This Slide Is to Be Used Only for Titles

Anxiety Disorders:

A Focus on Sleep and Improving

Patient Outcomes

Thursday, March 6, 2008

Savannah, Georgia

Presented at the 28th Annual Conference

Anxiety Disorders Association of America

Introductions and

Program Objectives

Mark H. Pollack, MD

Director, Center for Anxiety and

Traumatic Stress Disorders

Massachusetts General Hospital

Professor of Psychiatry

Harvard Medical School



Program Faculty




Center for Anxiety and




Boston, Massachusetts



Michael W. Otto, PhD

Center for Anxiety and Related

Disorders

Boston University




Daniel S. Lewin, PhD, D.ABSM

Children’s National Medical Center

George Washington University

School of Medicine



Naomi M. Simon, MD, MSc

Center for Anxiety and







W. Vaughn McCall, MD, MS

Wake Forest University School of Medicine

Winston-Salem, North Carolina



Program Agenda

9:00

9:15

–9:15 am

–10:15 am

Introductions and Program Objectives Mark H. Pollack, MD

Sleep-Wake Cycle Disturbances and Anxiety

Mark H. Pollack, MD

10:15 –11:15 am Psychosocial Interventions for

Insomnia: Methods, Outcomes, and

Applications to Patients with Anxiety and Mood Disorders

11:15 am – 12:15 pm An Overview of Sleep Disorders &

Pharmacotherapy

12:15 –1:15 pm Lunch served

1:15 –2:00 pm Evaluating and Treating Comorbid

Sleep and Psychiatric Disorders in

Children

2:00 –2:45 pm Evaluation and Management of

Insomnia in Home-Dwelling

Older Persons

2:45 –3:45 pm

3:45 –4:00 pm

Anxiety and Insomnia in Women

Discussion and Q&A

Michael W. Otto, PhD

Mark H. Pollack, MD

Daniel S. Lewin, PhD,

D.ABSM

W. Vaughn McCall, MD, MS

Naomi M. Simon, MD, MSc

Faculty

Learning Objectives



After participating in this educational activity, the participant should be better able to:

– Discuss and relate both naturally occurring sleep compared to the effect of sleep disorders in the various patient populations

– Improve the ability to differentially diagnose patients with anxiety disorders and to understand the interplay with sleep, particularly insomnia

– Engage patients and develop a management plan for those with sleep and anxiety disorders

– Identify which patients to refer to other providers based on differential diagnosis



Disclosures



Dr. Mark H. Pollack has received grants or research support from AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics,

Forest, GlaxoSmithKline, Janssen, Lilly, NARSAD, NIDA, NIMH,

Pfizer, Roche, Sepracor, UCB, and Wyeth. He has been a consultant for AstraZeneca, Brain Cells, Bristol-Myers Squibb,

Cephalon, Dov, Forest, GlaxoSmithKline, Janssen, Jazz, Lilly,

Medavante, Neurocrine, Neurogen, Novartis, Otsuka, Pfizer,

Predix, Roche, sanofi-aventis, Sepracor, Solvay, Tikvah,

Transcept, UCB, and Wyeth. He has been a speakers bureau member for Bristol-Myers Squibb, Forest, GlaxoSmithKline,

Janssen, Lilly, Pfizer, Solvay, and Wyeth, and has equity in

Medavante and Mensante.



Dr. Michael W. Otto has been a consultant for Jazz and

Organon.



Disclosures



Dr. Daniel S. Lewin has no financial relationships over the past

12 months with any commercial organizations having a direct or indirect interest in the subject matter of his presentation.



Dr. Naomi M. Simon has received grants or research support from AstraZeneca, Bristol-Myers Squibb, Cephalon, Forest,

GlaxoSmithKline, Janssen, Lilly, NARSAD, NIMH, Pfizer,

Sepracor, and UCB. She has received honoraria for speaking from Forest, Janssen, Lilly, Pfizer, Sepracor, and UCB, and has been a consultant for Paramount Biosciences and Solvay.



Dr. W. Vaughn McCall has received grants or research support from GlaxoSmithKline, sanofi-aventis, and Sepracor. He has been a consultant for Sepracor and a speakers bureau member for GlaxoSmithKline and Sepracor.



Unlabeled Uses



Please note that these presentations may discuss unapproved or unlabeled uses of drugs or devices. Any product mentioned in the presentations should be used in accordance with the prescribing information provided by the manufacturer.



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- Thank You.



Sleep-Wake Cycle

Disturbances and Anxiety


Director, Center for Anxiety and







Disclosure



Dr. Mark H. Pollack has received grants or research support from AstraZeneca, Bristol-Myers Squibb, Cephalon,

Cyberonics, Forest, GlaxoSmithKline, Janssen, Lilly,

NARSAD, NIDA, NIMH, Pfizer, Roche, Sepracor, UCB, and

Wyeth. He has been a consultant for AstraZeneca, Brain

Cells, Bristol-Myers Squibb, Cephalon, Dov, Forest,

GlaxoSmithKline, Janssen, Jazz, Lilly, Medavante,

Neurocrine, Neurogen, Novartis, Otsuka, Pfizer, Predix,

Roche, sanofi-aventis, Sepracor, Solvay, Tikvah, Transcept,

UCB, and Wyeth. He has been a speakers bureau member for Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen,

Lilly, Pfizer, Solvay, and Wyeth, and has equity in Medavante and Mensante.



Objectives



Review prevalence and public health impact of insomnia



Describe relationship between anxiety disorders and insomnia



Discuss issues related to treatment of sleep and anxiety



What Is “Insomnia”?



Insomnia is a subjective complaint (symptom) of one or more of the following:

– Inadequate sleep quality

– Insufficient amount of sleep

– Dissatisfaction with sleep timing

– Not feeling rested after habitual sleep episode


Anxiety Disorders Association of America Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346.

Insomnia Prevalence and Impact



Prevalence of chronic insomnia in adults is 10%-15% 1,2

– With varying degrees of severity

–

Another 20%-30% have transient or occasional sleep problems



Chronic insomnia is associated with 3-5 :

– Absenteeism

– Accidents

– Memory impairment

– Greater health care utilization

1. Léger D, et al. J Sleep Res. 2000;9:35-42.

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

3. Simon G, VonKorff M. Am J Psychiatry. 1997;154:1417-1423.

4. Benca RM. Psychiatr Serv. 2005;56:332-343.

5. Kim K, et al. Sleep. 2000;23:41-47.



Consequences of Chronic

Insomnia

Societal and Clinical Impact of Insomnia



Societal

– High direct and indirect costs

– Increased utilization of inpatient and outpatient healthcare resources

– Increased use of sleep-promoting medication

– Reduced quality of life

– Reduced daily functioning



Personal

–

Increased daytime sleepiness with consequent psychomotor impairment

– Increased risk of depression or anxiety

– Increased risk of alcohol/drug abuse or dependence

–

Poorer outcomes in medical and psychiatric illnesses


Anxiety Disorders Association of America Thase ME. Gen Hosp Psychiatry. 2005; 27:100-112.

Sleep and Psychiatric Illness:

Bidirectional Relationship?



Insomnia adversely affects quality of life in anxiety disorders



Treatment of chronic insomnia may prevent the development and persistence of mood and anxiety disorders

Anxiety/Mood

Disorders

?

Insomnia

Mellinger GD, et al. Arch Gen Psychiatry. 1985;42:225-232.

Lustberg L, Reynolds CF. Sleep Med Rev. 2000;4:253-262.

Stein MB, Barrett-Connor E. Am J Geriatr Psychiatry. 2002;10:568-574.

(after Stein, 2005)



Prevalence of Psychiatric

Disorders in Insomnia Sufferers

Drug Abuse

Other Psychiatric Disorder

Alcohol Abuse

Dysthymia

Major Depression

Anxiety Disorders

No Psychiatric Disorder

0

4.2

5.1

7.0

8.6

Ford DE, Kamerow DB. JAMA. 1989;262:1479-1484.

10

14.0

23.9

59.5

20 30 40

% of Respondents

50 60



Insomnia Is a Risk Factor for

Psychiatric Disorders

Incidence (%) Over 3.5 years

12

10

8

6

4

2

0

18

16

14

*

*

Depression Anxiety

*95% CI for odds ratio excludes 1.0.

Insomnia, n=240

No Insomnia, n=739

Alcohol Abuse

*

Drug Abuse

Breslau N, et al. Biol Psychiatry. 1996;39:411-418.



Insomnia and Mental Disorder

Trajectory

Insomnia Depressive Disorder 40%

Insomnia-Depressive Disorder 22%

Anxiety Disorder Insomnia 34%

Insomnia-Anxiety Disorder 38%


Anxiety Disorders Association of America Ohayon MM, Roth MT. J Psychiatr Res. 2003;37:9-15.

Causes of Chronic Insomnia In

Psychiatric Illness



Is the underlying psychiatric disorder adequately treated?

– A comorbid psychiatric disorder?



Substance use/abuse?



Medical illness?



Medication side-effect?



Primary sleep disorders?


Anxiety Disorders Association of America Thase ME. Gen Hosp Psychiatry. 2005; 27:100-112.

GAD and Sleep Disturbance



Sleep disturbance is one of the criteria for the diagnosis of GAD



Fatigue and irritability (two other criteria), may be consequences of sleep loss



Excessive and uncontrollable worry (the core cognitive symptom of GAD) at bedtime may generate and maintain insomnia by interfering with ability to fall asleep


Anxiety Disorders Association of America Mellman TA. Psychiatr Clin N Am. 2006;29:1047-1058.

Characteristics of Sleep Disturbance in Generalized Anxiety Disorder

60

50

40

30

20

10

0

90

80

70

77.3

47.4

At least one type Initial insomnia

63.6

Note: Insomnia severity was not associated with GAD severity.

Total N=44.

Belanger L, et al. J Anxiety Disord. 2004;18:561-571.

Sleep

Maintenance

56.8

Early morning awakening



GAD and Sleep Parameters



By PSG patients with GAD have:

– Increased sleep latency

– Increased wake time after sleep onset

– Reduced total sleep time and lower sleep efficiency 1


Anxiety Disorders Association of America Monti JM, Monti D. Sleep Med Rev. 2000;4:263-276.

GAD and Sleep Parameters

 Sleep in “pure” GAD differentiated from major depression

– Reduction in REM latency seen in endogenous major depression is generally not seen in nondepressed patients with GAD 1-3



However , differences in sleep of uncertain clinical diagnostic utility given high rates of depressive comorbidity in practice

1. Saletu-Zyhlarz G, et al. Neuropsychobiology. 1997;36:117-29.

2. Arriaga F, Paiva T. Neuropsychobiology. 1990-1991;24(3):109-14.

3. Papadimitriou GN, et al. J Affect Disord. 1988;15:113-8.



Disordered Sleep in PTSD



Difficulty falling asleep — greater onset latency



Difficulty with sleep maintenance

–

REM-related awakenings and nightmares



Changes in REM

– More total REM or higher REM density

– Fragmented (more frequent short duration)

– Reduced heart-rate variability (NE-related)



Sleep disturbances at one-month post-trauma may predict PTSD evolution and ultimate chronicity

Mellman TA, et al. Am J Psychiatry. 1995;152:110-115.

Mellman TA, et al. Sleep. 1997;20:46-51.

Mellman TA, et al. Am J Psychiatry. 2002;159:1696-1701.

DeViva JC, et al. Behav Sleep Med. 2004;2:162-176.

Hurwitz TD, et al. Biol Psychiatry. 1998;44:1066-1073.

Ross RJ, et al. Sleep. 1994;17:723-732.

Ross RJ, et al. Biol Psychiatry. 1999;45:938-941.

Koren D, et al. Am J Psychiatry. 2002;159:855-857.



How Might the Pathophysiology of

Anxiety Disorders Impair Sleep?

 “Hyperarousal” theory

– Increased arousal (amygdala? brain stem?)

– Increased cortical activity due to ruminations



Comorbid conditions and drugs

– Affective disorders

– Substance abuse

– Prescribed Rx (e.g., antidepressants)



How Might Disturbed Sleep Influence

Pathogenesis and Treatment of Anxiety Disorders?



Disturbed sleep the night before an event

– Effects on emotional learning

• Shifts bias towards negative emotional learning



Encoding Results: Behavioral

Sleep Deprivation Sleep Control

1.2

1.0

0.8

*

1.6

1.4

1.2

1.0

** n.s.

n.s.

0.6

0.8

0.6

0.4

0.4

0.2

0.2

0.0

0.0

ALL MEMORY TYPES

*p ≤0.05, **p≤0.01

Walker MP, Stickgold, R. Annu Rev Psychol. 2006;57:139:166.

Positive Negative Neutral

MEMORY TYPES SEPARATED



Animal Studies of Sleep Deprivation Effects on Fear Conditioning and Extinction



Sleep (REM and NREM) deprivation before conditioning in rats (Ruskin et al, 2004)

– No change in amygdala-based fear conditioning

– Deficits in hippocampal-based contextual memory



REM deprivation in rats after conditioning

(Silvestri, 2005)

– Normal retention of conditioned fear

– Impaired extinction consolidation

Ruskin DN, et al. Eur J Neurosci. 2004;19:3121-3124.

Silvestri AJ. Physiol Behav. 2005;84:343-349.



Sleep Disturbance and Anxiety:

Moderating Factors



Poor sleep shifts the bias toward negative emotional learning and may disrupt extinction consolidation and recall

Thus, poor sleep quality may:

– Contribute to the pathogenesis of anxiety disorders and/or:

– Undermine the effectiveness of treatment



Treatment Goals for Anxiety and Insomnia



Improve anxiety and the associated symptomatology



Improve sleep

– Reduce time it takes to fall asleep

– Increase sleep time to levels that support daytime functioning

–

Reduce awakenings during the night

– Eliminate nightmares and/or unwanted sleep behavior

–

Enhance subjective sleep quality

– Restore confidence in the patient’s ability to sleep and to handle sleeplessness


Anxiety Disorders Association of America Mellman TA. Psychiatr Clin N Am. 2006;29:1047-1058.

General Principles in the

Management of Insomnia



Treat underlying cause(s)



Promote good sleep habits



Initiate behavioral intervention



Prescribe sedatives, hypnotics: use in combination with behavioral management


Anxiety Disorders Association of America Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346.

CBT Approaches to Insomnia May Be

Helpful in Setting Anxiety Disorders

Technique

Sleep Hygiene

Stimulus Control Therapy

Sleep Restriction

Relaxation

Paradoxical Intention

Cognitive-Behavioral

Therapy (CBT)

Morin, CM. J Clin Psychiatry. 2004;65(suppl 16):33-40.

Aim

Promote habits that help sleep; provide rationale for subsequent instructions

Strengthen bed and bedroom as sleep stimulus

Restrict time in bed to improve sleep depth & consolidation

Reduce arousal and decrease anxiety

Mitigate performance anxiety that impedes sleep onset

Combines sleep reduction, stimulus control techniques, and sleep restriction with cognitive therapy, addressing thoughts and beliefs that interfere with sleep



Treatment of Anxiety and

Insomnia



Pharmacologic and cognitive-behavioral therapy of anxiety improves associated sleep disturbance

Belanger L, et al. J Anxiety Disord. 2004;18:561-571.

Morin CM, et al. JAMA. 1999;281:991-999.

Rosenthal M. J Clin Psychiatry. 2003;64:1245-1249.



Reduction in Sleep Disturbance During

Treatment for GAD with Paroxetine and Tiagabine

14

12

10

8

*

*

6

4

2

0

Baseline Wk 4 Wk 10

Tiagabine (n=20)

*p<0.05 relative to baseline.

No significant difference between treatments.

Rosenthal M. J Clin Psychiatry. 2003;64:1245-1249.

*

*

Baseline Wk 4 Wk 10

Paroxetine (n=20)



Impact of Worry-Focused CBT for GAD vs. Waitlist on Concomitant Insomnia

14

12

10

8

6

Baseline

4

2

0

CBT for GAD

p<0.01; N=44.

Belanger L, et al. J Anxiety Disord. 2004;18:561-571.

Endpoint

Waitlist Control




Insomnia



Does targeted treatment of insomnia improves anxiety?



Targeted Insomnia Treatment in GAD:

Escitalopram (ESC) plus Eszopiclone or

Placebo – Effect on Sleep Latency

70

60

50

40

30

20

10

0

0 1

*

2

*

3 4

*

5

Double-Blind Treatment Period

*p<0.0005 vs. placebo

Pollack MH, et al. Arch Gen Psych (in press).

This information concerns a use that has not been approved by the US FDA.

6

*

7

Placebo + ESC

Eszopiclone + ESC

*

8 9

SB Run-Out

10



Targeted Insomnia Treatment in GAD:

Escitalopram (ESC) plus Eszopiclone or

Placebo – Effect on Anxiety (HAM-A)

30

25

20

15

10

5

*

*

*

0

BL 1 2 4

Week

6

*p<0.05 vs. placebo; Week 10 = end of single-blind placebo run-out period.



*

Placebo + ESC


*

*

8 10



Targeted Insomnia Treatment in GAD: Escitalopram

(ESC) Plus Eszopiclone or Placebo – Effect on Anxiety

(HAM-A excluding insomnia item)

30

25

20

15

10

5

*

*

0

BL 1 2 4

Week

6

*p<0.05 vs. placebo; Week 10 = end of single-blind placebo run-out period.



Placebo + ESC


8

*

10

*



Therapeutic Approach to

Nocturnal Panic (NP) Attacks



May occur as part of panic disorder

(44%-71% at least once) or PTSD

– Non-REM event in Stage II-III transition

– Not clear difference in sleep architecture or insomnia severity



Some support for CBT specific to NP



Lack data on pharmacotherapy approaches



May improve with treatment of primary disorder


Anxiety Disorders Association of America Craske MG, Tsao JC. Sleep Med Rev. 2005;9:173-184.

Limited Pharmacotherapy Data for

PTSD-Related Sleep Disturbance



SSRIs may have negative effects on sleep physiology with



REM and

 arousals

– But data support improved subjective sleep quality



Negative single-blind crossover of clonazepam

2 mg HS vs. placebo in combat PTSD

– No effect on nightmares

–

Only one person continued clonazepam after trial



Open support for trazodone (survey n=74)

–

Helpful for nightmares, sleep initiation, and maintenance in veterans with chronic PTSD

– Dosed 50-150 mg HS

–

12% reported priapism

Cates ME, et al. Ann Pharmacother. 2004:38:1395-1399.

Singareddy RK, Balon R. Ann Clin Psychiatry. 2002:14:183-190.




Hypnotic Medication in

Aftermath of Trauma



Admitted to medical trauma center and manifesting early PTSD symptoms (N=22)



Recalled incident and at least moderate impairment of sleep initiation or maintenance



Treated 14.3



10 days post-trauma



Randomized to receive temazepam x 7 days

(i.e., 30 mg x 5 nights and 15 mg x 2 nights) vs. placebo

Mellman TA, et al. J Clin Psychiatry. 2002;63:1183-1184.




Potential Impact of Early

Benzodiazepine on Recovery in PTSD

80

70

60

50

40

30

20

10

0

55

27

Temazepam Control

Acute improvement in sleep in temazepam group but no difference upon discontinuation.

Mellman TA, et al. J Clin Psychiatry. 2002;63:1183-1184.




Alpha

1

Adrenergic Antagonist for Nightmares and Insomnia in Chronic Combat PTSD:

Prazosin vs. Placebo

4

3.5

3

Prazosin (mean 9.5 mg HS)

Placebo

2.5

2

1.5

1

0.5

0

CAPS Nightmares

p<0.01; N=10. CAPS: Clinician-Administered PTSD Scale.

CAPS Insomnia

Raskind MA, et al. Am J Psychiatry. 2003;160:371-373.




Improved Sleep in Open-Label

Quetiapine for PTSD (N=20)

6

5

4

3

2

1

0

9

8

7

**

**

Quality

**

**

Global score Latency Duration

**p<0.01; PSQI = Pittsburgh Sleep Quality Index.

Robert S, et al. J Clin Psychopharmacol. 2005;25:387-388.




Summary



Sleep disturbance may resolve with treatment of primary anxiety disorder, but not always



Treatment approaches for primary insomnia are likely useful in setting anxiety

– May provide more rapid relief and improve overall outcomes



All patients should be educated about sleep hygiene rules



Both CBT and pharmacologic approaches to insomnia appear to be effective










- Thank You.



Psychosocial Interventions for Insomnia: Methods,

Outcomes, and Applications to Patients with Anxiety and Mood Disorders

Michael W. Otto, PhD

Director, Center for Anxiety and Related Disorders

Professor of Psychology

Boston University



Disclosure



Dr. Michael W. Otto has been a consultant for Jazz Pharmaceuticals and Organon.



Overview of

Interventions



History of Interventions



Relaxation

– Schultz and Luthe (1959)

– Jacobson (1964)

– Borkovec & Fowler (1973)

– Nicassion & Bootzin (1974)



Conditioning Model & Stimulus Control

– 1970s Bootzin



Attention to Cognitive Arousal and Cognitive Distortions

– Psychoeducation and cognitive restructuring (Edinger)



Second Generation Treatments

– Comprehensive CBT (Edinger, Morin, Espie)



Stimulus Control



Conditioning Model



Re-associate bed and bedtime with sleep rather than

– Anxiety

– Frustration

– Effort



In bed when sleepy and only for sleep



Use sleep restriction to drive a positive

(sleep-filled) association with bed



Stimulus Control Approach to

Treatment of Insomnia



Go to bed only when sleepy



Use the bed or bedroom only for sleeping

– Do not read, watch TV, or eat in bed



Go to bed when sleepy



Get out of bed when unable to sleep



Arise at the same time every morning



Do not nap during the day

Morin CM. J Clin Psychiatry. 2004;65(suppl 16):33-40.

Bootzin RR, et al. In: Hauri PJ, ed. Case Studies in Insomnia. 1991:19-28.






Select time in bed to represent the average total sleep time (plus 30 minutes)



Work with the patient on sleep onset and offset time



Joyfully explain rationale and likelihood of less time in bed (and potential for fatigue)



Adjust time in bed according to the target of

85% sleep efficiency



Cognitive Interventions



Also oriented to re-associating meanings associated with bed, bedtime, and sleep



Eliminate anxiogenic, arousal-inducing, and catastrophic thoughts



Targeting both daytime functioning and sleep performance



Includes informational interventions (sleep hygiene)



Principles of Sleep Hygiene



Reduce time in bed; regular sleep/wake cycle 1-3



Regular exercise in the morning and/or afternoon 1,3



Avoid exposure to bright light at night 1,3



Avoid heavy meals or drinking within 3 hours of bed 1



Enhance sleep environment 1,3



Avoid caffeine, alcohol, and nicotine 1,3



Practice relaxing bedtime routine 1-3

 Avoid “watching the clock”

1 NHLBI Working Group on Insomnia. 1998. NIH Publication 98-4088.

2 Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346.

3 Lippmann S, et al. South Med J. 2001;94:866-873.

CBT for Insomnia

Technique

Sleep Hygiene

Stimulus Control

Therapy


Relaxation

Paradoxical Intention

Cognitive-Behavioral

Therapy (CBT)

Aim

Promote habits that help sleep; provide rationale for subsequent instructions

Strengthen bed and bedroom as sleep stimulus

Restrict time in bed to improve sleep depth

& consolidation

Reduce arousal and decrease anxiety

Mitigate performance anxiety that impedes sleep onset

Combines sleep reduction, stimulus control techniques, and sleep restriction with cognitive therapy, addressing thoughts and beliefs that interfere with sleep




Overview of the Evidence for Efficacy



Big Picture on Meta-analyses



CBT for Insomnia produces meaningful improvements in 70% to 80% of patients with insomnia



Treatment gains are maintained over time



Meta-analysis of Nonpharmacologic

Interventions for Insomnia



59 treatment outcome studies (2,102) patients



Interventions (mean of 5 hours of therapy)



Effect sizes

– d = 0.88 for sleep latency

– d = 0.65 for time awake after sleep onset



Better off than 81% and 74% of untreated control subjects



Stimulus Control and Sleep Restriction



Great maintenance of treatment gains

Morin CM, et al. Am J Psychiatry. 1994;151:1172

–

1180.



Efficacy of Nonpharmacologic

Interventions for Insomnia

Meta-Analysis of 59 Trials (N = 2,102)

Pretreatment Posttreatment

70

60

50

40

30

20

10

0

Sleep-Onset Latency

P<0.001*

Control

Conditions

Nonpharmacologic

Treatments

30

20

10

0

80

Time Awake After Sleep Onset

P<0.001*

70

60

50

40

Control

Conditions

Nonpharmacologic

Treatments

*Control group posttreatment vs. nopharmacologic group posttreatment.

Morin CM, et al. Am J Psychiatry. 1994;151:1172

–

1180.



Meta-analysis of Behavioral

Treatments for Insomnia



23 randomized trials



Moderate to large effect sizes



CBT = BT = Relaxation



Middle aged and older adults achieve similar outcomes


Anxiety Disorders Association of America Irwin MR, et al. Health Psychol. 2006;25:3-14.

Comparative Meta-analysis of Behavioral

Treatments vs. Pharmacotherapy for Insomnia



21 randomized trials (470 subjects), use of pre- to post-treatment d scores



Limited to CBT studies utilizing stimulus control and/or sleep restriction



Medications: flurazepam, lorazepam, temazepam, triazolam, quazepam, zolpidem







Generally no difference in outcomes, but

Irwin MR, et al. Health Psychol. 2006;25:3-14.










CBT showed advantage for greater reductions in sleep latency than medications

(43% vs. 30%)










CBT showed advantage for greater reductions in sleep latency than medications

(43% vs. 30%)



Total sleep time improvements modest in both treatments: 12% pharmacotherapy, 6%

CBT



Sleep quality: 20% pharmacotherapy, 28%

CBT



Comparison Trial of

CBT and Pharmacotherapy



No differences in total sleep time



More normal sleepers with CBT alone

60

50

40

30

20

10

0

90

80

70

Combined CBT

CBT = 4 individual and 1 phone session over 8 weeks.

Med = zolpidem, nightly for 1 mo, taper over 12 days .

Jacobs GD, et al. Arch Intern Med. 2004;164:1888-1896.

Med Placebo

Pre

Mid

Post

1-mo FU

Post = 2-wk no treatment period.



Comparison Trial of CBT and

Pharmacotherapy (Late-Life Insomnia)

100

90

80

70

60

50

40

30

20

10

0

Combined

CBT = 8 weekly group sessions.

Med = temazepam x 8 weeks.


CBT Med

Pre

Post

3-mo FU

12-mo FU

24-mo FU

Placebo



CBT, Temazepam, or the Combination for

Chronic, Primary Late-Life Insomnia




CBT for BZ Tapering for Sleep



Discontinuing benzodiazepines (BZs) after chronic use

– 76 older adults (mean age 62.5 years) with chronic insomnia and mean 19.3 years of BZ medications (67 mg diazepam equiv.)

– 3 conditions

• Slow taper (over 10 weeks), 25% every 2 weeks

• Group CBT

• Group CBT plus slow taper



Morin CM, et al. Am J Psychiatry. 2004;161:332-342.




Greater likelihood of drug-free participants with CBT+ slow taper



Everyone gets better in terms of sleep over time, only significant difference was in total sleep time (more benefits for CBT)





60

50

40

30

20

10

0

90

80

70

Post

3-mo

12-mo

Med Taper

ITT = intent-to-treat


CBT CBT+MT




160

140

120

100

80

60

40

20

0

Med Taper


CBT

Pre

Post

3-mo

12-mo

CBT+MT



A Range of Modalities of Treatment Work



Comparison of:

– Individual therapy

– Group therapy

– Telephone consultation



All offered

– Stimulus control

– Sleep restriction

– Cognitive therapy

– Sleep hygiene

Bastien CH, et al. J Consult Clin Psychol. 2004;72:653-659.



A Range of Modalities of Treatment Work



Results

– All three led to significant improvements that were maintained at 6-month follow-up on selfreport

– Total wake time dropped to almost half

– 80% sleep efficiency ranged from 56% to 82% at follow-up


Anxiety Disorders Association of America Bastien CH, et al. J Consult Clin Psychol. 2004;72:653-659.

Comparison of Three Methods of Delivering CBT

180

160

140

120

100

80

60

40

20

0

Pre

Post

3-mo FU

6-mo FU

Individual Group Telephone


Anxiety Disorders Association of America Bastien CH, et al. J Consult Clin Psychol. 2004;72:653-659.


Insomnia



Pharmacologic and cognitive-behavioral therapy of anxiety improves associated sleep disturbance



Insomnia and GAD

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Difficulties Initiating

Sleep

Difficulties

Maintaining Sleep

Wake Too Early




Impact on Concomitant Insomnia of

Worry-Focused CBT for GAD vs. Waitlist

14

12

10

8

6

4

2

0

Baseline

CBT for GAD

P<0.01, CBT endpoint vs. waitlist endpoint; N=44.


Endpoint

Waitlist Control



Insomnia and CBT for PTSD

(Collaboration with Resick)



188 patients randomized to CPT, Prolonged

Exposure, or Minimal Attention

– Twice weekly sessions over 6 weeks

– Analysis of patients who received CPT or PE

CPT = cognitive processing therapy

Gutner CA, et al. In prep.







92% of the sample had sleep disturbance

(greater than 5 on PSQI)



PSQI scores linked to CAPS score at baseline (r = 0.53)

PSQI = Pittsburgh Sleep Quality Index.

CAPS = Clinician-Administered PTSD Scale.

Gutner CA, et al. In prep.







Significant improvement in PSQI scores with

CBT (M 10.6 to 7.4)



Improvements linked to CAPS changes

(r = 0.47)


Anxiety Disorders Association of America Gutner CA, et al. In prep.



 AND…



PSQI scores at post-treatment predict

3-month follow-up CAPS (over and above posttreatment CAPS scores)







Consistent with depression studies

– Poorer treatment response (Buysee et al,

1997; Dew et al, 1996; Winokur & Reynolds,

1994)

– Risk for relapse (Reynolds et al, 1997; Brower et al, 2001)







PSQI scores at post-treatment predict

3-month follow-up CAPS (over and above posttreatment CAPS scores)

– Consistent with depression studies

• Poorer treatment response (Buysee et al,

1997; Dew et al, 1996; Winokur &

Reynolds, 1994)



But

• Risk for relapse (Reynolds et al, 1997;

Brower et al, 2001)







But



Failure to replicate in the next study







Conclusions

– Given results to date – be confident that some pre-treatment sleep disruption will resolve with CBT

– Some will not

– Treating the residual sleep symptoms may help ultimate outcome



Assessment and the Application of CBT for Insomnia



Books I Like



Perlis, Jungquist, Smith, & Posner (2005).

Cognitive Behavioral Treatment of Insomnia .

New York: Springer.



Edinger & Carney (2008). Overcoming

Insomnia: A Cognitive-Behavioral Therapy

Approach Workbook (Treatments that Work).

New York: Oxford University Press USA.



Keep Sleep Logs



Time to bed



Time to fall asleep



Time awakening in the AM



Time up in the AM



Naps



Rating of quality of sleep



Rating of feeling rested



Sleep Logs



Attend to erratic bed times



Attend to erratic rising times



Attend to ratings of sleep quality vs. sleep time



Changes to sleep latency with changed bed times



Time awakening in the AM



Naps



Rating of quality of sleep



Rating of feeling rested



Sleep Log – Edinger & Carney

Edinger JD, Carney CE. Overcoming Insomnia: A Cognitive-Behavioral

Therapy Approach Workbook. New York: Oxford UP USA, 2008.



Sleep Questionnaires



Insomnia Severity Index (Morin, 1993)

– 7 item questionnaire that indicates perceived insomnia severity



Pittsburgh Sleep Quality Index (Buysee et al,

1989)

– Four open-ended questions and 19 self-rated items

• Score over 5 indicates sleep problems



Epworth Sleepiness Scale (Johns, 1991)

Morin CM. Insomnia: Psychological Assessment and Management. New York: Guilford Press, 1993.

Buysse DJ, et al. Psychiatry Res. 1989;28:193-213.

Johns MW. Sleep. 1991;14:540-545.



Stimulus Control Approach to

Treatment of Insomnia



Go to bed only when sleepy



Use the bed or bedroom only for sleeping

– Do not read, watch TV, or eat in bed



Go to bed when sleepy



Get out of bed when unable to sleep



Arise at the same time every morning



Do not nap during the day


Bootzin RR, et al. In: Hauri PJ, ed. Case Studies in Insomnia. 1991:19-28.






Select time in bed to represent the average total sleep time (plus 30 minutes)



Work with the patient on sleep onset and offset time



Joyfully explain rationale and likelihood of less time in bed (and potential for fatigue)



Adjust time in bed according to the target of

85% sleep efficiency



Sleep Titration for

Restriction Treatment



Sleep efficiency >90% – add 20 min sleep



Sleep efficiency 85%-90%



Sleep efficiency <85% – reduce total sleep opportunity



Assess noncompliance



Assess sleep hygiene

Perlis ML, et al. Cognitive Behavioral Treatment of Insomnia. New York: Springer, 2005.



Nonadherence



Assess prescribed time to bed and time out of bed

– vs. actual times

– vs. naps




Nonadherence

 Wanted to but couldn’t

– “not tonight; I will start tomorrow night”

– “It is so warm and comfy in bed; the cold will wake me right up if I get out of bed”




Nonadherence to Sleep Restriction



Intervention

– “it is a bad thing to be awake when reason sleeps”

– 30%-50% improvement short term

– Add the cost:

• 3 nights of insomnia per week for years

• 150 nights of insomnia per year

• vs. 14 to 21 really bad nights trying program




Nonadherence



Simply could not

– Fell asleep early



Intervention

– Reschedule activities in evening

• Exercise

• Activities

• Cold compress




Nonadherence



Did not want to



Intervention

– Review rationale and cost of current strategies




Perceptions of Sleep Quality



Impairments in daytime functioning are only indirectly linked to objective amounts of sleep



False feedback about hours slept

– Increased negative thoughts about sleep

– Monitoring of sleep-related symptoms

– Amount of daytime sleepiness

– Changes in behavior linked to sleep concerns

(e.g., canceling appointments or reducing exercise)


Anxiety Disorders Association of America Semler CN, Harvey AG. Behav Res Ther 2005;43:843-856.

Cognitive Biases



Tendency to attend to negative vs. positive stimuli (e.g., dot probe task)



Negative bias is linked to anxiety disorders



Greater negative bias is predictive of greater anxiety in response to a stressful event (e.g., an accident video)

MacLeod C, et al. J Abnorm Psychol. 2002;111:107-123.

Mackintosh B, et al. Behav Ther. 2006;37:209-222.



Cognitive Biases – Insomnia



Those with Primary Insomnia vs. good sleepers vs. those with delayed sleep phase disorder:

– Greater bias toward sleep related words among Primary Insomniacs 1

– Also an interpretative bias toward threatrelated interpretations of sleep stimuli 2

1. MacMahon KM, et al. Sleep. 2006;29:1420-1427.

2. Ree MJ, et al. Sleep. 2006;29:1359-1362.



Value of Placebo for Sleep



Placebo Condition

– 7.5 min sleep onset latency, 19.6 min subjective

– 21.4 min WASO (Wake-time After Sleep Onset)

– 18.3 min Total Sleep Time (objective)

– 31.1 min Total Sleep Time (subjective)



Differences

– Placebo beats waitlist for sleep onset latency and Total Sleep Time



Cognitive Interventions for Insomnia



Decrease misattribution and amplification of consequences insomnia

– e.g., “I can’t function at work without 8 hours of sleep.”



Correct unrealistic sleep expectations

– e.g., “I should never wake up at night.”



Decrease performance anxiety and learned helplessness



Correct faulty beliefs and dysfunctional sleep-related practices

– Sleep hygiene rules and target maladaptive coping

– Educate about causes of insomnia


Anxiety Disorders Association of America Morin CM. J Clin Psychiatry. 2004;65(suppl 16):33-40.

Cognitive Restructuring in Session

(Belanger, Savard & Morin)

“Close your eyes and imagine the following: It is

3AM and you have been tossing and turning for hours. You have an important meeting tomorrow, but can’t seem to get to sleep. Tell me your thoughts at this moment.”


Anxiety Disorders Association of America Belanger L, et al. Behav Sleep Med. 2006;4:179-198.

Cognitive Restructuring



Examine the evidence for the thought



Generate alternative explanations



De-catastrophize

 Debunk “shoulds”



Find the logical error



Test out its helpfulness



Cognitive Errors of Depression



All-or-nothing thinking



Overgeneralization



Mental filter



Disqualifying the positive



Jumping to conclusions



Personalization


Anxiety Disorders Association of America Burns DD. Feeling Good: The New Mood Therapy. 1980.

Questions Used to Formulate

Rational Response



What is the evidence that the automatic thought is true? Not true?



Is there an alternative explanation?



What is the worst that could happen?

Would I live through it?

 What’s the best that could happen?

 What’s the most realistic outcome?



Questions Used to Formulate

Rational Response

(cont’d)



What is the effect of my believing the automatic thought?



What is the cognitive error?



If a friend were in this situation and had this thought, what would I tell him/her?



Automatic Thought Record

Automatic

Thought

Rate belief

0%-100%

Feeling(s)

Rate intensity

0%-100%

Response

What is the error?

What is a more helpful way to think about the event?

Outcome

Re-rate belief in automatic thought and intensity of feeling

Adapted from a worksheet in use by J. Beck and A.T. Beck.



Relaxation Training



Tense Relax Method



7 seconds tension, at least twice as long relaxation



Feel the difference (repeat the difference)



Use of cued-relaxation



Use of imagery

 “Enjoying being in bed”



Worry Time



Early evening



Select place (desk)



Paper and pencil



40 min followed by relaxation



Delay next worry till next worry time



Session 1: Edinger & Carney



Psychoeducation

– 2 goals

• Overcome misconceptions and anxiety-provoking beliefs about sleep

• Develop rationale for interventions to follow



How much sleep do you need?

– Great variability (6-8 hours vs. 3-4 vs. 10-12)

– Find sleep that allows alertness and energy during day

–

Get rid of old notions about needs

– Circadian rhythms



Cost of sleeping in and naps

– Don’t try to recover sleep

– Don’t worry about lost sleep





Session 1: Rules for Healthier

Sleeping (Edinger & Carney)



Select a standard wake-up time



Use the bed only for sleeping

 Get up when you can’t sleep

 Don’t worry or plan in bed



Avoid daytime napping



Go to bed when you are sleepy but not before the time suggested



Time in Bed Prescription

– Time in BED = Average Totals Sleep Time + 30 minutes

– With success, adjust by 15 minutes (targeting >85% sleep efficiency)





Session 1: Sleep Hygiene

(Edinger & Charney)



Limit caffeine



Limit alcohol



Moderate exercise (late afternoon, early evening)



Manage hunger (night snack)



Quiet and dark bedroom (white noise machine – NewYorker)



Not too warm in the bedroom (below 75 °)





Session 2: Edinger & Charney



Managing expectations

– With consistent adherence to the behavioral strategies – expect marked changes in wake time during the night within 2 to 3 weeks

– Expect some sleepiness as the program starts

• Caution about dangerous activities





Session 2: Cognitive Restructuring

(Edinger & Charney)



Structured worry time

– Write it out

– Proposed solutions

– Dispense with thinking through worries till the next evening (well before bedtime)












- Thank You.



An Overview of

Sleep Disorders &

Pharmacotherapy


Director, Center for Anxiety and Traumatic

Stress Disorders




After John Winkelman, MD, PhD



Disclosure



Dr. Mark H. Pollack has received grants or research support from AstraZeneca, Bristol-Myers Squibb, Cephalon,

Cyberonics, Forest, GlaxoSmithKline, Janssen, Lilly,

NARSAD, NIDA, NIMH, Pfizer, Roche, Sepracor, UCB, and

Wyeth. He has been a consultant for AstraZeneca, Brain

Cells, Bristol-Myers Squibb, Cephalon, Dov, Forest,

GlaxoSmithKline, Janssen, Jazz, Lilly, Medavante,

Neurocrine, Neurogen, Novartis, Otsuka, Pfizer, Predix,

Roche, sanofi-aventis, Sepracor, Solvay, Tikvah, Transcept,

UCB, and Wyeth. He has been a speakers bureau member for Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen,

Lilly, Pfizer, Solvay, and Wyeth, and has equity in Medavante and Mensante.



Sleep Disorders



Insomnias

– Primary insomnia, psychiatric/medical disorders, RLS, medications



Hypersomnias

– Sleep apnea, medications, periodic leg movements of sleep



Parasomnias

– Sleepwalking, sleep terrors, REM sleep behavior disorder



Circadian rhythm disorders

– Shift work sleep disorder, delayed sleep phase disorder



DSM-IV Insomnia

Primary

Insomnia

Without clear precipitant;

“hyperarousal”

Insomnia

Difficulty initiating or maintaining sleep, or nonrestorative sleep for

≥1 month

Comorbid

Insomnia

Associated with a psychiatric, medical, or sleep disorder

MUST cause distress or impairment in social, occupational, or other areas of functioning



Prevalence of Chronic Insomnia in the General Adult Population

20

15

10

5

10.2

17.7

16.8

9.0

11.7

10.0

0

Ford

1989

Ohayon

1998

Ohayon

2001

Ancoli-

Israel

1999

Ishigooka

1999

Simon

1997



Consequences of

Insomnia

Why Should We Care?



Insomnia Is a Risk Factor for


Incidence (%) Over 3.5 years

12

10

8

6

4

2

0

18

16

14

*

*

Depression Anxiety

*95% CI for odds ratio excludes 1.0.

Insomnia, n=240

No Insomnia, n=739

Alcohol Abuse

*

Drug Abuse

Breslau N, et al. Biol Psychiatry. 1996;39:411-418.



Transient and Short-Term Insomnia are

Caused by Identifiable Precipitants

Transient Insomnia



Lasts several days



Consequence of acute stress or environmental changes

– Unfamiliar sleep environment

– Situational stress

–

Acute medical illness

–

Shift work

–

Jet lag

–

Caffeine, alcohol, nicotine, or drug side effects

Short-Term Insomnia

 Up to 3 weeks’ duration



Major life stressors

–

Hospitalization

–

Emotional trauma

–

Pain

– Marriage

– Divorce

– Moving

– Bereavement



Chronic Insomnia Requires a Thorough Evaluation

Symptoms

Treatment

Differential Diagnosis

Diagnosis



Chronic Insomnia Is

Often Multifactorial



Psychiatric illness(es)



Primary sleep disorder(s)



Medical illness(es)



Medication(s)

Treat the underlying cause(s)!



Empiric Treatment of Insomnia

Is Often Necessary



Underlying causes of insomnia are often:

– Not apparent

– Not fully treatable



Differential Diagnosis of

Chronic Insomnia



Primary psychiatric disorders



Medication-related



Licit and illicit substances



Medical disorders







Restless Legs Syndrome (RLS) and

Periodic Limb Movement Disorder (PLMD)

 “Conditioned” insomnia



Sleep schedule disorders



Everybody with Chronic Insomnia

Must Practice Good Sleep Hygiene



Standardize wake time



Limit amount of time awake in bed



Limit napping



Remove clock from vision



Avoid caffeine (after noon) and alcohol

(after 6 pm)



Avoid stressful activities in evening



Psychiatric Disorders Are Present in 40% of Those with Insomnia

Drug Abuse

Other Psychiatric Disorder

Alcohol Abuse

Dysthymia

Major Depression

Anxiety Disorders

No Psychiatric Disorder

0

4.2

5.1

7.0

8.6

Ford DE, Kamerow DB. JAMA. 1989;262:1479-1484.

10

14.0

23.9

59.5

20 30 40

% of Respondents

50 60



All Psychiatric Disorders

Produce Insomnia

Mania > Schizophrenia >

Depression and Anxiety Disorders



Sleep Disturbance Is the Most Common

Refractory Symptom in Treated MDD

30

25

20

15

10

5

0

50

45

40

35

Subthreshold

Threshold

SYMPTOMS

MDD = major depressive disorder.

Nierenberg AA, et al. J Clin Psychiatry. 1999;60:221-225.



Insomnia Related to Medications



Antidepressants



Stimulants



Steroids, bronchodilators



Decongestants



Dopaminergic antagonists (akathisia)



Insomnia in Elderly Is Not Related to Age, But to Medical Illness



Cardiac: angina,

PND



Pulmonary: COPD, coughing



GI: Nocturnal reflux



Musculoskeletal pain



Endocrine: Hypo/ hyperthyroidism, diabetes, menopause



Neurologic:

Dementia,

Parkinson’s, CVA, migraine



Urinary: Nocturia, renal failure



Licit Substances



Caffeine

– Sleepiness can overcome stimulant effects, but awakenings are common



Alcohol

– Produces 3-4 hours of good sleep, followed by increased wakefulness in the second half of the night



Restless Legs Syndrome (RLS) –

Diagnosis

Minimal Criteria



Urge to move legs, usually with uncomfortable leg sensations



Onset or worsening of symptoms at rest or inactivity, such as when lying or sitting



Relief with movement – partial or total relief from discomfort by walking or stretching



Worsening of symptoms in the evening and at night

Additional Features



Sleep disturbance



Involuntary leg movements



Positive RLS family history



Response to dopaminergic therapy



Prevalence by Age and Gender from the REST Population-Based Survey

RLS Sufferers (n=116)

8

6

4

2

All

Men

Women

0

20-29 30-39 40-49 50-59 60-69 70-79

AGE GROUP (years)

Allen RP, et al. Arch Intern Med. 2005;165:1286-1292.

80+



Pathophysiology of RLS



Idiopathic



Familial (30%-60%)



Iron Deficiency



Renal Failure



Peripheral

Neuropathy



Rheumatoid Arthritis



Medication-Induced

(especially SRIs)



Fibromyalgia



Pregnancy



Iron Deficiency and RLS



Reductions in 1) CSF ferritin and 2) substantia nigra iron by MRI, transcranial ultrasound, and on autopsy



Fe is a cofactor in the hydroxylation of tyrosine into L-DOPA



Serum iron deficiency is present in a minority of

RLS patients



Iron repletion may be effective in iron-deficient patients with RLS (ferritin <40)



Pharmacologic Treatment of

Moderate to Severe RLS

DOPAMINERGIC AGENTS

Pramipexole 0.125 – 1.0

* , Ropinirole * 0.5-4.0 mg q8pm

Persistent sleep disruption

Partial response Non-response

Add sedative (e.g., trazodone, benzo, gabapentin)

Add gabapentin or opiate

Reassess diagnosis

*FDA-approved for RLS



Sleep Schedule Disorders



Delayed Sleep Phase Syndrome

– Most common in adolescents

– Initial insomnia and difficulty awakening in AM

– Daytime sleepiness



Advanced Sleep Phase Syndrome

– Most common in the elderly

– Early AM awakening



Conditioned or

Psychophysiological Insomnia



Begins with an acute insomnia and is then maintained by negative associations and anxiety regarding sleep initiation (“insomnia phobia”) as well as by poor sleep hygiene



Treatment of

Conditioned Insomnia



Improve sleep hygiene



Cognitive Behavioral Therapy



Hypnotics intermittently or chronically, if CBT fails



Pharmacologic Interventions for

Primary Insomnia



FDA-approved

– Nonselective BZ-receptor agonists

– Selective GABA-receptor agonists

– Melatonin-receptor agonists



Non –FDA-approved

– Sedating antidepressants

– Sedating anticonvulsants

– Sedating antipsychotics


Anxiety Disorders Association of America This information concerns a use that has not been approved by the US FDA.

Hypnotic Medications

Drug

BENZODIAZEPINES

Estazolam (ProSom



)

Flurazepam (Dalmane

®

)

Quazepam (Doral

®

)

Temazepam (Restoril

®

)

Triazolam (Halcion

®

)

NONBENZODIAZEPINES

Zolpidem (Ambien ® )

Zolpidem ER (Ambien CR ® )

Zaleplon (Sonata ® )

Eszopiclone (Lunesta ® )

MELATONIN RECEPTOR AGONIST

Ramelteon (Rozerem



)

Half-Life (hrs)

8-24

48-120

48-120

8-20

2-4

1.5-2.4

2.8-2.9

~1

5-7

1-2.6


Doses (mg)

1, 2

15, 30

7.5, 15

7.5, 15, 22.5, 30

0.125, 0.25

5, 10

6.25, 12.5

5, 10

1, 2, 3

8



Fears Regarding BzRAs Lead to

Undertreatment of Insomnia

BENEFITS

FEARS

•

Efficacy of medications

•

Wide range of T

1/2

• Fears of “addiction,” abuse

•

Package label restrictions




No Evidence of Tolerance with 6 Months of

Nightly Use of Eszopiclone for Insomnia

30

20

10

0

60

40

50

Median Sleep Latency

*

1

*

2

* * * *

20

10

0

60

50

40

30

3 4

Months

5 6

Eszopiclone 3 mg (n = 593)

†

Median Wake-Time

After Sleep Onset

† † ‡ †

1 2 3 4

Months

Placebo (n = 195)

5

†

6

*p<0.005; † p<0.05; ‡ p=0.07.

Krystal AD, et al. Sleep. 2003;26:793-799.



Current Status of BzRA Risks in the Treatment of Insomnia



Motor vehicle accidents in elderly: long T

1/2



Hip fractures in elderly: long T

1/2



Anterograde amnesia: T agents?

1/2

-dependent



Abuse: rarely seen outside of drug abusers



Tolerance: no evidence from recent 12- and agents

26-week studies



Rebound insomnia: depends upon dose, duration of use, and speed of taper

Hemmelgarn B, et al. JAMA. 1997;278:27-31.

Cumming RG, Le Couteur DG. CNS Drugs. 2003;17:825-837.

Woods JH, Winger G. Psychopharmacology. 1995;118:107-115.

Krystal AD, et al. Sleep. 2003;26:793-799.




Antidepressants in the Treatment of Insomnia:

Mirtazapine, Trazodone, Amitriptyline, Doxepin



Advantages: Little abuse liability



Disadvantages: Probably not as effective as BzRAs, daytime sedation, weight gain, anticholinergic side effects, switch into mania in bipolar disorder




Atypical Antipsychotics in the Treatment of Insomnia:

Olanzapine, Quetiapine, Risperidone, Ziprasidone



Advantages: Anxiolytic, mood stabilizing in bipolar disorder, little abuse liability



Disadvantages: Less effective than

BzRAs, daytime sedation, weight gain, risks of extrapyramidal symptoms and glucose + lipid abnormalities




Anticonvulsants in the Treatment of Insomnia:

Gabapentin, Topiramate, Tiagabine



Advantages: Little abuse liability



Disadvantages: Less effective than BzRAs, cognitive impairment, daytime sedation




Issues with Non-BzRA Hypnotics in the

Treatment of Insomnia (e.g., antidepressants, anticonvulsants, antipsychotics)



Paucity of short-term efficacy data



Absence of long-term efficacy data



Assumptions of lack of tolerance and rebound insomnia are unsubstantiated



Anecdotally less effective hypnotics than

BzRAs



May have deleterious side effects




Hypersomnia vs. Fatigue



Hypersomnia

– Excessive daytime somnolence

(see algorithm, next slide)



Fatigue

– Lack of energy, “tiredness”

– Multiple medical and psychiatric etiologies




Excessive Daytime Sleepiness

Inadequate

Sleep Time

 Voluntary restriction

 Shift work sleep disorder

 Delayed Sleep Phase

Disorder

Poor Sleep

Quality

 Sleep apnea

 Periodic Limb

Movement Disorder

 Pharmacologic or environmental disturbances

Excessive

Sleep Drive

 Narcolepsy

 Idiopathic

Hypersomnia

 Medications



Obstruction of the Airway =

Apnea

Site of upper airway collapse



Sleep apnea prevalence is 4% of males, 2% of females



Risk factors include obesity, upper airway narrowing, sedatives



Loud snoring, witnessed apneas, excessive daytime sleepiness



Prevalence of Obstructive Sleep

Apnea Syndrome (OSAS)



Males = 4%



Females = 2% (post-menopausal prevalence rises to equal males)

Young T, et al. N Engl J Med. 1993;328:1230-1235.



Treatment of OSAS



Nasal Continuous Positive Airway

Pressure (CPAP)



Weight loss



Improve upper airway patency with nasal steroids, surgery, dental device



When to Refer for Sleep Study?



Suspicion of sleep apnea (loud snoring PLUS one of the following):

– Daytime somnolence

– Witnessed apneas

– Refractory hypertension

– Refractory sleep complaints



Abnormal behaviors or movements during sleep



Unexplained excessive daytime sleepiness



Refractory sleep complaints, particularly repetitive brief awakenings



Therapeutic Approaches to




Insomnia is extremely common, particularly among those with medical and psychiatric illness



Potential underlying causes must be assessed to optimize treatment



Insomnia can be both a symptom and a disorder



The cause of insomnia is often multifactorial





(cont’d)



Risks of untreated insomnia must be carefully assessed



Sleep hygiene and CBT should be first-line treatments



Medications can be used intermittently or, when necessary, chronically to treat insomnia





(cont’d)



Long-term treatment

– Regular reassessment of risks and benefits of both insomnia and pharmacotherapy

– If discontinuing medication, use CBT and carefully taper to minimize the return of insomnia

– Consultation and/or polysomnography in refractory insomnia is encouraged










- Thank You.



Evaluating and

Treating Comorbid

Sleep and Psychiatric

Disorders in Children


Director, Pediatric Behavioral Medicine Program

Associate Director, Pediatric Sleep Disorders Program

Children’s National Medical Center

Associate Professor of Psychiatry and Pediatrics

George Washington University School of Medicine



Disclosure



Dr. Daniel S. Lewin has no financial relationships over the past 12 months with any commercial organizations having a direct or indirect interest in the subject matter of his presentation



Outline



Developmental changes in sleep



Evaluating sleep and psychiatric disorders



Treatment of common sleep disorders associated with behavior problems and psychiatric disorders



Comorbid Sleep and




Bi-directional links between affective disorders (depression and anxiety) and sleep problems

– Serotonin and norepinephrine

– Hyperarousal and cognitive disinhibition

(rumination & worry)



Shared or common phenotypes

– ADHD & signs of disordered sleep



Change in Distribution of Sleep

Stages – Birth Through Adolescence

16

14

12

10

8

6

4

2

0

NREM

REM

Term 1 mo.

6 mo.

12 mo. 2 yrs.

5 yrs.

10 yrs. 16 yrs.

Anders T, et al. In: Ferber R, Kryger M, eds. Principles and Practice

of Sleep Medicine in the Child. Philadelphia: WB Saunders, 1995, pp. 7-18.



Estimated Norms for

24-Hour Sleep Duration

AGE GROUP

Infants (3-11 mo.)

Toddlers (12-35 mo.)

Pre-K and K (3-5 yrs.)

School-aged (6-10 yrs.)

11-15 yrs.

16-18 yrs.

POLL DATA

(NSF ’05 & ’06)

12.7

11.7

10.4

9.5

8.4-7.2

7.2-6.9

POPULATION DATA

Iglowstein ’03

(Switzerland)

14.2-13.9 (1.7)

13.5-12.5 (1.2)

12.5-11.4 (0.9)

11-9.9 (0.6)

9.6-8.1 (0.7)

National Sleep Foundation. Sleep in America polls, 2005 & 2006. Available at: http://www.sleepfoundation.org/site/c.huIXKjM0IxF/b.2417353.

Iglowstein I, et al. Pediatrics. 2003;111:302-307.



Child and Adolescent

Sleep Patterns

African American Children – Ages 6-18 (n=42)

490

480

470

460

450

440

430

420

Sun Mon Tue Wed

DAY

Thu Fri

Alfano C, et al. Sleep. 2007;30(abstract suppl):A96.

Presented at: APSS 2007, Minneapolis, MN.

Sat



Sleep Drive

SLEEP LOAD

WAKE

Circadian

Cycle

ALERTING

SIGNAL

SLEEP

9 AM 3 PM

Day - awake

9 PM 3 AM

Night - asleep

9 AM

NHLBI Sleep Academic Award, Gerald Rosen.



Assessment Techniques –

The Clinical Interview



Thorough history

– Observation of parent-child interactions

– Sleep history: B.E.A.R.S

– Other sleep disorders

– Medical history (GERD, pain)

– Developmental history

– Psychiatric history

– Family (psych history, schedule, marital, attachment)



The Sleep Habits Assessment

B edtime

E

DS

(Excessive Daytime

Somnolence)



Routine



Resistance



Fears



Hyperactivity



Irritability



Difficulty waking

A wakenings

R egularity

S noring



Call-outs



Partial arousal



Restlessness



Schedule



Age



Volume



Pauses



Periodicity

Adapted from: Mindell JA, Owens JA. A Clinical Guide to Pediatric Sleep:

Diagnosis and Management of Sleep Problems. Philadelphia: Lippincott,

Williams & Wilkins, 2003.



Sleep Questionnaires



Pediatric Sleep Questionnaire (OSA 6-18)

– Chervin RD, et al. Sleep Med.

2000;1:21-32. http://www.saintpatrick.org/images/sleep_questionnaire.pdf



The Cleveland Adolescent Sleepiness

Questionnaire (12-18)

– Spilsbury JC, et al. J Clin Sleep Med . 2007;3:603-12.

 Children’s Sleep Habits Questionnaire (6 to 12)

– Owens J, et al. Sleep . 2000;23:1043-51.



Epworth Sleepiness Scale (Adult)

– Johns MW. Sleep . 1991;14:540-5.



When to Order a Sleep Study



Snoring +

– Gasps and pauses in respiration

– Academic or attention problems

– Other sleep disorders



Movement-related sleep disorder (RLS/PLMD)



Rule out narcolepsy, idiopathic hypersomnia



Persistent and treatment-resistant sleep disturbances



Normative values for nap studies (MSLT) are unreliable in children <10 years

RLS/PLMD = restless legs syndrome/periodic limb movement disorder;

MSLT = Multiple Sleep Latency Test.



Psychiatric/Behavioral

Questionnaires



Child Behavior Checklist (general behavior problems) http://www.aseba.org/

 Children’s Depression Inventory http://www.pearsonassessments.com/tests/cdi.htm



Vineland Adaptive Behavior Scale (developmental status) http://ags.pearsonassessments.com/group.asp?nGroupInfoID=a3000



Connors ADHD Rating Scales http://www.pearsonassessments.com/tests/crs-r.htm



BRIEF (Executive function and ADHD)

Gioia GA, et al. Neuropsychol Dev Cogn Sect C Child Neuropsychol . 2000;6:235-8.



SCARED (Anxiety)

Birmaher B, et al. J Am Acad Child Adolesc Psychiatry . 1997;36:545-53.

http://www.wpic.pitt.edu/research/city/Family/Anxiety/OnlineAnxietyScreen_files/PDF%20Files/Sc ared%20Parent-final.pdf



Visual Analogue Scales



← 100 mm →





Child Behavior Checklist



Factor analyzed scale



Over 1,000 Medline citations



Normative values for girls, boys, and

3 age groups



4 competence scales



3 problem summary scales



8 problem subscales







Signs of Disordered Sleep in the Child



Excessive time spent falling asleep



Repeated awakenings



Difficulty waking in the morning



Impaired daytime alertness



Parental sleep loss



Sleep-related impairment of the parent-child relationship



Pediatric Sleep Disorders

Category

Insomnia

Sleep-Related

Breathing

Hypersomnia

Disorder

Psychophysiological insomnia (307.42)

Behavior insomnia of childhood (V69.5)

- Sleep-onset association type

- Limit-setting type

Primary sleep apnea of infancy (770.81)

Obstructive sleep apnea, pediatric (327.23)

Congenital central alveolar hypoventilation

(327.25)

Narcolepsy (347)

Kleine-Levin syndrome (327.13)

Behaviorally induced insufficient sleep syndrome (307.44)

>0.02%

>0.01%

?

Prevalence

~20%-50%

10%-30%

0.5% (healthy)

~3%-5%

<0.01%

Age range

(yrs)

~6-18

0.5-~8

0.5-~3

~1-~8

0-0.2

0.2-18

Birth

?

~14

?

American Academy of Sleep Medicine. ICSD-2. Westchester, IL: AASM, 2005.



Pediatric Sleep Disorders

(cont’d)

Category

Circadian Rhythm

Sleep Disorder

Disorder

Delayed sleep phase syndrome

Advanced sleep phase syndrome

Parasomnias Confusional arousals (327.41)

Sleep walking (307.46)

Sleep terrors (307.46)

Sleep enuresis (788.36)

Sleep-Related

Movement

Disorder

Restless legs syndrome (333.99)

Periodic limb movement disorder (327.51)

Sleep-related rhythm movement disorder

(327.59)

Prevalence

>16%

?

17.5%

17%

1%-6.5%

By age

<16%

?

3%-6%

?

?

Age range

(yrs)

>12

0.5-6

<3-13

<3-18

<3-18

>4

>0.5




Child Behavior Checklist – Between-Group

Differences, OSA vs. Control, 6-10 years

60

55

Comparison (n=37)

OSA (n=76)

*

50

*

*

*

45

To ta l

In te rn ali zin g

E xte rn ali zin g

A tte nti on

A gg re ss io n

A nx

/D ep

W ith dr aw n

S oc ia l

S om ati c

*P<0.006, Bonferroni correction

Unpublished data.



Mean Rates of CBCL Sleep Items

Very true

1

Sleep Anxious Control

Often true

0.5

Never

0

Nightmares Overtired Sleeps < Sleeps > Talks/walks Trouble sleeping

Wets bed

Alfano CA, et al. Sleep Med. 2006;7:467-73.



Sleep Disorder Symptoms in Children

With Two or More Psychiatric Diagnoses

35

30

25

20

15

10

5

0

50

45

40

Combined

Child

Adolescent

B

SD

E

D

S

Hall T, et al. Sleep. 2006;29(abstract suppl):A333.

Presented at: APSS 2006, Salt Lake City, UT.

In so m in a

N ig ht m ar es

P ar as om nia s

S

D

B



Sleep-Related Anxiety vs. Fear



Bedtime and sleep-related fears are normal and state-related or transient



Sleep-related anxiety is a marker of psychopathology and is a more stable condition that is also present during the day



Early sleep disruption predicts later emergence of anxiety disorders and substance abuse (Gregory & Connor, 2002)

Gregory AM, O'Connor TG. J Am Acad Child Adolesc Psychiatry. 2002;41:964-71.



Hypothesized Links –

Sleep and ADHD



H1 – Sleep problems may account for symptoms of inattention and hyperactivity in 10%-20% of children diagnosed with ADHD

– Chervin et al, 2002; Gozal, 1998; Picchietti et al, 1998;

O’Brien et al, 2003; Cortese et al, 2006



H2 – ADHD is a disorder of HYPO-VIGILANCE

– Rubia K et al, 1999; Weinberger W et al, 1993; Lecendreaux M, et al, 2000



H3 - Underlying abnormalities in sleep/wake mechanisms are associated with ADHD

Chervin RD, et al. Sleep. 2002;25:213-8; Chervin RD, et al. Pediatrics. 109:449-5;

Gozal D. Pediatrics. 1998;102(3 Pt 1):616-20; Picchietti DL, et al. Mov Disord.

1999;14: 1000-7; O’Brien LM, et al. Pediatr Res. 2003;54:237-43; Cortese S, et al.

Sleep. 2006;29:504-11; Rubia K, et al. Behav Brain Res. 1998;94: 25-32; Weinberger

DR. Neurosciences. 1993;5:241-53; Lecendreaux M, et al. J Child Psychol

Psychiatry. 2000;41:803-12.



MSLT Results for ADHD and Control Groups at Each Nap (Mean Sleep Latency ± SEM)

Sleep Latency During MSLT

MSLT = Multiple Sleep Latency Test

Golan N, et al. Sleep. 2004;27:261-6.



A Few Key Principles



A tired child does not look like a tired adult



Neurobehavioral functioning should be a factor in intervention decisions



Prior to age 10 children are unreliable reporters of internal states



There is high comorbidity of sleep and psychiatric disorders in children



Behavioral Insomnias of

Childhood



Occur in as many as

50%, and 30% tell pediatricians about the problem



Difficulty falling asleep



Bedtime resistance



Difficulty staying asleep



Poor sleep quality



Too little sleep for parents and/or children



The Letting Down of Vigilance








Childhood



Sleep-Onset Association

Disorder

– Prevalence: 25%-30%

– Age group: 6-36 months

– Clinical features

• Delayed sleep onset & nighttime awakenings

• Sleep onset becomes associated with exogenous cues

• Sleep onset at bedtime or the middle of the night will not occur w/out cue



Limit-Setting Sleep Disorder

– Prevalence: 25%-30%

– Age group: 18-60 months

– Clinical features

• Delayed bedtime

• Parents reinforce undesirable behavior at bedtime

• Inconsistent limit-setting

• Otherwise normal nocturnal sleep


Mindell JA. J Pediatr Psychol. 1999;24:465-81.



Case Study 1 – Carl



24.5-month-old boy



Presenting complaint

– Erratic sleep/wake schedule

– Sleeps with mother in her bed every night

– Difficulty weaning



History

– Uncomplicated vaginal delivery to a 38-year-old

– History of colic and GERD

– Normal development



2.5 years

N = Nursing

= Irritable



Targets of Treatment



Bedtime Resistance

– Curtain calls

– Nighttime fears

– Bed/crib aversion

– Crying/tantrums



Nocturnal Awakenings

– Nighttime call-outs

– Crying




Childhood – Treatment



Identify and eliminate reinforcers or cues that delay an independent wake-sleep transition



Establish appropriate bed times



Establish appropriate bedtime routines




Childhood – Treatment



Extinction and its Variations

– Simple extinction (“Cry it out” – cold turkey)

• Ignore child’s attention seeking/inappropriate behavior

• Immediate withdrawal of parent, bottle, holding, breast feeding

– Graduated extinction (“Ferberize”): incremental withdrawal of parent involvement

• Increase visit intervals

• Decrease duration of visits



The Bedtime Pass (Moore et al, 2007)

– Child-controlled single visitation



Fading Approaches

–

Graduated increase in proximity

–

Graduated decrease in quality of interaction


Anxiety Disorders Association of America Moore BA, et al. J Pediatr Psychol. 2007;32:283-7.

Carl’s Treatment



Decrease frequency and duration of nursing



Limit sleep to own bedroom



Fade parents involvement in wake-to-sleep transition



Involve father in bedtime ritual



Introduce transitional object



Limit-setting during day



Autism and

Developmental Disorders



Sleep problems are particularly common among these populations

– Anxiety

– Impaired social perception

– Impairment in learning routines



Same treatment principles apply

– Pace of approach should be modified

– Applied behavioral analysis

• Response cost (delaying “sleep” as reward)



Bedtime Transition Cues



Psychophysiological Insomnia in

Children – Treatment



Psychophysiologic insomnia in children has not been adequately studied



Treatment approaches do not differ from those that have been established for adults

– Stimulus Control

– Sleep Restriction

– Sleep Hygiene Training

– Cognitive Therapy

– Relaxation



Developmental and mental health factors must be considered



Sleep Hygiene



Regular bed and wake times



Eliminate caffeine



Eliminate stimulating behavior before bedtime



No electronic media within an hour of bedtime



Quiet reading/snuggling



Establish and early evening worry time



Relaxation Training



Decrease somatic and cognitive arousal



Distraction

– Deep breathing

– Somatic relaxation (e.g., progressive muscle relaxation

– Cognitive techniques (guided imagery)



Obstructive Sleep Apnea

Syndrome (OSAS)



Pauses in breathing during sleep



How common is it?

– 1.1%-2.9% of 4-5 year-olds

– 18% of children w/ behavior & academic problems

(Gozal, 1998)



Causes: obstructed or narrow upper airway



Signs – Snoring, snorting, gasping, breathing pauses



Effects: Decreased oxygen and sleep disruption



Daytime effects: attention, mood, impulsivity

(Beebe, 2006)

Gozal D. Pediatrics. 1998;102(3 Pt 1):616-20.

Beebe DW. Sleep. 2006;29:1115-34.



OSA Treatment



Surgical interventions

– Adenoid and/or tonsillectomy

– UPPP (uvulopalatopharyngoplasty) – Adults

– Mandibular advancement

– Tracheostomy



Nasal CPAP/BiPAP



Palatal expansion



Weight loss



Sleep positioning










- Thank You.



Case Study 2 – Insomnia



13-year-old female



SOL 1-1.5 hours, no problems with WASO



Falls asleep with parent



Periodic use of Benadryl and melatonin



Limb discomfort at bedtime



Caffeine 1-2 times/week



Difficulty waking >5 days/week



Mild occasional snoring



Modified Epworth = 11; CDI = 5; SCARED =

80th%



9

9.75

7

8

10

8.5

8

8

8.25

9.5

10

10

9

1.5

1.5

1

Average total sleep time: 9.2 hours



Case Study 2 – Treatment



Sleep education



Address worry at bed time (worry diary, psychotherapy)



Consistent sleep environment



Stimulus Control



TIB restricted to 9 hours: 9-6 weekdays & 10-7 weekends



Eliminate naps >15 min



Relaxation Therapy (deep breathing, guided imagery, progressive muscle relaxation)



Rule out restless legs syndrome (iron panel)



Eliminate caffeine use



Melatonin @ 6:00 pm



Case Study 3 – Delayed Sleep

Phase Syndrome



16-year-old Hispanic female



Maintaining A/A- grade average



Single parent home, 2 younger siblings



Generalized Anxiety Disorder



Chronic fatigue and possible dysthymia



Shy and socially anxious



7.5

4

4.5

4

4.5

3.5

4.5

8.5

1.5



Delayed Sleep Phase Syndrome

(DSPS) – Assessment



Evaluate motivation (secondary gain)



Evaluate psychopathology



Sleep log & actigraphy



DSPS Treatment



Contract for at least 4 weeks



Modify involvement in highly rewarding activities



Chronotherapy (phase – advance/delay; acute sleep debt)



Light and temperature



Melatonin



Treatment



Fixed sleep schedule w/ weekend flexibility



Chronotherapy – gradual phase advanced



Eliminated caffeine



Light box 1 hour in AM



Stimulus Control



Referred for psychotherapy



Melatonin












- Thank You.



When to Use Sleep-Promoting

Medications



Pain



Acute trauma?



Major life stressor



Injury risk and safety issues



Severe developmental disability



Recurrent high-risk parasomnias



?Short term use in treatment-resistant insomnia?

30

25

20

15

10

5

0

Percentage of Physicians Prescribing

Specific Medications for Sleep Problems

0 to 2 3 to 5 6 to 12 13 +

Antihistamine

Alpha Agonist

Benzodiazepines

Chloral Hydrate

Antidepresant

Owens JA, et al. Pediatrics.

2003;111(5 Pt 1):e628-35.



Summary



Sleep and psychiatric disorders have similar phenotypes



Child psychiatry evaluations should include assessment of

– Insomnia

– Insufficient sleep

– Sleep disordered breathing



THANK YOU


Children’s National Medical Center,

Washington, DC dlewin@cnmc.org



Evaluation and

Management of Insomnia in Home-Dwelling

Older Persons

W. Vaughn McCall, MD, MS

Chair and Professor, Department of Psychiatry and Behavioral Medicine

Wake Forest University School of Medicine

Winston-Salem, North Carolina



Disclosures



Dr. W. Vaughn McCall has received grants or research support from GlaxoSmithKline, sanofi-aventis, and Sepracor. He has been a consultant for Sepracor and a speakers bureau member for GlaxoSmithKline and

Sepracor.



Sleep Is Important

Throughout the Life Cycle










- Thank You.



Sleep and Age

700

600

500

400

Total time in bed

Awake in bed

NREM stage 1

REM 300

200

NREM stage 2

100

NREM δ

10 20 30 40 50 60 70 80

Age in Years

Williams RL, et al. EEG of Human Sleep: Clinical Applications. 1974, p. 91.



The Prevalence of Obstructive Sleep

Apnea (OSA) Increases With Age

100

90

80

70

60

50

40

30

20

10

0

Habitual Snorers (19.0%)

Men 24.1%

Women 13.8%

30

25

20

15

10

5

0

AHI

≥10

OAHI >10

AHI

≥10 plus clinical symptoms of OSA

20-44 45-64

Age Groups

≥65

Age (Years)

Parati G, et al. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1671-R1683.

Stradling JR, et al. Thorax. 2004;59:73-78.

Ferini-Strambi L, et al. Minerva Med. 2004;95:187-202.



OSA and Depressive Symptoms



Mild OSA is associated with depressive symptoms 1



Treatment of OSA is associated with improvement of depressive symptoms (sometimes —4 out of 7 studies) 2

Comparison of Clinical and Laboratory Measures in

Men and Women With Obstructive Sleep Apnea

No.

Men

92

54.7

± 14.3

Women

29

54.4

± 13.5

Total

121

54.7

± 14.1

Age, y

RDI, no./h 58.0

± 25.9

50.7

± 30.7

56.2

± 27.2

ESS score

BDI score*

13.2 ± 6.0

8.1 ± 6.7

12.0

15.4

± 5.3

± 10.5

12.9

9.9

± 5.8

± 8.3

Data are presented as mean ± SD unless otherwise indicated.

BDI, Beck Depression Inventory; ESS, Epworth Sleepiness Scale; RDI, respiratory disturbance index.

*Men different from women, p <0.01.

McCall WV, et al. J Clin Sleep Med. 2006;2:424-426.

Saunamäki T, et al. Acta Neurol Scand. 2007;116:277-288.



OSA and Dementia



OSA is linked to cognitive impairment, defined as 1.5 SDs or more from the sample mean on MMSE or Trails B, especially in those with the APOE



4 allele



Treatment of OSA is associated with improvement of cognition

Association Between Sleep-Disordered Breathing and Clinically Significant

Cognitive Impairment (>1.5 Standard Deviations [SDs] from Mean Score)

Cognitive Measure

Mini-Mental State Examination

AHI (per SD)

AHI

SaO

≥30

2

<80%

CAI (per SD)

Odds Ratio (95% Confidence Interval)

Unadjusted

1.5 (1.1 – 2.0)

4.0 (1.8

– 9.1)

2.4 (1.0

– 5.6)

1.3 (1.1 – 1.6)

Multivariate Adjusted*

1.4 (1.03

1.4 (1.1

– 1.9)

3.4 (1.4

– 8.1)

2.7 (1.1

– 6.6)

– 1.7)

Trail Making Test Part B

AHI (per SD)

AHI ≥30

SaO

2

<80%

CAI (per SD)

1.2 (0.9

– 1.6)

1.7 (0.7 – 4.2)

1.2 (0.5

0.6 (0.2

– 3.0)

– 2.0)

1.1 (0.8

1.2 (0.5

1.2 (0.5

0.5 (0.2

– 1.5)

– 3.2)

– 3.2)

– 1.6)

*Adjusted for age, education, sex, and selective serotonin reuptake inhibitor use. AHI, apnea-hypopnea index;

SD, standard deviation; SaO

2

, blood oxygen saturation; CAI, central apnea index.

Spira AP, et al. J Am Geriatr Soc. 2008;56:45-50.



Sleep Disturbance and

Institutionalization

6

5

4

3

2

1

0

Nursing Home Placement by Insomnia

Nursing home placements represent percent of the sample permanently assigned to a nursing home over a 3.5-year follow-up period

Males

Females

6

5

4

3

2

1

0

0 1-3 4-14

Complaint Nights

15-42

0 1-3 4-14

Complaint Nights

15-42

Pollak CP, et al. J Geriatr Psychiatry Neurol. 1991;4:204-210.

Pollak CP, et al. J Community Health. 1990;15:123-135.










- Thank You.



What Is Insomnia?



Problems with falling asleep, staying asleep, or unrefreshing sleep leading to:

– Fatigue

– Concentration problems

– Irritability



Epidemiology of Insomnia



57% of older persons report some sort of chronic sleep disturbance 1



Annual incidence rate of 5% for chronic insomnia in the elderly 2

1 Foley DJ, et al. Sleep. 1995;18:425-432.

2 Foley DJ, et al. Sleep. 1999;22(suppl 2):S366-S372.



Epidemiology of Insomnia



57% of older people report some sort of chronic sleep disturbance



Annual incidence rate of 5% for chronic insomnia in the elderly

Prevalence of Chronic Sleep Complaints in Selected Subpopulations of Participants: EPESE 1982

Type of Sleep Problem

Trouble falling asleep

Awakes during night

Awakes too early

Naps during day

Awakes not rested Population

All participants n=9,282 (100%), average age=74.0

Not depressed* n=6,994 (75%), average age=73.8

And no physical limitation n=2,607 (28%), average age=72.0

And no respiratory symptom n=2,207 (24%), average age=72.0

And excellent SPHS n=679 (7%), average age=71.7

And no other risk factors

† n=175 (2%), average age=71.6

19.2

13.2

10.0

9.3

7.4

4.0

29.7

24.9

18.0

16.8

16.5

13.9

18.8

14.3

9.8

9.0

7.4

3.5

24.6

22.1

14.5

13.4

11.9

7.5

*And not using an anxiolitic/barbiturate medication.

†

Excludes those with any of the 7 selected chronic conditions and those taking OTC medications.

12.7

8.7

5.6

5.1

2.7

2.3

Difficulty initiating or maintaining sleep

42.7

36.1

27.7

25.8

24.3

17.9

Insomnia

28.7

21.9

16.6

15.4

13.4

7.5

Any chronic complaint

56.9

50.9

39.4

37.2

33.9

26.6


Anxiety Disorders Association of America Foley DJ, et al. Sleep. 1995;18:425-432.

Normal Aging of Sleep vs Insomnia



Comparison of 72 older adults with or without sleep complaints

–

42 poor sleepers

–

30 normal controls



Community residents

– Mean age, yr (SD): 66.8 (5.2)

– Female: 64%

– Married: 65%

– Unemployed: 67%



Assessments

– Sleep

– Mood

– Medical illness

– Lifestyle


Anxiety Disorders Association of America Morin CM, Gramling SE. Psychol Aging. 1989;4:290-294.

Normal Aging of Sleep vs Insomnia:

Comparison of Sleep Measures

Most Sleep Measures Were Significantly Different*

Sleep

Sleep-onset latency (min)

Number of awakenings

Wake-time after sleep onset (min)

Total nocturnal sleep (min)

Total sleep time/24 h (min)

Sleep efficiency (%)

*Mean age (SD) of the entire sample: 66.8 yr (5.2).

Poor sleepers mean (SD)

(n=42)

35.9 (25.8)

2.8 (1.3)

59.7 (31.0)

345.7 (73.8)

377.1 (80.5)

78.0 (8.4)

Good sleepers mean (SD)

(n=30)

15.1 (19.5)

1.2 (0.6)

15.0 (11.4)

387.3 (82.5)

412.9 (83.6)

92.3 (6.0)

Morin CM, Gramling SE. Psychol Aging. 1989;4:290-294.

p

<0.01

<0.001

<0.001

<0.05

NS

<0.001



Normal Aging of Sleep vs Insomnia:

Comparison of Mood Measures

Mood Measures Were Significantly Different

Mood

Depression (BDI)

Poor sleepers mean (SD)

10.9 (7.1)

Good sleepers mean (SD)

6.4 (5.3)

State anxiety (STAI)

Trait anxiety (STAI)

38.7 (10.6)

43.2 (10.5)

32.3 (9.6)

34.6 (10.3)

BDI=Beck Depression Inventory; STAI=State-Trait Anxiety Inventory.

p

<0.01

<0.05

<0.01

Morin CM, Gramling SE. Psychol Aging. 1989;4:290-294.










- Thank You.



Sleep Disturbances in Older

Persons: Underlying Causes



Fragmented nocturnal sleep is a significant cause of daytime sleepiness in older persons

– Continuity of both sleep and wakefulness is disrupted

– More likely to be chronic



Insomnia may be caused by or related to coexisting conditions

Carskadon MA, et al. Neurobiol Aging. 1982;3:321-327.

Martin J, et al. Clin Psychol Rev. 2000;20:783-805.



What Is the

Differential Diagnosis of Insomnia in

Older Persons?



Primary Sleep Disorders

Associated with Insomnia



Primary insomnia 1



Breathing-related sleep disorder 1



Circadian rhythm sleep disorder 1



Parasomnia 1



Obstructive sleep apnea 2



Restless legs syndrome 2



Periodic limb movement disorder 2

1. American Psychiatric Association. DSM-IV-TR. 2000:597-661.

2. Insomnia in Primary Care: Overcoming Diagnostic and Treatment Variables. 2004.

Available at: www.postgradmed.com/asr/insomnia/asr_insomnia.pdf. Accessed

January 19, 2006.



Sleep Apnea and Periodic Leg Movements of Sleep in Prediction of Sleep Complaints

70

Polysomnography in 100 Seniors ≥65 years

58

60

50

40

30

20

10

34

0

Sleep Apnea PLMS

…but the presence of sleep apnea and PLMS did not correlate with subjective sleep complaints

Dickel MJ, Mosko SS. Sleep. 1990;13:155-166.



Insomnia, Hypnotic Use, and Risk of Falls

Risk of Falls in 34,163 Nursing Home Residents ≥65 years

Insomnia No Insomnia

Hypnotic n=259 1.32 (1.02-1.70)

No hypnotic n=1,890 1.55 (1.41-1.71)

Hypnotic n=632 1.11 (0.94-1.31)

No hypnotic n=31,391 1 (ref)

0 0.5

1 1.5

2

Odds Ratio (95% Confidence Interval)

Models controlled for age, sex, functional status, cognitive status, intensity of resource utilization, illness burden, number of medications, emergency room visits, new admission.

Avidan AY, et al. J Am Geriatr Soc. 2005;53:955-962.



Have Behavioral

Treatments

Been Tested in

Older Persons?



30

25

20

15

10

5

0

Exercise Improves

Sleep Parameters

Baseline Posttest

28.4

p=0.007

26.1

23.8

14.6

7.5

7.0

6.5

6.0

5.5

5.0

4.5

Exercise n=20

Control n=23

6.0

6.8

p=0.047

Exercise n=20

Control n=23


Anxiety Disorders Association of America King AC, et al. JAMA. 1997;277:32-37.

5.8

6.0

Behavioral and Pharmacologic Therapies

Are Effective Alone and in Combination

Pretreatment Posttreatment*

80

70

60

50

Sleep Diary

80

70

60

50

Polysomnograph

40 40

30 30

20 20

10

0

10

0

CBT n=18

PCT n=20

Combined n=20

Condition

PBO n=20

CBT n=18

PCT n=20

Combined n=20

Condition

PBO n=20

*Sleep diary recording during final 2 treatment weeks; EEG on days 5 and 6 of treatment.

CBT=cognitive behavioral therapy; PCT=pharmacotherapy with temazepam; PBO=placebo.




Melatonin Treatment:

Garfinkel et al



12 elderly subjects with insomnia, mean (SD) age: 76 (8) years

– All with below-normal or delayed nightly peak excretion of the main melatonin metabolite



Randomized, double-blind crossover study

– 3 weeks of 2-mg controlled-release melatonin

– 1 week of washout



Actigraphy

– 3 weeks of placebo treatment


Anxiety Disorders Association of America Garfinkel D, et al. Lancet. 1995;346:541-544.

Melatonin Treatment:

Garfinkel et al

(cont’d)

Sleep efficiency, %, mean (SE)

Sleep latency, min, mean (SE)

Wake-time after sleep onset, min, mean (SE)

Placebo Melatonin

75 (3)

33 (7)

83 (4)

19 (5)

73 (13) 49 (14)

Total sleep time, min, mean (SE)

352 (19) 365 (20) p

<.001

.088

<.001

.49


Anxiety Disorders Association of America Garfinkel D, et al. Lancet. 1995;346:541-544.

Conclusion



Melatonin replacement therapy effectively improved sleep quality

Garfinkel D, et al. Lancet. 1995;346:541-544.



Eszopiclone 1 mg or 2 mg in the

Treatment of Insomnia in Older Persons

-Study 1-



Study objectives

– Evaluate safety and efficacy of eszopiclone (ESZ) in older persons with insomnia



Patient population

– 231 older persons (ages 64-85 y)

– Suffering from primary, chronic insomnia



Study design

– ESZ 1 mg or 2 mg or placebo was administered once nightly over 2 weeks


Anxiety Disorders Association of America Scharf M, et al. Sleep. 2005;28:720-727.

Study Results



Eszopiclone (ESZ) 1 mg was effective for sleep induction



ESZ 2 mg demonstrated significant improvement over placebo in sleep onset, measure of sleep maintenance, sleep duration, and sleep quality



Improvements in next-day assessments

(morning sleepiness, daytime alertness, ability to function) from baseline were noted with

ESZ 2 mg, and napping was reduced


Anxiety Disorders Association of America Scharf M, et al. Sleep. 2005;28:720-727.

Eszopiclone 2 mg in the Treatment of

Insomnia in Older Persons

-Study 2-



Study objectives

– Evaluate safety and efficacy of eszopiclone (ESZ) in older persons with insomnia



Patient population

– 264 older persons

– Suffering from primary, chronic insomnia



Study design

– ESZ 2 mg or placebo was administered once nightly over 2 weeks

– Efficacy endpoints were assessed through polysomnography (latency to persistent sleep, sleep efficiency, number of awakenings)

– Patient-reported data were collected via interactive voice response in the morning and evening

– Quality of life was also assessed through the Insomnia Severity Index and

SF-36 (a short-form measure of generic health status)


Anxiety Disorders Association of America McCall WV, et al. Curr Med Res Opin. 2006;22:1633-1642.

50

40

30

20

10

0

Latency to Persistent Sleep

(Polysomnography)

60

Placebo

ESZ 2.0 mg

***

***p<0.0001 vs placebo

***

***

Baseline Overall period Night 1 Night 14


Anxiety Disorders Association of America McCall WV, et al. Curr Med Res Opin. 2006;22:1633-1642.

Wake After Sleep Onset

(Polysomnography)

120

110

100

90

80

70

60

50

*

Baseline Overall Period

McCall WV, et al. Curr Med Res Opin. 2006;22:1633-1642.

*p<0.05 vs placebo

*

Placebo

ESZ 2.0 mg

Night 1 Night 14



Napping^

Number of Naps

(Median)

Total Nap Time (Minutes)

(Median)

3

2

1

0

5

4

*p<0.05

*

100

90

80

70

60

50

40

30

20

10

0

p=NS

Placebo ESZ 2.0 mg Placebo ESZ 2.0 mg

^Patients were encouraged not to nap in this study.

These numbers represent data from patients who napped and represents values from overall double-blind period.

Approximately 47% of patients in each group napped during the study.

McCall WV, et al. Curr Med Res Opin. 2006;22:1633-1642.



Ramelteon 4 mg or 8 mg in

Older Persons with Insomnia



Study objectives

– Assess efficacy of ramelteon in treating insomnia in older persons (aged 64-93 yrs)



Patient population

– 829 outpatients with primary insomnia



Study design

– Subjects received ramelteon 4 mg or 8 mg or placebo for 35 nights

– Sleep diaries were used to assess efficacy


Anxiety Disorders Association of America Roth T, et al. Sleep Medicine. 2006;7:312-318.

Study Results



Both 4 mg and 8 mg of ramelteon reduced patientreported sleep latency compared to placebo



No rebound insomnia during posttreatment

Roth T, et al. Sleep Medicine. 2006;7:312-318.



Zolpidem Tartrate Extended-Release

6.25 mg in Older Persons With Insomnia



Patient population

– Outpatients (≥65 years)

– Primary insomnia

– N=205



Study design

– Double-blind, randomized, parallel-group

– 3-week comparison of zolpidem tartrate extended-release 6.25 mg and placebo


Anxiety Disorders Association of America Walsh JK, et al. Am J Geriatr Psychiatry. 2008;16:44-57.

Study Results



Zolpidem tartrate extended release 6.25 mg decreased wake time after sleep onset for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment



Superior to placebo on objective measures

(polysomnography) of sleep induction



Superior to placebo on the patient reported global impression aid to sleep


Anxiety Disorders Association of America Walsh JK, et al. Am J Geriatr Psychiatry. 2008;16:44-57.

Summary



Behavioral and pharmacologic approaches are effective for management of insomnia in older persons



Insomnia is a significant problem with potentially severe consequences in older persons



Particular attention is needed to identify and address underlying medical or psychiatric coexisting conditions



Both behavioral and pharmacologic treatments are effective in this population


Anxiety Disorders Association of America Morin CM, et al. JAMA. 1999;281:991-999.

Conclusions:

Key Areas Needing Work



Placebo-controlled studies of hypnotics in older persons for periods longer than 2 weeks



Studies of sedating antidepressants

(doxepin) in older patients



Controlled studies in nursing home patients with sleep problems



Sophisticated measures of daytime function and adverse events as a result of hypnotics in older patients



Anxiety and

Insomnia in Women

Naomi M. Simon, MD, MSc

Associate Director

Center for Anxiety and Traumatic Stress Disorders


Associate Professor




Disclosure



Dr. Naomi M. Simon has received grants or research support from AstraZeneca,

Bristol-Myers Squibb, Cephalon, Forest,

GlaxoSmithKline, Janssen, Lilly, NARSAD,

NIMH, Pfizer, Sepracor, and UCB. She has received honoraria for speaking from

Forest, Janssen, Lilly, Pfizer, Sepracor, and

UCB, and has been a consultant for

Paramount Biosciences and Solvay.



Anxiety and Insomnia in Women



Epidemiology



Presentation and course



Menstrual fluctuations



Menopause



Pregnancy and postpartum



Treatment implications



Gender Differences in

Sleep Disturbances



Women of all ages report greater insomnia and inadequate sleep time



Objective findings less clear



Obstructive Sleep Apnea and Narcolepsy :

More common in men



Restless Legs Syndrome : Slight female predominance clinically



Menstrual phase, pregnancy & menopause :

Roles sleep disruption



Anxiety and mood disorders as risk factor


Anxiety Disorders Association of America Krishnan V, Collop N. Curr Opin Pulm Med. 2006;12(6):383-389.

Insomnia Is a Core Symptom in Anxiety Disorders



GAD : Worry and ruminations  insomnia



PTSD : Nightmares and hyperarousal  insomnia



Panic Disorder : Nocturnal panic and anticipatory anxiety  insomnia



Rule out comorbid MDD and Bipolar Disorder in setting significant insomnia

GAD= Generalized Anxiety Disorder; PTSD= Posttraumatic Stress Disorder;

MDD=major depressive disorder



Gender Differences in Anxiety

Begin in Childhood

Cumulative Hazard of Anxiety Disorder by

Age at Onset and Gender (N=1221)

0.14

0.12

Female

Male

0.10

0.08

0.06

0.04

0.02

0

1 3 5 7 9

Age (Years)

11 13 15

Lewinsohn PM, et al. J Abnorm Psychol. 1998;107(1):109-117.

17



Prevalence of Social Anxiety Disorder (SAD) by Gender in a Large Epidemiologic Study

National Comorbidity Survey (NCS) Lifetime Prevalence

18

15.5%

16

14

13.3%

12 11.1%

10

8

6

4

2

0

Overall Female Male

Kessler RC, et al. Arch Gen Psychiatry. 1994;51(1):8-19.



Epidemiology of Posttraumatic

Stress Disorder (PTSD)



Prevalence of trauma exposure is higher in men than in women (61% vs 51%)



Women exposed to trauma are twice as likely to develop PTSD than men exposed to trauma (20.4% vs 8.2%)



Lifetime prevalence of PTSD is twice as high in women than in men (10.4% vs 5.0%)


Anxiety Disorders Association of America Kessler RC, et al. Arch Gen Psychiatry. 1995;52(12):1048-1060.

Lifetime Prevalence Rates of Trauma and Their Association With PTSD

Trauma

Natural disaster

Criminal assault

Combat

Rape

Any trauma

%

Event

18.9

11.1

6.4

0.7

60.7

Men

%

PTSD

3.7

1.8

38.8

65.0

8.1

Women

%

Event

%

PTSD

15.2

6.9

–

9.2

51.2

21.3

–

45.9

20.4

Kessler RC, et al. Arch Gen Psychiatry. 1995;52(12):1048-1060.



Gender and Epidemiology of

Panic Disorder (PD)



Rates in NCS-R & worldwide: women 2x men 1,2



6-month prevalence highest in women ages

25-44 in Epidemiologic Catchment

Area (ECA) study 3



Agoraphobia: women 2-4x men 3

1. Kessler RC, et al. Arch Gen Psychiatry. 2006;63(4):415-424.

2. Weissman MM, et al. Arch Gen Psychiatry. 1997;54(4):305-309.

3. Weissman MM, Merikangas KR. J Clin Psychiatry. 1986;47(suppl):11-17.



Gender and the Presentation of Panic Disorder



No gender differences in panic attack severity 1



Women greater agoraphobic avoidance and need for companion to leave home 2



Higher rates of comorbid SAD and PTSD



Equivalent rates of comorbid depression 1



Onset more closely associated with life events in women 3

Starcevic V, et al. Depress Anxiety. 1998;8(1):8-13.

Turgeon L, et al. J Anxiety Disord. 1998;12(6):539-553.

Barzega G, et al. Acta Psychiatr Scand. 2001;103(3):189-195.



Gender Differences in Panic Symptoms:

Data from the NCS (N=274)



Greater in women

– Shortness of breath

– Feeling smothered

– Nausea



Greater in men

– Abdominal pain

– Sweating

Sheikh JI, et al. Am J Psychiatry. 2002;159(1):55-58.



Why Is Prevalence of Anxiety

Disorders Greater for Women?

Heritability

 Approximately

0.3-0.5 (moderate) for generalized anxiety disorder

(GAD), PD, and SAD

Environment





Cultural expectations

Societal roles – artifact of reporting?

 Life events

Other

Biological Factors





Modulation of serotonin by estrogen

Role of hormones and cyclic fluctuations on neurodevelopment?

1


Anxiety Disorders Association of America 1. Joffe H, Cohen LS. Biol Psychiatry. 1998;44(9):798-811.

Is Anxiety Sensitivity a Heritable Risk

Factor for Panic Disorder in Women?



Anxiety sensitivity (AS) is fear of physical sensations and cognitive dyscontrol



A twin study of 337 twin pairs found AS heritable only in women (0.37-0.48 of variance)



Hypothesized that AS may in part explain elevated rates of panic in women


Anxiety Disorders Association of America Jang KL, et al. J Gend Specif Med. 1999;2(2):39-44.

Impact of Gender on Relapse of Anxiety Disorders:

8-Year Prospective Data — HARP Study (N=558)

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

*

PD Without

Agoraphobia

PD With

Agoraphobia

HARP=Harvard/Brown Anxiety Research Program.

Yonkers KA, et al. Depress Anxiety. 2003;17(3):173-179.

Social Phobia

Women

Men

*p=0.009

GAD



Is There an Impact of Menstrual Cycle

Hormonal Fluctuation on Panic Disorder?

  anxiety and

 anxiety response to inhaled CO

2 in premenstrual phase vs midcycle in PD 1



Inconsistent reports of premenstrual exacerbation 2

– Patients with PD who have a somatic focus (or high anxiety sensitivity) may misinterpret physical premenstrual symptoms 3

Fishman SM, et al. J Psychiatr Res. 1994;28(2):165-170.

Basoglu C, et al. Compr Psychiatry. 2000;41(2):103-105.

Stein MB, et al. Am J Psychiatry. 1989;146(10):1299-1303.

Kaspi SP, et al. J Anxiety Disord. 1994;8:131-138.

Sigmon ST, et al. J Consult Clin Psychol. 2000;68(3):425-431.



Impact of Menstrual Cycle on Anxiety



PMS symptoms include anxiety, fatigue, and changes in sleep



Screening study found PD in 14% with PMS symptoms (n=426) 1



Women with PMS and GAD report a greater increase in anxiety premenstrually than those with GAD alone 2



Consider PMS/PMDD with cyclic changes in anxiety

PMDD=premenstrual dysphoric disorder.

1. Yonkers KA, et al. Arch Women Ment Health. 2003;6(4):287-292.

2. McLeod DR, et al. Acta Psychiatr Scand. 1993;88(4):248-251.



Menstrual-Related Problems Linked to Insomnia,

Fatigue, Anxiety, and Depression (N=11,648)

35

30

25

20

15

10

Menstrual Problems

No Menstrual Problems

5

0

Insomnia Excess Day Frequent Anxiety or

Sleepiness Depression

All p<0.05 in multivariate analyses.

Women aged 18-55: 19% reported menstrual problems = heavy bleeds, cramping, or PMS.

Strine TW, et al. J Womens Health (Larchmt). 2005;14(4):316-323.



Gender Differences in GAD Prevalence:

Is There an Impact of Perimenopause?

12

10

8

6

4

Lifetime Prevalence of GAD

Female

Male

2

0

15-24 25-34 35-44

Age Group (Years)

Adapted from: Wittchen HU, et al. Arch Gen Psychiatry. 1994;51(5):355-364.

Halbreich U. Depress Anxiety. 2003;17(3):107-110.



45



Core Menopausal Symptoms



Hot flashes: 60%-80%



Insomnia disorder: 26% (vs. 13%)



Major depression: 25%-33% (vs. 20%)



Less attention to anxiety

Gold E, et al. Am J Public Health. 2006;96(7):1226-1235.

Ohayon MM, et al. Arch Intern Med. 2006;166(12):1262-1268.

Freeman EW, et al. Arch Gen Psychiatry. 2006;63(4):375-382.

Cohen LS, et al. Arch Gen Psychiatry. 2006;63(4):385-390.



Prevalence of Panic Attacks in Postmenopausal

Women: An Ancillary Study to the Women’s

Health Initiative (N=3369)

25

20

Ages 50-59

Ages 60-69

Ages 70-79

15

*

10

5

0

Any

*p<0.05 in multivariate analyses.

Smoller JW, et al. Arch Intern Med. 2003;163(17):2041-2050.

Full-Blown Limited-Symptom



Correlates of Panic in Postmenopausal Women:

An Ancillary Study to the Women’s Health Initiative

(N=3369)



Strongly linked to negative life events



Associated with impaired social and role functioning



Not linked to reported use of hormone replacement therapy

Smoller JW, et al. Arch Intern Med. 2003;163(17):2041-2050.



Sertraline vs Imipramine in Chronic Depression:

Responder Analysis by Menopausal Status

100

80

Imipramine

Sertraline

*

57%

60

40

43%

20

(n=98) (n=203)

0

Premenopausal

*p=0.007, imipramine vs sertraline.

Kornstein SG, et al. Am J Psychiatry. 2000;157(9):1445-1452.

56% 57%

(n=25) (n=49)

Postmenopausal



Menopause and Anxiety

Disorders



Lack of data regarding impact of estrogen loss or replacement therapy on anxiety disorders



Perimenopause potentially associated with increased risk of recurrence of previously remitted anxiety disorder – data needed



Carefully follow patients with anxiety in perimenopause



Sleep Across Menopause

Transition

Subjective Sleep Quality

47.6

45.4

43.2

39.6

31.4

Pre Early peri

Late peri

Post

(no HT)

Surgical post

Objective Sleep Parameters



No difference by menopause status in

– Sleep latency

– Sleep efficiency

– Sleep staging

Adapted from Kravitz HM, et al. Menopause. 2003;10(1):19-28.

Shaver J, et al. Sleep. 1988;11(6):556-561.

Young T, et al. Sleep. 2003;26(6):667-672.



Potential Causes of Subjective Sleep

Disturbance During Peri/Postmenopause

 ↓ Sleep quality/insomnia

– Hot flashes

– Sleep apnea

– Chronic pain, poor health

– Anxiety

Ohayon MM, et al. Arch Intern Med. 2006;166(12):1262-1268.

Young T, et al. Sleep. 2003;26(6):667-672.

Hollander LE, et al. Obstet Gynecol. 2001;98(3):391-397.

Owens JF, Matthews KA. Maturitas. 1998;30(1):41-50.

Shaver J, et al. Sleep. 1988;11(6):556-561.

Freedman RR, Roehrs TA. Menopause. 2007;14(5):826-829.



Severity of Hot Flashes Associated with Likelihood of Insomnia Disorder

50 p<0.001

40

30

30.3

43.8

23.3

20

10

10.5

0

None Mild


Moderate Severe



Hot Flashes and Sleep

Subjective Sleep Quality



Consistent data

– Sleep quality worse in women with hot flashes

Objective Sleep Parameters



Contradictory data

1.

~ or ↑ # awakenings

2.

~ or ↓ sleep efficiency

3.

~ or ↑ REM latency

Erlik Y, et al. JAMA. 245(17):1741-1744; Freedman RR, Roehrs TA. Fertil Steril. 2004;82(1):138-144;

Savard J, et al. J Pain Symptom Manage. 2004;27(6):513-522; Young T, et al. Sleep. 2003;26(6):667-672;

Hollander LE, et al. Obstet Gynecol. 2001;98(3):391-397; Mourits MJ, et al. Br J Cancer. 2002;86(10):1546-1550;

Owens JF, Matthews KA. Maturitas. 1998;30(1):41-50; Shaver J, et al. Sleep. 1988;11(6):556-561;




Anxiety Severity Linked to Frequency and Severity of Hot Flashes

6 p<0.001

4.52

4

2.57

2

1

0

Low anxiety Moderate anxiety

Zung Anxiety Scale, adjusted for age, race, depression, BMI, time

Freeman EW, et al. Menopause. 2005;12(3):258-266.

High anxiety



Subjective Sleep Disturbance-Associated

Anxiety in Menopause (n=102)



Medication free (psychotropic & HRT) women age

44-56 with reported insomnia



Subjective report poor sleep quality on PSQI correlated

– Hamilton Anxiety Score (p<0.002)

– Hot flashes 1st half night (p<0.01)



Anxiety NOT linked to lab-based sleep efficiency

– Objective sleep disturbance found largely (53%) due to sleep apnea & periodic leg movements

– Conclude need to rule out sleep disorders

HRT=Hormone Replacement Therapy; PSQI=Pittsburgh Sleep Quality Index




Mechanisms of Objective Sleep

Disturbance During Peri/Postmenopause



Hot flashes?



Primary sleep disorders

– Sleep apnea

– Periodic limb movements

 Note: ↑ age as a confounding factor

Young T, et al. Am J Respir Crit Care Med. 2003;167(9):1181-1185.


Ohayon MM, et al. Sleep. 2004;27(7):1255-1273.



Sleep: NIH State-of-the-Science

Conference Statement



Moderate evidence that menopause is the cause of sleep disturbance in women

– Longitudinal cohort studies

– Observational studies



Role of vasomotor symptoms is unclear

NIH State-of-the-Science Panel. Ann Intern Med. 2005;142(12 Pt 1):1003-1013.



Zolpidem for Insomnia in

Peri- and Postmenopause



Zolpidem 10 mg vs placebo (N=141); 4 wks

– Improved PGI overall*

– Improved total sleep time*

– Decreased sleep latency (except weeks 2,3)

– No difference in LFS, GSD, RSQ

– Did not assess awakenings due to hot flushes

*p<0.05

PGI=Patient Global Impression; LFS=Lee Fatigue Scale; GSD=General Sleep Disturbance;

RSQ=Relationship Satisfaction Questionnaire

Dorsey CM, et al. Clin Ther. 2004;26(10):1578-1586.



Eszopiclone for Insomnia in Perimenopause



Eszopiclone 3 mg vs placebo (N=410); 4 wks

– Decreased sleep latency and improved quality*

– Improved next-day functioning*

– MADRS (8.36

±7.15 vs 9.97±6.86)*

– SDS (mean change -0.84

±2.29 vs -0.70±2.08)*

– Fewer awakenings due to hot flushes (0.29

±0.55

vs 0.37

±0.76)**

*p<0.05; **p=0.05.

MADR=Montgomery Asberg Depression Rating; SCS=Sheehan Disability Scale

Soares CN et al. Obstet Gyn. 200;108:1402-1410.



Sleep Disorders in Pregnancy



Subjective sleep disturbance common; objective measures minimal & mixed



Multiple potential biological and environmental causes



Increased rates, esp. first and third trimester:

– Insomnia and reduced sleep efficiency

– Restless Legs Syndrome (up to 25%)

– Nocturnal Awakenings

– Rarer Sleep Apnea



Can contribute to or be part of anxiety and mood disturbances

Sahota PK, et al. Curr Opin Pulm Med. 2003;9(6):477-483.

Soares CN, Murray BJ. Psychiatr Clin North Am. 2006;29(4):1095-1113.



Risks of Untreated Anxiety in

Pregnancy



Risk due to sympathetic hyperarousal?



Preterm labor



Lower Apgar scores



Direct effects of fetal-placental or uteroplacental insufficiency



Potential increased risk of postpartum worsening of anxiety in mother


Anxiety Disorders Association of America Teixeira JM, et al. BMJ. 1999;318(7177):153-157.

High Maternal Trait Anxiety Inventory

(>38): Impact on the Newborn (N=166)



Lower weight babies

(34% vs 12% <2500 g, p<0.01)

 

Serotonin and dopamine (urine)



Reduced vagal tone



Less time in quiet or active alert states



Poorer motor organization and autonomic stability on Brazelton Neonatal Behavior

Assessment


Anxiety Disorders Association of America Field T, et al. Depress Anxiety. 2003;17(3):140-151.

Prospective Study of Relapse of Panic During

Pregnancy: Impact of Medication Discontinuation

60

50

40

30

20

54%

25%

10

0

Medication Discontinuation

Attempt (n=24)

Maintained

(n=12)

OR=2.8 for relapse (



Clinical Global Impressions-Severity of Illness Scale [CGI-S]



2) discontinuation in multivariate Cox model.

Cohen LS, et al. Presented at: 24th ADAA National Conference;

Mar 11-14, 2004; Miami, Fla.



Pregnancy: Course of

Panic Disorder

70

60

Retrospective Analysis With Variable

Medication Use and Discontinuation (N=49)

56%

58%

Baseline CGI 1-3 (n=25)

Baseline CGI 4-7 (n=24)

50

38%

40 36%

30

20

10

0

Same

CGI

4%

Better

(CGI

 

2)

4%

Worse

(CGI

 

2)

4%

0%

Mixed

Course

Note: 21/24 patients with CGI 4-7 on medications some portion of pregnancy.

14/25 patients with CGI 1-3 on medications.

Cohen LS, et al. J Clin Psychiatry. 1994;55(7):284-288.



Postpartum: Course of

Panic Disorder

Retrospective Analysis (N=40)

Discontinued

On medication by third trimester

70

60

50

65%

40

30

20

10

0

Same or Better CGI

(



CGI



2)

Cohen LS, et al. J Clin Psychiatry. 1994;55(7):284-288.

35%

Worse



Psychotropic Drug Use in Pregnancy



Drugs used when risk to mother and fetus from disorder outweighs risks of pharmacotherapy



Optimum risk/benefit decision for psychiatrically ill pregnant women



Patients with similar illness histories make different decisions



No decision is risk-free



See: www.womensmentalhealth.org



Management of Insomnia in

Pregnancy



Start with assessment and diagnosis



Address sleep hygiene and pregnancy related issues

– Adjust fluids night if nocturia

– Pillow support



Behavioral therapy



As with anxiety, consider severity insomnia, examine current data re teratogenic risks, weigh potential risks and benefits pharmacotherapy


Anxiety Disorders Association of America Pien GW, Schwab RJ. Sleep. 2004;27(7):1405-1417.

Cognitive-Behavioral Therapy (CBT)



Good option during pregnancy for both anxiety and insomnia



12-week program is standard for anxiety disorders



Focused on specific illnesses



May be used first-line or for patients with intolerance or dislike of medication



Potential Gender Differences in

Pharmacokinetics and Dose Effects?



Minimal, mixed data on metabolism of antidepressants

– Enzymes and plasma levels



Role of estrogen on serotonin?

– Impact on SSRI efficacy in depression



No clinical difference in treatment/dosing to date

Yonkers KA, Brawman-Mintzer O. J Clin Psychiatry. 2002;63(7):610-615.

Schneider LS, et al. Am J Geriatr Psychiatry. 1997;5(2):97-106.

This information concerns a use that has not been approved by the US FDA.



Lack of Gender Differences in

Response of GAD to SSRIs (N=370)

100

90

80

70

60

50

40

30

20

10

0

64% p<0.003

40%

Men

LOCF, endpoint 12 weeks.

Steiner M, et al. Hum Psychopharmacol. 2005;20:3-13.

This information concerns a use that has not been approved by the US FDA.

62% p<0.001

Sertraline

Placebo

Women

34%



Gender and Anxiety Disorders:

Conclusions

  rates of anxiety disorders and reported insomnia in women



Insomnia core feature anxiety disorders



Consider life cycle

– Pregnancy and postpartum

– Menstrual fluctuations

– Perimenopause



Consider CBT strategies and counsel about medications in pregnancy



No clear significant gender differences in pharmacotherapy










- Thank You.

