Insomnia in Patients with Psychiatric Disorders: Causes, Consequences, Best Practices, and Emerging Treatments

Craig Chepke, MD, FAPA Karl Doghramji, MD Adjunct Assistant Professor of Psychiatry Professor of Psychiatry, Neurology, and University of North Carolina School of Medicine Medicine Medical Director, Jefferson Sleep Medical Director, Excel Psychiatric Disorders Center Associates Thomas Jefferson University Huntersville, North Carolina Philadelphia, Pennsylvania Educational grant support was provided from Eisai. Faculty Disclosure

• Dr. Chepke: Consultant—Janssen, Neurocrine Biosciences, Otsuka; Grant/Research Support—Acadia, Harmony, Neurocrine Biosciences; Speakers Bureau—Acadia, Allergan, Eisai, Intracellular, Ironshore, Janssen, Jazz, Neurocrine Biosciences, Otsuka, Sunovion, Takeda, Teva. • Dr. Doghramji: Consultant—Eisai, Harmony, Jazz, Merck, Pfizer; Educational/Research Grant—Eisai, Harmony, Inspire, Jazz; Stock—Merck; Stock (Spouse)—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). – The off-label use of diphenhydramine, tiagabine, melatonin, tryptophan, valerian, trazodone, and quetiapine; and the investigational use of daridorexant and for the treatment of will be discussed.

• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.

• This activity has been independently reviewed for balance.

• Brand names are included in this presentation for participant clarification purposes only. No product promotion should be inferred. Learning Objectives

• Evaluate common root causes and the link between insomnia and psychiatric disorders

• Review guideline-directed best practices for treatment of primary insomnia

• Discuss current and emerging agents for the treatment of insomnia, including their pharmacodynamics and safety/efficacy data The Burden of Insomnia: An Overview

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

Insomnia is the second most common health-related complaint worldwide

Every Night 54% A Few 33% Nights Per of the population Week reports at least 1 21% insomnia symptom a Never few nights per week or more often 2% 19% 25% Rarely A Few Nights Per Month

National Sleep Foundation. 2005 Adult Sleep Habits and Styles. www.sleepfoundation.org/professionals/sleep-americar-polls/2005-adult-sleep- habits-and-styles. Accessed June 3, 2020. Buscemi N, et al. Manifestations and Management of Chronic Insomnia in Adults: Summary. 2005 June. In: AHRQ Evidence Report Summaries. Rockville (MD): Agency for Healthcare Research and Quality (US); 1998–2005. 125. www.ncbi.nlm.nih.gov/books/NBK11906/. Accessed June 3, 2020. Sleep report. www.sleepreviewmag.com. Accessed October 28, 2015. Influences on Sleep

Genetic and Epigenetic

Substances Personality and Features Thoughts, Comorbid Health Attitudes, and Beliefs Conditions Sleep about Sleep

Bedroom Life Environment Circumstances

Daily Behaviors and Routines

Doghramji K, et al. Clinical Management of Insomnia. West Islip, New York: Professional Communications, Inc.; 2015. Prevalence of Medical Disorders in Individuals with Insomnia 100

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

80 Insomnia (n=137)

70

60 P<.001 50 P<.001

40 P<.001 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. Negative Outcomes Associated with Insomnia

• Diminished ability to enjoy family • Impaired concentration and and social relationships memory • Decreased quality of life • Increased incidence of pain • Increased absenteeism and poor • Enhanced risk of present and job performance future psychiatric disorders • Motor vehicle crashes • Hypertension • Increased risk of falls • Diabetes • Increased health care costs • Increased mortality

Ancoli-Israel S, et al. Sleep. 1999;22 Suppl 2:S347-S353. Impaired Driving in Insomnia

0.45 P=.008

0.40

0.35

P=.6 SDLP (m) SDLP

0.30 Insomniacs Good Sleepers

0.25 10 20 30 40 50 Time (min)

SDLP throughout the driving task. Significant effects of the dummy variable are indicated on the graph. The dummy variable represents the comparison between the period of the first 20 minutes and the period of the last 30 minutes of driving for each group. P<.05 was considered significant between periods. SDLP = standard deviation of lateral position. Perrier J, et al. Sleep. 2014;37(9):1565-1573. Insomnia Predicts Future Hypertension

45 95% CI: 1:42–2.70 95% CI: 1:45–2.45

40

35

30 Insomnia 25 No Insomnia

20

15

Incidence Incidence (%) HTN 10

5

0 Persistent Difficulty Persistent Difficulty Initiating Sleep Maintaining Sleep

N=9237 males. Followed for 4 years or until developed HTN. Adjusted for BMI, tobacco, alcohol, and job stress. BMI = body mass index; HTN = hypertension. Suka M, et al. J Occup Health. 2003;45(6):344-350. Enhanced Brain Activity in Wake-Promoting Areas in Insomnia

Measured in 7 patients with primary insomnia compared with 20 healthy controls

Brain structures did not show the expected decreased

metabolic activity in wake- Thalamus Thalamus ORX ORX promoting areas of the brain vPAG vPAG LDT Raphe LDT Raphe during the transition from BF TMN PPT BF TMN PPT

wake to sleep LC LC Hypothalamus Hypothalamus Pons Pons Medulla Medulla Brain Stem Brain Stem BF = basal forebrain; LC = locus coeruleus; LDT = laterodorsal tegmental nuclei; ORX = ; PPT = pedunculopontine; TMN = Orexin locus tuberomammillary nucleus; vPAG = ventral periaqueductal gray. Wake-promoting loci Adapted from Saper CB, et al. Nature. 2005;437(7063):1257-1263. Nofzinger EA, et al. Am J Psychiatry. 2004;161(11):2126-2128. Exploring the Relationship between Insomnia and Psychiatric Disorders 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 (%)

N=580. Ford DE, et al. JAMA. 1989;262(11):1479-1484. Sleep Impairments are Relevant across Many Psychiatric Disorders Depressive Disorders Anxiety Disorders Posttraumatic Stress Disorder

• 90% of patients with depression • Anxiety about consequences of • Nightmares complain about sleep quality poor sleep  worsening anxiety • Fear/avoidance of nightmares • Awake ruminating about perceived  worsening insomnia • Hypervigilance problems/deficiencies • Physiological symptoms of anxiety ‒ Fear of being unsafe while “just can’t settle down” asleep ‒ May be reluctant to take hypnotic Bipolar Disorder Psychotic Disorders ADHD

• A symptom and a trigger • Often driven by paranoia/fear • Difficulty stopping tasks and going ‒ Sleep deprivation can trigger to sleep mania in a stable patient • Sleep deprivation can then worsen ‒ Restoration of regular sleep is concentration  more an essential part of treatment disorganization  less sleep

ADHD = attention-deficit/hyperactivity disorder. Tsuno N, et al. J Clin Psychiatry. 2005;66(10):1254-1269. Krystal AD. Neurol Clin. 2012;30(4):1389-1413. Insomnia and Depression

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 • predicts future MDD • predicts worse outcomes in MDD (persistence, chronicity, suicidality) • or sleep loss may trigger a manic episode in patients with bipolar disorder

MDD = major depressive disorder. Baglioni C, et al. J Affect Disord. 2011;135(1-3):10-19. Cho HJ, et al. Am J Psychiatry. 2008;165(12):1543-1550. Insomnia Predicts Future Depression

Study Name Statistics for Each Study Odds Ratio and 95% CI Odds Lower Upper Ratio Limit Limit Z-value P-value Szklo-Coxe et al 2010 2.49 0.83 7.48 1.62 .10 Kim et al 2009 2.10 1.48 2.97 4.20 .00 Buysse et al 2008 1.60 1.16 2.21 2.85 .00 Cho et al 2008 3.05 1.07 8.72 2.08 .04 Jansson-Fröjmark & Lindblom 2008 3.51 2.11 5.83 4.84 .00 Roane & Taylor 2008 2.20 1.35 3.60 3.15 .00 Morphy et al 2007 2.71 1.37 5.37 2.86 .00 Perils et al 2006 6.86 1.30 36.14 2.27 .02 Hein et al 2003 2.40 1.28 4.51 2.72 .01 Roberts et al 2002 1.92 1.30 2.83 3.30 .00 Johnson et al 2000 1.53 0.36 6.56 0.57 .57 Mallon et al 2000 2.78 1.59 4.88 3.58 .00 Foley at al 1999 1.70 1.29 2.24 3.80 .00 Chang et al 1997 1.90 1.16 3.10 2.57 .01 Weissman et al 1997 5.40 2.59 11.26 4.50 .00 Breslau et al 1996 2.10 1.10 4.00 2.25 .02 Vollrath et al 1989 2.16 1.17 3.99 2.46 .01 FIXED MODEL 2.10 1.86 2.38 11.96 .00

0.01 0.1 1.0 10 100 Meta-analysis of 21 studies, OR 2.6 (CI 1.98–3.42). Baglioni C, et al. J Affect Disord. 2011;135(1-3):10-19. Insomnia is a Risk Factor for Suicide

• Insomnia is strongly associated with suicidal ideation cross- sectionally and longitudinally, even when controlling for hopelessness and depression • Insomnia is linked to death by suicide among adolescents, adults, and older adults • Mediators may be thwarted belongingness and hopelessness

Chu C, et al. J Clin Sleep Med. 2016;12(5):647-652. Woosley JA, et al. J Clin Sleep Med. 2014;10(11):1223-1230. Sleep Disturbances as Residual Symptoms following Acute MDD Remission 50

45 Subthreshold

40 Threshold

35

30

25

(n=108) 20

Participants (%) Participants 15

10

5

0 Mood Interest Weight Sleep Psycho- Fatigue Guilt Concentration Suicidal Disturbance motor Ideation

Patients with MDD (N=215) received fluoxetine 20 mg for 8 weeks. Presence of residual symptoms not predicted by baseline demographic characteristics or Axis I and Axis II coexisting conditions. Nierenberg AA, et al. J Clin Psychiatry. 1999;60(4):221-225. Sleep Disturbance Predicts Recurrence of Depression

1.0

0.9 No Sleep Disturbance Sleep Disturbance 0.8 Free Survival -

0.7 Proportion of

0.6 Depression

0.5 0 200 400 600 800 Days to Depression Recurrence

Cho HJ, et al. Am J Psychiatry. 2008;165(12):1543-1550. 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 • 10 to 20 mg vs PBO for persistent insomnia following stable antidepressant management for MDD – Results pending Hypnotics are not FDA indicated for treatment of MDD. PBO = placebo; RCT = randomized controlled trial; 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. Hypnotic Cotreatment in MDD Reduces Suicidal Ideation Least square mean scores on the Scale for Suicide Ideation for Least square mean scores for suicidal ideation on the participants in the Reducing Suicidal Ideation Through Insomnia Columbia–Suicide Severity Rating Scale for participants in the Treatment studya Reducing Suicidal Ideation Through Insomnia Treatment studya

12 12 11 Study 11 10 10 9 Withdrawal 7 8 7 6 6 5

Score 5 Score 4 4 3 3 2 2 1 1 0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 Weeks since Randomization Weeks since Randomization N= 51 50 49 47 46 44 41 39 N= 51 49 49 47 45 44 N= 52 51 47 43 40 39 38 37 N= 52 51 47 42 40 39

Controlled-Release Zolpidem Placebo aError bars indicate standard errors. McCall WV, et al. Am J Psychiatry. 2019;176(11):957-965. Treating Insomnia: Following Guideline-Recommended Best Practices

Craig Chepke, MD, FAPA Adjunct Assistant Professor of Psychiatry University of North Carolina School of Medicine Medical Director, Excel Psychiatric Associates Huntersville, North Carolina CBT-I and Other Behavioral Therapies

• Cognitive-Behavioral Therapy for • Brief Behavioral Therapy for Insomnia Insomnia (CBT-I) (BBTI) – Gold standard for behavioral – Created in 2011 to increase access treatment of insomnia to behavioral treatments for – 6 to 8 in-person visits over 8 insomnia weeks – Initial efficacy study performed by an NP with no prior experience in • Unguided CBT-I via smartphone sleep medicine or behavioral – Somryst™ (a/k/a “SHUTi”) interventions for insomnia – Validated, with durability for 18 – 2 in-person visits, 2 telephone months sessions over 4 weeks – Cleared by FDA as a prescription – Currently ongoing trial of BBTI digital therapeutic March 2020 delivered entirely via telehealth SHUTi = Sleep Healthy Using the Internet. Vedaa Ø, et al. J Clin Sleep Med. 2019;15(1):101-110. Levenson JC, et al. Trials. 2017;18(1):256. Gunn HE, et al. Sleep Med Clin. 2019;14(2):235-243. Don’t Forget Exercise!

• Meta-analysis of 14 studies (6 RCTs) • Significant effects in: assessing effects of exercise on – Subjective sleep quantity, sleep outcomes in adults 60+ years difficulty falling back to sleep – Moderate intensity exercise (100% of studies) 3×/week produced the highest – Sleep latency, wake after sleep number of significant onset, total sleep time (50% of improvements studies) – Session duration range 20–70 – Reduction in sleep medication minutes use (40% of studies) – Examples: Qi Gong, Tai chi, Silver Yoga • Large standardized effect size (Cohen’s d≥0.8) in 40% of studies

Vanderlinden J, et al. Int J Behav Nutr Phys Act. 2020;17(1):11. Approved Pharmacotherapies for Insomnia Disorder

• Benzodiazepine Receptor Agonists (BzRA) – Estazolam, flurazepam, quazepam, temazepam, triazolam • Nonbenzodiazepine BzRA (“Z-drugs”) – Eszopiclone, zaleplon, zolpidem • Melatonin Agonist – Ramelteon • H1 Antagonist – Doxepin low dose • Dual Antagonists (DORAs) – , suvorexant

Neubauer DN. In: Dringenberg H. (Ed.) Handbook of Sleep Research. Volume 30. Academic Press; 2019:639-648. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Limitations of Current Therapies

• Benzodiazepine Receptor Agonists (BzRA) – Abuse/dependence, respiratory depression, rebound insomnia, daytime cognitive and psychomotor impairment (agent/dose-dependent), Schedule IV • Nonbenzodiazepine BzRA (“Z-drugs”) – Conceptually similar to those of the benzodiazepines, also Schedule IV – As of April 2019, boxed warning of complex sleep behaviors • Ramelteon – Efficacy for sleep onset only – CYP1A2 metabolism sensitive to induction by smoking • Doxepin low dose – Efficacy for sleep maintenance only – Sedation/somnolence of 6 mg = 9% vs PBO = 4% (NNH = 20) NNH = number needed to harm. Vigo DE, et al. Psychiatry and Neuroscience Update. 2019;427-451. Zammit G. Drug Saf. 2009;32(9):735-748. Kuriyama A, et al. Sleep Med. 2014;15(4):385-392. Yeung WF, et al. Sleep Med Rev. 2015;19:75-83. FDA Drug Safety Communication. April 30, 2019. www.fda.gov/drugs/drug- safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia. Accessed June 15, 2020. 2017 AASM Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults

Recommendations NOT Recommended • Difficulties with sleep onset • Diphenhydramine – Ramelteon, triazolam, zaleplon • Tiagabine • Difficulties with sleep • Melatonin, tryptophan, valerian maintenance • Suvorexant for sleep-onset – Doxepin low dose, suvorexant insomnia • Difficulties with onset and • Trazodone maintenance – Eszopiclone, temazepam, Evaluated but no formal statement zolpidem • Quetiapine

AASM = American Academy of Sleep Medicine. Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349. Limitations of Off-Label Therapies Trazodone Melatonin • Insufficient evidence of efficacy • Insufficient evidence of efficacy • Retrospective study of 348,449 • Physiologic dose is 0.1–0.3 mg Veterans: Suicide attempt hazard – Unclear effect of chronic 61% higher with trazodone (< 200 mg) supraphysiologic dosing than zolpidem • May impair glucose tolerance – Boxed warning for suicidality < 25 years • The primary metabolite of trazodone Quetiapine (mCPP) is anxiogenic, pro-migraine • Insufficient evidence of efficacy – Metabolized by CYP450 2D6 • Anticholinergic, risk of weight gain, – Genetic polymorphism or those on metabolic syndrome, tardive 2D6 inhibitors (eg, fluoxetine, dyskinesia paroxetine, bupropion) may have adverse effects These agents are not FDA approved for insomnia. mCPP = m-Chlorophenylpiperazine. Rubio-Sastre P, et al. Sleep. 2014;37(10):1715-1719. Lavigne JE, et al. J Gen Intern Med. 2019;34(8):1554-1563. Rotzinger S, et al. Biol Psychiatry. 1998;44(11):1185-1191. Leone M, et al. Neurology. 2000;55(1):136-139. Orexin Antagonism for the Treatment of Insomnia

Mechanism of Action and Clinical Data Neurobiology of the Orexin System

• In 1998, 2 research groups discovered a group of neurons that released a neurotransmitter they called orexin (or hypocretin) • Orexin neurons originate in the hypothalamus and project widely to areas of the brain that regulate sleep and wake states • ~ 86 billion neurons in the human brain – Only 20,000 to 50,000 orexin neurons – 20% to 50% are GABA

ACh = acetylcholine; GABA = gamma-aminobutyric acid. Alexandre C, et al. Curr Opin Neurobiol. 2013;23(5):752-759. Li J, et al. Br J Pharmacol. 2014;171(2):332-350. Herculano-Houzel S. Front Hum Neurosci. 2009;3:31. Function of the Orexin Pathway

Awake Sleep ORX ORX

LC VLPO Raphe eVLPO TMN

LC VLPO Raphe eVLPO TMN

ON OFF

• Orexin stabilizes the wake-promoting • When orexin is inactive (or blocked), systems of the brain sleep-promoting systems predominate – LC (norepinephrine), Raphe (serotonin), – VLPO (GABA, ) TMN (histamine) – “Pressing on the brake petal” – “Pressing on the gas petal” VLPO = ventrolateral preoptic nucleus; eVLPO = extended VLPO. Adapted from Morin CM, et al. Nat Rev Dis Primers. 2015;1:15026. Suvorexant Clinical Data • Approved 2014 for insomnia • Label update January 2020 (Schedule IV) – 4-week study of patients with – Onset and/or maintenance of sleep insomnia who had mild-to- – 40% of patients ≥ 65 years in trials moderate Alzheimer’s disease • Antagonist of both orexin receptors – Significant improvements in total • Most Common AE sleep time, wake after sleep – Somnolence: 7% vs 3% with PBO onset compared to PBO – AEs with ≥ 2:1 ratio women over – Nonsignificant reduction in sleep men latency • Somnolence, headache, dry – Most common AEs mouth, abnormal dreams, cough, upper respiratory tract infection • Somnolence (4% vs 1% PBO), • No difference vs PBO falls (2% vs 0% PBO) – Morning driving performance AE = adverse effect. – Psychomotor performance US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. – Rebound insomnia Herring WJ, et al. Alzheimers Dement. 2020;16(3):541-551. Lemborexant Clinical Data

• Approved December 2019 for • Most common AE insomnia (Schedule IV) – Somnolence or fatigue – Onset and/or maintenance of sleep • PBO 1.3%, 5 mg 6.9%, 10 mg 9.6% • Antagonist of both orexin receptors • No difference vs PBO in – Morning cognitive performance, driving • 2 positive trials for insomnia performance, or body sway – 1-month trial vs PBO and zolpidem – Auditory awakening threshold CR in women ≥ 55 years and men ≥ – Rebound insomnia 65 years • Demonstrated safety in mild OSA – 6-month placebo-controlled phase, – Safety in COPD and moderate-to- followed by 6-month open-label severe OSA not yet studied extension in adults ≥ 18 years

COPD = chronic obstructive pulmonary disease; OSA = obstructive sleep apnea. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Lemborexant Short-Term Sleep Onset Efficacy

Objective Latency to Persistent Sleep Subjective Sleep Onset Latency Mean change from baseline LPS (primary end point) Mean change from baseline sSOL Placebo Placebo 40 Zolpidem 40 Zolpidem Lemborexant 5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 10 mg 20 20

0 a 0

a, b c, d a b c, f -20 c, d -20 c, f c, d c, d c, e

Mean Change (min) -40 Mean Change (min) -40

-60 -60 Baseline 1/2 Nights 29/30 Baseline First 7 Nights End of Month 1

Left: aP<.01 vs placebo. bP<.05 vs zolpidem. cP<.001 vs placebo. dP≤.001 vs zolpidem. Right: aP<.05 vs placebo. bP<.01 vs placebo. cP<.001 vs placebo. dP≤.01 vs zolpidem. eP<.05 vs zolpidem. fP<.001 vs zolpidem. Rosenberg R, et al. JAMA Netw Open. 2019;2(12):e1918254. Lemborexant Sleep Maintenance Efficacy

LSM change from baseline in WASO LSM change from baseline in WASO2H (key secondary end point) (key secondary end point)

0 0

-10 -20

-20 c c c -40 c c, e c, e c, e b, c c, e -30 c, d c, d c, d -60 Placebo Placebo LSM Change (min) LSM Change (min) -40 Zolpidem Zolpidem Lemborexant 5 mg Lemborexant 5 mg Lemborexant 10 mg Lemborexant 10 mg -80 -50 Baseline 1/2 Nights 29/30 Baseline 1/2 Nights 29/30

LSM = least squares mean; WASO = wake-after sleep onset; WASO2H = WASO in the second half of the night. aP<.01 vs placebo. bP<.05 vs zolpidem. cP<.001 vs placebo. dP≤.001 vs zolpidem. eP<.01 vs zolpidem. Rosenberg R, et al. JAMA Netw Open. 2019;2(12):e1918254. Lemborexant Long-Term Data Subjective Sleep Onset Latency ISI Daytime Functioning Subscale Treatment Period 1 Treatment Period 2 100 0

90

80 (Items4 - 7)

70 Improvement

quartiles) -5

rd 60 (min) 50 *‡

and3 ‡‡ 40 st **

sSOL † * -10 30 ** ** ** ** ** 20

Median (1 10

0 (SD)Mean infromChange ISI BL -15

BL Month 1 Month 3 Month 5 Daytime Functioning Score BL Month 3 Month 6 Month 9 Month 12 First 7 Nights Month 2 Month 4 Month 6

PBO (n=318) LEM5 (n=316) LEM10 (n=315) PBO LEM5 LEM10

*P<.001; †P<.01; ‡P<.0001. ISI = Insomnia Severity Index. Yardley J, et al. Presented at: Advances in Sleep and Circadian Science/Sleep Research Society; February 1–4, 2019; Clearwater, FL. Moline M, et al. Presented at: Neuroscience Education Institute Congress; November 7–10, 2019; Colorado Springs, CO. Emerging Orexin Antagonists

Daridorexant Seltorexant • Dual orexin receptor antagonist • Selective orexin-2 receptor • Half-life 6 hours (shorter than antagonist currently approved DORAs) – Orexin-2 receptor hypothesized to be more important than OxR-1 in insomnia • Currently in Phase 3 trials, adults and aging patients being studied • Clinical trials – Positive Phase 2b trial in insomnia – Also being investigated for treatment of MDD adjunctive to antidepressants • Positive Phase 2b trial vs placebo • Second Phase 2b trial compared to adjunctive quetiapine XR • Better results in both MDD trials for patients with insomnia symptoms These agents are investigational and not FDA approved for any indication. Dauvilliers Y, et al. Ann Neurol. 2020;87(3):347-356. Bonaventure P, et al. J Pharmacol Exp Ther. 2015;354(3):471-482. ClinicalTrials.gov Identifier: NCT03227224, NCT03321526. Using Patient and Disease Characteristics to Inform Treatment Decisions • Patient age • Need to awaken to auditory – Some therapies are better studied stimulus? eg, parent with a baby, or job than others in aging populations requiring overnight call • Onset-predominant? – Consider doxepin low dose, lemborexant, suvorexant – Consider ramelteon, zolpidem, zaleplon • Comorbid mild-to-moderate OSA or COPD? • Maintenance-predominant? – Consider ramelteon, suvorexant, – Most nights: doxepin low dose (lemborexant in mild OSA) – Infrequent: zolpidem low dose SL • Need for lowest abuse potential? PRN MOTN awakening – Consider ramelteon, doxepin • Onset and Maintenance? • Patient preference – Consider eszopiclone, lemborexant, – May refuse controlled agents or have suvorexant, zolpidem ER other choices we must consider Krystal AD. Psychiatr Clin North Am. 2015;38(4):843-860. Sun H, et al. J Clin Sleep Med. 2016;12(1):9-17. Cheng JY, et al. J Sleep Res. 2020:e13021. Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349. Summary

• Behavioral therapies are first-line, but access may be limited • There are still many unmet needs in insomnia pharmacotherapy – Especially in the aging (≥ 55 years) population • Current guidelines do not recommend most popular off-label treatments • Orexin antagonists may play a role for patients with insomnia – Suvorexant recently showed efficacy and safety in patients with Alzheimer’s disease – Lemborexant recently showed superiority to placebo for aging patients in a trial with a zolpidem active control • Above all, take the time to listen to what your patient’s goals are, solicit their preferences, and fully educate them so you can share the decision- making and create a personalized treatment plan for their needs Q&A