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.