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© Associated Professional Sleep Societies, LLC 1

Year In Review: Insomnia

Michael J. Sateia, M.D.Geisel School of Medicine at Dartmouth


Conflict of Interest Disclosures for Speakers

X 1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients, OR

2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.

Type of Potential Conflict Details of Potential Conflict

Grant/Research Support

Consultant

Speakers’ Bureaus

Financial support

Other

3. The material presented in this lecture has no relationship with any of these potential conflicts, OR

4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

1.

2.

3.


Overview

• Search: Insomnia / English– April 1, 2015 – April 1, 2016

• N = 1294 articles– 152 original research / meta-analyses

selected for further review– selected for presentation


Overview• Pathopysiology

– Vulnerability– Electrophysiologic characteristics

• Associated morbidity and consequences– Inflammation– CVD– Suicide

• Therapy– Pharmacotherapy– CBTi / I-CBT-I

• Practice considerations / education


Pathophysiology

Vulnerability

StressGenetic factors


Are primary insomnia patients more stress reactive?

Identifying At-Risk Individuals for Insomnia Using the Ford Insomnia Response to Stress Test (FIRST)

Kalmbach DA; Vivek Pillai V; Arnedt,JT; Drake CL

• One year prospective study of incident insomnia• Community sample = 2892• Baseline parental history of insomnia,

demographics, FISRT and insomnia symptoms• DSM-IV criteria to determine insomnia diagnosis

SLEEP 2016;39(2):449–456.


Stress Reactivity in InsomniaGehrman P, Hall M, Barilla H, Buysse D, Perlis M, et al

• Primary insomnia (PI) subjects vs. good sleepers (GS) (N=20/group)

• Response to stress (threat of mild electric shock) during the PSG recording

• Outcomes: PSG recordings, salivary cortisol, patient reports (STAI, VAS)

• No evidence of increased response to stress in PI group vs. GS

• Behavioral Sleep Medicine, 14:23–33, 2016


A Longitudinal Twin Study of Insomnia Symptoms in Adults

Lind MJ, Aggen SH, Kirkpatrick RM

• Analysis of data from Virginia Twin Adult Study (N=7500)

• Insomnia composite score from SCL-90• Data from multiple time points examined to

determine longitudinal stability of etiologic influences and determine sex differences

• Models include: – A: genetic factors– C: common environmental factors– E: environmental factors specific to individuals

SLEEP2015;38(9):1423–1430


Key Points

• Is insomnia associated with greater stress reactivity?– Subjective (questionnaire) measures of stress

reactivity suggest so, but…– At least some stress induction models have

failed to find increased response in an insomnia group

• Significant genetic vulnerability is demonstrated and may contribute to stress reactivity (among many other factors)


Is insomnia characterized by specific electrophysiologic and

anatomical alterations?


Information processing during NREM sleep and sleep quality in insomnia

Ceklic T and Bastien CH

• Evaluation of event-related potentials (ERPs) during NREM sleep in 29 insomnia subjects and 39 good sleepers

• The insomnia subjects demonstrated greater amplitude potentials during slow wave sleep

• Objectively better sleep was associated with a smaller N350 amplitude (p = 0.020)

• Subjectively better sleep was associated with smaller P2 (p < 0.001) and N350 amplitude (p = 0.006).

International Journal of Psychophysiology 98 (2015) 460–469


• Misperception of objectively poor night as good also showed smaller P2 (p < 0.001) and N350 (p = 0.010) amplitudes

• Regardless of quality of the night, insomnia subjects showed greater EP amplitudes, in general


Wake high-density EEG spatiospectral signatures of insomnia

Colombo MA, Ramautar JR, Wei Y

• 94 subjects (51 with DSM-5 insomnia disorder [ID] and 43 control [C] good sleepers)

• High density EEG during wake (eyes open and eyes closed)

• Between group differences in the 1.5 – 40 Hz range were evaluated (with correction for multiple comparisons)

Sleep. 2016 Feb 29. pii: sp-00449-15.[Epub ahead of print]


• Comparisons show lower power in a narrow band of upper range alpha (11.0-12.7 Hz) for insomnia vs. controls

• Power in a broad upper band range of beta activity (16.3-40 HZ) was increased in insomnia subjects relative to controls

• The differences were observed across broad regions of cortex – that is, the findings do not appear to be localized


Conclusions• The findings support the conclusion that hyperarousal

in ID is present during wake as well as sleep– Heightened auditory information processing during sleep,

and its correlation with subjectively poor sleep, is consistent with hyperarousal

• Diminished alpha activity during wake, particularly in the upper range, may suggest diminished inhibitory processes– This, in turn, may reflect relative inability to inhibit

irrelevant and interfering cognitions• Relative increases in the higher (beta) frequencies

across broad areas of cortex is consistent with hyperactivity of sensorimotor, cognitive and emotional-regulatory systems


Consequences and Associated Morbidity


Insomnia Symptoms Are Associated WithAbnormal Endothelial Function

Routledge FS, Dunbar SB, Higgins M, et al.

• Prior meta-analysis suggests nearly 50% increase in CV disease and mortality among insomnia sufferers although the direction of causality is unclear

• This study included 496 adults from the Emory-Georgia Tech Predictive Health Institute study

• Insomnia symptoms reported for ~ 40% of the group

J Cardiovasc Nurs. 2015 Oct 19. [Epub ahead of print]


• Subjects underwent brachial artery flow-mediated dilation study, a commonly employed measure of endothelial (dys)function

*adjusted for baseline artery diameter (P < .001), age (P = .012), and dyslipidemia (P = .020)

• Adjusted FMD ~ 10% lower in INS subjects• Does endothelial dysfunction in insomnia contribute

to increased risk for CVD?

Insomnia Good sleepers

Adjusted mean FMD*

6.13% (SD .28%) 6.83% (.26%)


Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies

and Experimental Sleep DeprivationIrwin MR, Olmstead R, and Carroll JE

• Meta-analysis of 72 studies (N > 50,000) including sleep quality data, C-reactive protein, IL-6 and TNF-α

• Disturbed sleep associated with elevated levels of CRP and IL-6 but not TNF-α

Biological Psychiatry ]]], 2015


The Association Between Insomniaand Increased Future Cardiovascular Events:

A Nationwide Population-Based StudyChien-Yi Hsu, Yung-Tai Chen, Mu-Hong Chen

• Random sample of 44,080 individuals from Taiwan National Health Research database– 22,040 with insomnia / 22,040 good sleepers

(matched for age, sex and comorbidities)• Ten-year follow-up, tracking acute

myocardial infarction and stroke• Incidence data adjusted for age, sex and

comorbiditiesPsychosomatic Medicine, V 77 • 743-751


HealthU.S. Suicide Rate Surges to a

30-Year HighAPRIL 22, 2016


Insomnia is associated with suicide attempt in middle aged and older adults with depression

Kay DB, Dombrovski, AY, Buysse DJ, et al.

– One hundred thirty-five older adults (age 40-87) with depression

– Comparison of three groups:• Suicide attempt group (72)• Suicidal ideation group (28)• Non-suicidal group (35)

– Insomnia severity derived from Hamilton Rating Scale for Depression (HRSD)

International Psychogeriatrics (2016), 28:4, 613–619


Adjusted for demographics, cognitive ability, alcohol dependence in the past month, severity of depressed mood, anxiety, and physical health burden


Sleep Duration and Insomnia Symptoms as Risk Factors for Suicidal Ideation in a Nationally Representative SampleChakravorty S, Katy Siu HY, Lalley-Chareczko L et al.

• Data on sleep duration, insomnia and suicidal ideation obtained on 6228 adults from the National Health and Nutritional Examination Survey

• Difficulty initiating and (especially) maintaining sleep were associated with suicidal ideation after adjustment for multiple factors

Prim Care Companion CNS Disord. 2015; 17(6): 10


• Insomnia severity remained a significant predictor of suicide attempt after accounting for these confounding variable

• Suicide attempters typically demonstrated at least two insomnia complaints (i.e. onset, maintenance or early awakening)

• Clinicians should be aware that high insomnia severity in depressed patients is significantly associated with suicide attempts


Management• Obstructive sleep apnea and insomnia (OSA

plus)• Cognitive-behavioral treatment

– Internet-based• Effectiveness• Applications and comorbidities

• Pharmacotherapy– Suvorexant– Dosing schedules

• Educational issues


What Is the Optimal Management for OSA plus (Obstructive Sleep Apnea and Insomnia)

Management of Obstructive Sleep Apnea and Comorbid Insomnia: A Mixed-Methods

EvaluationOng JC, Crawford MR, Kong A, Park M

et al.

• Pooled data for subjects receiving OSA only (13), CBT-I only (3) or combined treatment (16)

• Patient flow determined by standard clinical care


Treatment Outcome

Behavioral Sleep Medicine, DOI: 10.1080/15402002.2015.1087000


Patient Reports• Treatment satisfaction:

– PAP: 92.5% CBT-I 81.5%

• Identified primary sleep problem– OSA: 24% Insomnia: 24% Both: 48%

• First choice of treatment:– PAP: 48% Sleep med: 20% CBT-i: 8%

• Patients reported little impact on OSA symptoms from CBT-I but did find moderate improvement of sleep continuity from PAP


Sequencing issues• Unresolved insomnia may diminish PAP

adherence• Use of PAP may complicate adherence to

stimulus control• Patient confusion regarding how the two

disorders relate to one another• Most patients indicated a preference for PAP

first, despite complaints of difficulty sleeping with PAP

• Trial(s) to determine optimal sequencing issues currently underway


Guided Online or Face-to-Face Cognitive Behavioral Treatment for Insomnia:

A Randomized Wait-List Controlled TrialLancee J, van Straten A, Morina N

• Recruited subjects with DSM-5 insomnia disorder randomized to three groups (individual face-to-face CBT-I (30), guided online CBT-I (30) or wait list control (30)

• Outcomes included sleep diary data, ISI, depression scores (CES-D) and anxiety scores (HADS)

• Data collected at baseline, post-treatment, 3-month and 6-month follow-up

SLEEP 2016;39(1):183–191


Effectiveness of an online insomnia program (SHUTi) for prevention of depressive episodes

(the GoodNight Study):a randomised controlled trialChristensen H, Batterham PJ, Gosling JA et al.

• Subjects with chronic insomnia and subclinical depression symptoms were assigned to receive internet-based CBT-I (SHUTi) [574] or a placebo intervention (Healthwatch) [575]

• The primary outcome was depression symptoms at 6 months (PHQ-9, excluding sleep items).

• Secondary outcomes included:– current major depressive disorder and suicidal ideation at

6 months (Psychiatric Symptom Frequency scale (PSF)– insomnia symptoms– generalised anxiety symptoms– disability– cognitive functioning

Lancet Psychiatry, 2016, 3(4), 333-341


Internet-Based Cognitive Behavioral Therapyfor Insomnia (ICBT-i) Improves Comorbid

Anxiety and Depression—A Meta-Analysis ofRandomized Controlled TrialsYuan-yuan Ye, Yuan-feng Zhang, Jia Chen


Change in Dysfunctional Beliefs About Sleep in Behavior Therapy, Cognitive Therapy, and Cognitive-Behavioral Therapy

for InsomniaEidelman P, Talbot L, Ivers H, et al.

• 188 chronic insomnia subjects (age > 25 years) • Randomized to behavior therapy alone,

cognitive therapy alone or combined CBT-I• Outcome variables included Dysfunctional

Beliefs and Attitudes Survey (DBAS), Insomnia Severity Index (ISI) and sleep diary reports– Behavior therapy: Sleep restriction / stimulus control– Cognitive therapy: Cognitive restructuring– Combined therapy

Behavior Therapy 47 (2016) 102–115


• No significant effect of treatment group on post-treatment DBAS scores

• A significant effect of time on DBAS score was observed


• DBAS post-treatment score was a significant predictor of both ISI score and psychosocial impairment (Work and Social Adjustment Scale) (but not individual sleep variables)at post-treatment, 6 and 12 month follow-up

• No significant difference in predictive value of DBAS across treatment groups


Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled

Clinical Trials Herring WJ, Connor KM, Ivgy-May N et al.

• Two 3-month trials of suvorexant 20 mg (adults < 65 years) / 15 mg (older adults)

• Sleep diary, PSG and questionnaire data collected at 2 weeks, 1 month and 3 months

Biological Psychiatry 2016; 79:136–148


Suvorexant – Sleep Diary

a:p<.001 b: p <.01 c: p <.05


Suvorexant – PSG and ISI

a:p<.001; b: p <.01 c: p <.05


Suvorexant• Small improvements in subjective time to

sleep onset • PSG sleep latency shows mixed results,

especially at 3-month extension• Modest improvement in subjective TST• Small improvements in subjective WASO but

more robust WASO reduction on PSG measures

• No evidence of significant rebound, withdrawal or major adverse effects, including emergence of narcolepsy symptoms


Durability of treatment response to zolpidem with three different

maintenance regimens: a preliminary studyPerlis M, Grandner M, Zee J

• Seventy-four chronic insomnia subjects treated with zolpidem 10 mg x 4 weeks

• Responders were then randomized to one of four treatment arms:– Zolpidem 5 mg or 10 mg nightly (QHS-10/QHS-5)– Zolpidem 10 mg intermittently (3-5 nts/wk.) (IDS-10)– “Partial reinforcement” with zolpidem 10 mg (PRS-10)

• 50% active medication and 50% placebo


Sleep Medicine 16 (2015) 1160–1168


• All four strategies produced reasonable response survival at 12+ weeks - > 70-80%– Survival = maintenance of >50% of initial

gains and/or SE < 80%• ID-10 showed the poorest overall sleep

continuity


• Conclusions– The data are preliminary– Nightly dosing with 10 mg was not superior to

lower dose nightly dosing (QHS-5)– The data raise some questions about the relative

efficacy of intermittent dosing • despite the fact that the IDS-10 group received a larger

cumulative weekly dose than either the QHS-5 or PRS-10 groups

– The PRS strategy was effective but raises questions regarding the use of placebo in non-research applications


Referral Practices for Cognitive Behavioral Therapy for Insomnia: A Survey Study

Conroy DA, Ebben MR

• 239 physicians (internists/FPs, pediatricians, psychiatrists, surgeons, other specialists) from U Mich and Cornell

• “What treatment do you find most effective for improving sleep quality of patients with insomnia?”

Behavioural Neurology 2015, Article ID 819402

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