure
Clinical depression
-35
aP0.001 except congestive heart failure
association with pain, emotional role, and mental
health Graph adapted from Katz DA, McHorney CA.
J Fam Pract. 200251229-235. Taylor DJ,
Lichstein KL, Durrence HH, Reidel BW, Bush AJ.
Sleep. 2005281457-1464.
25
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?

26
Dreaming and Mood Regulation (contd)
  • 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

27
Dreaming and Mood Regulation (contd)
  • 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 21, 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
1970124-151.
28
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. 2006141261-270.
29
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. 2006141261-270.
30
Diagnosis and Treatment of Insomnia in Patients
With Psychiatric Disorders
  • Ruth M. Benca, MD, PhDUniversity of
    Wisconsin-Madison

31
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. National Institutes of Health State of the
    Science Conference Statement. Sleep.
    2005281049-1057.
  2. Chesson A Jr, Hartse K, Anderson WM, et al.
    Sleep. 200023(2)237-241.

32
Sleep Problems Are Often Multifactorial
  • Psychiatric illness-specific factors
  • Medications
  • Primary sleep disorders
  • Behavioral factors

33
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

34
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 felectroencephalographBenca RM,
Obermeyer WH, Thisted RA, Gillin JC. Arch Gen
Psych. 199249651-668.
35
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. 2007617-29.
36
Effects of Psychopharmacologic Agents on Sleep
(continued)
  • Antidepressants
  • Antipsychotics
  • Stimulants

37
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 bUnapprov
ed use by the US Food and Drug Administration
(FDA) Peterson MJ, Benca RM. Psychiatr Clin North
Am. 2006291009-1032 Lippman S, Mazour I,
Shahab. Southern Med J. 200194866-873.
38
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. 200520533-559 Argyropoulos SV and
Wilson SJ. Int Rev Psychiatry. 200517237-245.
39
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. 2007617-29 2. Armitage R, Cole
D, Suppes T, Ozcan ME. Prog Neuropsychopharmacol
Biol Psychiatry. 2004281065-1070 3. Giménez S,
Clos S, Romero S, Grasa E, Morte A, Barbanoj MJ.
Psychopharmacology (Berl). 2007190507-516. Epub
2007 Jan 5 4. Keshavan MS, Prasad KM, Montrose
DM, Miewald JM, Kupfer DJ. J Clin
Psychopharmacol. 200727703-705.
40
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. 1998137-160.
41
Primary Sleep Disorders and Psychiatric Illnesses
  • Obstructive sleep apnea
  • Restless legs/periodic limb movements
  • Narcolepsy

42
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. 200341195-1200.
43
Psychiatric Medications May Exacerbate Sleep
Apnea Through
  • Weight gain
  • Atypical antipsychotics
  • Antidepressants
  • Mood stabilizers
  • Muscle relaxation
  • Benzodiazepines
  • Barbiturates
  • Decreased arousal threshold

44
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.
200558510-514. Epub 2005 Jul 7 Nofzinger EA,
Fasiczka A, Berman S, Thase ME. J Clin
Psychiatry. 200061858-862.
45
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.
200458117-124 2. Ohayon MM, Priest RG, Caulet
M, Guilleminault C. Br J Psychiatry.
1996169459-467 3. Dahmen N, Kasten M, Mittag
K, Müller MJ. Eur J Health Econ. 20023(suppl
2)S94-S98.
46
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
  • Dahmen N, Kasten M, Mittag K, Müller MJ. Eur J
    Health Econ. 20023(suppl 2)S94-S98
  • Benca RM. J Clin Psychiatry. 200768 (suppl
    13)5-8.

47
Behavioral Factors Contributing to Sleep Problems
in Psychiatric Patients
  • Lack of daily structure
  • Irregular sleep patterns/napping
  • Psychosocial stressors

48
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.
200565927-947.
49
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.
1997336341-346.
50
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.
1997336341-346 2. NHLBI Working Group on
Insomnia. 1998. NIH Publication. 98-4088 3.
Lippmann S, Mazour I, Shahab H. South Med J.
200194866-873.
51
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. 1999221134-1156.
52
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. 2006291398-1414
2. Barion A, Zee PC. Sleep Med. 20078566-577.
Epub 2007 Mar 28.
53
Studies Show Effectiveness of Behavioral
Interventions in Insomnia
Meta-analysis of 59 Trials (N2,102)
Time Awake After Sleep Onset Plt0.001
Sleep-onset Latency Plt0.001
Pretreatment
Posttreatment
Pretreatment
Posttreatment
70
80
70
60
60
50
50
40
Minutes
Minutes
40
30
30
20
20
10
10
0
0
Control
Behavioral
Control
Behavioral
Conditions
Treatments
Conditions
Treatments
Morin CM, Culbert JP, Schwartz SM. Am J
Psychiatry. 19941511172-1180.
54
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
  • Benzodiazepine receptor agonists1
  • Melatonin receptor agonists
  • Antidepressants, sedatinga,1
  • Anticonvulsantsa,3
  • Atypical antipsychoticsa,2

aUnapproved 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.
1998137-160 2. National Institutes of Health
State of the Science Conference Statement. Sleep.
2005281049-1057 3. Lippmann S, Mazour I,
Shahab H. South Med J. 200194866-873 4. Smith
MT, Perlis ML, Park A, et al. Am J Psychiatry.
20021595-11.
55
Benzodiazepine Receptor Agonists
  • Allosteric modulators of ?-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

56
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 Gilmans The
Pharmacological Basis of Therapeutics. New York
McGraw-Hill 2001399-427 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/p
df/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.doralfor
sleep.com/PDF/Doral_PI.pdf. Accessed June 4, 2008.
57
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 Gilmans The
Pharmacological Basis of Therapeutics. New York
McGraw-Hill 2001399-427.
58
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. 20041013674-3679.
59
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. 200556332-343 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/am
bienCR.pdf. Accessed June 4, 2008 5. Sepracor.
Available at http//www.lunesta.com/PostedApprove
dLabelingText.pdf. Accessed June 4, 2008.
60
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

61
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
  • t1/21-2.6 hours major metabolite also acts as
    MT1 and MT2 receptors (t1/22-5 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. 200548301-310 2. Borja NL,
Daniel KL. Clin Ther. 2006281540-1555.
62
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.
63
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. 200194866-873 2.
Kupfer DJ, Reynolds CF. N Engl J Med.
1997336341-346 3. Warren M, Bick PA. Am J
Psychiatry. 1985141(9)11-3-1104. 4. Knobler HY,
Itzchaky S, Emanuel D, Mester R, Maizel S. Br J
Psychiatry. 1986149787-789. 5. Lennhoff M. J
Clin Psychiatry. 198748(10)423-424. 6. Zmitek
A. Br J Psychiatry. 1987151274-275. 7. Dubin H,
Spier S, Giannandrea P. Am J Psychiatry.
1997154(4)578-579. 8. Zaphiris HA, Blaidsdell
GD, Jermain DM. Ann Clin Psychiatry.
19968(4)207-210. 9. Liu CC, Liang KY, Liao SC. J
Psychopharmacol. 2008Epub ahead of print. 10.
Bhanji NH, Margolese HC, Saint-Laurent M,
Chouinard G. Int Clin Psychopharmacol.
200217(6)319-322. 11. Chengappa KN, Suppes T.
Berk M. Expert Rev Neurother. 20044(6 suppl
2)S17-S25. 12. Bowden CL. J Clin Psychiatry.
200566(supple 3)12-19. 13. Post RM, Altshuler
LL, Leverich GS, et al. Br J Psychiatry.
2006189124-131 14. Sharpley AL, Vassallo CM,
Cowen PS. Biol Psychiatry. 200047468-470 15.
Steiger A. J Psychiatr Res. 200741(7)537-552.
16. Karam-Hage M, Brower KJ. Psychiatry Clin
Neurosci. 200057542-544.
64
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.
2005281049-1057.
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