1. Sleep is Not Overrated: Management Strategies in The Primary Care Setting

2. Greg Mattingly, MD        Associate Clinical Professor Department of Psychiatry Washington University School of Medicine St. Louis, MO 2

3. Disclosures
Idiopathic Pulmonary Fibrosis: Ensuring an Accurate Diagnosis and Personalizing a Therapeutic Plan
Greg Mattingly, MD serves as a speaker for Allergan, Alkermes, Lundbeck, Merck, Neos, Otsuka, Shire, Sunovion, Takeda and Vanda. Dr. Mattingly also serves as a consultant for Alkermes, Allergan, Forum, Lundbeck, Merck, Otsuka, Perdue, Rhodes, Shire, Sunovion, Takeda and Vanda. Additionally, Dr. Mattingly is on the research team for Akili, Alcobra, Alkermes, Allergan, Boehringer, Forum, Janssen, Medgenics, NLS-1 Pharma AG, Reckitt Benckiser, Shire, Sunovion, Supernus and Takeda.
NACE - Emerging Challenges in Primary Care: 2014

4. Learning Objectives
Gain a better understanding of the prevalence and impact of sleep related problems.
Understand the interaction between sleep related disorders and other health conditions.
Learn the role for insomnia treatments approved for sleep initiation verses sleep maintenance.
Gain a better understanding for practical tips on how to improve sleep hygiene.

5. Matt 35-year-old husband and father of 2 (ages 5 and 3).
He is a manager at an advertising agency in the city with a commute that takes around an hour each way.
About 5 months ago, Matt’s estranged father passed away suddenly. His passing was a tremendous blow to Matt since he feels as though he should have “patched things up.”
He states that most of the time he can fall asleep without problem but he has difficulty staying asleep.
He often becomes sleepy late in the afternoon and is struggling at work and on his commute home.

6. Prevalence of Insomnia
Second highest health-related complaint world-wide
National Sleep Foundation N, et al. Agency for Healthcare Research and Quality.
AHRQ Publication No. 05-E :1. Evidence Report/Technology Assessment Number 125
Sleep Report, accessed

7. Gene 66 y.o. c/o unrefreshing sleep following retirement, 4 months ago
4-5 nights per week
Mind “spins” at bedtime
Washed out, low energy all day, moody, irritable
No medical contributors
MSE psychomotor slowing; mood “fine.” Affect restricted, no h/s ideation, sensorium clear. Cognitive functions intact

8. ARS QUESTION
What additional criterion must be met for Gene to satisfy criteria for DSM-5 insomnia disorder?
Duration of insomnia of at least 6 months
Has difficulty with insomnia on a nightly basis
Sleep laboratory confirmation of a sleep latency (time to fall asleep) of more than 1 hour
Does not suffer from major depressive disorder
Already meets diagnostic criteria for insomnia disorder

9. Insomnia Disorder
Dissatisfaction with sleep quantity or quality with one or more of the following: 1. Difficulty initiating sleep (children: w/o caregiver intervention) 2. Difficulty maintaining sleep (children: w/o caregiver intervention) Early morning awakening w/inability to return to sleep
Significant distress or impairment
> Three nights per week
> Three months
Adequate opportunity for sleep
Specify if:
With non–sleep disorder mental comorbidity
With other medical comorbidity
With other sleep disorder
Criteria F, G, and H not shown; not all specifiers shown
DSM-5, American Psychiatric Association, 2013

10. Impairments Associated with Insomnia
Diminished ability to enjoy family and social relationships
Decreased quality of life
Increased absenteeism and poor job performance
Motor vehicle crashes
Increased risk of falls
Impaired concentration and memory
Increased incidence of pain
Enhanced risk of present and future psychiatric disorders
Hypertension
Diabetes
Increased mortality
Ancoli-Israel S et al. (1999), Sleep 22(suppl 2):S347-S353

11. ARS QUESTION
Which of the following would be the most appropriate next step to treat Gene?
Exploration of behaviors just prior to bedtime and during the day
Asking about a family history of insomnia
A referral for neuropsychological testing
Treatment with an antidepressant
Short course of treatment with a hypnotic medication

12. The Do's of Sleep Hygiene
Awaken at the same time every morning
Increase exposure to bright light during the day
Establish a daily activity routine
Exercise regularly in the morning and/or afternoon
Set aside a worry time
Establish a comfortable sleep environment
Do something relaxing prior to bedtime
Try a warm bath
Hauri PJ. In: Hauri PJ, ed. Case Studies in Insomnia; New York, NY: Plenum; 1991:65

13. The Don'ts of Sleep Hygiene
Avoid…
Alcohol
Caffeine, nicotine, and other stimulants
Exposure to bright light during the night
Exercise within 3 hours of bedtime
Heavy meals or drinking within 3 hours of bedtime
Using your bed for things other than sleep (or sex)
Napping, unless a shift worker
Watching the clock
Trying to sleep
Noise
Excessive heat/cold in room
Hauri PJ. In: Hauri PJ, ed. Case Studies in Insomnia; New York, NY: Plenum; 1991:65

14. Evaluation and Management of Insomnia
Sleep history
Symptoms, duration, frequency, course, precipitants, treatments, responses
Sleep/wake schedule (sleep logs)
Bedtime and daytime activities
Extent of daytime impairment (Epworth Sleepiness Scale)
Severity (Insomnia Severity Index)
Identify and treat comorbid conditions
Address insomnia directly
Effective for a broad range of patients
Includes behavioral therapy and hypnotic medications

15. Increased Prevalence of Medical Disorders in Individuals With Insomnia
Community-based population of 772 adults
Taylor DJ, et al. Sleep. 2007;30:

16. Betty
84 y.o married woman complains of insomnia (initiation and maintenance) for 6 months, after an auto accident followed by brief LOC and full recovery
Tried diphenhydramine, DC’d due to side effects
Bed 10 pm to 5 am, sleep latency 1-2 hours, 10 brief awakenings, fatigued all day yet resists napping
No snoring, no limb movements, tosses and turns all night
Cardiomyopathy (recent EF 35%), mitral valve disease, osteoporosis, HTN, glaucoma, all stable
Meds: Ramipril, latanoprost
Exam: BMI 23, normal vital signs, PE, and MSE

17. ARS QUESTION
Which of the following would be the most appropriate next step to evaluate Betty?
Brain MRI
Polysomnography
Cognitive behavioral therapy
Melatonin 1-3 mg at bedtime
Zolpidem extended release 6.25 mg at bedtime

18. Sleep Disordered Breathing and Heart Failure
Sleep disordered breathing is present in 76% of heart failure patients
40% central (CSA)
36% obstructive sleep apnea (OSA)
Despite optimal medication ( ACE-I, AT-1-bl, diuretics, β-blockers, spironolactone and dig)
Preferred treatment options are positive airway pressure devices and nocturnal oxygen
Hypnotics (zolpidem and triazolam) raise the risk of respiratory suppression in the setting of primary CSA
May improve sleep quality
Modest negative effects on oxygen saturation
Last therapeutic option
Aurora RN et al. SLEEP 2012;35(1):17-40
Gatti RC et al. Sleep Aug 1;39(8): doi: /sleep.6006
Oldenburg O et al. Eur J Heart Fail Mar;9(3): Epub 2006 Oct 5

19. Selected Comorbid Conditions and Treatment Examples
Obstructive sleep apnea
CPAP, BIPAP, oral appliances, upper airway surgery
Restless legs syndrome
Alpha 2 delta ligands, dopaminergic agents
Major depressive disorder
Antidepressants
GERD
Proton pump inhibitors, H-2 receptor blocker
Shift work disorder
Bedtime melatonin, modafinil/armodafinil prior to shift, bright light therapy
Medication-induced insomnia
Dosage or medication change
Doghramji K et al. Focus VII (4): , 2009

20. Psychological and Behavioral Treatments for Primary Insomnia
Techniques
Method
Stimulus control therapy*
If unable to fall asleep within 20 minutes, get OOB and repeat as necessary
Relaxation therapies*
Biofeedback, progressive muscle relaxation
Restriction of time in bed (sleep restriction)
Decrease time in bed to equal time actually asleep and increase as sleep efficiency improves
Cognitive therapy
Talk therapy to dispel unrealistic and exaggerated notions about sleep
Paradoxic intention
Try to stay awake
Sleep hygiene education
Promote habits that help sleep; eliminate habits that interfere with sleep
Cognitive-Behavioral Therapy*
Combines sleep restriction, stimulus control and sleep hygiene education with cognitive therapy
*Standard Treatment according to American Academy of Sleep Medicine
Morgenthaler T et al. Sleep. 2006;29:1415
Bootzin RR, Perlis ML (1992), J Clin Psychiatry (53 Suppl):37-41

21. Internet-Based CBT for Insomnia
Context: Insomnia is a major health problem with significant
psychological, health, and economic consequences.
However, availability of one of the most effective
insomnia treatments, cognitive behavioral therapy,
is significantly limited. The Internet may be a key conduit
for delivering this intervention.
Objective: To evaluate the efficacy of a structured behavioral
Internet intervention for adults with insomnia.
Design, Setting, and Participants: Forty-five adults
were randomly assigned to an Internet intervention
(n=22) or wait-list control group (n=23). Forty-four eligible
participants (mean [SD] age, [11.03] years;
34 women) who had a history of sleep difficulties longer
than 10 years on average (mean [SD], [8.89] years)
were included in the analyses.
Intervention: The Internet intervention is based on wellestablished
face-to-face cognitive behavioral therapy incorporating
the primary components of sleep restriction,
stimulus control, sleep hygiene, cognitive
restructuring, and relapse prevention.
Main Outcome Measures: The Insomnia Severity Indexanddailysleepdiarydatawereusedtodeterminechanges
in insomnia severity and the main sleep variables, including
wake after sleep onset and sleep efficiency.
Results: Intention-to-treat analyses showed that scores
on the Insomnia Severity Index significantly improved
from (95% confidence interval [CI], to 17.39)
to 6.59 (95% CI, 4.73 to 8.45) for the Internet group but
did not change for the control group (16.27 [95% CI,
14.61 to 17.94] to [95% CI, to 17.36])
(F1,42=29.64; P.001). The Internet group maintained
their gains at the 6-month follow-up. Internet participants
also achieved significant decreases in wake after
sleep onset (55% [95% CI, 34% to 76%]) and increases
in sleep efficiency (16% [95% CI, 9% to 22%]) compared
with the nonsignificant control group changes of
wake after sleep onset (8% [95% CI, −17% to 33%) and
sleep efficiency (3%; 95% CI, −4% to 9%).
Conclusions: Participants who received the Internet intervention
for insomnia significantly improved their sleep,
whereas the control group did not have a significant
change. The Internet appears to have considerable potential
in delivering a structured behavioral program for
insomnia.
Ritterband et al. Arch Gen Psychiatry. 2009;66(7):

22. Nonprescription Agents for Insomnia: Limited Evidence for Hypnotic Efficacy
Meoli AL et al. J Clin Sleep Med 2005;1(2):

23. Nonprescription Agents for Insomnia: Insufficient Evidence for Hypnotic Efficacy
Meoli AL et al. J Clin Sleep Med 2005;1(2):

24. Melatonin Meta Analysis in Primary Sleep Disorders
19 placebo-controlled studies, 1683 subjects. Melatonin demonstrated efficacy in
Reducing sleep latency (WMD= 7.06 minutes)
Increasing total sleep time (WMD = 8.25 minutes
Effects magnified with longer duration and higher doses
Improved sleep quality (standardized mean difference = 0.22)
No significant effects of trial duration and melatonin dose
PLoS One May 17;8(5):e doi: /journal.pone Print 2013.
Meta-analysis: melatonin for the treatment of primary sleep disorders.
Ferracioli-Oda E1, Qawasmi A, Bloch MH.
Author information 1University of São Paulo Medical School, São Paulo, Brazil.
Abstract
STUDY OBJECTIVES: To investigate the efficacy of melatonin compared to placebo in improving sleep parameters in patients with primary sleep disorders.
DESIGN: PubMed was searched for randomized, placebo-controlled trials examining the effects of melatonin for the treatment of primary sleep disorders. Primary outcomes examined were improvement in sleep latency, sleep quality and total sleep time. Meta-regression was performed to examine the influence of dose and duration of melatonin on reported efficacy.
PARTICIPANTS: Adults and children diagnosed with primary sleep disorders.
INTERVENTIONS: Melatonin compared to placebo.
RESULTS: Nineteen studies involving 1683 subjects were included in this meta-analysis. Melatonin demonstrated significant efficacy in reducing sleep latency (weighted mean difference (WMD) = 7.06 minutes [95% CI 4.37 to 9.75], Z = 5.15, p<0.001) and increasing total sleep time (WMD = 8.25 minutes [95% CI 1.74 to 14.75], Z = 2.48, p = 0.013). Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time. Overall sleep quality was significantly improved in subjects taking melatonin (standardized mean difference = 0.22 [95% CI: 0.12 to 0.32], Z = 4.52, p<0.001) compared to placebo. No significant effects of trial duration and melatonin dose were observed on sleep quality.
CONCLUSION: This meta-analysis demonstrates that melatonin decreases sleep onset latency, increases total sleep time and improves overall sleep quality. The effects of melatonin on sleep are modest but do not appear to dissipate with continued melatonin use. Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents
Ferracioli-Oda E1, Qawasmi A, Bloch MH. PLoS One May 17;8(5):e doi: /journal.pone

25. Melatonin Impairs Glucose Tolerance
Acute Melatonin Administration in Humans Impairs Glucose Tolerance in Both
the Morning and Evening
Patricia Rubio-Sastre, PhD1; Frank A.J.L. Scheer, PhD2; Purificación Gómez-Abellán, PhD1; Juan A. Madrid, PhD1; Marta Garaulet, PhD1
1Department of Physiology, University of Murcia, IMIB-Arrixaca, Murcia, Spain; 2Division of Sleep and Circadian Disorders, Brigham and Women’s
Hospital, and Division of Sleep Medicine, Harvard Medical School, Boston, MA
Submitted for publication November, 2013
Submitted in final revised form April, 2014
Accepted for publication May, 2014
Address correspondence to: Marta Garaulet, Department of Physiology,
Faculty of Biology, University of Murcia.Campus de Espinardo, s/n ,
Murcia, Spain; Tel: ; Fax: ;
Study Objectives: To study the effect of melatonin administration on glucose metabolism in humans in the morning and evening.
Design: Placebo-controlled, single-blind design.
Setting: Laboratory assessments.
Participants: 21 healthy women (24 ± 6 y; body mass index: 23.0 ± 3.3 kg/m2).
Interventions: Glucose tolerance was assessed by oral glucose tolerance tests (OGTT; 75 g glucose) on 4 occasions: in the morning (9 AM), and
evening (9 PM); each occurring 15 minutes after melatonin (5 mg) and placebo administration on 4 non-consecutive days.
Measurements and Results: Melatonin administration impaired glucose tolerance. When administered in the morning, melatonin significantly
increased the incremental area under the curve (AUC) and maximum concentration (Cmax) of plasma glucose following OGTT by 186% and
21%, respectively, as compared to placebo; while in the evening, melatonin significantly increased glucose AUC and Cmax by 54% and 27%,
respectively. The effect of melatonin on the insulin response to the OGTT depended on the time of day (P < 0.05). In the morning, melatonin
decreased glucose tolerance primarily by decreasing insulin release, while in the evening, by decreasing insulin sensitivity.
Conclusions: Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. When administering melatonin,
the proximity to meal timing may need to be considered, particularly in those at risk for glucose intolerance.
Keywords: glucose tolerance, insulin resistance, melatonin, metabolic syndrome, oral glucose tolerance test
Citation: Rubio-Sastre P, Scheer FA, Gómez-Abellán P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose
tolerance in both the morning and evening. SLEEP 2014;37(10):
Comparison between the effects of placebo and melatonin administrations on plasma glucose and insulin concentrations in response to an oral load of glucose (75 g) performed in the morning (09:00 and evening (21:00). TF, time fasting; T30, 60, 90, 120, and 180, time after OGTT (min);
Rubio-Sastre P, et al. SLEEP 2014;37(10):

26. Prescription Agents for Insomnia
FDA-non-approved for insomnia
Sedating antidepressants-Trazadone, Mirtazapine, TCAs…
Antipsychotics-Quetiapine, Olanzapine, Asenapine
Anticonvulsants
FDA-approved hypnotics
Benzodiazepine receptor agonists (BzRA’s)
Benzodiazepines
Nonbenzodiazepines
Melatonin receptor agonist
H-1 receptor antagonist
Orexin receptor antagonist
Ancoli-Israel S, Roth T. Sleep. 1999;22(suppl 2):S347-S353.
Ford DE, Kamerow DB. JAMA. 1989;262:
Shochat T, et al. Sleep. 1999;22(suppl 2):S359-S365.
Smith MT, et al. Am J Psychiatry. 2002;159:5-11.

27. Insomnia Had Increased Metabolic Activity In Arousal Circuits (Even While Asleep)
Nofzinger E, American Journal of Psychiatry, 2004:

28. Insomnia and Hyperarousal
Increased
body metabolic rate
HPA axis activation
Sympathetic activation
Cognitive arousal
Heightened brain metabolism
EEG arousal

29. Orexin and The Sleep Arousal Switch
Adapted from Saper CB, et al. Nature 2005;437(7063):

30. Benzodiazepine Receptor Agonists: The Benzodiazepines
Medication
Dosage Range† (mg)
Onset of Action
Half-life (h)
Short-term Limitation?
Estazolam
0.5 – 2
Rapid
Yes
Flurazepam
15 – 30
Quazepam
7.5 – 15
Temazepam
Slow-Intermediate
Triazolam
0.25 – 0.50
†Normal adult dose. Dosage may require individualization MICROMEDEX.
PDR.

31. Selective Benzodiazapine Receptor Agonists
Zaleplon
Zolpidem ER
Eszopiclone
Dose – mg [elderly]
5,10,20 [5]
5,10 [5]
6.25,12.5 [6.25]
1,2,3 [1]
Tmax (hours) 1
1.6
1.5
Half-life [elderly] (hrs.)
2.5 [2.9]
2.8 [2.9]
6 [9]
Sleep latency ↓
Wake After Sleep Onset --
Total sleep time ↑
(20 mg)
Schedule IV
Physicians Desk Reference 31

32. MOTN, 4 hours remaining until AM awakening
Zolpidem Variants
Zolpidem SL
Oral Spray
Dose – mg [elderly]
5,10 [5]
Men: 3.5 Women: [1.75]
MOTN, 4 hours remaining until AM awakening
Tmax (hours)
1.6
1.4
0.9
1.3
Half-life [elderly] (hrs.)
2.5 [2.9]
2.9
2.7
2.5
Physicians Desk Reference 32

33. Newer Hypnotics Ramelteon Doxepin Suvorexant Mechanism
Melatonin agonist
H1 antagonist
Orexin antagonist
Dose – mg [elderly] 8
3,6 [3]
10-20
Tmax (hours)
0.75
3.5 2
Half-life [elderly] (hrs.)
1-2.6
15.3 12
Sleep latency ↓ --
Wake After Sleep Onset
Total sleep time ↑
Schedule
None IV
Physicians Desk Reference 33

34. Phase III Studies with Suvorexant
Reference
Dose (mg)
sTSO
Month 1
Month 3
sWASO
1 (trial 1)
15, 20
-5.4
-5.2
-2.4
30, 40
-7.4
-8.4
-9.5
-6.9
1 (trial 2)
-7.6
-7.7
-12.8
-13.2
-8.7
-8.9 2
-12.3
-9.7 (12 mos)
-9.0
-9.7 (12 mos)
Suvorexant 30 and 40 mg doses are not approved by the FDA
sTSO: Subjective time to sleep onset; sWASO: Subjective wake after sleep onset
sTST and sWASO changes in minutes
Changes from baseline, all comparisons statistically significant relative to placebo
Herring WJ et al. Biol Psychiatry. 2016;79(2):136–148
Michelson D. Lancet Neurol. 2014;13(5):461–471 34

35. Selected Considerations in Choosing a Hypnotic Agent
Initiation or maintenance insomnia
Initiation: Zaleplon, zolpidem, ramelteon
Maintenance: Doxepin low dose, zolpidem SL MOTN
Initiation and maintenance: Zolpidem ER, eszopiclone, suvorexant
Respiratory compromise; safety in mild to moderate OSA/COPD
Ramelteon, suvorexant
Abuse potential
Lowest: Ramelteon, doxepin
Prior failure of selected medication
Patient preference
Sun H, et al. J Clin Sleep Med 2016;12(1):9–17
Kryger et al. Sleep Breath (2007) 11:159–164

36. Adverse Effects of Hypnotics
Benzodiazepine receptor agonists
Daytime sedation, psychomotor and cognitive impairment (depending on dose and half-life)
Rebound insomnia
Respiratory depression in vulnerable populations
Melatonin receptor agonist
Headache, somnolence, fatigue, dizziness
Not recommended for use with fluvoxamine due to CYP 1A2 interaction
Mitler MM. Sleep. 2000;23:S39-S47; Holbrook AM et al. CMAJ. 2000;162:
MICROMEDEX. Available at: Package inserts for various compounds.
Charney DS et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. 2001:

37. Adverse Effects of Hypnotics
H1 receptor antagonist
Somnolence/sedation
Nausea
Upper respiratory tract infection
Orexin receptor antagonist
Somnolence
Risk of impaired alertness and motor coordination, including impaired driving; increases with dose
Contraindicated in narcolepsy
Mitler MM. Sleep. 2000;23:S39-S47; Holbrook AM et al. CMAJ. 2000;162:
MICROMEDEX. Available at: Package inserts for various compounds.
Charney DS et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. 2001:

38. Psychiatric Disorders Comorbid with Insomnia Point Prevalence
Drug abuse
4.2
5.1
7.0
8.6
14.0
23.9
59.5
Other psychiatric disorders
Alcohol abuse
Dysthymia
Major depression
Anxiety disorder
No psychiatric disorder
% of Patients
N=580. Ford DE, Kamerow DB (1989), JAMA 262(11):

39. John 50 year old Chemical Engineer
Recent onset MDD, underwent remission following 12- week course of antidepressant plus psychotherapy
Complains of persistent initiation and maintenance insomnia, whose onset was 3+ years ago
Lethargic all day, poor concentration, difficulty functioning
Hypothyroidism, TSH 4.0 uU/ml (WNL) on synthroid 100 mcg
Normal labs

40. Residual Symptoms Following Acute MDD Remission
Percentage of Subjects
Nierenberg AA. Keefe BR. Leslie VC. Alpert JE. Pava JA. Worthington JJ 3rd. Rosenbaum JF. Fava M. Residual symptoms in depressed patients who respond acutely to fluoxetine. Journal of Clinical Psychiatry. 60(4):221-5, 1999 Apr.
BACKGROUND: Antidepressants have unequivocal efficacy as compared with placebo, but many patients have residual symptoms despite a robust response to antidepressant therapy. The purpose of this study is to assess residual symptoms in outpatients who respond acutely to fluoxetine. METHOD: Two hundred and fifteen outpatients with major depressive disorder as assessed with the Structured Clinical Interview for DSM-III-R (SCID-P) were treated openly with fluoxetine 20 mg/day for 8 weeks. One hundred and eight (50.2%) were considered full responders (final 17-item Hamilton Rating Scale for Depression [HAM-D] score < or =7). Percentages of full responders who continued to have subthreshold or full major depressive disorder symptoms were calculated. The relationship between residual symptoms and Axis I and Axis II (assessed with SCID-II for personality disorders) comorbidity was assessed. RESULTS: Of the 108 responders, 19 (17.6%) had no subthreshold or threshold SCID-P major depressive disorder symptoms, while 28 (25.9%) had 1 symptom, and 61 (56.5%) had 2 or more symptoms. No statistically significant relationships were found between number of residual symptoms and selected Axis I comorbid conditions or total number of Axis II disorders. CONCLUSION: Less than 20% of full responders to fluoxetine by HAM-D criteria were free of all SCID-P subthreshold and threshold major depressive disorder symptoms after 8 weeks of treatment. While depressed patients benefit from antidepressants, most continue to have some symptoms of depression. The high prevalence of residual symptoms among antidepressant responders suggests the need for further study including whether residual symptoms abate with longer treatment or increased dose of fluoxetine. Other strategies, such as cognitive behavioral therapy, may be needed to address residual symptoms.
Symptoms
N=108; 215 MDD patients 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. Nierenberg et al. J Clin Psychiatry 1999;60:

41. Complex Relationship Between Insomnia and Mood Disorders
Is a common complaint in MDD
Is more likely to emerge prior to, than during or after, MDD first episode or recurrence
Is associated with higher rates of lifetime and current MDD and suicide
Its presence and persistence predict future MDD
Predicts poorer outcome in MDD (persistence, chronicity, suicidality)
Predicts the onset of mania in bipolar depression
McCall WV, Black CG. Current Psychiatry Reports 2013; 15:389; Judd L, Schettler P, Akiskal H. Arch Gen Psychiatry. 2008;65(4): ; Cho JH, et al. Am J Psychiatry : ; Breslau N et al. Biol Psychiatry. 1996;39: ; Ohayon and Roth, J Psychiatr Res, 2003; Perlis ML, et al. Biol Psychiatry. 1997;42:

42. Low Dose Sedating Antidepressants for Insomnia
Trazodone, doxepin, mirtazapine, paroxetine
Advantages
Sedating side effects
Low abuse risk
Large dose range
Disadvantages
Efficacy not well established for insomnia
Side effects include daytime sedation, anticholinergic effects, weight gain, drug-drug interactions
These agents are not FDA approved for insomnia
Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336: Sharpley AL, et al. Biol Psychiatry. 2000;47: Karam-Hage M, Brower KJ. Psychiatry Clin Neurosci. 2003;57: National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:

43. Low Dose Atypical Antipsychotics for Insomnia
Quetiapine, olanzapine
Advantages
At appropriate doses, effective for psychotic disorders
Low abuse potential
Sedation
Disadvantages
Not well investigated in insomnia disorder
Daytime sedation, anticholinergic effects, weight gain
Risk of extrapyramidal symptoms, possible TD
Glucose and lipid abnormalities
These agents are not FDA approved for insomnia
Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336: Sharpley AL, et al. Biol Psychiatry. 2000;47: Karam-Hage M, Brower KJ. Psychiatry Clin Neurosci. 2003;57: National Institutes of Health State of the Science Conference Statement. Sleep. 2005;28:

44. RCT's of Hypnotic Agents in Conjunction with SSRI in MDD
Zolpidem 10 mg vs PBO for persistent insomnia following SSRI (fluoxetine, sertraline, paroxetine) Rx for MDD or dysthymia
Improvement in subjective sleep measures
Zolpidem ER 12.5 mg plus escitalopram vs PBO plus escitalopram in MDD patients with insomnia
Improvement in next day functioning
Hypnotics are not FDA indicated for treatment of MDD;
Asnis GM et al. (1999), J Clin Psychiatry 60(10): ; Fava M, et al. Biol Psychiatry Jun 1;59(11): ; McCall WV, et al. J Clin Sleep Med 2010; 6:
Fava M, et al. J Clin Psychiatry Jul;72(7):

45. RCT's of Hypnotic Agents in Conjunction with SSRI in MDD
Eszopiclone 3 mg plus fluoxetine vs PBO plus fluoxetine in MDD patients with insomnia
Improved subjective sleep measures
Improved quality of life
higher overall MDD remission rates
Suvorexant mg vs PBO for persistent insomnia following stable antidepressant management for MDD
Study in progress at 3 sites
Hypnotics are not FDA indicated for treatment of MDD;
Asnis GM et al. (1999), J Clin Psychiatry 60(10): ; Fava M, et al. Biol Psychiatry Jun 1;59(11): ; McCall WV, et al. J Clin Sleep Med 2010; 6:
Fava M, et al. J Clin Psychiatry Jul;72(7):

46. Conclusions Insomnia is a prevalent condition
It is associated with psychological, cognitive, and systemic impairments
Its evaluation requires a systematic history, examination, and appropriate tests
Whenever possible, treat the comorbid disorder
Insomnia can be directly managed by cognitive behavioral therapy, pharmacological agents, and combined strategies