Insomnia in Patients with Psychiatric Disorders: Causes, Consequences, Best Practices, and Emerging Treatments Craig Chepke, MD, FAPA Adjunct Assistant Professor of Psychiatry University of North Carolina School of Medicine Medical Director, Excel Psychiatric Associates Huntersville, North Carolina Professor of Psychiatry, Neurology, and Medicine Medical Director, Jefferson Sleep Disorders Center Thomas Jefferson University Philadelphia, Pennsylvania Karl Doghramji, MD Educational grant support was provided from Eisai.
Transcript
Insomnia in Patients with Psychiatric Disorders:Causes, Consequences, Best Practices, and
Emerging Treatments
Craig Chepke, MD, FAPAAdjunct Assistant Professor of PsychiatryUniversity of North Carolina School of Medicine Medical Director, Excel Psychiatric AssociatesHuntersville, North Carolina
Professor of Psychiatry, Neurology, and MedicineMedical Director, Jefferson Sleep Disorders Center Thomas Jefferson UniversityPhiladelphia, Pennsylvania
Karl Doghramji, MD
Educational grant support was provided from Eisai.
Faculty Disclosure• Dr. Chepke: Consultant—Janssen, Neurocrine Biosciences, Otsuka;
• 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 seltorexant for the treatment of insomnia 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, MDProfessor of Psychiatry, Neurology, and Medicine
Medical Director, Jefferson Sleep Disorders Center Thomas Jefferson UniversityPhiladelphia, Pennsylvania
Insomnia DisorderA. 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 impairmentC. > 3 nights/weekD. > 3 monthsE. Adequate opportunity for sleepSpecify 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
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.
Insomnia is the second most common health-related complaint worldwide
54% of the population reports at least 1
insomnia symptom a few nights per week
or more often
Every Night
A Few Nights Per
Week
A Few Nights Per
Month
Rarely
Never
33%21%
25%19%2%
Influences on Sleep
Doghramji K, et al. Clinical Management of Insomnia. West Islip, New York: Professional Communications, Inc.; 2015.
Sleep
Genetic and Epigenetic
Personality Features
Life Circumstances
Daily Behaviors
and Routines
Bedroom Environment
Substances and
Medications
Comorbid HealthConditions
Thoughts,Attitudes, and Beliefs
about Sleep
Prevalence of Medical Disorders in Individuals with Insomnia
Community-based population of 772 adults. GI = gastrointestinal. Taylor DJ, et al. Sleep. 2007;30(2):213-218.
HeartDisease
0
70
100
30
90
50
Patie
nts
(%)
AnyMedical
Problems
Hyper-tension
GIProblems
BreathingProblems
Diabetes
40
80
10
60
20
ChronicPain
UrinaryProblems
Neuro-logical
Disease
Cancer
No Insomnia (n=401)Insomnia (n=137)
P<.05
P<.001
P<.05
P<.01P<.05
P<.001
P<.001
P<.001
Negative Outcomes 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• Increased health care costs
• Impaired concentration and memory
• Increased incidence of pain• Enhanced risk of present and
Ancoli-Israel S, et al. Sleep. 1999;22 Suppl 2:S347-S353.
Impaired Driving in Insomnia
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.
0.40
0.45
0.35
SDLP
(m)
Time (min)10
0.2540 50
0.30
20 30
InsomniacsGood Sleepers
P=.6
P=.008
Insomnia Predicts Future Hypertension
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.
45
5
0
Inci
denc
e H
TN (%
)25
Persistent DifficultyMaintaining Sleep
40
15
Persistent DifficultyInitiating Sleep
30
20
10
35
Insomnia No Insomnia
95% CI: 1:42–2.70 95% CI: 1:45–2.45
Enhanced Brain Activity in Wake-Promoting Areas in Insomnia
Brain structures did not show the expected decreased metabolic activity in wake-promoting areas of the brain during the transition from wake to sleep
BF = basal forebrain; LC = locus coeruleus; LDT = laterodorsaltegmental nuclei; ORX = orexin; PPT = pedunculopontine; TMN = tuberomammillary nucleus; vPAG = ventral periaqueductal gray.Adapted from Saper CB, et al. Nature. 2005;437(7063):1257-1263. Nofzinger EA, et al. Am J Psychiatry. 2004;161(11):2126-2128.
Measured in 7 patients with primary insomnia compared with 20 healthy controls
HypothalamusPons
Medulla
Brain StemBrain Stem
PonsHypothalamus
Medulla
vPAG
TMNBF
ORX
PPT
Thalamus
LDT
LC
Raphe
Orexin locusWake-promoting loci
vPAG
TMNBF
ORX
PPT
Thalamus
LDT
LC
Raphe
Exploring the Relationship between Insomnia and Psychiatric Disorders
Psychiatric Disorders Comorbid with InsomniaPoint Prevalence
N=580.Ford DE, et al. JAMA. 1989;262(11):1479-1484.
Dysthymia
Drug Abuse
No Psychiatric Disorder
Other Psychiatric DisordersAlcohol Abuse
Patients (%)10 600 40 5020 30
Major DepressionAnxiety Disorder
8.6
4.2
59.5
5.1
7.0
14.0
23.9
Sleep Impairments are Relevant across Many Psychiatric Disorders
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.
Depressive Disorders
• 90% of patients with depression complain about sleep quality
• Awake ruminating about perceived problems/deficiencies
Anxiety Disorders
• Anxiety about consequences of poor sleep worsening anxiety worsening insomnia
• Physiological symptoms of anxiety“just can’t settle down”
Posttraumatic Stress Disorder
• Nightmares• Fear/avoidance of nightmares• Hypervigilance
‒ Fear of being unsafe while asleep
‒ May be reluctant to take hypnotic
Bipolar Disorder
• A symptom and a trigger‒ Sleep deprivation can trigger
mania in a stable patient‒ Restoration of regular sleep is
an essential part of treatment
Psychotic Disorders
• Often driven by paranoia/fear
ADHD
• Difficulty stopping tasks and going to sleep
• Sleep deprivation can then worsen concentration more disorganization less sleep
Insomnia and DepressionInsomnia …• 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
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.
Study Name Statistics for Each Study Odds Ratio and 95% CIOddsRatio
LowerLimit
UpperLimit Z-value P-value
Szklo-Coxe et al 2010 2.49 0.83 7.48 1.62 .10Kim et al 2009 2.10 1.48 2.97 4.20 .00Buysse et al 2008 1.60 1.16 2.21 2.85 .00Cho et al 2008 3.05 1.07 8.72 2.08 .04Jansson-Fröjmark & Lindblom 2008 3.51 2.11 5.83 4.84 .00Roane & Taylor 2008 2.20 1.35 3.60 3.15 .00Morphy et al 2007 2.71 1.37 5.37 2.86 .00Perils et al 2006 6.86 1.30 36.14 2.27 .02Hein et al 2003 2.40 1.28 4.51 2.72 .01Roberts et al 2002 1.92 1.30 2.83 3.30 .00Johnson et al 2000 1.53 0.36 6.56 0.57 .57Mallon et al 2000 2.78 1.59 4.88 3.58 .00Foley at al 1999 1.70 1.29 2.24 3.80 .00Chang et al 1997 1.90 1.16 3.10 2.57 .01Weissman et al 1997 5.40 2.59 11.26 4.50 .00Breslau et al 1996 2.10 1.10 4.00 2.25 .02Vollrath et al 1989 2.16 1.17 3.99 2.46 .01FIXED MODEL 2.10 1.86 2.38 11.96 .00
1000.01 1.00.1 10
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
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.
Mood0
35
50
15
45
25
Part
icip
ants
(%)
(n=1
08)
SuicidalIdeation
Weight Psycho-motor
Guilt
20
40
5
30
10
ConcentrationFatigueSleepDisturbance
Interest
SubthresholdThreshold
Sleep Disturbance Predicts Recurrence of Depression
Cho HJ, et al. Am J Psychiatry. 2008;165(12):1543-1550.
No Sleep DisturbanceSleep Disturbance
0.8
1.0
0.7
Prop
ortio
n of
Dep
ress
ion-
Free
Sur
viva
l0.9
Days to Depression Recurrence8000
0.5400 600
0.6
200
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– 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
aError bars indicate standard errors.McCall WV, et al. Am J Psychiatry. 2019;176(11):957-965.
Least square mean scores on the Scale for Suicide Ideation for participants in the Reducing Suicidal Ideation Through Insomnia Treatment studya
3
12
Scor
e 7
0
9
2
11
5
8
1
10
4
6
Weeks since Randomization20 31 64 95 7 108
4947
5152
5051
4640
4743
4138
3937
4439
N=N=
Controlled-Release Zolpidem Placebo
Least square mean scores for suicidal ideation on the Columbia–Suicide Severity Rating Scale for participants in the Reducing Suicidal Ideation Through Insomnia Treatment studya
3
12
Scor
e
7
0
2
11
5
1
10
4
6
Weeks since Randomization20 31 64 5 7 8
4947
5152
4951
4540
4742
4439
N=N=
StudyMedicationWithdrawal
Treating Insomnia: Following Guideline-Recommended Best Practices
Craig Chepke, MD, FAPAAdjunct 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
Insomnia (CBT-I)– Gold standard for behavioral
treatment of insomnia– 6 to 8 in-person visits over 8
weeks
• Unguided CBT-I via smartphone– Somryst™ (a/k/a “SHUTi”)– Validated, with durability for 18
months– Cleared by FDA as a prescription
digital therapeutic March 2020
• Brief Behavioral Therapy for Insomnia (BBTI)– Created in 2011 to increase access
to behavioral treatments for insomnia
– Initial efficacy study performed by an NP with no prior experience in sleep medicine or behavioral interventions for insomnia
– 2 in-person visits, 2 telephone sessions over 4 weeks
– Currently ongoing trial of BBTI 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)
assessing effects of exercise on sleep outcomes in adults 60+ years– Moderate intensity exercise
3×/week produced the highest number of significant improvements
– Lemborexant, suvorexantNeubauer 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
• Difficulties with sleep onset– Ramelteon, triazolam, zaleplon
• Difficulties with sleep maintenance – Doxepin low dose, suvorexant
• Difficulties with onset and maintenance– Eszopiclone, temazepam,
zolpidem
• Diphenhydramine• Tiagabine• Melatonin, tryptophan, valerian• Suvorexant for sleep-onset
insomnia• Trazodone
Evaluated but no formal statement• Quetiapine
Recommendations NOT Recommended
AASM = American Academy of Sleep Medicine.Sateia MJ, et al. J Clin Sleep Med. 2017;13(2):307-349.
Limitations of Off-Label TherapiesTrazodone
• Insufficient evidence of efficacy• Retrospective study of 348,449
Veterans: Suicide attempt hazard 61% higher with trazodone (< 200 mg) than zolpidem– Boxed warning for suicidality < 25
years• The primary metabolite of trazodone
(mCPP) is anxiogenic, pro-migraine– Metabolized by CYP450 2D6 – Genetic polymorphism or those on
2D6 inhibitors (eg, fluoxetine, paroxetine, bupropion) may have adverse effects
Melatonin • Insufficient evidence of efficacy• Physiologic dose is 0.1–0.3 mg
– Unclear effect of chronic supraphysiologic dosing
• May impair glucose tolerance
Quetiapine• Insufficient evidence of efficacy• Anticholinergic, risk of weight gain,
metabolic syndrome, tardive dyskinesia
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
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.
• In 1998, 2 research groups discovered a group of neurons that released a peptide 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
Function of the Orexin Pathway
• Orexin stabilizes the wake-promoting systems of the brain– LC (norepinephrine), Raphe (serotonin),
TMN (histamine)– “Pressing on the gas petal”
• When orexin is inactive (or blocked), sleep-promoting systems predominate – VLPO (GABA, galanin)– “Pressing on the brake petal”
VLPO = ventrolateral preoptic nucleus; eVLPO = extended VLPO.Adapted from Morin CM, et al. Nat Rev Dis Primers. 2015;1:15026.
OFF
SleepORX
LCRapheTMN
VLPOeVLPO
ON
Awake
VLPOeVLPO
LCRapheTMN
ORX
Suvorexant Clinical Data• Approved 2014 for insomnia
(Schedule IV)– Onset and/or maintenance of sleep– 40% of patients ≥ 65 years in trials
• Antagonist of both orexin receptors• Most Common AE
– Somnolence: 7% vs 3% with PBO – AEs with ≥ 2:1 ratio women over
• No difference vs PBO– Morning driving performance– Psychomotor performance– Rebound insomnia
• Label update January 2020– 4-week study of patients with
insomnia who had mild-to-moderate Alzheimer’s disease
– Significant improvements in total sleep time, wake after sleep onset compared to PBO
– Nonsignificant reduction in sleep latency
– Most common AEs • Somnolence (4% vs 1% PBO),
falls (2% vs 0% PBO)AE = adverse effect.
US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.
Herring WJ, et al. Alzheimers Dement. 2020;16(3):541-551.
Lemborexant Clinical Data• Approved December 2019 for
insomnia (Schedule IV)– Onset and/or maintenance of sleep
• Antagonist of both orexin receptors
• 2 positive trials for insomnia– 1-month trial vs PBO and zolpidem
CR in women ≥ 55 years and men ≥ 65 years
– 6-month placebo-controlled phase, followed by 6-month open-label extension in adults ≥ 18 years
• Most common AE– Somnolence or fatigue
• PBO 1.3%, 5 mg 6.9%, 10 mg 9.6%• No difference vs PBO in
– Morning cognitive performance, driving performance, or body sway
– Auditory awakening threshold– Rebound insomnia
• Demonstrated safety in mild OSA– Safety in COPD and moderate-to-
severe OSA not yet studied
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/.
c, d
Lemborexant Short-Term Sleep Onset Efficacy
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.
Objective Latency to Persistent SleepMean change from baseline LPS (primary end point)
Subjective Sleep Onset LatencyMean change from baseline sSOL
20
40
0
Mea
n C
hang
e (m
in)
Nights 29/30Baseline
-60
-20
-40
1/2
a
20
40
0
Mea
n C
hang
e (m
in)
End ofMonth 1
Baseline
-60
-20
-40
First 7 Nights
c, d
c, d
a
c, da, b
c, ec, f
bc, f
PlaceboZolpidemLemborexant 5 mgLemborexant 10 mg
PlaceboZolpidemLemborexant 5 mgLemborexant 10 mg
Lemborexant Sleep Maintenance Efficacy
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.
LSM change from baseline in WASO (key secondary end point)
PlaceboZolpidemLemborexant 5 mgLemborexant 10 mg
-20
0
-40
LSM
Cha
nge
(min
)
Nights 29/30Baseline
-80
-60
1/2
LSM change from baseline in WASO2H (key secondary end point)
*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.
Subjective Sleep Onset Latency
30
100
Med
ian
(1st
and
3rd
quar
tiles
)sS
OL
(min
) 70
0
90
20
50
80
10
40
60
Month 1BLFirst 7 Nights
Month 3Month 2
Month 5Month 6Month 4
PBO LEM10LEM5
0
Mea
n (S
D) C
hang
e fr
om B
L in
ISI
Day
time
Func
tioni
ng S
core
(Ite
ms
4-7)
-15
-5
-10
Month 3BL Month 9Month 6 Month 12
Treatment Period 1
Improvem
ent
Treatment Period 2
**†* ** ** ** ** **
*‡
‡‡
PBO (n=318) LEM10 (n=315)LEM5 (n=316)
Emerging Orexin AntagonistsDaridorexant
• Dual orexin receptor antagonist• Half-life 6 hours (shorter than
currently approved DORAs)• Currently in Phase 3 trials, adults
and aging patients being studied
Seltorexant• Selective orexin-2 receptor
antagonist – Orexin-2 receptor hypothesized to be
more important than OxR-1 in insomnia• 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 symptomsThese 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– Some therapies are better studied
than others in aging populations• Onset-predominant?
– Consider eszopiclone, lemborexant, suvorexant, zolpidem ER
• Need to awaken to auditory stimulus? eg, parent with a baby, or job requiring overnight call– Consider doxepin low dose,
lemborexant, suvorexant• Comorbid mild-to-moderate OSA or
COPD?– Consider ramelteon, suvorexant,
(lemborexant in mild OSA)• Need for lowest abuse potential?
– Consider ramelteon, doxepin• Patient preference
– May refuse controlled agents or have 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
