Title to be Placed Here - Medscape

Title to be Placed Here - Medscape

Sleep: Considerations in the Patient With Psychiatric Disorders Rafael Pelayo, MD Topics Definition of insomnia Epidemiology of insomnia with psychiatric disorders Specific features of sleep and sleep disturbances in psychiatric disorders Diagnostic evaluation of insomnia/sleep problems in psychiatric disorders Causes/etiologies of sleep problems in specific psychiatric disorders Behavioral treatment Medication treatment Respondents (%) Sleep in America:

2005 National Sleep Foundation Poll 60 Weekdays Weekends 49% 50 31% 40 30 24% 16% 20

10% 24% 26% 15% 10 0 <6 6 to 6.9 7 to 7.9 8 Hours of Sleep/Night

N=1,506 adults Mean=6.8 hours on weekdays; 7.4 hours on weekends National Sleep Foundation. 2005 Sleep in America Poll: Summary of findings. Available at: http://www.kintera.org/atf/cf/{F6BF2668-A1B4-4FE8-8D1A-A5D39340D9CB}/2005_summary_of_findings.pdf. Accessed January 23, 2008. Sleep in America: Frequency of A Good Nights Sleep Every night/Almost every night 49% A few nights per week 24% A few nights per month 13%

Rarely N=1,506 adults Never 3% 0% 26% 10% 10% 20%

30% 40% 50% 60% 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. 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 (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. 2005;28:1049-1057. 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. 2005;28:1049-1057. Comorbid Insomnia Psychiatric disorders Depression Anxiety Medical conditions Cardiopulmonary Musculoskeletal Comorbid insomnia Sleep disorders Obstructive sleep apnea Restless legs syndrome Circadian rhythm

Pharmacological agents Prescription/OTC medications Nicotine Substance abuse Impairments Associated With Insomnia Impaired cognitive functioning Negative quality-of-life measures Increased incidence of bodily pain, poor general health Increased future risk of psychiatric disorders Decreased job performance, increased absenteeism Increased risk of accidents Increased healthcare costs Model of Chronic Insomnia Predisposing Factors

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

Preclinical Onset Adapted from: Spielman et al Short-term Chronic Insomnia Depression 40%-60% of outpatients and up to 90% of inpatients with a major depressive episode experience sleep problems Sleep in Depressed Patients Patients experience:

Difficulty falling asleep Frequent awakenings Waking too early in the morning (terminal insomnia) Fatigue when awake Place of Chronic Insomnia in the Course of Depressive and Anxiety Disorders 9.0 7.8 8.0 7.0 Rate (%) 6.0 5.0

5.0 4.0 3.1 3.0 1.6 2.0 1.0 0.9 0.6 0.0 1 month 1-6 months 6-12 months

1-5 years Insomnia duration Ohayon MM, Roth T. J Psychiatr Res. 2003;37:9-15. 5-10 years 10 years Sleep Timing Sleep timing is influenced by homeostatic and circadian factors The less we sleep, the more sleep we need and vice versa Twice a day our alertness level peaks Twice a day our sleepiness peaks Sleep Stages Electroencephalography

Recordings Awake Typical Nighttime Sleep Pattern in a Young Adult Awake Stage 1 and REMa Stage 1 Stage 2 Stage 2 Stage 3 Stage 3

Stage 4 Delta 4 1 Rapid eye movement a 2 3 4 5 6 Time (hours) 7 Key Polysomnographic Terms

Sleep latency REM latency Sleep efficiency Wake after sleep onset (WASO) Percent REM sleep Percent slow-wave sleep (SWS) Percent stage 1 Polysomnographic Changes in Depression Prolonged sleep latency Increased WASO Decreased SWS Polysomnographic Changes in

Depression (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 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 Armitage R. Can J Psychiatry. 2000;45:803-809. Roberts RE, Shema SJ, Kaplan GA, Strawbridge WJ. Am J Psychiatry. 2000;157:81-88. Posternak MA, Zimmerman M. Arch Gen Psychiatry. 2002;59:70-76. Horwath E, Johnson J, Weissman MM, Hornig C. J Affect Disord. 1992;26:117-125. 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-Balriaux M, Copinschi G, Penev PD, Van Cauter E. J Clin Endocrinol Metab.

2004;89:5762-5771. 4. Spiegel K, Sheridan JF, Van Cauter E. JAMA. 2002;288:1471-1472. Insomnia By Age Group 30 25 20 % 15 10 5 0 18-34 35-49 50-64

Age Group Mellinger GD, Balter MB, Uhlenhuth EH. Arch Gen Psychiatry. 1985;42:225-232. 65-79 Insomnia and Depression Striking association between insomnia and depression Insomnia early marker for onset of depression May be linked by common pathophysiology1 Need to treat both insomnia and depression 1. Benca RM. Mood disorders. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia, PA: Elsevier/Saunders; 2005:1311-1326. Impact of Insomnia on Quality of Life Insomnia is associated with reduced mental health, vitality, and social functions

Deviation From Reference Group Impact on SF-36 HRQOL Domainsa (N=3,445) 5 Physical Function Role, Physical Pain Health Perception Vitality Social

Role, Emotional 0 -5 -10 -15 -20 -25 -30 -35 Mild insomnia Severe insomnia Congestive heart failure Clinical depression

P0.001 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. a Mental Health Dreaming and Mood Regulation Why do we feel better after a good night of sleep? What is it about sleep that restores us both physiologically and psychologically? Dreaming and Mood Regulation (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

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 2:1, with fear, anxiety, and anger as the most commonly identified1 Patients suffering from an episode of major depression typically have reduced recall of dreams and absence of dream affect 1. Snyder, F. The phenomenology of dreaming. In: Madow L, Snow L, eds. The psychodynamic implications of the physiological studies on dreams. Springfield, IL: C.C. Thomas; 1970:124-151. Relation of Dreams to Waking Concerns

To test that dreams are influenced by the presleep waking emotional concerns of the sleeper and have an effect on waking adaptation, 20 depressed and 10 control subjects, who were all going through a divorce, were enrolled in a repeated measures study lasting 5 months A Current Concerns test was administered on 3 occasions before nights when every REM period was interrupted to record recalled mental content The degree of waking concern about the ex-spouse correlated significantly with the number of dreams in which the former partner appeared as a dream character Those who were in remission at the follow-up evaluation had a higher percentage of well-developed dreams than those who remained depressed Dreams of the former spouse reported by those in remission differed from those who remained depressed in the expression of dream affect and in the within-dream linkage among units of associated memory material Dreams of the former spouse that are reported by those who are not in remission lack affect and connection to other memories

Cartwright R, Agargun MY, Kirkby J, Friedman JK. Psychiatry Res. 2006;141:261-270. REM Sleep Reduction, Mood Regulation, and Remission in Untreated Depression The contribution of REM pressure through repeated, mild, reduction of REM sleep to remission from untreated depression was studied over a 5-month period in 20 depressed and 10 control volunteers 60% of the depressed were in remission at the end of the study 64% of the variance in remission could be accounted for by 4 variables: The initial level of self-reported symptoms The reported diurnal variability in mood The degree of overnight reduction in depressed mood following interruptions of REM sleep

The quality of dream reports from these awakenings Increased REM pressure is beneficial for those who are able to construct well-organized dreams Increased REM pressure is beneficial for those who are able to construct well-organized dreams Cartwright R, Agargun MY, Kirkby J, Friedman JK. Psychiatry Res. 2006;141:261-270. Diagnosis and Treatment of Insomnia in Patients With Psychiatric Disorders Ruth M. Benca, MD, PhD University of Wisconsin-Madison Evaluation of Insomnia Relies on a Subjective Report1,2

Based primarily on subjective report of patient and/or family Medical history, physical examination, and laboratory testing to assess comorbid conditions Sleep diaries and questionnaires useful for diagnosis and to assess treatment response Actigraphy Polysomnography not usually indicated 1. 2. National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:1049-1057. Chesson A Jr, Hartse K, Anderson WM, et al. Sleep. 2000;23(2):237-241. Sleep Problems Are Often Multifactorial

Psychiatric illness-specific factors Medications Primary sleep disorders Behavioral factors Psychiatric Illness-specific Factors Mood disorders Diurnal mood variation Rapid cycling Seasonal and circadian rhythm abnormalities Anxiety disorders Nocturnal panic attacks Posttraumatic stress disorder and anxiety dreams Schizophrenia Exacerbation of psychosis at night Psychiatric Disorders Associated With

Objective Changes in Sleep Architecture TSTa SEb SLc SWSd REM Le Mood Alcoholism Anxiety disorders Schizophrenia Insomnia Comparison of sleep EEGf in groups of patients with psychiatric disorders or insomnia to age-matched normal controls

Total sleep time; bsleep efficiency; csleep latency ; dslow-wave sleep; erapid eye movement latency; felectroencephalograph Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Arch Gen Psych. 1992;49:651-668. a 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 Selective serotonin reuptake inhibitors Unapproved use by the US Food and Drug Administration (FDA) Peterson MJ, Benca RM. Psychiatr Clin North Am. 2006;29:1009-1032; a b 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 Rapid 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. a 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. Gimnez 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 Periodic 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. a

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, Mller MJ. Eur J Health Econ. 2002;3(suppl 2):S94-S98. Narcolepsy and Schizophrenia (continued)

Psychotic form of narcolepsy vs stimulant-induced psychotic disorder?1,2 Stimulants may lead to psychotic symptoms in narcoleptics Misdiagnosis may lead to inappropriate treatment2 Reports of treatment-refractive schizophrenia that turns out to be stimulant-responsive narcolepsy Comorbid disorders can create treatment dilemmas2 Stimulants often exacerbate psychotic symptoms Antipsychotics may exacerbate sleepiness 1. Dahmen N, Kasten M, Mittag K, Mller 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 bedtime 2,3 Heavy meals or drinking alcohol within 3 hours of bed2 Exposure to bright light during the night2,3 Practice a relaxing routine around bedtime1-3 Reduce time in bed; regular sleep/wake cycle1-3 1. Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346; 2. NHLBI Working Group on Insomnia. 1998. NIH Publication. 98-4088; 3. Lippmann S, Mazour I, Shahab H. South Med J. 2001;94:866-873. Cognitive Behavioral Therapy for Sleep Change maladaptive sleep habits Decrease autonomic and cognitive arousal Modify dysfunctional beliefs and attitudes about sleep

Morin CM, Hauri PJ, Espie CA, Spielman AJ, Buysse DJ, Bootzin RR. Sleep. 1999;22:1134-1156. Behavioral Techniques 1. Stimulus control therapy: positive association made between the bed and bedroom1 2. Sleep restriction: limit time in bed to increase homeostatic sleep drive1 3. Relaxation training: decrease arousal and anxiety1 4. Circadian rhythm entrainment: reinforce or reset biological rhythm using light and/or chronotherapy1,2 1. Morin CM, Bootzin RR, Buysse DJ, Edinger JD, Espie CA, Lichstein KL. Sleep. 2006;29:13981414; 2. Barion A, Zee PC. Sleep Med. 2007;8:566-577. Epub 2007 Mar 28. Studies Show Effectiveness of Behavioral Interventions in Insomnia Meta-analysis of 59 Trials (N=2,102) Sleep-onset Latency P<0.001

Pretreatment Time Awake After Sleep Onset P<0.001 Posttreatment Pretreatment 70 80 60 70 60 Minutes 50 Minutes

Posttreatment 40 30 50 40 30 20 20 10 10 0

0 Control Conditions Behavioral Treatments Morin CM, Culbert JP, Schwartz SM. Am J Psychiatry. 1994;151:1172-1180. Control Conditions Behavioral Treatments Pharmacologic Treatment Over-the-counter (OTC) agentsa Antihistamines1

Herbs2 Melatonin3 23% Of patients with insomnia use OTC remedies to self-medicate 4 28% Of patients with insomnia use alcohol to self-medicate 4 Prescription agents Benzodiazepine receptor agonists1 Melatonin receptor agonists Antidepressants, sedatinga,1 Anticonvulsantsa,3

Atypical antipsychoticsa,2 Unapproved 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. a 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 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; 2001:399-427; 2. Pfizer Inc. Available at: http://www.pfizer.com/files/products/ uspi_halcion.pdf. Accessed June 4, 2008; 3. Mallinckrodt Pharmaceuticals. Available at: http://www.restoril.com. Accessed June 4, 2008 ; 4. Abbott. Available at: http://www.rxabbott.com/pdf/prosom.pdf. Accessed June 4, 2008; 5. West-ward Pharmaceutical Corp Available at: http://www.rxlist.com/cgi/generic/fluraz_cp.htm. Accessed June 4, 2008; 6. Questcor Pharmaceuticals. Available at: http://www.doralforsleep.com/PDF/Doral_PI.pdf. Accessed June 4, 2008. Limitations to Benzodiazepine Use Potential adverse effects Residual sedation Related to dose and elimination half-life Potential impairment of psychomotor skills Tolerance May require larger doses Risk of symptoms on withdrawal Potential for abuse Especially in those with history of drug abuse Charney DS, Mihic SJ, Harris RA. In: Hardman JG, Limbird LE, eds. Goodman & Gilmans 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, Lw K, Tobler I. Proc Natl Acad Sci U S A. 2004;101:3674-3679. Newer Agents: Benzodiazepine Receptor Agonists May have adverse events similar to benzodiazepines Headache, drowsiness, dizziness, nausea, amnesia Dose reduction needed in elderly Potential for dependence in vulnerable populations Agents

Zaleplon: dose, 5-20 mg; t1/2 1 hour1,2 Zolpidem: dose, 5-15 mg; t1/2 2.5 hours3 Zolpidem MR: dose 6.25-12.5 mg, t1/2 2.8 hours4 Eszopiclone: dose, 1-3 mg; t1/2 ~6 hours1,5 1. Benca RM. Psychiatr Serv. 2005;56:332-343; 2. King Pharmaceuticals. Available at: http://www.kingpharm.com/kingpharm/ uploads/pdf_inserts/Sonata_PI_and_MedGuide.pdf. Accessed June 4, 2008; 3. Sanofi-Aventis Corporation. Available at: http://products.sanofi-aventis.us/ambien/ambien.pdf; Accessed June 4, 2008; 4. Sanofi-Aventis Corporation. Available at: http://products.sanofi-aventis.us/ambien_cr/ambienCR.pdf. Accessed June 4, 2008; 5. Sepracor. Available at: http://www.lunesta.com/PostedApprovedLabelingText.pdf. Accessed June 4, 2008. Potential Differences Between Newer Benzodiazepine Receptor Agonists vs Benzodiazepines Receptor selectivity and/or shorter half-life may lead to:

Reduced side effects Reduced withdrawal symptoms Preserved sleep architecture at therapeutic doses Rapid onset of action Increased risk for amnesia? Indication for newer agents (eszopiclone, zolpidem MR) does not limit length of use Melatonin-receptor Agonist: Ramelteon Selective agonist of MT1, MT2 receptors1 Melatonin receptors associated with regulation of sleepiness and circadian rhythms1 No affinity for other receptors involved in sleep and wakefulness (eg, GABA, norepinephrine, serotonin, dopamine, acetylcholine) 2 t1/2=1-2.6 hours; major metabolite also acts as MT1 and MT2 receptors (t1/2=2-5 hours) 2 Indication does not limit duration of use2

Primarily useful for sleep onset2 No WASO effect2 1. Kato K, Hirai K, Nishiyama K, et al. Neuropharmacology. 2005;48:301-310; 2. Borja NL, Daniel KL. Clin Ther. 2006;28:1540-1555. US Food and Drug Administration Request for Label Change to Sedative-hypnotic Agents Revision of product labeling to include potential adverse events 1 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

Unapproved 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. a Summary Cognitive behavior therapy is effective, unlikely to have adverse effects, and may provide long-lasting benefits More practitioners need to provide this therapy Treatment should begin with behavioral therapy before turning to pharmacotherapy Pharmacotherapy is effective in treating insomnia related to psychiatric illness Many medications approved for insomnia have not been evaluated for long-term use

Newer benzodiazepine receptor agonists appear to have fewer side effects and less severe reactions than benzodiazepines Some studies suggest that treating insomnia in patients with psychiatric disorders may improve the response to treatment for depression National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:1049-1057.

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