Tackling Insomnia As Part of the Complete Approach to Mental Healthcare

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Tackling Insomnia as Part of the Complete Approach to Mental Healthcare

Karl Doghramji, MD Professor of Psychiatry, Neurology, and Medicine Medical Director, Jefferson Sleep Disorders Center Thomas Jefferson University Philadelphia, Pennsylvania

Educational grant support was provided from Eisai. Faculty Disclosure

• Dr. Doghramji: Consultant—Eisai, Purdue, Merck, Pfizer; Stock—Merck. Disclosure

• The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). – Dr. Doghramji will be discussing off-label use of medications in this presentation and will identify those medications.

• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. • This activity has been independently reviewed for balance. Learning Objectives

• Discuss the relationship between insomnia and comorbid psychiatric disorders and the resulting implications for diagnosis and co-treatment • Evaluate current guideline recommendations for insomnia management with respect to the present standard of care and unmet needs with existing therapies • Review the latest clinical data surrounding the mechanisms of action and risk/benefit profiles of emerging pharmacotherapies for insomnia for informed therapeutic decision-making Mr. A

• 58-year-old accountant, c/o unrefreshing sleep • Onset 4 months ago • Frequency 4 to 5 nights/week • Mind “spins” at bedtime • Feels washed out during day; low energy • Moody, irritable • Curtailed social activities • Medical history: Hypertension, controlled with losartan • Exam: Nl vital signs, BMI 38 • MSE: Psychomotor slowing; mood “fine”. Affect restricted, no h/s ideation, sensorium clear. Cognitive functions intact • Recent blood tests, including CBC, blood chemistry tests, LFTs, and TSH are WNL What additional criterion must be met to satisfy criteria for DSM-5 insomnia disorder?

1. Duration of insomnia must be > 6 months 2. Difficulty with insomnia must occur nightly 3. Sleep laboratory confirmation of a sleep latency (time to fall asleep) > 1 hour 4. Must not meet criteria for MDD 5. Meets diagnostic criteria for insomnia disorder

Use your keypad to answer now! Insomnia Disorder A. Dissatisfaction with sleep quantity or quality with ≥ 1 of the following: 1. Difficulty initiating sleep (children: w/o caregiver intervention) 2. Difficulty maintaining sleep (children: w/o caregiver intervention) 3. Early morning awakening w/ inability to return to sleep B. Significant distress or impairment C. > 3 nights/week D. > 3 months E. 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. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013. Impairments Associated with Insomnia

• Diminished ability to enjoy • Impaired concentration and family and social relationships memory • Decreased quality of life • Increased incidence of pain • Increased absenteeism and • Enhanced risk of present and poor job performance future psychiatric disorders • Motor vehicle crashes • Hypertension • Increased risk of falls • Diabetes • Increased health care costs • Increased mortality Which of the following would be the most appropriate next step?

1. Exploration of sleep and wake patterns 2. Asking about a family history of insomnia 3. A referral for neuropsychological testing 4. Treatment with an antidepressant agent 5. Short course of treatment with a hypnotic medication (sleeping pill)

Use your keypad to answer now! Sleep Pattern

Middle Terminal

Initial

11 PM 7 AM

W = wake; S = sleep. Copyright: Karl Doghramji, MD. Sleep Pattern: Diagnostic and Therapeutic Implications • Diagnosis – Terminal insomnia (early morning awakening) – Initial insomnia (prolonged sleep latency) • Depression • Irregular waking times or shift • Advanced sleep phase work disorder • Delayed sleep phase disorder • Shiftwork disorder • Daytime stimulants/caffeine • Therapy • Restless legs syndrome – Hypnotic medications are – Middle insomnia (sleep approved for reduction in sleep discontinuity) latency, enhancement of sleep maintenance, or both • Depression • Sleep apnea syndrome • Periodic limb movements in sleep Sleep/Wake Diary

AM PM

Day Date12 1 2 3 4 5 6 7 8 9 101112 1 2 3 4 5 6 7 8 9 1011

Sun 12/9  

Mon 12/10  

Tue 12/11  

Wed 12/12  

Thu 12/13  

Fri 12/14  

Sat 12/15  

 into bed;  out of bed. National Heart, Lung, and Blood Institute. www.nhlbi.nih.gov/health-topics/all-publications-and-resources/sleep-diary. Accessed March 19, 2019. American Academy of Sleep Medicine. http://yoursleep.aasmnet.org/pdf/sleepdiary.pdf. Accessed March 19, 2019. Actigraphy

Morgenthaler T, et al.; Standards of Practice Committee; American Academy of Sleep Medicine. Sleep. 2007;30(4):519-529. Insomnia Evaluation and Management Algorithm

Insomnia Disorder Treat Is insomnia NO No further comorbid persistent? treatment needed condition first

Obtain details about YES YES course of insomnia Treat with Is insomnia behavioral therapy associated with comorbid medical Is use of insomnia YES Is insomnia contributing or psychiatric medication unsafe condition? in this patient? NO to decreased daytime YES Treat with behavioral functioning and quality and/or pharmacologic of life or worsening NO therapy of chief complaint? Does insomnia YES NO occur in isolation? Possible short sleeper; supportive reassurance

Doghramji K, et al. Clinical Management of Insomnia. Second Edition. 2015. Department of Psychiatry and Human Behavior Faculty Papers. Paper 25. Increased Prevalence of Medical Disorders in Individuals with Insomnia 100

90 No Insomnia (n=401) P<.001

80 Insomnia (n=137)

60 P<.001 50 P<.001

40 P<.001 Patients (%) Patients 30 P<.05 P<.01 20 P<.05 P<.05 10

0 Heart Cancer Hyper- Neuro- Breathing Urinary Diabetes Chronic GI Any Disease tension logical Problems Problems Pain Problems Medical Disease Problems

Community-based population of 772 adults. GI = gastrointestinal. Taylor DJ, et al. Sleep. 2007;30(2):213-218. Psychiatric Disorders Comorbid with Insomnia Point Prevalence

Drug Abuse 4.2 Other Psychiatric Disorders 5.1 Alcohol Abuse 7.0 Dysthymia 8.6 Major Depression 14.0 Anxiety Disorder 23.9 No Psychiatric Disorder 59.5

0 10 20 30 40 50 60 Patients (%)

• Insomnia is highly prevalent in psychiatric patients • It has consequences: Daytime impairment, risk of future psychiatric and medical disorders, and others

N=580. Ford DE, et al. JAMA. 1989;262(11):1479-1484. Additional Information • Sleep study negative for OSA (AHI < 5) • Sleep/wake pattern – Reads, watches TV until bedtime – Bedtime 10 PM – Sleep latency 1–2 hours – Wakes up 4–5 × @ 10–30 minutes – Has a midnight snack – Can’t fall back to sleep after 4:30 AM – Lies in bed until 6 AM (9–11 AM on weekends) • 3–4 drinks with dinner • 2 espressos to stay awake in the afternoon

AHI = Apnea-Hypopnea Index; OSA = obstructive sleep apnea. The Dos of Sleep Hygiene

• Get OOB 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

OOB = out of bed. Hauri PJ. In: Hauri PJ, ed. Case Studies in Insomnia; New York, NY: Plenum; 1991:65 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 . Effect of Blue Light Blocking on Sleep 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 Decrease time in bed to equal time actually asleep and increase as sleep efficiency improves (sleep restriction) 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 Combines sleep restriction, stimulus control, and sleep hygiene education with cognitive CBT* therapy

*Standard Treatment according to American Academy of Sleep Medicine. CBT = cognitive-behavioral therapy. Morgenthaler T, et al.; American Academy of Sleep Medicine. Sleep. 2006;29(11):1415-1419. Bootzin RR, et al. J Clin Psychiatry. 1992;53 Suppl:37-41. Meta-analytic Support for Efficacy of CBT-i • 20 RCTs (1162 participants [64% female; mean age, 56 years]) • Approaches to CBT-i incorporated at least 3 of the following: cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation • At the posttreatment time point – SOL improved by 19.03 (95% CI, 14.12 to 23.93) minutes, – WASO improved by 26.00 (CI, 15.48 to 36.52) minutes, – TST improved by 7.61 (CI, 0.51 to 15.74) minutes, and – SE% improved by 9.91% (CI, 8.09% to 11.73%) • Changes seemed to be sustained at later time points. No adverse outcomes were reported CBT-i = CBT for insomnia; RCT = randomized controlled trial; SE% = sleep efficiency; SOL = sleep onset latency; TST = total sleep time; WASO = wake after sleep onset. Trauer JM, et al. Ann Intern Med. 2015;163(3):191-204. Pharmacotherapy vs CBT for Insomnia

Start with Pharmacotherapy Start with CBT

Lack of specific cognitive, or behavioral factors Need for sustained clinical improvement

Need for rapid improvement History of, or present, substance use/abuse

Time limitations Multiple comorbid medical conditions

Limited finances Hypnotic discontinuation

Shortage of trained therapists

• CBT and pharmacologic agents are effective for the direct management of insomnia • Selection of hypnotic should be based on the patient’s clinical needs Doghramji K, et al. Integrating psychotherapy and pharmacology in insomnia. In: de Oliveira, et al (Eds). Integrating Psychotherapy and Psychopharmacology (Clinical Topics in Psychology and Psychiatry). First Edition. New York, NY: Routledge; 2014. Mr. A

• 4 weeks of sleep hygiene measures and blue light filter glasses prior to bedtime result in mild improvement in insomnia and associated fatigue • You recommend a hypnotic agent • Mr. A asks for your recommendation of a natural compound instead

Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349. According to the 2017 American Academy of Sleep Medicine Clinical Practice Guidelines for the Pharmacologic Treatment of Chronic Insomnia in Adults, which of the following natural compounds is appropriate for Mr. A?

1. Melatonin 2. Valerian 3. Hops 4. Chamomile 5. None of the above

Use your keypad to answer now! We suggest that clinicians not use …

• Trazodone • Tiagabine • Diphenhydramine • Melatonin • Tryptophan • Valerian

Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349. Nonprescription Agents for Insomnia: Limited Evidence for Hypnotic Efficacy

Product Latin Name (or Generic Name) Adverse Effects Valerian root V. officinalis L. Restless sleep, GI upset, headache, contact allergies, mydriasis, possible carcinogen, possible hepatotoxicity First-generation histamine-1- Diphenhydramine hydrochloride, Vomiting, depression, malaise, drowsiness, impaired receptor antagonists diphenhydramine citrate, doxylamine mentation, extrapyramidal reactions, rhabdomyolysis, succinate dry mouth, weakness, GI upset, headache, impotence, urinary retention, increased intraocular pressure

Meolie AL, et al.; Clinical Practice Review Committee; American Academy of Sleep Medicine. J Clin Sleep Med. 2005;1(2):173-187. Nonprescription Agents for Insomnia: Insufficient Evidence for Hypnotic Efficacy

Product Latin Name Adverse Effects Hops Humulus lupulus Unknown Chamomile Matricaria recutita Vomiting, allergic reactions Lemon balm Melissa officinalis Unknown Fatigue, GI upset, dizziness, anxiety, headache, St. John’s wort Hypericum perforatum photosensitivity, phototoxicity

Patrinia root Patrinia Scabiosaefolia Fisch Nausea

Niacin Niacin, niacinamide, vitamin B3 None known at recommended daily allowances

Magnesium Magnesium None known at recommended daily allowances

Vitamin B , cyanocobalamin, None known at recommended hydroxocobalamin, daily Vitamin B 12 12 hydroxocobalamin, methylcobalamin allowances

Dietary changes Unknown Yoku-kan-san-ka chimpi-hange Unknown

Meolie AL, et al.; Clinical Practice Review Committee; American Academy of Sleep Medicine. J Clin Sleep Med. 2005;1(2):173-187. Nonprescription Agents for Insomnia: No Evidence of Hypnotic Efficacy or Significant Safety Concerns Product Latin or Scientific Name Adverse Effects Passionflower Passiflora incarnata Dizziness, confusion, ataxia, possible prolonged QT Californian poppy Eschscholzia californica Unknown Wild lettuce Lactuca virosa Possible hallucinogenic Scullcap Seizures, possible hepatotoxicity Calcium None known at recommended daily allowances Vitamin A None known at recommended daily allowances 5-hydroxytryptophan Unknown Natrum muriaticum Unknown

Jamaican dogwood Piscidia piscipula Toxicity to humans Alcohol Dependence, neurotoxicity, cardiotoxicity, myelosuppression, hepatotoxicity, respiratory depression, sedation, depression

L-tryptophan L-2-amino-3-(indole-3-yl) propionic acid Eosinophilia myalgia syndrome Kava kava Piper methysticum Hepatotoxicity

Meolie AL, et al.; Clinical Practice Review Committee; American Academy of Sleep Medicine. J Clin Sleep Med. 2005;1(2):173-187. Melatonin in Primary Sleep Disorders

• 19 placebo-controlled studies, 1683 participants, 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 • Concerns regarding adverse effects – Acute melatonin administration in humans impairs glucose tolerance in AM and PM

WMD = weighted mean difference. Ferracioli-Oda E, et al. PLoS One. 2013;8(5):e63773. Rubio-Sastre P, et al. Sleep. 2014;37(10):1715-1719. Prescription Agents for Insomnia

• FDA-non-approved for insomnia – Sedating antidepressants – Antipsychotics – Anticonvulsants • FDA-approved hypnotics – Benzodiazepine receptor agonists • Benzodiazepines • Nonbenzodiazepines – Melatonin receptor agonist – H1 receptor antagonist – Orexin receptor antagonist 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, et al. N Engl J Med. 1997;336(5):341-346. Sharpley AL, et al. Biol Psychiatry. 2000;47(5):468-470. Karam-Hage M, et al. Psychiatry Clin Neurosci. 2003;57(5):542-544. National Institutes of Health. Sleep. 2005;28(9):1049-1057. 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 tardive dyskinesia – Glucose and lipid abnormalities

Posterior lateral hypothalamus (orexin)

5-HT = serotonin; Ach = acetylcholine; BF = basal forebrain; DA = dopamine; DR = dorsal raphe nucleus; GABA = gamma-aminobutyric acid; Gal = galanin; LC = locus coeruleus; LH = lateral hypothalamic; MCH = melanin-concentrating hormone; NE = norepinephrine; ORX = orexin; PPT/LDT = pedunculopontine and laterodorsal tegmental; TMN = tuberomammillary nucleus; VLPO = ventrolateral preoptic nucleus; vPAG = ventral periaqueductal gray matter. Modified from Fuller PM, et al. J Biol Rhythms. 2006;21(6):482-493. Silber MH, et al. Neurology. 2001;56(12):1616-1618. Orexins/Hypocretins

• Hypothalamic peptides – Localized in the dorsolateral hypothalamus – Wide projections throughout the brain – Projections found in the spinal column • Peptide neurotransmitters – Arousal – Locomotion – Metabolism – Increase blood pressure/heart rate

Peyron C, et al. J Neurosci. 1998;18(23):9996-10015. Moore RY, et al. Arch Ital Biol. 2001;139(3):195-205. Silber MH, et al. Neurology. 2001;56(12):1616-1618. Elevated Plasma Orexin-A Levels in Insomnia Disorder

120

* 100

Orexin-A(pg/mL) Level 20

0 Normal Sleepers Insomnia Patients

228 patients with insomnia disorder vs 282 normal sleepers. Tang S, et al. Peptides. 2017;88:55-61. Benzodiazepine Receptor Agonists: Benzodiazepines

Dosage Range† Half-life Short-term Medication Onset of Action (mg) (h) Limitation?

Estazolam 0.5–2 Rapid 10–24 Yes

Flurazepam 15–30 Rapid 47–100 Yes

Quazepam 7.5–15 Rapid 39–100 Yes

Slow– Temazepam 7.5–15 9.5–12.4 Yes Intermediate

Triazolam 0.25–0.50 Rapid 1.5–5.5 Yes

†Normal adult dose. Dosage may require individualization. MICROMEDEX. www.micromedex.com. PDR. www.PDR.net. Mr. A accepts your recommendation of a prescription hypnotic agent. What is the least appropriate medication for Mr. A?

1. Zolpidem ER 2. Ramelteon 3. Eszopiclone 4. Doxepin low dose 5. Suvorexant

Use your keypad to answer now! Selective Benzodiazepine Receptor Agonists

Zaleplon Zolpidem 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 1 Half-life (hours) [elderly] 1 2.5 [2.9] 2.8 [2.9] 6 [9]

Sleep Latency ↓ ↓ ↓ ↓

Wake after Sleep Onset -- -- ↓ ↓

↑ Total Sleep Time ↑ ↑ ↑ (20 mg) Schedule IV IV IV IV

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Newer Hypnotics

Ramelteon Doxepin Suvorexant Melatonin receptor Dual orexin receptor Mechanism H1 receptor antagonist agonist antagonist Dose (mg) [elderly] 8 3, 6 [3] 10–20

Tmax (hours) 0.75 3.5 2 Half-life (hours) 1–2.6 15.3 12 [elderly] Sleep Latency ↓ -- ↓

Wake after Sleep Onset -- ↓ ↓

Total Sleep Time -- -- ↑

Schedule None None IV

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Zolpidem Variants

Zolpidem Zolpidem SL Zolpidem SL Zolpidem Oral Spray

Men: 3.5; Women: 1.75 [1.75] Dose (mg) [elderly] 5,10 [5] 5,10 [5] 5,10 [5] MOTN, 4 hours remaining until AM awakening

Tmax (hours) 1.6 1.4 1.3 0.9

Half-life (hours) [elderly] 2.5 [2.9] 2.9 2.5 2.7

MOTN = middle-of-the-night; SL = sublingual. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Adverse Effects of Hypnotics

• Benzodiazepine receptor agonists • H1 receptor antagonist – Daytime sedation, psychomotor and – Somnolence/sedation cognitive impairment (depending on – Nausea dose and half-life) – Upper respiratory tract infection – Rebound insomnia • Orexin receptor antagonist – Respiratory depression in vulnerable – Somnolence populations – Risk of impaired alertness and motor – DEA Schedule IV coordination, including impaired • Melatonin receptor agonist driving; increases with dose – Headache, somnolence, fatigue, – Contraindicated in narcolepsy dizziness – DEA Schedule IV – Not recommended for use with fluvoxamine due to CYP 1A2 interaction Mitler MM. Sleep. 2000;23 Suppl 1:S39-S47. Holbrook AM, et al. CMAJ. 2000;162(2):225-233. Charney DS, et al. In: Hardman JG, et al (Eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Tenth Edition. McGraw Hill; 2001:399-427. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. MICROMEDEX. www.micromedex.com. Driving Safety: MOTN Low-Dose Zolpidem SL

7.5

5.0

+2.5 cm threshold 2.5 for impairment

-2.5 cm threshold -2.5 for impairment SDLP(cm) Placebo Change from -5.0 M F M F M F ZST 4h ZST 3h ZOP

SDLP = standard deviation of lateral position; ZOP = zopiclone; ZST = zolpidem sublingual tablet. Vermeeren A, et al. Sleep. 2014;37(3):489-496. Zolpidem-Induced Parasomnias

• Spontaneous reports • Sleep-driving; preparing and eating food, making phone calls, or having sex • Amnesia for events • Risk factors – Co-use of alcohol or sedatives – Use at doses exceeding the maximum recommended dose – Sleep disorder: OSA or PLMS – H/O parasomnia – Ingestion at unusual bedtime – Ingestion while agitated or not typically asleep – Ingestion when sleep deprived – Poor management of pill bottles – Living alone

PLMS = periodic limb movements of sleep. Poceta JS. J Clin Sleep Med. 2011;7(6):632-638. 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

COPD = chronic obstructive pulmonary disease. PDR. www.PDR.net. Sun H, et al. J Clin Sleep Med. 2016;12(1):9-17. Kryger M, et al. Sleep Breath. 2007;11(3):159-164. Mr. A returns following a few weeks of hypnotic therapy

• Sleep has improved • Mood disturbance has worsened • Baseline indicators of MDD – Low mood – Anhedonia – Insomnia – Fatigue – Psychomotor slowing • You elect to start an antidepressant agent Complex Relationship between Insomnia and Mood Disorders • Insomnia – 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

• A systematic evaluation for comorbidities is essential • Whenever possible, treat the comorbid disorder

McCall WV, et al. Curr Psychiatry Rep. 2013;15(9):389. Judd LL, et al. Arch Gen Psychiatry. 2008;65(4):386-394. Cho HJ, et al. Am J Psychiatry. 2008;165(12):1543-1550. Breslau N, et al. Biol Psychiatry. 1996;39(6):411-418. Ohayon MM, et al. J Psychiatr Res. 2003;37(1):9-15. Perlis ML, et al. Biol Psychiatry. 1997;42(10):904-913. RCTs 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 subjective sleep measures – Improvement in next day functioning • 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 10 to 20 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. PBO = placebo; SSRI = selective serotonin reuptake inhibitor. Asnis GM, et al. J Clin Psychiatry. 1999;60(10):668-676. Fava M, et al. Biol Psychiatry. 2006;59(11):1052-1060. Fava M, et al. J Clin Psychiatry. 2011;72(7):914-928. McCall WV, et al. J Clin Sleep Med. 2010;6(4):322-329. ClinicalTrials.gov Identifier: NCT02669030. Hypnotics Under Development

• Dual and single orexin receptor • Melatonin receptor agonists antagonists – Controlled release melatonin for – Lemborexant elderly (Circadin®) – TCS OX2 29 – Piromelatine – Seltorexant – Others • Benzodiazepine receptor agonists • Beta-blockers – Controlled release zaleplon • Histamine H1 antagonists

– Inhaled zaleplon • 5-HT2A receptor antagonists – Lorediplon • Adenosine receptor agonists – EVT 201 • Angiotensin II receptor 1 antagonist • Cannabinoid agonist Lemborexant • Dual orexin receptor antagonist; is thought to regulate sleep and wake by dampening wakefulness without hindering the ability to awaken to external stimuli • Controlled study in insomnia disorder demonstrated improvement in sleep latency and continuity • Phase 2 study under way for irregular sleep-wake rhythm disorder and mild to moderate Alzheimer’s dementia • New drug application (NDA) submitted to FDA for insomnia disorder January 15, 2019 – SUNRISE 1 and SUNRISE 2; N=~2000 – SUNRISE 1: 1-month, double-blind, placebo-controlled study; Phase 3 head-to-head comparison vs zolpidem ER; objectively assessed sleep parameters (time to sleep onset, sleep efficiency, and wake after sleep onset) – SUNRISE 2: 12-month study; subjectively assessed for ability to fall asleep and stay asleep based on patient self reports (sleep diaries) • Adverse effects: Somnolence, headache, sleep paralysis, rapid eye movements abnormal sleep, nightmare, abnormal dreams, dizziness, back pain, hypnagogic hallucinations, myalgia, feeling drunk Murphy P, et al. J Clin Sleep Med. 2017;13(11):1289-1299. Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1). ClinicalTrials.gov Identifier: NCT02783729. Long-term Study of Lemborexant in Insomnia Disorder (SUNRISE 2). ClinicalTrials.gov Identifier: NCT02952820. Lemborexant Morning Driving Performance and MOTN Body Sway

Means with 95% CI Lemborexant 2.5 mg 10 Zopiclone 7.5 mg Lemborexant 5 mg 8 Lemborexant 10 mg 6 4 2 2.4 30 0 -2 Placebo (N=56) -2.4 20 -4 Zolpidem 6.25 mg (N=56)

-6 10 Lemborexant 5 mg (N=56) from Placebo Value(cm) Placebo from

Individual SDLP Difference Individual SDLP -8 Lemborexant 10 mg (N=56) -10 0 ZOP LEM 2.5 LEM 5 LEM 10 ZOP LEM 2.5 LEM 5 LEM 10 CI) Mean (95% LS in Body Sway (units*) Sway in Body (N=48) (N=32) (N=32) (N=32) (N=48) (N=32) (N=32) (N=32) Baseline Change from -10 Day 2 Day 9 Middle of the Night

*A unit of body sway is defined as 1/3 degree angle of arc movement of the ataxiameter. Dashed horizontal line indicates threshold for clinically meaningful change from baseline. Vermeeren A, et al. Sleep. 2018 Dec 31;[Epub ahead of print]. Murphy P, et al. Auditory awakening threshold to evaluate ability to awaken after administration of lemborexant versus zolpidem. Sleep. 2018;41(Suppl 1):A156- A157. Practical Take-Aways • Insomnia is highly prevalent in psychiatric patients • It has consequences: Daytime impairment, risk of future psychiatric and medical disorders, and others

• CBT and pharmacologic agents are effective for the direct management of insomnia • Selection of hypnotic should be based on the patient’s clinical needs • A systematic evaluation for comorbidities is essential • Whenever possible, treat the comorbid disorder Q&A