NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Cost Effective Options in the
Treatment of Insomnia:
A Presentation from NC-ACCEPT:
The NC Academic Consortium for Cost Effective
Psychopharmacologic Treatment
Supported by Community Care of NC and the NC AHEC Program
1
W. Vaughn McCall, M.D., M.S.
Wake Forest Baptist Medical Center
Revised 5/10/2011
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
The four academic departments of psychiatry in North Carolina at the
University of NC at Chapel Hill, Eastern Carolina, Wake Forest and Duke
University and the North Carolina Psychiatric Association with the
support of Community Care of North Carolina and the North Carolina
Area Health Education Center Program are committed to conserving
resources and improving psychiatric medication prescribing. Toward that
effort we formed NC ACCEPT: The North Carolina Academic
Consortium for Cost Effective Psychopharmacologic Treatment.
The goal of NC ACCEPT is to engage in a dialogue about cost effective
use of psychiatric medications with clinicians and trainees in psychiatry
and primary care. By promoting discussion about evidence-based
approaches to prescribing we will encourage appropriate use of generic
medications, reduce unnecessary use of multiple medications, and
encourage discontinuing medications when they are no longer needed.
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Objectives
•
•
•
The participant will be able to describe the role of
insomnia as a risk factor for incident psychiatric illness
The participant will be able to discuss the impact of
insomnia on the course of psychiatric illness
The participant will be able to propose a variety of
strategies for managing insomnia
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
There are no disclosures to be made for
this program. This program did not
receive any commercial support.
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
$60,000,000
$50,000,000
$50,799,374
$40,000,000
Top 15 NC Medicaid (DMA) Medication Expense Items
FY 2010 By Medication
(all strengths of medication aggregated)
$39,018,801
$30,000,000
$30,292,268
$20,000,000
$20,901,793
$17,850,045
$16,354,412
$14,452,879
$10,000,000
$12,194,509
$10,137,283
$14,669,114
$17,213,592
$0
$13,354,291
$12,081,078
$9,573,614
$9,226,600
NC Academic Consortium
$9,000,000
$8,000,000
Comparison of Aggregated
Seroquel Use
NC-DMA
SFY 2009 and 2010
for Cost Effective
Pharmacologic Treatment
$8,996,827
$8,443,635
$7,000,000
$6,000,000
$6,271,970
$7,508,502
$5,861,869
$5,000,000
$3,669,153
$4,000,000
$3,000,000
$2,000,000
$2,385,850
$2,517,088
$4,222,352
$3,807,541
$4,292,262
$4,277,316
$2,554,187
$1,834,008
$2,372,354
$1,000,000
$0
SEROQUEL 25
SEROQUEL XR
SEROQUEL XR
MG
400 MG
300 MG
SEROQUEL
400 MG
SEROQUEL 50
MG
SFY 2009 Units
SFY 2010 Units
SFY 2009 Dollars
SFY 2010 Dollars
SEROQUEL
100 MG
SEROQUEL
200 MG
SEROQUEL
300 MG
$8,561,724
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Question #1
•
The most common cause of chronic insomnia is:
a) psychiatric illness
b) medical illness
c) primary insomnia
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Percent of Patients
DSM-IV Diagnoses in Chronic Insomnia
50
45
40
35
30
25
20
15
10
5
0
N=216
Mental
Disorder
Primary
Insomnia
DSPS=delayed sleep phase syndrome
OSAS=obstructive sleep apnea syndrome
Buysse DJ et al. Am J Psychiatry. 1994;151: 1351-1360
DSPS
OSAS
Medical
Disorder
NC Academic Consortium
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Pharmacologic Treatment
Psychiatric Correlates of Insomnia
Insomnia as a Precursor to Psychiatric Disorder
•
•
•
1.
2.
Unresolved insomnia ↑ the odds of new Ψ disorder over
one year (especially major depression episode (MDE)
and panic disorder)1
Unclear whether preceding insomnia is an early
symptom of MDE or a modifiable risk factor
Sleep deprivation (insomnia?) is probably a modifiable
risk factor for mania2
Ford and Kamerow JAMA 1989
Wehr et al
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Persistent Insomnia and Subsequent Psychiatric Disorders
Any Psychiatric Disorder
Major Depression
Anxiety Disorders
Alcohol Abuse
% Patients
40
35
33.6
30
25
25.6
20
15
10
5
0
12.7
0.6
2.5
7.4
Resolved Insomnia
14
*
Unresolved Insomnia
At 1-Year Follow-Up
Adapted from Ford DE and Kamerow DB, 1989.
3.4
NC Academic Consortium
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Pharmacologic Treatment
Psychiatric Correlates of Insomnia
Insomnia During MDE
•
•
Insomnia is an independent contributor towards poor
quality of life in depressed patients1
Insomnia intensity is related to suicidal ideation intensity
in depressed patients, and is predictive of suicide in
some studies2
1.
McCall WV, Reboussin BA, Cohen W. Subjective measurement of insomnia and
quality of life in depressed inpatients. J Sleep Res 2000; 9:43-48.
2.
McCall WV, Blocker JN, D’Agostino, Jr R, Kimball J, Boggs N, Lasater B,
Rosenquist, PB. Insomnia Severity is an Indicator of Suicidal Ideation During a
Depression Clinical Trial. Sleep Medicine 2010;11:822-827
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Question #2
•
The most common residual symptom in an otherwise
successfully SSRI-treated case of depression is:
a)
b)
c)
sad mood
insomnia
poor appetite
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
50
45
40
35
30
25
20
15
10
5
0
lI
de
at
io
n
io
n
ra
t
Su
ce
nt
ic
id
a
ui
lt
G
C
on
Fa
tig
ue
ee
Ps
p
yc
ho
m
ot
or
Sl
ei
gh
t
W
In
te
M
re
st
Subthreshold
Threshold
oo
d
% of Remitting Subjects (n=108)
Frequency of Major Depressive Disorder Residual Symptoms
Among Remitters (HAMD-17 7) After 8 Weeks of Treatment
Nierenberg AA, et al. J Clin Psychiatry. 1999;60(4):221-225.
Patients with MDD (N=215) received a fixed dose of fluoxetine 20 mg for 8 weeks. Presence of residual symptoms not predicted
by baseline demographic characteristics or Axis I and Axis II comorbid conditions.
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Co-administration of a sleep aid with an
antidepressant is the rule, not the exception
• What are the implications of hypnotics co-administered
with antidepressants?
– 60% of sertraline and fluoxetine patients were prescribed
something for sleep
• Cook and Conner (1995): Clin Drug Invest
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Question #3
•
Complications of residual insomnia after treatment of
depression include:
a)
b)
c)
metabolic syndrome
low serum cortisol
increased rate of depressive relapse
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Psychiatric Correlates of Insomnia
Insomnia after MDE
Residual insomnia in otherwise successfully treated
cases of depression
–
Is predictive of relapse1
1.
Reynolds, Am J Psychiatry, 1997
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Evaluation of Persistent Insomnia in
Psychiatric Disorder
•
•
•
•
•
Incomplete response
Iatrogenesis
Medical disorder
Primary sleep disorder
Poor sleep habits – conditioned insomnia
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Ancillary Assessment of Insomnia
•
•
•
•
Sleep Logs
Psychometric Tests
Blood Work
Polysomnography
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Sleep Logs
• Sleep logs record bedtime, sleep latency, number and
duration of wakenings, and up time. They also include
substance use and naps.
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Blood Work in the Assessment of
Insomnia
• Thyroid panels are commonly obtained in chronic
insomnia evaluations, but thyroid abnormalities have not
been shown to be more common in insomniacs than in
good sleepers
• A ferritin, B12, and thyroid panel are warranted in
insomnia secondary to Restless Leg Syndrome.
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
The Role of Polysomnography in the
Assessment of Insomnia
• Polysomnography (PSG) is generally not indicated in the
assessment of insomnia1
• PSG may be justified if excessive daytime sleepiness is
also present, or if there is high clinical suspicion for sleep
apnea, periodic limb movement disorder, nocturnal
hypoxemia, or refractory insomnia2
1. Sleep 1995;18:35-37
2. McCall WV, Blocker JN, D’Agostino, Jr R, Kimball J, Boggs N, Lasater B, Rosenquist, PB. Insomnia Severity is
an Indicator of Suicidal Ideation During a Depression Clinical Trial. Sleep Medicine 2010;11:822-827
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Non-pharmacologic Treatment of Insomnia
• Includes changes in diet and activity such as elimination
of caffeine and alcohol
• Includes specific behavioral therapies such as sleep
restriction and stimulus control therapy, which when
combined is called CBT-Insomnia (CBT-I)
• CBT-I is efficacious in controlled clinical trials of primary
insomnia, and some early evidence for efficacy in
psychiatric insomniacs 1,2
1. Sleep 1999;22:1134
2. J Clin Psychiatry 1998;59:693-699
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
CBT for insomnia versus temazepam 30mg in primary
insomnia of the aged
Figure 2. Changes in Wake After Sleep Onset From Pretreatment to Posttreatment as
Measured by Sleep Diaries and Nocturnal Polysomnography Sleep diary data are based on 2
weeks of self-monitoring at baseline (before treatment) and the last 2 weeks of treatment.
Morin, C. M. et al. JAMA 1999;281:991-999
Copyright restrictions may apply.
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Prescribed Pharmacologic Treatment of
Insomnia
• On-label
– Benzodiazepines
– Benzodiazepine receptor agonists
– Melatonin receptor agonists
– Low dose TCA
• Off-label (partial list)
– Quetiapine
– Trazodone
– Mirtazapine
– Gabapentin
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Clonazepam (CLZ) for insomnia secondary
to depression
• In 80 depressed patients receiving fluoxetine, the coadministration of CLZ 0.5-1.0 QHS for 21 days was
superior to placebo in improving HRSD sleep items over 3
weeks1
• In 50 depressed patients receiving fluoxetine, the coadministration of CLZ 0.5-1.0 QHS for 18 weeks was
superior to placebo in HRSD sleep items only for the first 3
weeks2
1.
Londborg PD et al, 2000
2.
Smith WT et al, 2002
NC Academic Consortium
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Pharmacologic Treatment
Is Extended Clonazepam Cotherapy of Fluoxetine Effective
for Outpatients with Major Depression?
HAM-D Score
Smith WT, et al. J Affect Disord. 2002; Aug; 70(3): 251-259
0
14
42
Day Number
84
126
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Pros and Cons of Benzodiazepines
• Pros
– Some are FDA approved for sleep (not clonazepam)
– inexpensive
• Cons
– Tolerance, dependence
– Daytime sleepiness, delayed reaction time
– Falls, amnesia, behavioral disinhibition
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Zolpidem as add-on Tx for SSRI in
Depression
• 190 patients already on SSRIs for a number of weeks who
had persistent insomnia were randomized to have either
zolpidem 10 mg or placebo as add on therapy
• Improvement in “Global Well Being”
• Improvement in sleep
• Non-significant improvement in depression
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
HAM-D Total Score- Change from Baseline
Zolpidem for Persistent Insomnia in SSRI-Tx Depressed
Patients
0
N=190
week 1
week 2
week 3
week 4
-0.5
-1
zolpidem
placebo
-1.5
-2
-2.5
-3
Asnis GM, et al. J Clin Psych. 1999; Oct; 60(10): 668-676
P=NS
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Pros and Cons of zolpidem-immediate release
• Pros
– FDA indicated for sleep
– Useful in depressed patients
– Inexpensive
• Cons
– Approved for short-term use only
– A controlled substance possibly with tolerance and dependence
– Hallucinations, falls, cognitive problems
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Change from Baseline in HAM-D17 (LOCF) (N=545)
All Items
LS Mean Change
Week 4
Excluding Insomnia Items
Week 4
Week 8
0
0
-2
-2
-4
-4
-6
-6
-6
-6.7
-8
-8
-10
-12
-10.9
p=0.01
-12.9
-14
-16
-8.4
-8
-9.6
p=0.02
-10
-12
Week 8
p=0.16
-9.5
p=0.04
-14
Placebo+Fluoxetine
-16
Eszopiclone+Fluoxetine
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Pros and Cons of Eszopiclone
• Pros
– FDA approved for sleep
– Indicated for open-ended use
– Several positive studies in depressed and anxious insomniacs
• Cons
– A controlled substance
– Possible tolerance and dependence
– Expensive
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Pros and Cons of Ramelteon
• A Melatonin-1 receptor agonist
• Pros
– Mild efficacy for sleep onset
– No liability for tolerance or dependence
– No effects on cognition or balance
• Cons
– No efficacy for sleep maintenance
– Expensive
NC Academic Consortium
Low dose doxepin (a TCA)
for Cost Effective
Pharmacologic Treatment
Roth et al. Sleep 2007, 30:1555-1561
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Pros and Cons of Low Dose Doxepin
• Pros
– FDA approved for sleep
– Effective for sleep maintenance problems
– Not a controlled substance
– Approved for open-ended duration of use
– Inexpensive as the generic, down to 10 mg capsules
• Cons
– Not particularly effective for sleep onset problems
– Despite it being a TCA, not yet studied as an add-on to SSRIs
– Expensive as the branded Silenor™ at 3 and 6 mg
NC Academic Consortium
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Pharmacologic Treatment
MADRS Insomnia item in depressed insomniacs Rx FLX with and without Quetiapine
Garakani et al. Int Clin Psychopharm 2008;23:269-275
© 2008 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
2
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Weight gain and EPS effects of Low dose
Quetiapine
• 43 patients of mixed diagnoses received quetiapine 100
mg at bedtime for insomnia, as an add-on to other stabledosed psychotropics. At the end of 11 months, average
weight gain was 5 pounds1
• Two patients are described who received quetiapine 2550 mg as add-on therapy for insomnia, and both
developed akathisia2
1. Cates et al. Community Mental Health J. 2009;45:251-254
2. Catalano et al. Psychosomatics 2005;46:291-301
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
$60,000,000
$50,000,000
$50,799,374
$40,000,000
Top 15 NC Medicaid (DMA) Medication Expense Items
FY 2010 By Medication
(all strengths of medication aggregated)
$39,018,801
$30,000,000
$30,292,268
$20,000,000
$20,901,793
$17,850,045
$16,354,412
$14,452,879
$10,000,000
$12,194,509
$10,137,283
$14,669,114
$17,213,592
$0
$13,354,291
$12,081,078
$9,226,600
$9,573,614
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Pros and Cons of Quetiapine
• Pros
– Several studies showing sleep benefit in depressed patients
– Not a controlled substance
• Cons
– Not FDA indicated for sleep
– Metabolic effects possible at low doses
– Akathisia possible at low doses
– Effects of low doses on cognition and balance are unknown
– Very expensive
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Low-dose Trazodone (50-100 mg) in depressed and nondepressed insomniacs with self report and PSG
•
•
•
1.
2.
3.
In non-depressed insomniacs, it is comparable to
zolpidem for the first week by patient-report, but
somewhat weaker the second week.1
In non-depressed insomniacs, it is associated with
improved alertness the morning after dosing, compared
with placebo.2
In depressed insomniacs on SSRIs, TRZ is associated
with improved self-reported sleep, as compared with
placebo.3
Walsh et al. Human Psychopharmacology 1998;13191-198
Roth A, McCall WV, Ligouri A. (in press)
Nierenberg AA et al. Am J Psychiatry 1994; 151:1069-1072
NC Academic Consortium
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Pharmacologic Treatment
New Data on Trazodone: Alertness, Memory,
and Motor stamina
NC Academic Consortium
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Pharmacologic Treatment
Pros and Cons of Trazodone
• Pros
– Effective for insomnia in some patients
– Not a controlled substance
– May improve alertness
– Inexpensive
• Cons
– Not FDA approved for sleep
– Adverse memory effects?
– Priapism (unlikely at low doses)
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Mirtazapine 30 mg
•
•
1.
2.
Mirtazapine mono-therapy improves self-reported sleep
in depressed insomniacs in an open trial.1
Mirtazapine mono-therapy improves PSG- sleep in
depressed insomniacs in an open trial.2
Winokur et al. Biol Psych 2000; 48:75-78
Shen et al. Can J Psychiatry 2006;51:27-34
NC Academic Consortium
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Pharmacologic Treatment
Pros and Cons of Mirtazapine
• Pros
– Effective for sleep
– Not a controlled substance
– Inexpensive
• Cons
– Not FDA approved for sleep
– Weight gain is possible
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Gabapentin 300 bid and 600 qhs in 33 abstinent alcoholics
Mason et al. Addict Biol.2009;14:73-83
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Gabapentin 300 bid and 600 qhs in 33 abstinent alcoholics
Mason et al. Addict Biol.2009;14:73-83
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Gabapentin 1500 mg versus placebo qhs in 21 abstinent
alcoholics over 6 weeks: Better sleep was associated with
better drinking outcomes
Brower et al. Alcohol Clin Exp Res 2008;32:1429-1438
NC Academic Consortium
for Cost Effective
Pharmacologic Treatment
Pros and Cons of Gabapentin
• Pros
– May be helpful in sleep of alcoholics
– May curb alcoholic cravings
– Is not a controlled substance
– Excreted unchanged by the kidneys
– Inexpensive
• Cons
–?
NC Academic Consortium
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Pharmacologic Treatment
Alternatives to Quetiapine for insomnia
Summary
• Taking a careful sleep history, and identifying
opportunities to limit time in bed, limit naps, and fix wake
up time are key
• Manage unreasonable sleep expectations
• Consider generic zolpidem, trazodone, doxepin,
mirtazapine, and gabapentin
• Gabapentin is emerging as a favored treatment for
insomnia associated with alcoholism
NC Academic Consortium
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Supplemental Slides
Cost Effective Options in the Treatment of Insomnia
NC Academic Consortium
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Quetiapine
Philip NS et al. Ann Clin Psychiatry. 2008 Jan-Mar;20:15-20
• Background: Inpatient orders at Butler Hospital (Brown University) for
quetiapine were obtained from October 2004 to March 2006 and
divided into standing or prn .
• RESULTS: The most common diagnoses in patients receiving
standing dose quetiapine were depressive disorders, followed by
substance-related, bipolar, and psychotic disorders with a median
dose of 200 mg/day. Only 28.5% of patients had one of the diagnoses
for which quetiapine is approved.
• Patients receiving prn dosing had a similar distribution of diagnoses.
The most common prn dose was 50 mg, given for agitation or
insomnia.
NC Academic Consortium
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Insomnia in Older Patients
• Sleep subjectively lightens with age, with more wake time after sleep
•
•
•
•
onset, and more light sleep seen in the polysomnogram . However,
these age-related changes by themselves do not constitute insomnia
Insomnia diagnoses should be reserved for those who are
significantly distressed, and/or have corresponding daytime
symptoms
The rates of unanticipated primary sleep disorders (such as sleep
apnea) increase with age. Therefore, insomnia ‘treatment-failure’
may justify a laboratory exam
CBT for insomnia has been proven to be effective in older persons
If medications are prescribed for sleep, then lower doses are
recommended
NC Academic Consortium
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Pharmacologic Treatment
Non-prescription drugs for insomnia
• Diphenhydramine and doxylamine (Tylenol PM; Unisom)
– Efficacy may not be sustained
– May have daytime hangover, but no efficacy
– Significant anticholinergic effects
• Melatonin
– Helpful for circadian rhythm problems, but low efficacy for
standard insomnia problems
• Valerian root
– Several studies supporting efficacy, few side effects
– Variable quality of the product
NC Academic Consortium
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Chloral hydrate
• Sustained efficacy beyond a few nights has not been
proven
• Hepatotoxic
• More respiratory depression in overdose, as compared
with benzodiazepines
NC Academic Consortium
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Pharmacologic Treatment
Study Schematic for Hypnotic Treatment of GAD
Screening
Double-blind Treatment
Run-out
Open-label Escitalopram 10mg
Eszopiclone 3 mg
Single-blind
PBO
Single-blind
PBO
Placebo
V1
Window
Week
-2
V2
7-10
V3
7
0
V4
7
1
V5
14
2
V6
14
4
Daily Sleep Diary
Randomize
N = 700 randomized / 420 complete
V7
14
6
V8
14
8
10
NC Academic Consortium
Disposition
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Pharmacologic Treatment
Screened Patients
N=945
Randomized
N=595
LEX + Placebo
N=301
Discontinued
Adverse Event
Lost to follow up
Protocol Viol
Insomnia Rx Fail
Other
N=68
N=17
N=18
N=12
N=3
N=18
Completed
N=233
77.4%
LEX + Eszopiclone
N=294
22.6%
5.6%
6.0%
4.0%
1.0%
6.0%
Discontinued
Adverse Event
Lost to follow up
Protocol Viol
Insomnia Rx Fail
Other
N=65
N=16
N=17
N=11
N=2
N=19
Completed
N=229
77.9%
22.1%
5.4%
5.8%
3.7%
0.7%
6.4%
NC Academic Consortium
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Change from Baseline in HAM-A Key Secondary #2 (Wk 8)
Week of Study
1
2
4
6
8
10
LS Mean Chg
0
-2
-4
-6
*
-8
-10
-12
*
*
-14
Week 10 = SBRO
*p<0.05 vs placebo
*
*
*
Placebo+LEX
Eszopiclone+LEX
p values reflect results from change from baseline analyses using ANCOVA
NC Academic Consortium
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Change from Baseline in HAM-A Excluding Insomnia Item
Week of Study
1
2
4
6
8
10
LS Mean Chg
0
-2
-4
-6
-8
-10
*
-12
Week 10 = SBRO
*
*
*
Placebo+LEX
Eszopiclone+LEX
*p<0.05 vs placebo
p values reflect results from change from baseline analyses using ANCOVA