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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

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Sleep: Considerations in the Patient With Psychiatric Disorders

Rafael Pelayo, MD


  • 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

Sleep in America:2005 National Sleep Foundation Poll








Respondents (%)












6 to 6.9

7 to 7.9


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:{F6BF2668-A1B4-4FE8-8D1A-A5D39340D9CB}/2005_summary_of_findings.pdf. Accessed January 23, 2008.

Of the adults getting “a good night’s sleep,” only 26% get a few nights per month or less

Sleep in America:Frequency of “A Good Night’s Sleep”






N=1,506 adults


National Sleep Foundation. 2005 Sleep in America Poll: Summary of findings. Available at:{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

  • Medical conditions

    • Cardiopulmonary

    • Musculoskeletal

  • Psychiatric disorders

    • Depression

    • Anxiety

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

Predisposing Factors







Model of Chronic Insomnia

Precipitating Factors

Perpetuating Factors

  • Biological traits

  • Psychological traits

  • Social factors

  • Medical illness

  • Psychiatric illness

  • Stressful life events

  • Excessive time in bed

  • Napping

  • Conditioning

Adapted from: Spielman et al

  • 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








Rate (%)










1 month

1-6 months

6-12 months

1-5 years

5-10 years

10 years

Insomnia duration

Place of Chronic Insomnia in the Course of Depressive and Anxiety Disorders

Ohayon MM, Roth T. J Psychiatr Res. 2003;37:9-15.

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

Sleep Stages



Typical Nighttime Sleep Pattern

in a Young Adult



Stage 1

and REMa

Stage 1

Stage 2

Stage 2

Stage 3

Stage 3

Stage 4

Delta 4








Time (hours)

aRapid eye movement

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


Age Group

Mellinger GD, Balter MB, Uhlenhuth EH. Arch Gen Psychiatry. 1985;42:225-232.

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

Impact on SF-36 HRQOL Domainsa (N=3,445)





Deviation From Reference Group




Mild insomnia

Severe insomnia


Congestive heart failure

Clinical depression


aP≤0.001 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.

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, PhDUniversity 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

  • 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

  • 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. 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

bUnapproved use by the US Food and Drug Administration (FDA)

Peterson MJ, Benca RM. Psychiatr Clin North Am. 2006;29:1009-1032;

Lippman S, Mazour I, Shahab. Southern Med J. 2001;94:866-873.

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

  • 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

  • Stimulus control therapy: positive association made between the bed and bedroom1

  • Sleep restriction: limit time in bed to increase homeostatic sleep drive1

  • Relaxation training: decrease arousal and anxiety1

  • 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

Time Awake After Sleep Onset P<0.001
































Morin CM, Culbert JP, Schwartz SM. Am J Psychiatry. 1994;151:1172-1180.

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.; 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: uspi_halcion.pdf. Accessed June 4, 2008; 3. Mallinckrodt Pharmaceuticals. Available at: Accessed June 4, 2008 ; 4. Abbott. Available at: Accessed June 4, 2008; 5. West-ward Pharmaceutical Corp Available at: Accessed June 4, 2008; 6. Questcor Pharmaceuticals. Available at: 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: uploads/pdf_inserts/Sonata_PI_and_MedGuide.pdf. Accessed June 4, 2008; 3. Sanofi-Aventis Corporation. Available at:; Accessed June 4, 2008; 4. Sanofi-Aventis Corporation. Available at: Accessed June 4, 2008; 5. Sepracor. Available at: 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.


  • 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.

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