Clinical Practice Guideline for the Treatment of Intrinsic Circadian

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A systematic literature review and meta-analyses (where

appropriate) were performed and the GRADE approach was

used to update the previous American Academy of Sleep

Medicine Practice Parameters on the treatment of intrinsic

circadian rhythm sleep-wake disorders. Available data

allowed for positive endorsement (at a second-tier degree of

con dence) of strategically timed melatonin (for the treatment

of DSWPD, blind adults with N24SWD, and children/

adolescents with ISWRD and comorbid neurological disorders),

and light therapy with or without accompanying behavioral

interventions (adults with ASWPD, children/adolescents with

DSWPD, and elderly with dementia). Recommendations

against the use of melatonin and discrete sleep-promoting

medications are provided for demented elderly patients, at a

second- and  rst-tier degree of con dence, respectively. No

recommendations were provided for remaining treatments/

populations, due to either insuf cient or absent data. Areas

where further research is needed are discussed.

Keywords: circadian rhythms, DSWPD, ASWPD, N24SWD,

ISWRD

Citation: Auger RR, Burgess HJ, Emens JS, Deriy LV,

Thomas SM, Sharkey KM. Clinical practice guideline for the

treatment of intrinsic circadian rhythm sleep-wake disorders:

advanced sleep-wake phase disorder (ASWPD), delayed

sleep-wake phase disorder (DSWPD), non-24-hour sleep-

wake rhythm disorder (N24SWD), and irregular sleep-wake

rhythm disorder (ISWRD). An update for 2015. J Clin Sleep

Med 2015;11(10):1199 –1236 .

pii: jc-00358-15

http://dx.doi.org/10.5664/jcsm.5100

SUMMARY

Purpose

The present document replaces/updates the previous Ameri-

can Academy of Sleep Medicine (AASM) Practice Parameters

pertaining to the intrinsic CRSWDs (i.e., ASWPD, DSWPD,

N24SWD, and ISWRD). The treatment of remaining CRSWDs

is not addressed.

Methodology

The AASM commissioned a Task Force (TF) of 4 members

with expertise in the  eld of CRSWDs, appointed a Board of

Directors (BOD) liaison, and assigned a Science and Research

Department staff member to manage the project. PICO (Pa-

tient, Population or Problem, Intervention, Comparison, and

Outcomes) questions were developed by the TF and approved

by the BOD. Extensive literature searches were performed to

identify articles of interest, and relevant data were extracted by

Clinical Practice Guideline for the Treatment of Intrinsic

Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-

Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase

Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder

(N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD).

An Update for 2015

An American Academy of Sleep Medicine Clinical Practice Guideline

R. Robert Auger, MD

; Helen J. Burgess, PhD

; Jonathan S. Emens, MD

; Ludmila V. Deriy, PhD

; Sherene M. Thomas, PhD

;

Katherine M. Sharkey, MD, PhD

Mayo Center for Sleep Medicine, Rochester, MN;

Rush University Medical Center, Chicago, IL;

Portland VA Medical Center,

Portland, OR;

American Academy of Sleep Medicine, Darien, IL;

Brown University, Providence, RI

the TF. The TF developed consensus-based relevant outcomes,

rated their relative importance, and determined clinical signi -

cance thresholds. Extracted data were pooled across studies

for each outcome measure in accordance with PICO questions,

and based upon CRSWD diagnosis, study design, patient pop-

ulation, outcome of interest, and method of derivation. Statis-

tical analyses were performed using dedicated software, and

meta-analyses were completed when applicable. The GRADE

(Grading of Recommendations Assessment, Development,

and Evaluation) approach was used to develop recommenda-

tion statements and to determine the direction and strengths of

these recommendations based upon a composite assessment of

evidence quality, bene ts versus harms analyses, and patient

values and preferences.

Findings

Available data allowed for positive endorsement (at a sec-

ond-tier degree of con dence) of strategically timed melatonin

(for the treatment of DSWPD, blind adults with N24SWD, and

S P E C I A L A RT I C L E S

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RR Auger, HJ Burgess, JS Emens et al.

children/adolescents with ISWRD and comorbid neurologi-

cal disorders), and light therapy with or without accompany-

ing behavioral interventions (adults with ASWPD, children/

adolescents with DSWPD, and elderly with dementia and

ISWRD). Recommendations against the use of melatonin and

discrete sleep-promoting medications are provided for de-

mented elderly patients, at a second- and rst-tier degree of

condence, respectively. No recommendations were provided

for remaining treatments/populations, due to either insufcient

or absent data.

Recommendations are as Follows

ASWPD

5.1.4a The TF suggests that clinicians treat adult ASWPD

patients with evening light therapy (versus no treatment).

[WEAK FOR]

DSWPD

5.2.6.1a The TF suggests that clinicians treat DSWPD in

adults with and without depression with strategically timed

melatonin (versus no treatment). [WEAK FOR]

5.2.6.2.1a The TF suggests that clinicians treat children

and adolescents with DSWPD (and no comorbidities) with

strategically timed melatonin (versus no treatment). [WEAK

FOR]

5.2.6.2.2a The TF suggests that clinicians treat children

and adolescents with DSWPD comorbid with psychiatric

conditions with strategically timed melatonin (versus no

treatment). [WEAK FOR]

5.2.9.2a The TF suggests that clinicians treat children

and adolescents with DSWPD with post-awakening light

therapy in conjunction with behavioral treatments (versus no

treatment). [WEAK FOR]

N24SWD

5.3.6.1a The TF suggests that clinicians use strategically

timed melatonin for the treatment of N24SWD in blind adults

(versus no treatment). [WEAK FOR]

ISWRD

5.4.4a The TF suggests that clinicians treat ISWRD in

elderly patients with dementia with light therapy (versus no

treatment). [WEAK FOR]

5.4.5a The TF recommends that clinicians avoid the use

of sleep-promoting medications to treat demented elderly

patients with ISWRD (versus no treatment). [STRONG

AGAINST]

5.4.6.1a The TF suggests that clinicians avoid the use of

melatonin as a treatment for ISWRD in older people with

dementia (versus no treatment). [WEAK AGAINST]

5.4.6.2a The TF suggests that clinicians use strategically

timed melatonin as a treatment for ISWRD in children/

adolescents with neurologic disorders (versus no treatment).

[WEAK FOR]

5.4.9.1a The TF suggests that clinicians avoid the use

of combined treatments consisting of light therapy in

combination with melatonin in demented, elderly patients

with ISWRD (versus no treatment). [WEAK AGAINST]

Conclusion

Use of the GRADE system for this updated Clinical Prac-

tice Guideline represents a major change. This update should

provide clinicians with heightened condence with respect to

prescribing select treatments and, equally importantly, should

serve as a roadmap for future studies that will propel higher

qualit y, more sophisticated therapies for the i nt rinsic CRSWDs.

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

1.0 INTRODUCTION

The American Academy of Sleep Medicine (AASM) pro-

duced the rst Practice Parameters (and associated reviews) for

the evaluation and treatment of circadian rhythm sleep-wake

disorders (CRSWDs) in 2007.

1–3

The purpose of the present

publication is to provide an evidence-based update of existing

recommendations for the treatment of the intrinsic CRSWDs:

advanced sleep-wake phase disorder (ASWPD), delayed sleep-

wake phase disorder (DSWPD), non-24-hour sleep-wake

rhythm disorder (N24SWD), and irregular sleep-wake rhythm

disorder (ISWRD). The extrinsic or predominantly environ-

mentally inuenced CRSWDs, namely shift work and jet lag

disorder, are not addressed in this paper.

2.0 BACKGROUND

Reviewed studies that included patients with an explicitly

stated CRSWD predominantly utilized the International Classi-

cation of Sleep Disorders, Second Edition (ICSD-2)

diagnostic

criteria, despite the fact that International Classication of Sleep

Disorders, Third Edition (ICSD-3)

nomenclature is referenced

throughout the manuscript. Important modications to the In-

ternational Classication of Sleep Disorders include incorpora-

tion of the word “wake” (the ICSD-2 referred solely to circadian

rhythm sleep disorders), which highlights the signicant impair-

ments these conditions exert on daytime functioning. Caregiver

input is also emphasized in the ICSD-3, particularly with respect

to diagnostic assessments among cognitively impaired and pedi-

atric patients. Other major changes include the recommendation

that CRSWD diagnoses are ascertained via actigraphy derived

data when possible (with inclusion of both work/school and

free days), to provide objective longitudinal documentation of

sleep-wake patterns. Consistent with this emphasis on objective

measures, circadian phase assessments (e.g., dim light melato-

nin onset, or DLMO) are also recommended, if feasible. Other

changes include a de-emphasis on “conventional” and “socially

acceptable” clock times (recognizing the relative nature of these

terms, and instead highlighting patients’ subjective concerns),

extensive additions to the “Pathology and Pathophysiology” and

“Polysomnographic and Other Objective Findings” sections, and

new descriptions of “Developmental Issues” and “Clinical and

Pathophysiologic Subtypes.”

In many instances, this review incorporated trials with par-

ticipants who were not recruited in strict accordance with In-

ternational Classication of Sleep Disorders criteria, but who

nonetheless described symptoms consistent with a CRSWD

(based upon Task Force consensus). Examples include pediat-

ric/adolescent patients with “idiopathic sleep-onset insomnia,”

whose symptoms were consistent with DSWPD, as well as

select populations of institutionalized elderly patients, among

whom varied descriptions of insomnia, nighttime wakefulness,

and daytime napping selectively appeared to be representative

of ISWRD, despite the fact that this condition was not named

explicitly. A similar approach was taken for this latter group of

patients during literature review and development of the previ-

ous Practice Parameters.

1,3

A brief scientic background is required. The two-process

model for sleep regulation delineates two principle mechanisms

for the governance of sleep and wakefulness: “Process S” and

“Process C.”

The homeostatic drive to sleep (Process S) is pro-

portional to the duration of wakefulness. In contrast, Process C

creates a drive for wakefulness that variably opposes Process S

and is dependent upon circadian (“approximately daily”) rhythms

intrinsic to the individual. Master coordination of this sleep/wake

rhythm is provided by the neurons of the suprachiasmatic nuclei

located within the hypothalamus.

7–10

As this intrinsic period is

typically slightly longer than 24 hours in humans

11,12

synchroni-

zation to the 24-hour day (entrainment) is accomplished by vari-

ous environmental inputs, the most important of which is light

and dark exposure.

Failure to synchronize can alter the phase

relationships between internal rhythms and the light/dark cycle,

which may manifest in the form of circadian rhythm sleep-wake

disorders (CRSWDs). The intrinsic CRSWDs refer to those con-

ditions that are thought to exist predominantly due to innate phe-

nomena, although exogenous components contribute to varying

degrees in all of these disorders.

The intrinsic CRSWDs are briey characterized as follows.

DSWPD manifests as a delay of the major sleep episode with

respect to the patient’s desired timing or the timing required to

attend to social, educational, and/or occupational demands. Pa-

tients report extreme difculty both with falling asleep at bed-

times considered typical among their peers, and with waking at

the required or desired times, but sleep quality is typically re-

ported as normal when the individual sleeps at the delayed times.

In contrast, an advance of the major sleep episode with respect

to the patient’s desired or required sleep-wake times character-

izes ASWPD. ASWPD patients report extreme difculty staying

awake during evening hours and frequently note falling asleep

before completion of pertinent work, social, or family obligations.

In addition, wake time is undesirably early, and considered atypi-

cal in comparison to peers. For both conditions, symptoms must

be present for at least 3 months and schedules need to be docu-

mented with sleep diaries and/or wrist actigraphy for a period of

at least 7 days.

N24SWD is diagnosed when patients fail to entrain to the

24-hour light-dark cycle and clock times. Thus, patients exhibit

sleep-wake patterns that show a progressive delay (usually) or

advance, depending upon the period length (tau) of their en-

dogenous circadian rhythms. During a symptomatic period, the

time of high sleep propensity gradually shifts, such that patients

experience daytime hypersomnolence and nighttime insomnia.

Most patients with N24SWD are totally blind, but this disorder

also occurs among sighted individuals. In contrast to the other

CRSWDs, a N24SWD diagnosis requires at least 14 days of doc-

umentation of progressively shifting sleep-wake times with sleep

diaries and/or actigraphy.

Patients with ISWRD lack a clear circadian pattern of sleep-

wake behavior. Thus, aficted individuals experience pro-

longed periods of wakefulness during the typical nocturnal

sleep episode in addition to excessive sleepiness and prolonged

sleep bouts during daytime hours. Sleep is fragmented and

frequently insufcient. ISWRD is observed more commonly

among patients with neurodevelopmental or neurodegenera-

tive disorders, and can pose particular challenges for caregiv-

ers. Documentation (sleep diaries and/or actigraphy) of multiple

non-circadian sleep-wake bouts for a period of at least 7 days is

required for diagnosis.

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RR Auger, HJ Burgess, JS Emens et al.

Interventions for CRSWDs can be broadly categorized as fol-

lows: (1) prescribed timing of sleep-wake and/or physical activity/

exercise, (2) strategic receipt and/or avoidance of light, (3) use of

medications and/or supplements to phase shift and/or to promote

sleep or wakefulness, and (4) alternate interventions that exert ef-

fects by altering bodily functions to impact sleep/wake behaviors

(i.e., somatic interventions).

Light is strategically timed according to phase response

cur ves (PRCs).

In brief, light can suppress melatonin secretion

and phase shift circadian timing in humans,

leading to the use

of timed light exposure as a treatment for CRSWDs. Light timed

in the evening and before the core body temperature minimum

(CBT

min

) leads to phase delays, and light timed after the CBT-

min

in the morning leads to phase advances.

Larger effects are

observed with greater intensities of light and longer durations

of light, but the increases are nonlinear.

16,17

Additionally, the re-

sponse to light is modied by prior exposure to light or “light

histor y,”

18,19

such that a history of less light exposure leads to a

greater response to light. Just as light exposure can shift circa-

dian timing, so too can the strategic avoidance or reduction of

light.

20,21

Finally, the human circadian system is most sensitive

to short wavelength blue light (~480 nm),

22,23

although at bright

intensities phase shifts to white broad spectrum light and blue

enriched light are similar, presumably due to a saturation of

photoreceptors.

24,25

Less is known about the variables contributing to melatonin

response.

The melatonin PRC is approximately 180 degrees out

of phase with the light PRC, such that dosing in the afternoon/

evening shifts rhythms earlier and dosing in the morning shifts

rhythms later. As the CBT

min

serves as the “inection point” be-

tween delaying and advancing effects for light, the DLMO serves

as the approximate inection point for advancing and delaying

effects of melatonin. Optimal dosing of melatonin for circadian

effects remains unclear, and studies suggest that timing is more

important than dose (PRCs for doses above 5 mg have not been

published). In addition to phase shifting effects, melatonin may

also have direct soporic effects, particularly at higher doses.

3.0 METHODS

3.1 Expert Task Force

In order to develop these Clinical Practice Guidelines, the

American Academy of Sleep Medicine (AASM) commissioned

a Task Force (TF) of four members with expertise in the eld of

CRSWDs, appointed an AASM Board of Directors (BOD) liai-

son, and assigned an AASM Science and Research Department

staff member to manage the project. Prior to appointment, the

content experts were required to disclose all potential conicts

of interest according to AASM policy. None were declared. The

TF performed an extensive review of the scientic literature

and assessed the available evidence employing the methodol-

ogy of evidence-based medicine (specically, meta-analysis

and the Grading of Recommendations Assessment, Develop-

ment and Evaluation system, or GRADE) to draft recommenda-

tions. The present paper was approved by the AASM BOD and

replaces the previous Practice Parameters.

The AASM expects

these guidelines to have a positive impact on clinical decision-

making and patient outcomes. These recommendations reect

the state of knowledge at the time of publication and will be

revised when the availability of new information necessitates.

3.2 PICO Questions

Eight PICO (Patient, Population or Problem, Intervention,

Comparison, and Outcomes) questions were developed, based

on both the inquiries raised in the previous AASM publica-

tions

1,3

and an investigation of systematic reviews, meta-anal-

yses, and guidelines published subsequently (Table 1). The

AASM BOD ultimately approved these questions. In addition,

combination treatments were also reviewed for the four intrin-

sic CRSWDs included in this guideline.

3.3 Literature Searches

Literature search #1 was performed in PubMed using broad

terms (see Appendix), in order to identify systematic reviews,

meta-analyses or relevant practice guidelines published sub-

sequent to availability of the previous AASM Practice Pa-

rameters. Examination of discovered papers (n = 93) enabled

elucidation of Practice Parameter recommendations requir-

ing revisions, and also assisted with further renement of the

PICO questions. The next literature search (#2) targeted treat-

ment trials involving intrinsic CRSWDs that addressed at least

one PICO question. This search utilized PubMed, Embase, and

PsycInfo databases.

At least two TF members carefully assessed the abstract of

each retrieved article (n = 2,063), to determine whether the

publication should be included for further consideration. The

following list of general exclusion criteria was used:

Table 1—PICO question parameters.

Population Intervention Comparison Outcomes

Patients diagnosed

with intrinsic

CRSWDs

(ASWPD, DSWPD,

N24SWD, ISWRD)

1. Prescribed sleep-wake scheduling

2. Timed physical activity/exercise

3. Strategic avoidance of light (e.g., with the use of eyewear)

4. Light therapy

5. Sleep-promoting medications (hypnotics/sedatives/

neuroleptics/other novel agents)

6. Timed oral administration of melatonin or agonists

7. Wakefulness-promoting medications (e.g., modanil,

traditional stimulants)

8. Other somatic interventions

9. Combination treatments

Control group, those

treated with placebo

or, when a comparison

group was not available,

measurements performed

“before” (baseline) and

“after” treatment

Physiologic circadian phase

markers (DLMO [saliva/plasma],

urinary melatonin metabolite,

constant routine CBT

Min

)

Total sleep time (TST)

Initial sleep latency (ISL)

Sleep onset time (SOT)

Sleep offset time (SOffT )

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

1. Diagnosis or not treatment

2. Not CRSWD

3. Not intrinsic CRSWD (shift work or jet-lag disorder)

4. Wrong publication type (review, editorial, etc.)

5. Not human subjects

6. Mechanistic or methodological study

7. Study was published before October 2006

When there were questions or disagreements, the full text

of the article was reviewed in detail until consensus was

reached. The same search terms, databases and inclusion/ex-

clusion criteria were used for literature search #3, although

new date limitations were applied (June, 2012–March, 2014),

with the intention to capture articles published after comple-

tion of search #2. Four hundred fty-three additional publica-

tions were retrieved, and TF assessments occurred in the same

manner described above. Finally, TF members selected several

literature reviews (by consensus), and screened reference lists

to identify other articles of potential interest. This “pearling”

process served as a “spot control” for the previous searches,

and ensured that important articles were not missed. All dupli-

cate references were eliminated.

Since new inclusion/exclusion criteria were used in this

project, investigations cited in the previous Practice Param-

eters

were not necessarily incorporated into the current analy-

sis. Studies that did not meet inclusion criteria were selectively

used for discussion purposes, but were neither included in the

GRADE reports nor used as a basis for recommendations. The

TF made a particular effort to discuss those studies (contain-

ing either patients or healthy subjects) that might spur and/or

improve future clinical research for the reviewed CRSWDs.

A nal PubMed search was conducted to identify harms

or adverse effects attributed to the relevant interventions:

light therapy (PICO 4), hypnotics (PICO 5), and melatonin

(PICO 6) (see Appendix). Limitations were imposed to select

for English-language “meta-analyses” and “systematic re-

views” pertaining to human subjects. The titles and abstracts

of articles produced by these searches were reviewed for rel-

evance, and pertinent publications were examined. Other cited

articles from the “Harms and Adverse Effects” section were

culled from prior searches (but deemed ineligible for quantita-

tive analysis) or were provided via TF members’ preemptive

awareness and consensus regarding relevancy. Adverse effects

of combined treatments were addressed based on the singular

components of combinations.

3.4 Treatment Efficacy Outcomes

During the process of data extraction, the TF developed

a list of patient-oriented clinically relevant outcomes and

rated their relative importance. Physiologic circadian phase

markers, total sleep time (TST), initial sleep latency (ISL),

sleep onset time (SOT), and sleep offset time (SOffT) were

deemed CRITICAL for making recommendations, and a sig-

nicance threshold was dened for each outcome based upon

consensus (Table 2), as no published standards exist. Sleep

parameters were alternately evaluated with polysomnogra-

phy (PSG), wrist actigraphy, or sleep diaries. Although both

wakefulness after sleep onset and sleep efciency were also

commonly reported, the two variables were rated as IMPOR-

TANT (but not CRITICAL) by the TF. As such, related data

did not factor into clinical recommendations. A unique sce-

nario arose for N24SWD, for which entrainment status (i.e.,

whether the biological clock is synchronized to the 24-hour

day) was solely utilized as a CRITICAL outcome measure,

as it denes this CRSWD physiologically (see section 5.3 in

this paper).

3.5 Extraction of Evidence

Quantitative data pertaining to the outcomes of interest as

well as information necessary for systematic evaluation and

grading of the evidence were extracted from accepted articles

using a dedicated spreadsheet. Articles determined to lack

quantitative data or with data presented in a format incompat-

ible with desired statistical analyses were rejected at this stage,

but used selectively for further discussion. In instances where

desired data were available but not presented in the desired for-

mat, the authors were contacted, and raw data were acquired if

possible. Data were pooled across the studies for each outcome

measure in accordance with PICO questions and based on

diagnosis, study design, patient population, clinical outcome

of interest, and method of derivation (e.g., PSG derived data

were analyzed separately from data derived from actigraphy

or sleep diaries).

3.6 Statistical Analyses

Meta-analyses were completed (in the few instances pos-

sible) using the random effects model. All computations were

performed using the Review Manager software,

and included

calculations of the mean difference (MD) ± standard deviation

(SD) for CRITICAL outcomes. Values analyzed in this manner

are displayed to the hundredths place. Age demographics and

information regarding melatonin doses are presented in the

format provided by the associated study (mean ± SD if avail-

able) but, in an effort to maintain consistency, are displayed

only to the tenths place in instances where the authors pro-

vided values with numerical place values of lower hierarchy.

The results of meta-analyses are depicted in gures within the

Table 2—CRITICAL outcomes and their TF-dened clinical signicance thresholds.

Diagnosis

Clinical Signicance Thresholds

Circadian Phase

(change in minutes)

TST (change in

minutes)

ISL (change in

minutes)

SOT (change in

minutes)

SOffT (change in

minutes)

Entrainment

Status

ASWPD 30 30 15 15 15 N/A

DSWPD 30 30 15 15 15 N/A

ISWRD 30 30 15 15 15 N/A

N24SWD N/A N/A N/A N/A N/A Yes/No

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RR Auger, HJ Burgess, JS Emens et al.

text, in association with a “forest plot.” Summary of ndings

tables for all investigations are presented in the Appendix.

When studies contained placebo/control groups, the evalu-

ation of the effect of treatment was performed by comparison

of averaged posttreatment and averaged post-placebo/control

group values, regardless of the authors’ approaches. In studies

with crossover or “before-after” designs where there was no

placebo/control group, posttreatment values were compared to

baseline values. Our use of this methodology occasionally pro-

duced results that differed from those reported in the original

publications (e.g.

27–29

3.7 Interpretation of Clinical Significance of Results

Interpretation of clinical signicance was ascertained via

comparisons with predened thresholds (see Table 2 and

Figure 1). For meta-analyses, the pooled MD (black diamond)

on “forest plots” depicts the average response or magnitude of

effect across all studies, the width of the diamond represents

the associated 95% condence interval (CI), and the “no ef-

fect” line represents nil benet from the intervention. The dot-

ted lines on the left and right sides (equidistant from the “no

effect” line) represent clinical decision thresholds dened by

the TF (Figures 1A, 1B, and 1C). The right side represents an

increase in the outcome measure, while the left represents a

decrease. An increase in some outcome measures, such as TST,

represents improvement. If the black diamond of TST data lies

beyond the clinical signicance threshold on the right side, the

result of a treatment is interpreted as a clinically signicant

improvement (Figure 1A). If, however, the diamond lies to the

left of the “clinical signicance” line, the decrease is regarded

as a clinically signicant undesired outcome, and the treatment

is deemed contraindicated. When improvement is signied by

a decrease in the outcome measure (e.g., ISL), the interpreta-

tion is reversed.

When the condence interval crosses the clinical signi-

cance threshold on one side, the evidence is graded one level

down (Figure 1B) for “serious imprecision.” When the con-

dence interval crosses the clinical signicance threshold on

both sides of the no effect line, the evidence is graded two lev-

els down for “very serious imprecision” (Figure 1C). Since

the Review Manager software does not operate with clinical

signicance thresholds, these dotted lines are not depicted in

the gures associated with the actual data. The interpretation

of clinical signicance from results of individual studies was

accomplished in the same manner, but forest plots were not

created.

3.8 Quality of Evidence

The GRADE approach was used for the assessment of qual-

ity of evidence

30–37

(also see: http://www.gradeworkinggroup.

org/publications/JCE_series.htm). In contrast to other meth-

ods, an estimate of effect is generated for critical outcomes

across studies, as opposed to an evaluation of individual stud-

ies. Multiple aspects of quality of evidence are assessed, with

downgrading of evidence as applicable (see Table 3).

GRADE assigns high quality to evidence from randomized

controlled trials while evidence from observational studies is

considered low quality. However, high quality evidence can

be graded down, and low quality evidence can be graded up,

based upon the factors described below (see Table 3). The

analysis of risk of bias includes review of the presence/ab-

sence of blinding, allocation concealment, loss to follow up,

or selective outcome reporting. Indirectness occurs when

the question being addressed is different than the available

evidence in terms of population, intervention, comparator, or

outcome. There is inconsistency when there is unexplained

heterogeneity of the results. Imprecision is described in sec-

tion 3.7 in this paper.

In GRADE, there are 4 specic categories for assessing the

quality of a body of evidence.

High: corresponds to a high level of certainty that the true

effect lies close to that of the estimate of the effect.

Moderate: corresponds to a moderate level of certainty in

the effect estimate; the true effect is likely to be close to

the estimate of the effect, but there is a possibility that it

is substantially different.

No effect line

Clinical significance

threshold defined by the TF

Clinical significance

threshold defined by the TF

Clinical significance

threshold defined by the TF

Figure 1—Guide for interpretation of clinical signicance of the results.

Examples of (A) clinically signicant improvement; (B) “serious” imprecision, grade one level down; (C) “very serious” imprecision, grade two levels down.

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

Low: corresponds to a low level of certainty in the effect

estimate; the true effect may be substantially different

from the estimate of the effect.

Very low: corresponds to very little certainty in the effect

estimate; the true effect is likely to be substantially

different from the estimate of effect.

The body of evidence for each outcome was assessed and

graded, taking into account quality considerations based on

the quantitative analysis and other major factors described

above. CRITICAL outcome results are presented as summary

of ndings tables organized by PICO question and patient pop-

ulation (see Appendix, Tables S1–S12).

A cumulative quality grade for a particular PICO question

and patient population is predicated upon the lowest level of

evidence assigned to one of the CRITICAL outcomes. Thus, if

a recommendation was based upon two outcomes, one of mod-

erate and one of low quality, the overall grade would be low.

3.9 Strength of Recommendations

The TF developed recommendation statements and deter-

mined the strengths of these recommendations based on the

balance of the following major factors:

1. Level of evidence—based on an assessment of the

quality of evidence using GRADE criteria (see Table 3),

the TF categorized the evidence as:

a. High

b. Moderate

c. Low

d. Ver y Low

2. Benets vs. Harms—based upon CRITICAL outcomes

and analysis of any harms/side effects, the TF assessed

whether:

a. Benets outweighed harms

b. Benets equaled harms

c. Harms outweighed benets

d. The balance between benets and harms was unclear

3. Patient values and preferences—based on the clinical

expertise of the TF and relevant published data,

including discussion in the referenced papers about

tolerability, compliance, and patients’ experiences with

the treatments in question, the TF judged whether:

a. The vast majority of well-informed patients (> 90%)

would most likely use this patient-care strategy,

compared to alternative patient-care strategies or no

treatment

b. The majority of well-informed patients would most

likely use this patient-care strategy, compared to

alternative patient-care strategies or no treatment

c. The majority of well-informed patients would most

likely NOT use this patient-care strategy, compared

to alternative patient-care strategies or no treatment

d. The vast majority of patients (> 90%) would most

likely NOT use this patient-care strategy, compared

to alternative patient-care strategies or no treatment

Taking these variables into consideration, each recommen-

dation statement was given a “strength value” of Strong For,

Weak For, Weak Against or Strong Against (see Table 4). As

an example, a body of evidence could be rated VERY LOW,

while another could be rated MODERATE, and yet both could

generate a WEAK FOR recommendation, based upon the

above mentioned factors.

There were multiple cases when the TF chose to make “No

Recommendation,” which reects either a complete lack of

available evidence (no studies were published) or situations

when evidence was available but either did not meet review

inclusion criteria or was considered insufcient to support a

recommendation (see Appendix, Tables S5 and S6). It needs

to be emphasized that “No Recommendation” does not mean

that treatments should not be tried but that, in the absence of

sufcient and conclusive evidence, clinicians should use their

best judgment to decide in each particular case whether or not

a treatment should be used. At the step of review of the ex-

tracted evidence, the TF made a decision to exclude studies

with fewer than 10 subjects if the study constituted a single

source of evidence, as it was felt that afliated data were insuf-

cient to support a recommendation.

Table 3—Summary of GRADE approach to rating quality of evidence (from Guyatt et al.

Study Design

Initial Quality of a

Body of Evidence Downgrade if Upgrade if Quality of a Body of Evidence

Randomized trials High → Risk of bias

−1 Serious

−2 Very serious

Inconsistency

−1 Serious

−2 Very serious

Indirectness

−1 Serious

−2 Very serious

Imprecision

−1 Serious

−2 Very serious

Publication bias

−1 Serious

−2 Very serious

Large effect

+1 Large

+2 Very large

Dose response

+1 Evidence of a

gradient

All plausible residual

confounding

+1 Would reduce

a demonstrated

effect

+1 Would suggest

a spurious

effect if no

effect was

observed

High (four plus:

⊕⊕⊕⊕)

Moderate (three plus: ⊕⊕⊕⊝)

Observational studies Low → Low (two plus: ⊕⊕⊝⊝)

Very Low (one plus: ⊕⊝⊝⊝)

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4.0 HARMS AND ADVERSE EFFECTS

4.1 Light Therapy

No studies/reviews were identied that specically ad-

dressed potential harms among patients with CRSWDs. In

their Cochrane Systematic Review for the treatment of non-

seasonal depression, Tuunainen and colleagues

found that

hypomania was the sole side effect that was more common

among patients receiving light therapy versus controls (Rela-

tive Risk 4.91 [CI 1.66–4.46]). Nevertheless, light treatment

has been safely used for the treatment of bipolar depression,

with careful monitoring.

Other commonly described side effects include eyestrain,

nausea, and agitation, albeit with predominant spontaneous

remission. Treatment-emergent headaches also commonly re-

mit,

but light therapy can induce migraines in approximately

one-third of those susceptible.

Finally, although commercially available products do not

emit ultraviolet light, patients with eye disease and/or those

using photosensitizing medications should only use light

therapy with periodic ophthalmological and/or dermatologi-

cal monitoring of the underlying condition.

40,42,43

Reassuringly,

one study reported no changes in extensive ophthalmologic ex-

aminations among seasonal affective disorder patients without

preexisting conditions after up to 6 years of daily use in the fall

and winter months.

4.2 Melatonin

Melatonin is considered a dietary supplement, and is there-

fore not subject to the scrutiny afforded to United States Food

and Drug Administration (FDA)-approved medications. Con-

cerns have been raised about the purity of available prepara-

tions, as well as the reliability of stated doses. Formulations

that are United States Pharmacopeial Convention Veried can

be considered most reliable in this regard.

Few identied papers addressed risks or side effects speci-

cally among patients with CRSWDs. In general, melatonin is

associated with a lack of reported serious adverse effects.

44–48

review by the National Academy of Sciences stated that short-

term use of ≤ 10 mg/daily (higher than typical chronobiotic

doses) appears to be safe in healthy adults but recommended

caution in children/adolescents and women of reproductive

age (see further below). Adverse effects such as headaches,

somnolence, hypotension, hypertension, gastrointestinal up-

set, and exacerbation of alopecia areata have been reported

at higher melatonin doses in healthy adults, and the same

effects have been reported at lower doses among those with

relevant preexisting conditions. Melatonin has also been asso-

ciated with an increase in depressive symptoms,

and caution

is advised when prescribing to patients taking warfarin and to

patients with epilepsy, as a result of various case reports sub-

mitted to the World Health Organization.

A recent publica-

tion described impairment in glucose tolerance among healthy

women

subsequent to acute melatonin administration.

Studies that address long-term effects are scarce, as are stud-

ies that specically involve pediatric/adolescent populations.

A randomized, placebo-controlled trial that investigated the

toxicology of a 28-day treatment with 10 mg melatonin (solely

comprised of healthy male adult participants) revealed no

group differences with respect to adverse effects on polysom-

nographically recorded sleep, subjective sleepiness, numerous

clinical laboratory examinations, or other subjectively recorded

events.

Similarly, in a meta-analysis that reviewed controlled

trials with melatonin (n = 10 studies, over 200 subjects) used

for ≤ 3 months, there were few reports of adverse events.

A long-term follow-up study of pediatric patients with

DSWPD + attention decit hyperactivity disorder (ADHD)

who utilized melatonin doses up to 10 mg (mean follow-up time

of approximately 4 years) detected no serious adverse events

as a result of serial interviews with the children’s parents, and

65% of participants continued to use the medication daily.

follow-up open-label prospective study of subjects with neu-

rodevelopmental disabilities comorbid with DSWPD who re-

ceived controlled-release melatonin (max dosage 15 mg) up to

3.8 years similarly described no adverse events.

53,54

Patients and

Table 4—Denitions of AASM strengths of recommendations.

AASM Strength of Recommendation Example Characteristics Guiding Recommendation

FOR

STRONG

• There is a high degree of clinical certainty in the net benets of this patient-care strategy.

• The vast majority of well-informed patients would most likely choose this patient-care strategy, compared to

alternative patient-care strategies or no treatment.

WEAK

• There is a lower degree of clinical certainty in the balance between benets vs. harms (e.g., net benets) of

this patient-care strategy.

• The majority of well-informed patients would most likely choose this patient-care strategy, compared to

alternative patient-care strategies or no treatment.

AGAINST

WEAK

• There is a lower degree of clinical certainty in the balance between benets vs. harms (e.g., net harms) of

this patient-care strategy.

• The majority of well-informed patients would most likely not choose this patient-care strategy, compared to

alternative patient-care strategies or no treatment.

STRONG

• There is a high degree of clinical certainty in the net harms of this patient-care strategy.

• The vast majority of well-informed patients would most likely not choose this patient-care strategy,

compared to alternative patient-care strategies or no treatment.

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

caregivers are nevertheless frequently wary to use this supple-

ment, due to concerns related to potential adverse effects on

growth hormone regulation (10 mg dose),

and on reproductive

function/development (3 mg dose).

Possibly relevant to the

latter concern, Tanner stages were assessed serially in a ques-

tionnaire-based study involving children/adolescents (mean du-

ration ~3 years), in an effort to compare pubertal development

among those using melatonin (mean dose ~3 mg) during pre-

puberty to non-melatonin users in the general Dutch population

(controls).

No signicant group differences were detected.

4.3 Hypnotics

General adversities attributed to sedative-hypnotics (though

not specically among patients with CRSWDs) include in-

creased risks for falls, headaches, nausea, medication-med-

ication interactions, and drug dependence,

58,59

with elderly

patients at specic high risk.

60–62

Data regarding the use of

hypnotics specically among demented older adults (a popu-

lation of interest for this review, see section 5.4 in this paper)

are scarce,

but their cognitive and other vulnerabilities would

appear to place them at even greater risk than non-demented

elderly adults.

Benzodiazepines in particular are associated with an in-

creased incidence of confusion, impaired motor performance,

anterograde amnesia, daytime sleepiness, and physiologic

dependence.

The newer generation nonbenzodiazepine ben-

zodiazepine receptor agonists (e.g., zolpidem, zaleplon, eszop-

iclone) have shorter half-lives and fewer overall side effects,

but high quality data to support their use with demented older

adults are nonexistent.

63,64

Commonly used over-the-counter

antihistamines have very high rates of side effects, includ-

ing cognitive impairment, daytime somnolence, and anticho-

linergic responses.

Trazodone, a sedating antidepressant, is

widely used off-label as a hypnotic, despite the fact that there

is virtually no evidence-based data to support its efcacy

with older adults.

Moreover, it is associated with signicant

risks, including priapism, orthostatic hypotension, and car-

diac arrhythmias.

Finally, the off-label use of neuroleptics

for dementia-related behavioral disturbances (including sleep

disturbances) is associated with a “black box” warning, due to

increased mortality risks (approximately twofold higher than

that associated with placebo-treated patients), mostly due to

cardiovascular or infectious causes.

5.0 RECOMMENDATIONS FOR TREATMENTS OF

INTRINSIC CRSWDs

There were 8 different treatments, in addition to combi-

nation treatments, that were reviewed for the four intrinsic

CRSWDs included in this guideline. The strengths of the rec-

ommendations, for those intrinsic CRSWD treatments that

have recommendations, are shown in Table 5. The full recom-

mendation statements, including all GRADE components that

were considered when determining the direction and strength

of the recommendation, are shown in Table 6.

5.1 Recommendations for the Treatment of ASWPD

ASWPD is characterized by a stable advance (earlier tim-

ing) of the major sleep episode, such that habitual sleep onset

and offset typically occur two or more hours prior to required

or desired sleep times. Affected individuals complain of early

morning or maintenance insomnia and excessive evening

sleepiness. When allowed to maintain an advanced schedule,

sleep quality and quantity are improved.

5.1.1 Prescribed Sleep-Wake Scheduling for Patients with

ASWPD

Sleep-wake scheduling has only been described in one case

report, but favorably affected the predened CRITICAL out-

comes (SOT and SOffT, both subjective) in ASWPD.

No new

studies were identied.

In the report of a 62-year-old male, sleep times were ad-

vanced 3 hours every 2 days for 2 weeks and then stabilized at

the desired times, which were maintained at 5 months follow-

up. This treatment was designated as an OPTION in the 2007

Practice Parameters, but the current TF did not regard a single

case report as sufcient evidence for a recommendation.

There is insufcient evidence to support the use of pre-

scribed sleep-wake scheduling as a treatment for patients

with ASWPD (versus no treatment). No recommendation.

5.1.2 Timed Physical Activity/Exercise for Patients with

ASWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of timed physi-

cal activity or exercise as a treatment for patients with

ASWPD. No recommendation.

5.1.3 Strategic Avoidance of Light for Patients with ASWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of strategic avoid-

ance of light as a treatment for patients with ASWPD. No

recommendation.

5.1.4 Light Therapy for Patients with ASWPD

No treatment trials of light therapy in ASWPD have been

published since the 2007 Practice Parameters, which recom-

mended this therapy as an OPTION. Most of the previously

referenced studies

68–71

were not included for the current

analysis, as participants were not clearly diagnosed with

ASWPD. Discrete benets from this treatment are difcult

to ascertain given methodological limitations within the

two reviewed studies

72,73

(discussed further below), and the

cumulative level of evidence was VERY LOW (Appendix,

Table S1).

Only one randomized Advanced Sleep Phase Disorder

(ASPD)/ASWPD treatment trial was identied (also refer-

enced in the previously published Practice Parameters).

parallel group design was used to test 28 days of daily evening

exposure to a white broad-spectrum light (~265 lux) versus a

dim red light control (~2 lux) among 47 patients (mean age

70.0 ± 6.4 years). The light source consisted of a rice paper

shade over a vertical light tube, and the protocol instructed

subjects to sit within 1 meter of the light source, for 2–3 hours

in duration, ending 1 hour before habitual bedtime. There

were no signicant posttreatment group differences with

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respect to most predened CRITICAL outcomes, namely

circadian phase (urinary 6-sulfatoxymelatonin [aMT6s] acro-

phase), ISL (actigraphy and subjective), SOT (actigraphy and

subjective), SOffT (actigraphy and subjective), and TST (sub-

jective). Total sleep time (actigraphy) signicantly decreased

posttreatment within the active treatment group (mean differ-

ence 34.62 minutes [CI −0.96 to −68.28]), possibly due to a

nonsignicant delay in SOT. Importantly, while photosensors

attached to the light source indicated good compliance with

the scheduled light therapy on and off times, light exposure

data on wrist worn photometers suggested that, on average,

patients were only adjacent to the light source for about half

of the scheduled treatment duration. Nonetheless, the treat-

ment was well tolerated, and the majority of the patients who

received the white broad spectrum light source asked to keep

it for long-term personal use.

Given the low intensity of light used in this study, the TF

questioned the applicability of the results, and elected to ex-

pand the GRADE analysis to include a non-randomized trial

(Appendix, Table S1). A parallel group design study by

Campbell and colleagues

(also referenced in the previous

Practice Parameters) tested 12 days of a daily evening expo-

sure to bright white light (4,000 lux) versus a dim red light (~50

lux) control in 16 patients with ASWPD (mean age 70.4 ± 4.9

years). The light source consisted of two light boxes (proxim-

ity to source not specied), and therapy was for 2 hours in

duration, between 20:00 and 23:00 (ending before habitual

bedtime). The treatment signicantly delayed circadian phase

(CBT

Min

, mean difference 141.00 minutes [CI 26.10–255.90]),

and increased TST (PSG, mean difference 51.30 minutes [CI

2.69–99.91]), but both values crossed the threshold of the pre-

determined clinically signicant minimal change (see Table 2

and Appendix, Table S1). There were no signicant changes

in ISL, SOT, or SOffT (PSG) posttreatment relative to the con-

trol condition (Appendix, Table S1).

The results of studies that tested evening light therapy in

patients complaining of insomnia (not eligible for the current

review, as subjects were not discreetly diagnosed with AS-

WPD) are generally favorable. For example, in studies of pa-

tients with early-morning awakenings, evening light delayed

circadian timing,

70,71

delayed SOffT

and increased TST,

70,71

although positive effects were not always observed.

Eve-

ning light therapy also phase delayed circadian timing and

SOT in patients with sleep maintenance insomnia.

In other-

wise healthy older adults with sleep complaints, evening light

therapy delayed the DLMO, but there was no observed effect

on ISL and TST, while sleep timing remained xed by the

study protocol.

Table 5 —Overview of AASM recommendation status for Intrinsic CRSWD treatments

Treatment ASWPD DSWPD N24SWD ISWRD

Prescribed sleep-wake

scheduling

No Recommendation No Recommendation No Recommendation No Recommendation

Timed physical activity/

exercise

No Recommendation No Recommendation No Recommendation No Recommendation

Strategic avoidance of light No Recommendation No Recommendation No Recommendation No Recommendation

Light therapy 5.1.4a WEAK FOR (adults) No Recommendation No Recommendation

5.4.4a WEAK FOR

(elderly with dementia)

Sleep-promoting

medications

No Recommendation No Recommendation No Recommendation

5.4.5a STRONG AGAINST

(elderly with dementia)

Timed oral administration of

melatonin or agonists

No Recommendation

5.2.6.1a WEAK FOR

(adults with and without

depression)

5.2.6.2.1a WEAK FOR

(children/adolescents

without comorbidities)

5.2.6.2.2a WEAK FOR

(children/adolescents with

psychiatric comorbidities)

5.3.6.1a WEAK FOR

(blind adults)

No Recommendation

(sighted)

5.4.6.1a WEAK AGAINST

(elderly with dementia)

5.4.6.2a WEAK FOR

(children/adolescents with

neurologic disorders)

Wakefulness-promoting

medications

No Recommendation No Recommendation No Recommendation No Recommendation

Other somatic interventions No Recommendation No Recommendation No Recommendation No Recommendation

Combination treatments No Recommendation

No Recommendation

(adults)

5.2.9.2a WEAK FOR (light

therapy + multicomponent

behavioral interventions for

children/adolescents)

No Recommendation

5.4.9.1a WEAK AGAINST

(combination treatment

of light and melatonin for

demented, elderly patients)

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

Table 6—Recommendation statements for treatment of patients with intrinsic CRSWDs.

Treatment

(PICO Question) Recommendation Statement

Direction and

Strength of

Recommendation

Quality of

Evidence

Benets/

Harms

Assessment

Patients’ Values and

Preferences

Advanced Sleep-Wake Phase Disorder (ASWPD)

5.1.4 Light

therapy

(PICO Question 4)

5.1.4a The TF suggests that clinicians treat

adult ASWPD patients with evening light

therapy (versus no treatment)

WEAK FOR VERY LOW Benets

closely

balanced with

harms

The majority of patients

would use this treatment.

Delayed Sleep-Wake Phase Disorder (DSWPD)

5.2.6 Timed oral

administration

of melatonin or

agonists

(PICO Question 6)

5.2.6.1a The TF suggests that clinicians

treat DSWPD in adults with and without

depression with strategically timed melatonin

(versus no treatment)

WEAK FOR LOW Uncertainty in

the estimates

of benets/

harms

The majority of patients

would use this treatment.

5.2.6.2.1a The TF suggests that clinicians

treat children and adolescents with DSWPD

(and no comorbidities) with strategically timed

melatonin (versus no treatment)

WEAK FOR MODERATE Uncertainty in

the estimates

of benets/

harms

The majority of patients

would use this treatment,

with appropriate informed

consent from the patient

and caregiver.

5.2.6.2.2a The TF suggests that clinicians

treat children and adolescents with DSWPD

comorbid with psychiatric conditions with

strategically timed melatonin (versus no

treatment)

WEAK FOR LOW Uncertainty in

the estimates

of benets/

harms

The majority of patients

would use this treatment,

with appropriate informed

consent from the patient

and caregiver.

5.2.9 Combination

Treatments

5.2.9.2a The TF suggests that clinicians treat

children/adolescents with DSWPD with post-

awakening light therapy in conjunction with

behavioral treatments (versus no treatment)

WEAK FOR LOW Benets

outweigh

harms

The majority of patients

would use this treatment,

particularly with active

caregiver support.

Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD)

5.3.6 Timed oral

administration

of melatonin or

agonists

(PICO Question 6)

5.3.6.1a The TF suggests that clinicians

use strategically timed melatonin for the

treatment of N24SWD in blind adults (versus

no treatment)

WEAK FOR LOW Benets

outweigh

harms

The majority of patients

would use this treatment.

Irregular Sleep-Wake Rhythm Disorder (ISWRD)

5.4.4 Light

Therapy

(PICO Question 4)

5.4.4a The TF suggests that clinicians treat

ISWRD in elderly patients with dementia with

light therapy (versus no treatment)

WEAK FOR VERY LOW Benets

closely

balanced with

harms

The majority of well-

informed patients and/or

caregivers of would elect to

use this treatment.

5.4.5 Sleep-

promoting

medications

(PICO Question 5)

5.4.5a The TF recommends that clinicians

avoid the use of sleep-promoting medications

to treat demented elderly patients with

ISWRD (versus no treatment)

STRONG

AGAINST

NONE* Harms

outweigh

benets

The vast majority of well-

informed patients and/or

caregivers would NOT elect

to use this treatment.

5.4.6 Timed oral

administration

of melatonin or

agonists

(PICO Question 6)

5.4.6.1a The TF suggests that clinicians

avoid the use of melatonin as a treatment for

ISWRD in older people with dementia (versus

no treatment)

WEAK AGAINST LOW Harms

outweigh

benets

The majority of patients

and/or caregivers would

NOT elect to use this

treatment.

5.4.6.2a The TF suggests that clinicians use

strategically timed melatonin as a treatment

for ISWRD in children/adolescents with

neurologic disorders (versus no treatment)

WEAK FOR MODERATE Benets

outweigh

harms

The majority of patients

and/or caregivers would

elect to use this treatment.

5.4.9 Combination

treatments

5.4.9.1a The TF suggests that clinicians

avoid the use of light therapy combined with

melatonin in demented, elderly patients with

ISWRD (versus no treatment)

WEAK AGAINST VERY LOW Harms

outweigh

benets

The majority of patients

and/or caregivers would

NOT elect to use this

treatment.

* Although no randomized controlled trials have examined sleep-promoting medications for the treatment of ISWRD, other extant literature indicates that

administration of hypnotics to demented elderly patients increases risks of falls and other untoward outcomes (see separate “Harms and Adverse Effects”

section).

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5.1.4a The TF suggests that clinicians treat adult ASWPD

patients with evening light therapy (versus no treatment).

[WEAK FOR]

Summary: No treatment trials of light therapy in ASWPD

have been published since the 2007 Practice Parameters, which

recommended this therapy as an OPTION. The largest effects

were seen after a 12-day treatment of 2 hours of bright white

broad spectrum light (~4,000 lux) from 2 light boxes (proxim-

ity to source not specied), timed to occur daily between 20:00

and 23:00, and ending before habitual bedtime.

Nevertheless,

the overall quality of evidence derived from the analyses of

two publications

72,73

was VERY LOW (Appendix, Table S1),

with potential benets of light therapy closely balanced with

the harm/burden. Associated risks are minimal, as detailed

separately in the “Harms and Adverse Effects” section. Pa-

tients report reasonable compliance and high satisfaction with

this treatment,

and light boxes are available over the counter

in the U.S., at relatively affordable prices. Thus, the majority

of well-informed patients would choose light therapy versus

no treatment.

5.1.5 Sleep-Promoting Medications for Patients with ASWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of sleep-promot-

ing medications as a treatment for patients with ASWPD.

No recommendation.

5.1.6 Timed Oral Administration of Melatonin or Agonists for

Patients with ASWPD

The administration of a low dose of melatonin after early

morning awakenings and upon nal arising in the morning

was indicated as an OPTION for ASWPD in the 2007 Practice

Parameters, based on expert consensus alone. No new studies

were identied.

There is no evidence to support the use of melatonin

or agonists as a treatment for patients with ASWPD. No

recommendation.

5.1.7 Wakefulness-Promoting Medications for Patients with

ASWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of wakefulness-

promoting medications as a treatment for patients with

ASWPD. No recommendation.

5.1.8 Other Somatic Interventions for Patients with ASWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of other somatic

interventions as a treatment for patients with ASWPD. No

recommendation.

5.1.9 Combination Treatments for Patients with ASWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of combination

treatments for patients with ASWPD. No recommendation.

5.2 Recommendations for the Treatment of DSWPD

DSWPD is characterized by habitual sleep-wake timing that

is delayed, usually greater than two hours, relative to conven-

tional or socially acceptable timing. Affected individuals com-

plain of difculty falling asleep at a time required to obtain

sufcient sleep duration on a school or work night, and experi-

ence difculties arising at the required times. When allowed to

follow his or her preferred schedule, sleep quality and quantity

are typically reported as normal.

5.2.1 Prescribed Sleep-Wake Scheduling for Patients with

DSWPD

The previous recommendation was designated as an OP-

TION (specically with respect to chronotherapy, a prescribed

progressive delay of the sleep/wake schedule until the desired

schedule is reached), based upon two studies with adult partici-

pants.

75,76

The 1993 study by Ito and colleagues,

reviewed pre-

viously, was not included in the current analysis, as it did not

investigate discrete sleep outcomes, but instead incorporated

subjective assessments of global functioning. The 1981 study

by Czeisler and colleagues

was excluded due to a low number

of subjects (n = 5). There is one report of an adult DSWPD

patient who developed free-running circadian rhythms after

engaging in this treatment.

Although ineligible for current analyses, 3 studies were

published subsequent to availability of the previous Practice

Parameters that may bear relevance to the use of prescribed

sleep-wake scheduling (other than chronotherapy) as a ther-

apy for adolescent patients.

78–80

Two groups

79,80

described

potentially meaningful outcomes, but the parameters of inter-

est were different from those specically dened by the TF,

and, in the case of the de Sousa study,

all participants were

healthy adolescents (i.e., not aficted with DSWPD). Similarly,

the Sharkey group (2011) studied a cohort with subthreshold

DSWPD (the general CRSWD social/occupational impairment

criterion was not applied), such that participants did not meet

inclusion criteria for this review.

While a 6-day prescribed

advanced sleep schedule (with adjunctive strategic avoidance

of evening light) resulted in concomitant advances in DLMO,

the majority of participants exhibited decreased TST.

There is insufcient evidence to support prescribed sleep-

wake scheduling as a stand-alone treatment (versus no

treatment) for patients with DSWPD. No recommendation.

5.2.2 Timed Physical Activity/Exercise for Patients with

DSWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of timed physi-

cal activity or exercise as a treatment for patients with

DSWPD. No recommendation.

5.2.3 Strategic Avoidance of Light for Patients with DSWPD

No recommendation was made in the 2007 Practice Parameters.

A relevant open-label study was published subsequently, but

it did not meet inclusion criteria for the present analysis, as pre-

dened critical outcomes were not employed (i.e., solely submea-

sures from the Pittsburgh Sleep Quality Index were utilized).

Adult subjects with DSWPD + ADHD were instructed to wear

1211

Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

amber glasses that blocked wavelengths ≤ 530 nm “…from sun-

down until bedtime every evening,” for a minimum of 3 hours,

and for a period of 2 weeks. Concomitant instructions included

the use of only oor and table lamps (i.e., avoidance of overhead

lights) during the evening. If a participant awoke during the

night, he/she was instructed to don the glasses prior to light

exposure. In addition, subjects were given specic instructions

to avoid/minimize caffeine, nicotine, and alcohol. Outcomes

were compared to a weeklong baseline assessment period. As

determined by the Pittsburgh Sleep Quality Index, signicant

improvements in TST, ISL, and sleep quality were noted. In a

separate study potentially related to the treatment of DSWPD,

adult insomnia patients who wore “blue blocker” (< 550 nm)

glasses during the 3 hours prior to habitual bedtime demon-

strated improved subjective sleep quality

compared with the

placebo intervention (yellow-tinted glasses that blocked only

ultraviolet light). Importantly, there are no tangible risks asso-

ciated with these interventions.

There is insufcient evidence to support the use of stra-

tegic avoidance of light as a treatment for patients with

DSWPD (versus no treatment). No recommendation.

5.2.4 Light Therapy for Patients with DSWPD

The previously published recommendation was designated

as a GUIDELINE and was based on two studies.

28,83

The

Rosenthal study was not analyzed for current purposes due

to a lack of rigorously reported sleep-related outcomes.

The

Cole study

is included in a separate section (see Combination

Treatments, below). A separate open-label light therapy trial

was identied,

but ultimately rejected due to a small number

of subjects (n = 6). Only one study pertaining to adult DSWPD

populations has been published subsequent to the release of the

previous CRSWD Practice Parameters in 2007 (also reviewed

in the Combination Treatments section below).

There is insufcient evidence to support efcacy of post-

awakening light therapy (monotherapy) as a treatment for

DSWPD (versus no treatment). No recommendation.

5.2.5 Sleep-Promoting Medications for Patients with DSWPD

No recommendation was made in the 2007 Practice

Parameters.

There are isolated reports regarding the use of hypnotics

in DSWPD (typically as an adjunctive treatment with chrono-

therapy), but there is insufcient rigor in methodology for pur-

poses of evidence analysis.

75,86

Two reports describe DSWPD

patients’ resistance to the effects of traditional hypnotics.

87,88

Nevertheless, a laboratory-based study that imposed a 4-hour

phase advance on healthy subjects described sleep-related ben-

ets (PSG and subjective measures) with zolpidem.

There is insufcient evidence to support the use of sleep-

promoting medications as a treatment for patients with

DSWPD (versus no treatment). No recommendation.

5.2.6 Timed Oral Administration of Melatonin or Agonists for

Patients with DSWPD

5.2.6.1 Melatonin for adult patients with dswpd

The previously published recommendation was designated

as a GUIDELINE, and was supported by four studies.

27,90 –92

Two of these publications

91,92

did not meet inclusion criteria

for the present review, due to an insufcient number of sub-

jects,

or due to design and reporting limitations

that hin-

dered comparisons with the included investigations. One study

was published subsequent to availability of the previous Prac-

tice Parameters.

The three reviewed investigations provide

contradictory information regarding sleep/circadian-related

effects of melatonin among adults with DSWPD. Level of re-

viewed evidence: LOW (Appendix, Table S2).

In a randomized double-blinded placebo-controlled study

(parallel design, n = 11, mean age 28.2 ± 5.7 years

), Mundey

and colleagues utilized either 0.3 or 3.0 mg melatonin (versus

placebo) between 15:00–21:30 (1.5–6.5 hours before baseline

DLMO), with an advance in timing of 1 hour after 2 weeks, for

a total treatment duration of 29 days. No improvements in ac-

tigraphically determined sleep parameters were observed, and

our analysis demonstrated no group difference with respect

to the timing of DLMO

(Appendix, Table S2). As the pres-

ent review did not analyze outcomes relative to the timing of

melatonin administration, however, it is important to note that

the authors reported an inverse relationship between the tim-

ing of melatonin administration (irrespective of dose) and the

magnitude of DLMO phase advance, such that earlier timing

of the former (in relation to DLMO) resulted in greater phase

advances. No such correlation was identied with respect to

CBT

Min

(assessed only within the active treatment groups).

The Kayumov and Rahman studies (same investigative

group) demonstrated substantial select PSG-measured ben-

ets in sleep parameters (TST, ISL), but an afliated circadian

phase marker was not employed.

90,93

Solely the Mundey group

included such a measure. The Rahman study

(n = 20, ran-

domized, double-blind, placebo-controlled, crossover design,

mean age 30.8 ± 12.4 and 35.6 ± 14.0 years for females and

males, respectively) utilized 5 mg melatonin administered

between 19:00–21:00, for a period of 28 days. The Kayumov

study

(n = 20, same design/age distribution) used the same

dose, but scheduled it at 19:00 the rst week, between 19:00–

21:00 during the second and third weeks (according to sub-

jects’ preferences), and at a consistent time during the fourth

week (average chosen time 21:00). Analyses among a subset of

depressed patients from both studies (n = 28) demonstrated a

statistically signicant increase in TST (mean difference 41.44

minutes, [CI 13.19–69.70]), but the level of evidence was down-

graded due to inconsistency and imprecision (see Figure 2 and

Tables 2 and 3). More denitive results were obtained from an

analysis of a subset of non-depressed patients from the Rah-

man study (Appendix, Table S2) (n = 12, TST = 56.00 minutes

[CI 48.51–63.49]).

ISL was polysomnographically assessed with the same

subcategorization of groups. Among the depressed subgroup

(n = 28), sleep latency decreased by 43.52 minutes [CI −34.45

to −52.60] (see Figure 3 and Appendix, Table S2). Among

the non-depressed subjects from the Rahman study (n = 12),

sleep latency decreased by 37.70 minutes [CI −31.75 to −43.65]

(Appendix, Table S2).

5.2.6.1a The TF suggests that clinicians treat DSWPD

in adults with and without depression with strategically

timed melatonin (versus no treatment). [WEAK FOR]

1212

Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

RR Auger, HJ Burgess, JS Emens et al.

Summary: The previously published recommendation was

designated as a GUIDELINE. The overall quality of evidence

from the analyses of the three accepted/reviewed studies

27,90,93

was LOW (Figures 2 and 3 and Appendix, Table S2), and

data regarding the sleep/circadian-related effects of melatonin

were contradictory. Positive results were obtained with a 5 mg

dose timed between 19:00–21:00 (no circadian-based timing),

for a period of 28 days.

90,93

The Rahman study

was the sole

study identied subsequent to publication of the previous Prac-

tice Parameters. Taking into account the discussion regarding

potential safety/adverse effects of melatonin (see separate

“Harms and Adverse Effects” section), the benets/harms ratio

remains uncertain, but clinical experience suggests frequent

acceptance of this treatment among adults versus no treatment.

5.2.6.2. Melatonin for children/adolescents with dswpd

5.2.6.2.1 Melatonin for children/adolescents with DSWPD and no

comorbidities

No studies were previously reviewed which directly ad-

dressed the pediatric/adolescent population. Strategically

timed melatonin at the dose specied below is effective for

children/adolescents with DSWPD. Level of reviewed evi-

dence: MODERATE (Appendix, Table S3).

One randomized, placebo-controlled double-blinded study

was reviewed (unpublished raw data provided courtesy of au-

thor).

Participants ranged in age from 6–12 years. The three

active treatment groups received melatonin at dosages of 0.05

mg/kg, 0.1 mg/kg, and 0.15 mg/kg, with respective mean doses

of 1.6 ± 0.4 mg (n = 16), 2.9 ± 0.9 mg (n = 19), and 4.4 ± 1.0 mg

(n = 18). Seventeen participants were allocated to the placebo

group. The duration of treatment was 6 nights, with instruc-

tions to take melatonin 1.5–2.0 hours prior to habitual bedtime

(unclear if equivalent to habitual sleep onset time), with con-

sistent nightly timing.

The data of 64 participants were utilized for actigraphy/

sleep-related analyses. With respect to CRITICAL outcomes,

sleep onset time favorably advanced in comparison to placebo

among the 0.1 and 0.15 mg/kg groups (mean difference −33.70

minutes [CI −10.95 to −56.46] and −42.77 minutes [CI −21.77

to −63.78], respectively), but the condence interval of the

value associated with the lower dose crossed the threshold of

the predetermined clinically signicant minimal change (see

Table 2 and Appendix, Table S3). Statistical differences were

not observed with the 0.05 mg/kg group. Nevertheless, sleep

latency improved among all three groups (statistical and clini-

cally signicant differences) in comparison to placebo (mean

difference −38.39 minutes [CI −18.24 to −58.53], −44.24 min-

utes [CI −24.04 to −64.44], and −43.80 minutes [CI −24.06 to

−63.54], respectively, in order of ascending dosage).

With respect to DLMO analyses, no signicant differences

were noted among any of the three treatment groups in com-

parison to placebo. However, the authors separately calculated

individualized outcomes based upon melatonin use in relation

to both DLMO (circadian) and clock time of administration

(TOA). These analyses were not compatible with the Review

Manager software used in this project. Data were depicted

solely within gures (i.e., no raw representation). As with the

previously discussed Mundey study,

a positive relationship

between DLMO phase advances and an earlier circadian TOA

was described (no relationship observed with respect to clock

TOA), but no differences were observed between the various

melatonin dosage groups. On the contrary, no advantages be-

tween clock versus circadian TOA were demonstrated in rela-

tion to sleep onset and initial sleep latency times.

5.2.6.2.1a The TF suggests that clinicians treat children

and adolescents with DSWPD (and no comorbidities)

with strategically timed melatonin (versus no treatment).

[WEAK FOR]

Figure 2—Meta-analysis of data for PSG determined TST in response to melatonin treatment of adult patients with DSWPD

and comorbid depression.

Figure 3—Meta-analysis of data for PSG determined ISL in response to melatonin treatment of adult patients with DSWPD

and comorbid depression.

1213

Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

Summary: This is a new recommendation in comparison to

the prior Practice Parameter, as no studies were previously re-

viewed which directly addressed the pediatric/adolescent pop-

ulation. The level of reviewed evidence from a singular study

was MODERATE (Appendix, Table S3). Optimal results

were obtained with a dose of 0.15 mg/kg, taken 1.5–2.0 hours

prior to habitual bedtime, for 6 nights. Although no serious

adverse reactions have been described in relation to melatonin

use to date, relevant concerns have been raised by select stud-

ies with respect to the pediatric/adolescent population,

and

rigorous long-term data are lacking (see separate “Harms and

Adverse Effects” section). As such, the benets/harms assess-

ment is uncertain. Clinical experience nevertheless supports

frequent acceptance of this therapy versus no treatment, with

appropriate informed consent from the patient and caregiver.

5.2.6.2.2 Melatonin for children/adolescents with DSWPD and psychi-

atric comorbidities

This is a new recommendation in comparison to the previ-

ous Practice Parameters, as no studies specically addressed

this patient population. Strategically timed fast-release mela-

tonin at dosages ranging from 3–5 mg may be effective for

children/adolescents with DSWPD and psychiatric comorbidi-

ties. Level of reviewed evidence: LOW (Appendix, Table S4)

Two randomized, placebo-controlled studies by the same

group examined the use of melatonin for DSWPD among chil-

dren/adolescents with various psychiatric comorbidities (all

were diagnosed with ADHD).

95,96

Participants aged 6–12 years

received fast-release melatonin (one of several instances where

melatonin formulation was specied) for 4 weeks at dosages

of 3 or 5 mg, at either 18:00 or 19:00. The more recent study

based dosage on weight (3 mg if < 40 kg; 5 mg if > 40 kg,

taken at 19:00), while the earlier protocol

uniformly provided

5 mg at 18:00. Combined analyses (n = 132) revealed an ad-

vance in DLMO of nearly 1 hour in comparison to placebo

(mean difference −54.22 minutes [CI −31.67 to −76.78]) (see

Figure 4). Actigraphically assessed sleep-onset time (n = 130)

also advanced (mean difference −36.57 minutes [CI −16.96 to

−56.18]) (see Figure 5). Other actigraphically derived sleep pa-

rameters were obtained only in the more recent study (n = 105).

A signicant decrease in ISL was detected (mean difference

−18.70 minutes [CI −7.01 to −30.39], but the condence interval

crossed the threshold of the predetermined clinically signi-

cant minimal change (see Table 2 and Appendix, Table S4).

No signicant group differences were noted with respect to

TST.

Previously published subjective assessments failed to

demonstrate signicant group differences in TST (n = 31), ISL

(n = 33), or sleep-onset (n = 33) or offset (n = 32) times.

Although not accepted for analysis for this review due to con-

cerns regarding patient heterogeneity, a randomized placebo-

controlled study by Wasdell and colleagues (which contained

an admixture of DSWPD and insomnia patients) explored the

effects of 5 mg controlled-release melatonin (10 days) among

approximately 50 children with neurodevelopmental disabili-

ties (ages 2–18, mean 7.4 years).

Melatonin was administered

20–30 minutes prior to the caregiver determined desired time

of sleep onset. Signicant improvements were observed in sub-

jectively and actigraphically recorded TST, ISL, and clinician-

and caregiver-assessed overall sleep disorder severity and

other functional and health dimensions. During the 3-month

open-label phase of the trial, escalation of the melatonin dos-

age provided no denitive benets. A separate follow-up open-

label prospective study (duration up to 3.8 years) demonstrated

continued caregiver-reported benets on sleep, overall health,

behavior, education, and learning.

5.2.6.2.2a The TF suggests that clinicians treat children

and adolescents with DSWPD comorbid with psychiatric

conditions with strategically timed melatonin (versus no

treatment). [WEAK FOR]

Figure 5—Meta-analysis of data for actigraphically-determined SOT in response to melatonin treatment of children/

adolescents with DSWPD and comorbid psychiatric conditions.

Figure 4—Meta-analysis of data for DLMO in response to melatonin treatment of children/adolescents with DSWPD and

comorbid psychiatric conditions.

1214

Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

RR Auger, HJ Burgess, JS Emens et al.

Summary: This is a new recommendation in comparison to

the previous Practice Parameters, as no studies specically ad-

dressed this patient population. The overall quality of evidence

from the analyses of the two reviewed studies

95,96

was LOW

(see Figures 4 and 5 and Appendix, Table S4). A fast-release

formulation of melatonin was utilized, with dosages ranging

from 3–5 mg, taken between 18:00–19:00 (no circadian-based

timing), for 4 weeks. In the pooled analysis, actigraphically

assessed sleep onset time advanced in conjunction with an

advance in the circadian phase marker (DLMO). Although no

serious adverse reactions have been described in relation to

melatonin use to date, relevant concerns have been raised by

select studies with respect to the pediatric/adolescent popu-

lation, and rigorous long-term data are lacking (see separate

“Harms and Adverse Effects” section). As such, the benets/

harms assessment is uncertain. Clinical experience neverthe-

less supports frequent acceptance of this therapy versus no

treatment, with appropriate informed consent from the patient

and caregiver.

5.2.7 Wakefulness-Promoting Medications for Patients with

DSWPD

No recommendation was made in the 2007 Practice Param-

eters, and no new studies were identied.

There is no evidence to support the use of wakefulness-

promoting medications as a treatment for patients with

DSWPD. No recommendation.

5.2.8 Other Somatic Interventions for Patients with DSWPD

In the previous Practice Parameters, oral vitamin B12 ther-

apy was described as “not indicated,” designated at the GUIDE-

LINE level. No subsequent relevant studies (involving B12 or

separate somatic interventions) have been published. There

is no clear evidence of benet from oral vitamin B12 among

adults with DSWPD. Level of reviewed evidence: VERY LOW

(Appendix, Table S5).

In a multicenter study

that contained predominantly adult

DSWPD patients (n = 50, mean age 26.8 ± 1.3 years), partic-

ipants received 3 mg total daily dose of vitamin B12 (three

times daily divided dosing) versus placebo (double-blinded)

for a period of 4 weeks. No clinically signicant differences

were observed with respect to subjectively assessed TST and

SOT (see Table 2 and Appendix, Table S5). Remaining sleep

parameters were not compatible with the TF’s predened clini-

cal outcomes (ISL was evaluated according to a 5-point Likert

scale).

There is insufcient evidence to support the use of oral

vitamin B12 (and no evidence to support alternate somatic

interventions) among patients with DSWPD (versus no

treatment). No recommendation.

5.2.9 Combination Treatments for Patients with DSWPD

Combination treatments for DSWPD were not addressed

separately in the previous Practice Parameters and associated

review papers, but one of the reviewed studies

was addressed

in the singular light therapy category. The combination treat-

ments sections throughout the paper contain studies that ex-

plicitly denote dual treatment interventions, although the

TF acknowledges that other reviewed studies may have also

employed multicomponent treatment strategies, but failed to

mention or emphasize their nature in the published method-

ologies or to include proper controls for all components of the

treatment.

5.2.9.1. light/coMbination treatMents for adults with

dswpd

There is no evidence to support efcacy of light therapy

(provided by means other than a “light box”) in association

with concomitant behavioral instructions among adults. Level

of reviewed evidence: VERY LOW (Appendix, Table S6).

In a randomized parallel clinical trial (n = 54) involving

adults (mean age 25 ± 6 years) with DSWPD, Cole and col-

leagues (2002)

used a light mask that exposed participants to

2700 lux of white broad spectrum light on closed eyelids (about

57 lux at the cornea) for a period of 26 days, and compared it

to an inactive condition (0.1 lux of red light, estimated corneal

illuminance = 0.007 lux). Light therapy commenced (at an in-

tensity of < 0.01 lux) 4 hours before the scheduled rise time,

proceeded with ramped intensity for 1 hour, and remained at

full brightness until arising. Volunteers were not informed of

the hypotheses of the study and were blinded to the treatment

received by the other group. The study personnel who inter-

acted with participants and scored data were also blind to treat-

ment assignments.

Both groups received concomitant behavioral instructions.

Subsequent to the rst 2 treatment days, subjects were asked to

advance both bedtime and time of arising (in equal measure) on

a daily basis, to achieve a cumulative advance of at least 1 hour

per week (≤ 15 minutes daily, unless he/she experienced spon-

taneous awakening > 15 minutes ahead of schedule 2 days in a

row). Subjects were also asked to stop advancing sleep if he/she

achieved a preselected target wakeup time, but were allowed

to change the target time if he/she wished. Participants were

urged to avoid naps during the treatment interval, and were

provided specic instructions to minimize late-afternoon and

evening light exposure on all treatment days. Specic interven-

tions included shading of windows between 17:00 and dusk and

utilization of dark wraparound form-tting goggles (2% trans-

mittance) if necessary to go outdoors during this time interval.

Subjects were also instructed to use the minimum practical

amount of articial room light from 17:00 to bedtime.

As determined by the acrophase of aMT6s excretion, there

were no group phase differences. Similarly, there were no dif-

ferences in (predominantly actigraphically measured, n = 2

sleep logs) sleep onset or offset times. When the group was

subdivided according to whether the baseline acrophase was

later or earlier than 06:00 (n = 23 and n = 22, respectively, used

as a measure to divide groups by the degree to which they were

physiologically delayed), signicant differences were noted

solely for the former group, but the condence interval crossed

the threshold of the predetermined clinically signicant mini-

mal change (mean difference −83.00 minutes in comparison to

the inactive condition [CI −8.09 to −157.91]) (see Table 2 and

Appendix, Table S6). No signicant differences were noted

with respect to actigraphically determined sleep onset and off-

set times among either subgroup. The light mask was never-

theless described as well tolerated, with little (actigraphically

measured) sleep disturbance.

1215

Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

A separate group

performed a randomized controlled trial

of 7 days duration (n = 18, mean age 28.2 ± 10.6 years) using

post-awakening morning blue light in association with a grad-

ually advancing sleep/wake schedule. The portable source con-

tained light-emitting diodes (LEDs; 470 nm peak wavelength

with irradiance of 65 μW/cm

) attached to the lower rims of

spectacle frames, approximately 15 mm from the cornea, for

a duration of 2 hours, immediately after arising. While a bed-

time was not prescribed, subjects were instructed to advance

wake times by 30 minutes daily. The presence or absence of

blinding procedures was not specied. As compared to the

control group (lighting exposure unspecied), DLMO ad-

vanced by 2.53 hours (reported verbally and depicted in a g-

ure). However, there were no group differences in subjectively

assessed TST, SOT, or SOffT. Among other design limitations,

many details were missing with respect to methodology, and

there was high imprecision in the reported results.

Despite the present uncertainty as to benets, there are few

major risks associated with a trial of one of these “non-light

box” interventions. A review of adverse effects associated

with light interventions in general is addressed elsewhere (see

“Harms and Adverse Effects” section). It is interesting that the

light mask worn during the sleep episode in the Cole protocol

was well tolerated, with little (actigraphically measured) sleep

disturbance, as compliance with post-awakening light therapy

can be poor.

A laboratory-based study from Figueiro and Rea shows

promise for future “light masks” in the treatment of CRSWDs,

based upon optimal eyelid transmittance using green LEDs

(max wavelength of 527 nm) and individualized dose assess-

ments to predict optimal circadian benet.

Particularly rel-

evant to the discussion of combination therapies, at least three

laboratory-based studies among healthy adults describe a

synergistic effect (with respect to circadian phase advances)

when strategically timed light and melatonin therapy are used

together.

100–102

In addition, although physiologic phase assess-

ments were not employed, a separate case series described suc-

cess with this treatment combination among DSWPD patients

in the eld (age range 15–60 years). Three milligrams melatonin

was taken 2 hours prior to desired bedtime in conjunction with

either outdoor or 5000 lux white broad spectrum light exposure,

for a minimum of 30 minutes, between 06:00–08:00. During a

median follow-up period of 6.4 weeks, 82% reported improve-

ments of sleep patterns, with a mean sleep phase advance of ap-

proximately 2 hours.

103

Reported outcomes were unfortunately

not compatible with those selected by the TF for this review.

There is insufcient evidence to support the use of novel

forms of light therapy (i.e., via means other than a “light

box”), in association with concomitant behavioral instruc-

tions among adults with DSWPD (versus no treatment). No

recommendation.

5.2.9.2 light/coMbination treatMents for children/

adolescents with dswpd

Post-awakening light therapy in conjunction with behav-

ioral instructions is effective among adolescents with DSWPD,

but a physiologic circadian correlate is lacking. Level of re-

viewed evidence: LOW (Appendix, Table S7). This is a new

recommendation, based both upon the novel cohort (solely

children/adolescents) and light/behavioral multicomponent

interventions.

One non-blinded randomized controlled trial

104

was identi-

ed (n = 40), composed of adolescents aged 13–18 (mean ages

14.7 ± 1.7 and 14.7 ± 1.8 years in the active and control groups,

respectively). The minority of participants (20%) had mental

health comorbidities, and was spread evenly across the two

groups. Over a period of 8 weeks, active subjects (n = 23) were

exposed to either post-awakening natural sunlight (when avail-

able) or a broad spectrum lamp (~1000 lux, proximity to source

not specied) for ≥ 30 minutes (2 hours maximum), with the

time of administration advanced 30 minutes daily from “natu-

ral” wake time, until a target time of 06:00 was reached (3–5

weeks). Light therapy was subsequently discontinued and a reg-

ular rise time between 06:30–07:30 was advised. Concomitant

multicomponent behavioral education/interventions (includ-

ing instructions to “reduce evening light”) were provided in

six 45–60 minute sessions (with parental involvement), either

weekly (rst 4 sessions) or biweekly (last 2 sessions). Compli-

ance was monitored with sleep diaries, but afliated data were

not provided. An objective measure was not employed to mea-

sure light therapy compliance specically. The control group

was designated to a waitlist (n = 17).

Solely completed participants’ data were analyzed (i.e. an

intention-to-treat analysis was not undertaken). With respect

to CRITICAL outcomes during weekday assessments, sig-

nicant differences were detected with respect to subjective

TST (mean difference 72.00 minutes [CI 37.35 to 106.65]), and

ISL (mean difference −43.10 minutes [CI −22.46 to −63.74]).

Sleep onset and offset times also demonstrated signicant

group differences, but the condence interval crossed the

threshold of the predetermined clinically signicant minimal

change (mean difference −42.00 minutes [CI −2.74 to −81.26]

and −23.00 minutes [CI −0.87 to −45.13], respectively) (see

Table 2 and Appendix, Table S7). Weekend assessments

demonstrated benecial signicant differences for sleep onset

times (mean difference −93.9 minutes [CI −49.09 to −138.71]).

Signicant favorable differences were also noted with respect

to ISL and sleep offset times, but the condence interval again

overlapped the threshold of the predetermined clinically sig-

nicant minimal change (mean difference −26.5 minutes [CI

−4.37 to −48.63] and −51.0 minutes [CI −10.82 to −91.18], re-

spectively). No weekend differences were noted for TST. With

the exception of weekday sleep offset times, 6-month follow-

up assessments (n = 15) revealed no signicant differences in

comparison to the values observed immediately posttreatment.

5.2.9.2a The TF suggests that clinicians treat children

and adolescents with DSWPD with post-awakening light

therapy in conjunction with behavioral treatments (versus

no treatment). [WEAK FOR]

Summary: This is a new recommendation, based both upon

the novel cohort (solely children/adolescents) and light/behav-

ioral multicomponent interventions. The level of reviewed evi-

dence

104

was LOW (Appendix, Table S7), and solely weekday

data were considered with respect to determination of the rec-

ommendation, as this information is presumably most relevant

in the clinical setting. Light therapy occurred via exposure to

natural sunlight (when available), or with use of a white broad

1216

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RR Auger, HJ Burgess, JS Emens et al.

spectrum lamp (~1000 lux, proximity to source not specied),

for ≥ 0.5 hours (2 hours maximum), with the time of adminis-

tration advanced by 0.5 hours daily from “natural” wake time,

until a target time of 06:00 was reached. Light therapy was sub-

sequently discontinued, and behavioral interventions ensued.

Follow-up data are promising. Overall, a benets/harms ratio

analysis favors a trial of treatment, as children/adolescents with

DSWPD represent a particularly challenging patient population

(for a multitude of reasons), and the suggested interventions

pose no apparent safety concerns (see separate “Harms and Ad-

verse Effects” section). Clinical experience suggests that mo-

tivated patients would accept this treatment option versus no

treatment, particularly with active caregiver support.

5.3 Recommendations for the Treatment of N24SWD

N24SWD occurs when the hypothalamic circadian pace-

maker fails to entrain (synchronize) to the 24-hour day. As a

result, individuals can suffer from periodic nighttime insom-

nia and daytime somnolence as the circadian rhythms of sleep

propensity and alertness drift in and out of synchrony with the

24-hour day.

The condition primarily occurs in blind individu-

als, and at least 50% of the totally blind (i.e., those with no light

perception) are thought to suffer from the disorder.

105

While the

etiology in the blind is a loss of photic input to the pacemaker,

106

the pathophysiology among sighted individuals is unknown.

As stated above, entrainment status was uniquely utilized as

an outcome measure, as it physiologically denes this disorder

(just as elevated blood pressures characterize essential hyper-

tension). This was the sole outcome variable rated as CRITI-

CAL for N24SWD.

5.3.1 Prescribed Sleep-Wake Scheduling for Patients with

N24SWD

The previously published Practice Parameters

recom-

mended prescribed sleep-wake scheduling at an OPTION

level, noting that it may be a useful method to improve the

entrainment of circadian rhythms among sighted patients with

N24SWD. However, this guideline was created in the absence

of discrete evidence, as there have been no published trials

among sighted or blind patients.

There is some evidence that sleep timing (independent of

the timing of light exposure) is able to reset the circadian pace-

maker in humans,

20,107–109

and prescribed sleep-wake schedul-

ing therefore represents a potential therapeutic intervention

for N24SWD. However, this evidence is indirect, as data were

culled from basic science experiments conducted among non-

clinical populations.

There is no evidence to support the use of prescribed

sleep-wake scheduling in patients with N24SWD. No

recommendation.

5.3.2 Timed Physical Activity/Exercise for Patients with

N24SWD

There was no recommendation in the previous Practice Param-

eters

regarding timed physical activity/exercise as a treatment

for patients with N24SWD. Physical activity has been demon-

strated to reset the timing of the circadian pacemaker among

healthy subjects

110

and therefore represents another potential

therapy. Indeed, the circadian pacemaker can be entrained in

blind individuals in the absence of circadian photoreception.

111

As with prescribed sleep-wake scheduling, however, there have

not been any published trials. The evidence is therefore indirect

and insufcient to serve as the basis of a recommendation.

There is no evidence to support the use of timed physi-

cal activity or exercise in patients with N24SWD. No

recommendation.

5.3.3 Strategic Avoidance of Light for Patients with N24SWD

There is one case report that includes strategic avoidance of

light, and it is included below in the combination treatments

section.

112

The previous Practice Parameters

provided no per-

tinent recommendations.

There is no evidence to support the use of strategic avoid-

ance of light (as monotherapy) in patients with N24SWD.

No recommendation.

5.3.4 Light Therapy for Patients with N24SWD

The previous Practice Parameters recommended this treat-

ment at an OPTION level (for sighted individuals), based on

5 case series/reports,

112–116

all composed of 1–2 subjects. The

small numbers of study participants prevented inclusion for the

present report, and no studies have been published subsequently.

There is some experimental evidence that light is capable of

resetting the circadian pacemaker in the absence of conscious

light perception,

117

and most blind individuals who retain such

photic input to the circadian pacemaker would not be expected

to have N24SWD. However, some such individuals may have

insufcient exposure to light to maintain entrainment and

therefore timed light exposure may be a potential therapeu-

tic intervention in a subset of blind individuals with N24SWD.

However, as noted, there have been no studies that examined

this question.

There is insufcient evidence to support the use of light

therapy in patients with N24SWD (versus no treatment).

No recommendation.

5.3.5 Sleep-Promoting Medications for Patients with N24SWD

The previous Practice Parameters did not make any rec-

ommendation for the use of sleep-promoting medications in

N24SWD, and no new studies were identied.

There is no evidence to support the use of sleep-

promoting medications in patients with N24SWD. No

recommendation.

5.3.6 Timed Oral Administration of Melatonin or Agonists for

Patients with N24SWD

5.3.6.1 Melatonin for blind adult patients with n24swd

The previously published recommendation was designated

at the GUIDELINE level,

based upon 4 case reports

118–121

and

5 small observational studies.

122–126

Some of these studies, and

others, have examined important treatment parameters and

outcomes, including dose,

125,127,128

phase angle of entrainment,

126

and circadian time of administration,

129

but many were small,

often uncontrolled trials. Three placebo-controlled, crossover

studies from the previous Practice Parameters were eligible for

the current review,

122–124

and, despite the relatively large odds

ratio, the overall level of evidence for the CRITICAL outcome

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

(circadian entrainment) was LOW (Appendix, Table S8), as

the data are from small observational investigations.

Sack and colleagues (n = 7, mean age 47.3 ± 5.0 years) ad-

ministered 10 mg of melatonin 1 hour prior to preferred bed-

time,

123

while Lockley et al. (n = 7, mean age 44.6 ± 8.4 years)

122

and Hack et al. (n = 10, mean age 48.2 ± 12.5 years)

124

adminis-

tered 5 mg and 0.5 mg of melatonin, respectively, at 21:00. The

duration of treatment for these studies was 26–81 days. Re-

sults (excluding subjects without placebo control or complete

CRITICAL outcome data) were combined for meta-analysis

of entrainment as a dichotomous outcome (Yes/No), using the

Mantel-Haezel test (see Figure 6 and Appendix, Table S8).

The odds ratio for entrainment was 21.18 [CI 3.22–39.17]. In

other words, the likelihood of entrainment with melatonin

was ~21 times higher in comparison to placebo. Although the

evidence level can only be graded as LOW due to the fact that

these are small observational studies, this is the best evidence

to date that melatonin is an effective treatment for N24SWD.

Taken together, these placebo-controlled studies represent the

largest number of N24SWD patients whose entrainment status

was assessed subsequent to melatonin treatment.

5.3.6.1a The TF suggests that clinicians use strategically

timed melatonin for the treatment of N24SWD in blind

adults (versus no treatment). [WEAK FOR]

Summary: This recommendation was designated at the

GUIDELINE level (for the blind) in the previous Practice Pa-

rameters.

Only 3 studies

122–124

met inclusion criteria for the

present analysis and the level of evidence from these small

trials was LOW (Figure 6 and Appendix, Table S8). Doses

ranged between 0.5–10.0 mg, and were administered either

1 hour prior to preferred bedtime, or at a xed clock hour

(21:00), for a period of 26–81 days. Patient preference would

be expected to favor the use of easily obtained and inexpensive

melatonin that requires once daily dosing. No serious adverse

reactions to melatonin have been described to date (see sepa-

rate “Harms and Adverse Effects” section), and therefore the

benets of use appear to outweigh any potential harms. A ma-

jority of well-informed patients and caregivers would therefore

accept this treatment option versus no treatment.

5.3.6.2 Melatonin for sighted patients with n24swd

The recommendation for sighted individuals was provided

at an OPTION level in the previous Practice Parameters,

based upon 4 case series.

115,130–132

None of these studies were

eligible for the current review, based upon insufcient num-

bers of subjects.

There is insufcient evidence to support the use of mela-

tonin among sighted patients with N24SWD (versus no

treatment). No recommendation.

5.3.7 Wakefulness-Promoting Medications for Patients with

N24SWD

The previous Practice Parameters did not make any per-

tinent recommendations regarding the use of wakefulness-

promoting medications in N24SWD, and no new studies were

identied.

As noted above, both sleep and activity have the potential

to reset the circadian pacemaker and therefore it is reasonable

to think that medications that promote either sleep or wakeful-

ness might be useful in the treatment of this disorder, either by

entrainment of the biological clock or by improving alertness

and sleep when individuals are sleeping out of synchrony with

the circadian pacemaker. Similar to sleep-wake scheduling

and physical activity however, there have not been any studies

of either of these approaches in N24SWD.

There is no evidence to support the use of wakefulness-

promoting medications in patients with N24SWD. No

recommendation.

5.3.8 Other Somatic Interventions for Patients with N24SWD

The previous Practice Parameters cited “insufcient evi-

dence” to support the use of oral vitamin B12 for use in sighted

individuals with N24SWD (OPTION), based on 2 open-label

case reports.

133,134

No studies have since been published per-

taining to the use of vitamin B12 (or other alternate somatic

interventions) for N24SWD.

There is insufcient evidence to support the use of oral

vitamin B12 (and no evidence to support alternate somatic

interventions) among patients with N24SWD (versus no

treatment). No recommendation.

5.3.9 Combination Treatments for Patients with N24SWD

The previous Practice Parameters did not discuss the use of

combination treatments in N24SWD. There are 4 uncontrolled

case reports involving a combination of treatments in sighted

individuals with N24SWD.

112,116,135,136

However, these studies

did not meet inclusion criteria for the present review.

Figure 6—Meta-analysis of evidence for entrainment as a result of melatonin treatment of blind adult patients with N24SWD.

1218

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RR Auger, HJ Burgess, JS Emens et al.

There is insufcient evidence to support the use of com-

bination treatments in patients with N24SWD (versus no

treatment). No recommendation.

5.4 Recommendations for the Treatment of ISWRD

ISWRD is diagnosed when patients exhibit no clear cir-

cadian pattern of sleep-wake behavior. Aficted individuals

demonstrate wakefulness during conventional sleeping hours

and bouts of sleep during the day.

The condition is observed

most commonly among patients with neurodevelopmental or

neurodegenerative disorders, and can pose particular chal-

lenges for caregivers.

5.4.1 Prescribed Sleep-Wake Scheduling for Patients with

ISWRD

There was no recommendation in the previous Practice

Parameters regarding prescribed sleep-wake scheduling as a

stand-alone treatment for patients with ISWRD, and no new

studies were identied. However, prescribed schedules have

been tested in combination with other modalities (see section

5.4.9, “Combination Treatments”).

There is no evidence to support the use of prescribed

sleep-wake scheduling as a stand-alone treatment for pa-

tients with ISWRD. No recommendation.

5.4.2 Timed Physical Activity/Exercise for Patients with

ISWRD

There was no recommendation in the previous Practice Pa-

rameters regarding timed physical activity/exercise as a sole

treatment for patients with ISWRD, and no new studies were

identied. However, scheduled activity has been used in com-

bination with other modalities (see section 5.4.9, “Combination

Treatments”).

There is no evidence to support the use of timed physical

activity or exercise as a stand-alone treatment for patients

with ISWRD. No recommendation.

5.4.3 Strategic Avoidance of Light for Patients with ISWRD

There was no recommendation in the previous Practice Pa-

rameters regarding strategic avoidance of light as a treatment

for patients with ISWRD, and no new studies were identied.

There is no evidence to support the use of strategic avoid-

ance of light as a treatment for patients with ISWRD. No

recommendation.

5.4.4 Light Therapy for ISWRD in Elderly Patients with

Dementia

In contrast to the present review, the 2007 Practice Param-

eters

did not separate ISWRD treatment recommendations by

patient subgroup. The section that follows (and other sections)

is subcategorized as warranted.

The recommendation in the 2007 Practice Parameters was

designated as an OPTION, but only one

137

of the previously

reviewed studies

138–145

and one new study

146

met inclusion cri-

teria for the current document. Although neither demonstrated

improvements in CRITICAL outcomes, one

137

showed that

light therapy improved behavioral symptoms, an area of sig-

nicant clinical importance. The cumulative level of analyzed

evidence was VERY LOW (Appendix, Table S9).

Both reviewed light therapy studies examined institutional-

ized elderly subjects with dementia.

137,146

In their randomized

clinical trial of 50 nursing home patients (mean age 86 ± 8

years), Dowling and colleagues compared 60 minutes of light

therapy scheduled from 09:30–10:30 (1.5 hours after the nurs-

ing home’s set rise time) 5 days per week for a period of 10

weeks, to a dim-light control condition consisting of indoor

light of 150–200 lux.

146

Bright light was delivered via white

broad-spectrum light boxes, positioned on tables and located

approximately 30 to 34 inches from participants’ eyes. Light

levels in the direction of gaze were monitored for each partici-

pant during each treatment session to maintain levels > 2500

lux. At the end of the intervention, average actigraphically

measured TST did not differ between active and control groups.

A second open-label study tested light therapy of 2 hours du-

ration between 09:00–11:00 among 14 patients (mean age 75

years, range 61–83) with sleep disturbances. Patients were

treated for 4 weeks with white broad-spectrum tabletop light

boxes that produced 3000–5000 lux and were positioned at a

distance of 1 meter from the participants. As with the Dowl-

ing study, no improvements in TST (subjective) were demon-

strated, but the study did show improvement of caregiver-rated

behavioral symptoms, including decreases in wandering, vio-

lent behavior, restlessness, and symptoms of delirium.

137

Other research that was ineligible for this review may none-

theless inform clinicians’ decision-making regarding the use

of light therapy among demented elderly patients with ISWRD.

Riemersma van der Lek and colleagues

147

randomized twelve

assisted-living facilities in the Netherlands to common areas

that were lit with ceiling xtures that emitted either bright

white broad spectrum (1000 lux) or dim light (300 lux). Par-

ticipants in the bright light facilities had lower TST compared

to participants living in a dim light facility at two follow-up

assessments (6 weeks and 6 months after the change in facil-

ity light levels). Other outcomes, including cognitive decits

and depression, were improved in association with the light

intervention, however. Additional studies cited in the previous

Practice Parameters and associated review

1,3

treated subjects

with white broad-spectrum articial light or outdoor light at

levels ranging from 1000–8000 lux. Durations of daily light

exposure ranged from 45–120 minutes and treatment dura-

tions lasted from 10 days to 11 weeks.

138–145

Although presently

dened CRITICAL sleep outcomes were not analyzed, some

of these studies showed positive effects of light exposure on

24-hour rest-activity rhythms, with more consolidated rest pe-

riods at night and more activity and fewer naps during the day.

5.4.4a The TF suggests that clinicians treat ISWRD in

elderly patients with dementia with light therapy (versus

no treatment). [WEAK FOR]

Summary: This recommendation was designated as an

OPTION in the 2007 Practice Parameters, and only one sub-

sequent study has been published that met inclusion criteria

for the current document.

146

The cumulative level of reviewed

evidence (2 studies)

137,146

was VERY LOW (Appendix, Table

S9), and none of the TF-dened CRITICAL outcomes showed

improvement. Behavioral symptoms nevertheless improved in

the sole study that measured this outcome.

137

The interventions

consisted of white broad spectrum light therapy, 2500–5000

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

lux (~1 meter from participants), 1–2 hours in duration, be-

tween 09:00–11:00, for a period of 4–10 weeks.

137,146

Benets of

treatment are closely balanced with harm/burden. In addition

to the general side effects reported in the “Harms and Adverse

Effects” section, other side effects in this population range from

complaints of eye irritation

138

to agitation and confusion,

141

and

these potential drawbacks should be considered when recom-

mending treatment. Furthermore, depending on the method

and setting of light delivery, treatment may be labor intensive,

and modest improvements in outcomes may not justify associ-

ated costs. Nevertheless, clinical experience suggests that the

majority of well-informed patients and/or caregivers of elderly,

demented patients with ISWRD would choose light therapy in

comparison to no intervention.

5.4.5 Sleep-Promoting Medications for ISWRD in Elderly

Patients with Dementia

There was no recommendation in the previous Practice Pa-

rameters regarding sleep-promoting medications for patients

with ISWRD, and no new studies have been published. Various

investigations have concluded, however, that hypnotic medica-

tions increase risks of adverse events within this population

(see “Harms and Adverse Effects” section).

5.4.5a The TF recommends that clinicians avoid the use

of sleep-promoting medications to treat demented elderly

patients with ISWRD (versus no treatment). [STRONG

AGAINST]

Summary: This is a new recommendation in comparison

to the previous Practice Parameters, which did not address the

use of sleep-promoting medications (other than melatonin) for

ISWRD. Although no relevant subsequent studies have been

published, other extant literature indicates that administration

of hypnotics to demented elderly patients increases risks of

falls and other untoward outcomes Altered pharmacokinetics

observed with aging may be one mechanism by which hypnot-

ics increase adverse events in older adults.

148

Risk appears to

be increased even further in elderly patients with dementia,

149

particularly when used in combination with other medica-

tions

150

(also see separate “Harms and Adverse Effects” sec-

tion). Thus, the risk of harm from use of hypnotics in demented

elderly patients with ISWRD outweighs potential positive ef-

fects. As such, the vast majority of well-informed patients and/

or caregivers would not select this treatment.

5.4.6 Timed Oral Administration of Melatonin or Agonists for

Patients with ISWRD

5.4.6.1 Melatonin for elderly patients with deMentia and

iswrd

In the 2007 Practice Parameters, melatonin was deemed

“not indicated” for this specic population, based upon two

studies,

151,152

only one of which was eligible for the current re-

view.

151

No subsequently published relevant studies were iden-

tied. Melatonin administration did not signicantly improve

the predened CRITICAL outcome of TST. Level of evidence:

LOW (Appendix, Table S10).

Twenty-ve patients with dementia and ISWRD (mean age

84.2 ± 7.6 years) were enrolled in a double-blind crossover trial

of 6 mg slow-release melatonin versus placebo.

151

Participants

were studied for a 2-week baseline period and were then ran-

domized to receive either 6 mg slow-release melatonin or pla-

cebo for 2 weeks at their usual bedtimes, followed by a 1-week

washout period and crossover to the second study period.

Mean TST estimated with actigraphy did not differ between

the two groups.

Other research may inform clinical decision-making in this

area. Singer and colleagues examined the effects of treatment

with 2.5 mg slow-release or 10 mg immediate-release melatonin

administered 1 hour before bedtime (versus placebo) on acti-

graphically estimated TST in patients with Alzheimer’s disease

and sleep disturbance.

152

The patients in this study did not have

discreet diagnoses of ISWRD and data were therefore not eli-

gible for inclusion in the present review. Nevertheless, in keeping

with the results of Serfaty and colleagues,

151

this large, well-

designed trial also failed to show an improvement in TST with

either dose of melatonin compared to placebo. Riemersma van

der Lek and colleagues

147

published another potentially relevant

combination study among dementia patients in assisted living in

whom ISWRD was not specically identied. In contrast to the

other studies, the melatonin-only arm (2.5 mg immediate-release

formulation administered approximately one hour before bed-

time) demonstrated decreased actigraphic ISL and increased TST

compared to placebo. However, detrimental effects of melatonin

on mood and daytime functioning were also observed.

5.4.6.1a The TF suggests that clinicians avoid the use of

melatonin as a treatment for ISWRD in older people with

dementia (versus no treatment). [WEAK AGAINST]

Summary: Melatonin was deemed “not indicated” for the

treatment of ISWRD in older people with dementia (OPTION)

in the previous Practice Parameters. The present recommen-

dation against melatonin treatment is based on one reviewed

study that failed to show benet with respect to the CRITICAL

outcome of TST (Level of evidence: LOW (Appendix, Table

S10).

151

Furthermore, there is evidence that melatonin could be

harmful in this population.

147

Thus, the risk-benet ratio sug-

gests that the potential for harms outweighs the possibility for

benets. Clinical experience therefore dictates that the ma-

jority of older patients with dementia and/or their caregivers

would not favorably accept a trial of melatonin.

5.4.6.2 Melatonin in children/adolescents with iswrd

and neurologic disorders

Melatonin was recommended at the OPTION level in the

previous Practice Parameters for children with various neuro-

logic disorders,

based upon four studies,

153–156

none of which

was eligible for the current review, due to an insufcient num-

ber of participants or grouping of participants with different

CRSWDs. One new eligible study was identied,

157

and mela-

tonin was shown to improve select predened CRITICAL out-

comes (TST, ISL), although the condence interval associated

with both values crossed the threshold of the predetermined

clinically signicant minimal change (see Table 2). The level of

reviewed evidence was MODERATE (Appendix, Table S11).

Wright and colleagues

157

performed a double-blind, ran-

domized, controlled, crossover trial in 16 children (mean age

9 ± 2.9 years) with autism spectrum disorder. The protocol

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Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

RR Auger, HJ Burgess, JS Emens et al.

consisted of 1-month baseline, 3-months melatonin vs. placebo,

1-month washout, 3-months melatonin vs. placebo (cross-

over), and 1-month medication free. Melatonin dosing (using

a “standard release” formulation administered 30–40 minutes

before planned bedtime) started at 2 mg, and parents were

given the option of increasing the dose by 2 mg every 3 days,

until 50% or more improvement in sleep was observed, up

to 10 mg. The average nal dose during the melatonin arm

was 7 ± 3.0 mg (range 2–10 mg). Parents’ subjective reports of

ISL and TST were improved, although both values crossed the

threshold of the predetermined clinically signicant minimal

change (mean difference −51.71 minutes [CI −13.49 to −89.93]

and 48.45 minutes [CI 6.29–90.61 minutes], respectively) (see

Table 2).

Studies that were not eligible for analysis may nonetheless

provide additional relevant clinical information. In an open-

label observational trial in ve children with severe develop-

mental disabilities and disrupted sleep-wake patterns, Pillar

and colleagues

153

found that 3 mg melatonin administered

at 18:30 increased actigraphically recorded TST. Other trials

have tested the effects of melatonin for nocturnal sleep distur-

bance in children with a range of neurodevelopmental difcul-

ties.

154 –156

Many of the children included in these studies had

at least one comorbid disability (e.g., epilepsy, blindness), and

all had disturbed sleep-wake patterns. Although considerable

inter-individual variability was observed in the response to

melatonin, all of the studies showed signicant improvements

in at least one sleep measure. Another important nding from

these studies is the relative safety of melatonin in this popula-

tion as no signicant side effects were observed.

5.4.6.2a The TF suggests that clinicians use strategically

timed melatonin as a treatment for ISWRD in children/

adolescents with neurologic disorders (versus no

treatment). [WEAK FOR]

Summary: This recommendation was designated as an OP-

TION in the 2007 Practice Parameters, but none of the reviewed

studies were eligible for the current analysis. One subsequently

published eligible study was identied, with a MODERATE

level of evidence

157

(Appendix, Table S11). The data indicate

that melatonin administration of 2–10 mg during the hour be-

fore planned bedtime may improve CRITICAL sleep outcomes

in children/adolescents with neurologic disorders and ISWRD;

although condence intervals associated with positive values

crossed the threshold of the predetermined clinically signi-

cant minimal change (see Table 2). Another caveat is that this

recommendation is culled from a small sample of patients

with a range of developmental disorders. As such, it may not

generalize to all children/adolescents with ISWRD/neurologic

disorders. Although no serious adverse reactions have been

described in relation to melatonin use to date, relevant con-

cerns have been raised by select studies with respect to the

pediatric/adolescent population,

and rigorous long-term data

are lacking (see separate “Harms and Adverse Effects” sec-

tion). Nevertheless, clinical experience suggests that a majority

of patients and caregivers would accept this treatment option

(versus no treatment), particularly taking into account signi-

cant burdens associated with the neurologic disabilities and

severe associated sleep disturbances.

5.4.7 Wakefulness-Promoting Medications for Patients with

ISWRD

There was no recommendation in the previous Practice Pa-

rameters regarding wakefulness-promoting medications as a

treatment for patients with ISWRD, and no new studies were

published.

There is no evidence to support the use of wakefulness-

promoting medications as a treatment for patients with IS-

WRD. No recommendation.

5.4.8 Other Somatic Interventions for Patients with ISWRD

There was no recommendation in the previous Practice Pa-

rameters regarding other somatic interventions as a treatment

for patients with ISWRD, and no subsequent relevant studies

have been published.

There is no evidence to support the use of other somatic

interventions for the treatment of patients with ISWRD.

No recommendation.

5.4.9 Combination Treatments in Demented Elderly Adults

with ISWRD

This recommendation was designated as a GUIDELINE

in the previous Practice Parameters,

based upon two stud-

ies, neither of which were included in the present analysis, ei-

ther because participants did not clearly have a diagnosis of

ISWRD

158

or because predened CRITICAL outcomes were

not measured.

159

One randomized controlled trial pertaining to

the treatment of demented elderly patients with ISWRD

146

was

published subsequent to 2007, and did not demonstrate benet

with respect to predened CRITICAL outcomes. The level of

reviewed evidence was VERY LOW (Appendix, Table S12).

Dowling and colleagues

146

examined sleep-related out-

comes from the combination of light treatment (> 2500 lux

white broad spectrum light delivered by light boxes at a dis-

tance of 30–34 inches from the eye between 09:30–10:30 for 10

weeks) and either melatonin (5 mg immediate-release between

17:00–18:00) or placebo among 32 nursing home patients with

Alzheimer’s disease (mean age 86 ± 8 years). The dim-light

control condition was exposed to indoor light of 150–200 lux

(see additional study details in section 5.4.4.1 in this paper).

The intervention did not signicantly improve actigraphically

estimated TST, the sole investigated CRITICAL outcome.

Various other studies were ineligible for the current analy-

sis, but nonetheless bear potential relevance to clinicians. Two

non-blinded, randomized trials examined multimodal treat-

ments that included daytime activity, bright light exposure,

and sleep scheduling in community-dwelling elderly patients

with dementia.

158,160

The results demonstrated signicant de-

creases in nighttime wakefulness, and greater adherence to the

intervention was associated with more improvement. Combi-

nation treatments involving prescribed sleep-wake scheduling,

light exposure and increased daytime activity have also been

examined in two 5-day studies among demented, elderly nurs-

ing home residents.

159,161

Participants were required to be out of

bed from 08:00 to 20:00, had scheduled low-intensity physical

activity 3 times per day, and exposure to at least 30 minutes of

outdoor sunlight daily. Other procedures included implemen-

tation of a structured nighttime routine by caregivers, and min-

imization of nighttime noise and interventions. Although these

1221

Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

studies did not measure outcomes dened by the TF, the multi-

modal interventions signicantly improved daytime function-

ing and amplitude of rest-activity rhythms. The investigations

were restricted by constraints inherent to the nursing home

environment (e.g., high dropout rate, inability to blind raters

to condition), yet both had relatively large sample sizes. An

additional caveat is that many more participants were screened

than were eligible for participation, such that the results may

not generalize to all patients with dementia.

5.4.9.1a The TF suggests that clinicians avoid the use

of combined treatments consisting of light therapy in

combination with melatonin in demented, elderly patients

with ISWRD (versus no treatment). [WEAK AGAINST]

Summary: This recommendation was designated as a

GUIDELINE in the previous Practice Parameters. One rel-

evant randomized controlled trial

146

was published subsequent

to 2007. The level of reviewed evidence from this single study

was VERY LOW (Appendix, Table S12). Including melatonin

as part of a combination treatment with light therapy does not

appear to confer additional benet

146

and may increase the po-

tential for harms.

147

Clinical experience suggests that patients/

caregivers would carefully consider the risks of depression

and withdrawn behaviors with treatments that include melato-

nin. Thus, the majority of patients/caregivers would not accept

combination treatments consisting of melatonin and bright

light (versus no treatment). Other combination treatments (e.g.,

bright light, scheduled sleep-wake, and physical activity) are

worthy of further investigation.

5.4.9.2 coMbination treatMents for children/adolescents

with iswrd

The previous Practice Parameters recommendation was des-

ignated at the OPTION level, based upon the results of one

study.

162

No new studies were identied. The previously cited

investigation was an open trial in children with moderate-to-

severe mental retardation and associated nocturnal sleep dis-

turbances, and employed combination treatment with light

therapy, prescribed sleep-wake schedules, and timed daytime

activit y.

162

Five of 14 patients showed improvements in TST

measured on sleep diaries (completed by parents). However, as

it was not clear that these patients met diagnostic criteria for

ISWRD, this study was not eligible for analysis in the present

review.

There is insufcient evidence to support the use of com-

bination treatments in children/adolescents with ISWRD

(versus no treatment). No recommendation.

6.0 CONCLUSIONS AND FUTURE DIRECTIONS

Circadian-based basic science developments continue to

outpace clinical research pertaining to CRSWDs. Since pub-

lication of the prior Practice Parameters,

relatively few new

studies have emerged, although it is encouraging that inves-

tigations specically oriented to the pediatric/adolescent and

other “special” populations have been published. The major

change with the present review is the use of the GRADE sys-

tem of analysis. While more rigorous in many respects than the

previously employed evidence-based assessment, derived data

is designed to be more clinically relevant, as the GRADE sys-

tem requires a combined consideration of strength of evidence,

in conjunction with risk/benet analyses and determination

of patient values and preferences. As such, many previously

endorsed practice recommendations have been negated, and

numerous PICO questions remain unanswered. While this cer-

tainly points out the signicant gaps with respect to the clinical

CRSWD research (highlighted by the prior Standards of Prac-

tice group),

these updated Practice Parameters are intended

to provide clinicians with heightened condence in prescrib-

ing treatments and, equally importantly, they should serve as

a roadmap for future studies that will propel higher quality,

more sophisticated CRSWD therapies.

Generally speaking, larger more rigorously designed stud-

ies (randomized placebo-controlled trials) with ICSD-3 de-

ned CRSWDs

are required, and replication of results from

separate centers is essential. Clinical research pertaining to

ASWPD and ISWRD in particular has suffered signicantly

due to a lack of adherence to International Classication of

Sleep Disorders diagnostic criteria. In the specic case of AS-

WPD, one can only conjecture that the results of light therapy

studies that address sleep maintenance/early-morning awak-

ening difculties are applicable to the treatment of ASWPD,

and uncertainty will remain unless strict terminology are used.

Others have raised concerns about the frequency at which one

actually encounters patients with this condition in the clinical

arena,

163

a topic that is beyond the scope of this discussion. As

for ISWRD, the term is rarely used in the medical literature,

presumably because the comorbid disorders that frequently

overlap (e.g., dementia, developmental disabilities) tend to

overshadow the CRSWD. Nevertheless, sleep disturbances are

among the most onerous of difculties for caregivers of these

patients. Thus, lack of consideration of the formal diagnosis of

ISWRD in studies of sleep in these populations makes it dif-

cult to identify effective treatments for this important clinical

problem.

More specically, future studies could advance the eld by

including detailed therapeutic information, such as the method

and means of treatment delivery (e.g., protective eyewear vs. vo-

litional avoidance of light, light therapy intensity/wavelength/

proximity, continuous versus pulsed light administration [in-

cluding gradually versus abruptly changing illumination

164

melatonin formulation, etc.), relationship of treatment timing

with respect to a dened physiologic circadian phase marker or

other sleep parameter, inclusion/exclusion of prescribed sleep/

wake schedules or other behavioral interventions, and study en-

vironment (laboratory vs. non-laboratory). Regarding the latter

factor, eld-based studies are sorely needed, and one must be

cautious not to let tightly controlled bench research prema-

turely dictate clinical treatment. As a prime example, there are

currently no data to support devices that solely deliver blue

short wavelength light in the treatment of CRSWDs, and two

laboratory-based studies that describe no additional benet

with blue-enriched bright light,

24,25

despite the fact that these

wavelengths have been identied as especially important for

circadian phase resetting in non-clinical experiments.

importantly, compliance with post-awakening “light boxes” in

the eld is very poor,

and studies that examine the bypassing

of this compliance barrier are particularly intriguing.

28,99,165,166

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Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

RR Auger, HJ Burgess, JS Emens et al.

Future research should address “dose” of light including lux

level and duration,

and should also consider season

167

and

other environmental factors that affect overall light exposure

histor y.

Finally, more such studies specically targeting

CRSWD populations are desired.

From the standpoint of outcomes, similar clinically relevant

sleep-related measures will be required for inter-study com-

parative purposes (PSG vs. actigraphy vs. subjective reports,

physiologic or nonphysiologic circadian marker), along with

systematic measures of treatment compliance, to accurately

inform clinical practice. In the instance of ISWRD, it should

be determined whether separate outcome measures (e.g., circa-

dian amplitude, rest-activity cycle variations) may be superior

indicators of treatment efcacy. For all CRSWDs, measures

of daytime functioning/alertness could enhance clinical

relevance.

Inter-study medication comparisons will require equivalent

dosing (analyzed melatonin study doses ranged from 0.3–10.0

mg), timing (with respect to clock time, typical sleep onset

time or other physiologic/non-physiologic circadian marker),

and treatment durations, to accurately gauge benet. This

guideline does not address specic medication/supplement

doses (but rather states those cited in the literature). Optimal

dosing may vary between CRSWDs. Furthermore, signicant

inter-individual differences may also exist within singular

CRSWDs, as exemplied by a study of N24SWD subjects that

showed a tenfold variation in entraining doses.

136

The issue of

formulation may also be relevant in melatonin studies (regu-

lar- vs. sustained-release vs. sublingual, etc.), and one group

suggested that slow exogenous melatonin metabolism could be

responsible for a lack of sustained effect in select instances.

168

Taking into account melatonin safety concerns (particularly

among children and those of reproductive age), future properly

powered studies should be performed to identity the lowest

effective melatonin dosage and duration of treatment (acute

and maintenance). Long-term physiologic studies are needed

to accurately ascertain any serious chronic risks, particularly

as melatonin supplements are not subject to FDA oversight.

In January of 2014, the FDA approved the melatonin ago-

nist Hetlioz

(tasimelteon) for the treatment of N24SWD

among the blind. This is the rst FDA-approved drug for any

CRSWD. Since the last date of our latest literature search, the

results of a peer-reviewed, randomized, placebo-controlled

study were published.

169

This is the largest treatment study

with N24SWD patients, and it demonstrated that Tasimelteon

safely and effectively treated aficted patients: entrainment

occurred in 20% (8 of 40) of patients receiving the drug com-

pared with 3% (1 of 38) receiving placebo. This entrainment

rate is lower than the 67% entrainment rate (12 of 18) found in

the current meta-analysis of melatonin treatment in N24SWD,

but this may have been a product of the short duration of treat-

ment with Tasimelteon prior to the assessment of entrain-

ment, as noted by the authors. Consistent with this hypothesis,

higher rates of entrainment were found during longer, open-

label treatment with tasimelteon. Direct comparisons between

Tasimelteon and melatonin have yet to be conducted. At least

two other investigations (involving ramelteon) also sug-

gest a potential future CRSWD treatment role for melatonin

agonists.

170,171

Related to long-term risks of circadian-based interventions

in general, research is needed to determine the minimum re-

quired duration of specic treatments (or to determine that

they are required indenitely), and/or to determine mainte-

nance treatment schedules. Further studies that investigate

multi-modal or combination therapies are needed to determine

whether combinations may prove to be synergistic, and/or to

extricate independent effects of treatment modalities, so that

relative successes and failures can be exploited for differ-

ing clinical scenarios. With respect to the latter point, in the

previously cited Gradisar study (involving adolescents with

DSWPD),

104

light therapy was discontinued (and apparently

not required) once a target wake time was reached, at which

time solely behavioral interventions ensued. It is not clear to

what degree this treatment could be generalized to all DSWPD

populations.

Demonstration of superiority (or lack thereof) of circadian

versus clock-hour TOA for interventions should engender

studies that aim to explore demonstrable benets of phase as-

sessments in the clinical setting, which in turn could serve to

delineate relative chronobiotic versus hypnotic effects of medi-

cations/supplements. Some of the reviewed interventions dem-

onstrated successful sleep-related outcomes without changes

in the circadian phase marker and vice versa. In the instance

that the importance of circadian TOA is demonstrated, it will

be necessary to determine light and melatonin phase PRCs for

adult populations aficted with CRSWDs (as they may dif-

fer from normal populations

15,172

) and to determine the same

for both aficted and healthy pediatric/adolescent popula-

tions. Complicating matters, alterations in phase relationships

between the circadian timing system and the timing of sleep

among those with CRSWDs could impact the ability of inter-

ventions to exert benets, even with knowledge of the PRC.

For example, longer intervals from various endogenous mela-

tonin parameters

173

and CBT

min

174 –176

to sleep offset have fre-

quently been described among adult patients with DSWPD

as compared to controls. However, this nding has not been

demonstrated among protocols in which subjects are forced to

maintain a more conventional sleep/wake schedule,

27,177,178

sug-

gesting that this observation may simply be a consequence of

longer habitual TST. Greater elucidation is required. On a sep-

arate note, effective treatments may need to address concomi-

tant impairment of homeostatic sleep processes in CRSWDs,

as has been demonstrated in DSWPD and among adolescents

in general.

179,180

Whether hypnotics have a role in this setting

deserves to be further explored.

Present guidelines predominantly reect biological under-

pinnings associated with CRSWDs. Studies are needed to

investigate and understand predominant exogenous and en-

dogenous contributors to the development and perpetuation

of CRSWDs, so that different subtypes (and possibly differ-

ent treatment/prophylactic regimens) can be identied. In the

case of adolescents/young adults (and, to a lesser degree, other

adults

181

), numerous exogenous factors, such as increased auton-

omy with respect to sleep time, employment, and involvement

in extracurricular activities have been identied as variables

contributing to the generally observed delay in sleep/wake pat-

terns,

182

but have not been studied among adolescent DSWPD

cohorts specically.

183,184

Additionally, repeated exposure to

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Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

frustrations at not being able to fall asleep at a desired time

can lead to the development of a concomitant conditioned in-

somnia, which can perpetuate sleep difculties. Exposure to

indoor lighting during evening hours

185 –188

and/or delays in

weekend wake times

189–191

have also been implicated as con-

tributors to persistently delayed sleep/wake times, but have not

been specically implicated in adolescent DSWPD.

192

Some

have urged that school lighting environments be optimized for

maximal circadian benets.

193

In the case of N24SWD, it may

be that the exogenous and endogenous contributors to the dis-

order differ between blind and sighted individuals and that this

may similarly necessitate different treatment regimens. Iden-

tication and manipulation of exogenous variables in trials of

CRSWDs may prove fruitful.

The associated development of clinical proles would en-

able clinicians to better ascertain which patients might respond

to suggested treatments, and related research is encouraged.

In the Gradisar study involving adolescents with DSWPD,

104

school non-attendance, unrestricted sleep during vacation pe-

riods, and (not surprisingly) amotivation were all noted to be

barriers to successful outcomes with light therapy. Patients t-

ting this prole are perhaps better suited to less complex inter-

ventions. In a separate study involving young adult subjects

with DSWPD and N24SWD receiving melatonin, a higher

response rate correlated indirectly with shorter habitual TST,

as well as a later age of onset.

131

Information such as this may

eventually allow clinicians to optimally tailor treatment.

In select cases, accommodation to a CRSWD patient’s cir-

cadian preference may be most practical, and further studies

examining implementation of such schedules are desirable.

Believing that some CRSWD cases are refractory to treat-

ment, Dagan and Abadi (2001)

194

recommended foregoing

therapy (specically among DSWPD patients), and instead

urged implementation of rehabilitation and accommodation to

the preferred sleep/wake schedule in select instances, includ-

ing support for disability from duties that require strict sleep/

wake schedules, and encouragement to pursue endeavors with

more exible scheduling. The benets of such accommodation

were demonstrated in a separate military-based study, with

evidence of superior performance and mood among those en-

abled to adapt a relatively delayed sleep/wake schedule, which

correlated with increased TST.

195

A later school start time may

be sought for adolescents, if practical and available. This inter-

vention alone can signicantly increase TST and mitigate as-

sociated impairments.

196 –199

Unfortunately, the implementation

of this policy change frequently encounters staunch political

resistance and is presently available in select regions only.

200

In sum, although much work remains, signicant progress

has been made in the recognition/treatment of CRSWDs since

the inception of Sleep Medicine as a distinct medical disci-

pline. Our aim with the present guidelines is to provide clini-

cians with immediate access to up-to-date information in order

to make properly informed treatment decisions. The circadian

system impacts a wide range of physiology, and treatment of

CRSWDs would therefore be expected to exert a wide-ranging

impact on manifold aspects of health. This publication should

serve as an impetus to address clinical research deciencies

and to promote novel inquiries for treatments of these chal-

lenging and interesting conditions.

ABBREVIATIONS

ADHD, attention decit hyperactivity disorder

aMT6s, 6-sulfatoxymelatonin (urinary metabolite of

melatonin)

CBT

Min

, core body temperature minimum

DLMO, dim light melatonin onset

GRADE, grading of recommendations assessment,

development and evaluation

ISL, initial sleep latency

PSG, polysomnography

SOT, sleep onset time

SOffT, sleep offset time

TF, task force

TOA, time of administration

TST, total sleep time

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sleep, mood, and behavior. Arch Pediatr Adolesc Med 2010;164:608–14.

200. Wahlstrom K. The prickly politics of school starting times. Phi Delta Kappa

1999;80:344–47.

ACKNOWLEDGMENTS

The authors acknowledge Dr. Ilene Rosen for serving as a board liaison for this

project and assuring that the guideline adhered to the standards set forth by the

Board of Directors of American Academy of Sleep Medicine. The authors also ac-

knowledge the contributions of the following individuals: Christine Stepanski, MS,

for performing literature searches #1 and #2; and Michelle M. Tangredi, PhD, for

managing the project at the initial steps. The authors are grateful to the organiza-

tions and individuals who provided their insights and suggestions during the public

comment period. Every comment was internally documented and addressed, and

decisions regarding corresponding amendments in the text were left to the TF’s

discretion. The project was funded by the American Academy of Sleep Medicine.

SUBMISSION & CORRESPONDENCE INFORMATION

Submitted for publication August, 2015

Accepted for publication August, 2015

Address correspondence to: R. Robert Auger, MD, Mayo Center for Sleep Medicine,

Rochester, MN; Email: research@aasmnet.org

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no nancial

conicts of interest. Drs. Deriy and Thomas are employed by the American Acad-

emy of Sleep Medicine.

APPENDIX

Search Terms and MeSH Used in the Literature

Search #1

Sleep disorders, circadian rhythm”[MeSH Terms] OR

(“sleep”[All Fields] AND “disorders”[All Fields] AND

“circadian”[All Fields] AND “rhythm”[All Fields])

OR “circadian rhythm sleep disorders”[All Fields] OR

(“circadian”[All Fields] AND “rhythm”[All Fields]

AND “sleep”[All Fields] AND “disorder”[All Fields]) OR

“circadian rhythm sleep disorder”[All Fields] OR (free[All

Fields] AND “running”[All Fields] AND “disorder”[All

Fields]) OR (irregular[All Fields] AND sleep-wake[All

Fields] AND rhythm[All Fields]) OR (non[All Fields] AND

24-hour[All Fields] AND (“sleep disorders”[MeSH Terms]

OR (“sleep”[All Fields] AND “disorders”[All Fields]) OR

“sleep disorders”[All Fields] OR (“sleep”[All Fields] AND

“disorder”[All Fields]) OR “sleep disorder”[All Fields])) OR

((“Blindness”[Mesh] OR (“blindness”[MeSH Terms] OR

“blindness”[All Fields] OR nonsighted[All Fields])) AND

(“sleep disorders”[MeSH Terms] OR (“sleep”[All Fields]

AND “disorders”[All Fields]) OR “sleep disorders”[All

Fields])) AND (Meta-Analysis[ptyp] OR Practice

Guideline[ptyp] OR systematic[sb]).

Terms for the Literature Search #2 in Pubmed

Database

((((circadian rhythm sleep disorders[tw] OR circadian rhythm

sleep disorder[tw] OR “Sleep Disorders, Circadian

Rhythm”[Mesh:noexp] OR “chronobiology disorders”[tw] OR

“Chronobiology Disorders”[Mesh:noexp] OR

hypernychthemeral[tw] OR circadian misalignment[tw] OR

circadian dysregulation[tw]) OR ((irregular[tw] OR non 24

hour[tw]) AND (sleep wake[tw] OR sleep-wake[tw])) OR

((advanced[tw] OR delayed[tw]) AND sleep phase[tw]) OR

(idiopathic[tw] AND chronic[tw] AND (sleep-onset[tw] OR

sleep onset[tw]) AND insomnia[tw]) OR ((nonentrained[tw] OR

non-entrained[tw]) AND (sleep[tw] OR “sleep”[mesh] OR

“Sleep Disorders”[Mesh:noexp] OR circadian[tw] OR

“Circadian Rhythm”[MeSH Terms])) OR ((DSPS[tw] OR

ASPS[tw] OR early morning awakening[tw] OR (phase

advance[All Fields] OR phase advance/delay[All Fields] OR

phase advanced[All Fields] OR phase advancement[All Fields]

1228

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RR Auger, HJ Burgess, JS Emens et al.

OR phase advancements[All Fields] OR phase advances[All

Fields]) OR (phase delay[All Fields] OR phase delay/arrest[All

Fields] OR phase delayed[All Fields] OR phase delaying[All

Fields] OR phase delays[All Fields]) OR (phase shift[All Fields]

OR phase shifted[All Fields] OR phase shifter[All Fields] OR

phase shifter/modulator[All Fields] OR phase shifters[All

Fields] OR phase shifting[All Fields] OR phase shiftkeying[All

Fields] OR phase shiftmeasurement[All Fields] OR phase

shifts[All Fields])) AND (sleep[tw] OR “sleep”[mesh] OR

“Sleep Disorders”[Mesh:noexp] OR circadian[tw] OR

“Circadian Rhythm”[MeSH Terms])) OR ((free running[tw]

AND (disorder[tw] OR rhythm[tw])) AND (sleep[tw] OR

“sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms])) OR

((dark therapy[tw] OR light therapy[tw] OR amber lenses[tw]

OR Blue light[tw] OR bright light[tw] AND blue blockers[tw]

OR blue-blocker[tw] OR blue blocker[tw] OR blue-blocker[tw]

OR eyewear[tw] OR Phototherapy[tw] OR

“Phototherapy”[Mesh]) AND (sleep[tw] OR “sleep”[mesh] OR

“Sleep Disorders”[Mesh:noexp] OR circadian[tw] OR

“Circadian Rhythm”[MeSH Terms])) OR “sleep phase

chronotherapy”[MeSH Terms] OR ((chronotherapy[tw] OR

chronotype[tw] OR “Chronotherapy”[Mesh:noexp]) AND

(sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms])) OR ((melatonin receptor agonists[tw]

OR melatonin receptor agonist[tw] OR melatonin agonist[tw]

OR melatonin agonists[tw] OR melatonin receptor

antagonists[tw] OR melatonin receptor antagonist[tw] OR

melatonin antagonist[tw] OR melatonin antagonists[tw] OR

“Receptors, Melatonin/drug effects”[Mesh] OR “Receptors,

Melatonin/agonists”[Mesh] OR “Receptors, Melatonin/

antagonists and inhibitors”[Mesh]) AND (sleep[tw] OR

“sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms])) OR

((melatonin[tw] OR “melatonin”[MeSH Terms] OR

ramelteon[tw] OR “ramelteon”[Substance] OR tasimelteon[tw]

OR “tasimelteon”[Supplementary Concept] OR

agomelatine[tw] OR “S 20098”[Supplementary Concept])

AND (sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms])) OR ((dim light melatonin onset[tw]

OR DLMO[tw]) AND (sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms])) OR ((Blindness[tw] OR blind

person[tw] OR blind people[tw] OR blind subject[tw] OR blind

subjects[tw] OR blind patient[tw] OR blind patients[tw] OR

“Visually Impaired Persons”[Mesh] OR enucleated[tw] OR

“Blindness”[Mesh] OR nonsighted[tw] OR (visual

impairement[All Fields] OR visual impairment[All Fields] OR

visual impairment/blindness[All Fields] OR visual

impairments[All Fields]) OR visually impaired[tw]) AND

(sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms])) OR ((“dementia”[MeSH Terms] OR

dementia[tw] OR “alzheimer disease”[MeSH Terms] OR

alzheimer[tw] OR alzheimers’s[tw]) AND (sleep[tw] OR

“sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms])) OR

((owl[tw] OR owls[tw] OR lark[tw] OR larks[tw] OR

morningness[tw] OR eveningness[tw] OR morning types[tw]

OR morning type[tw] OR evening types[tw] OR evening

type[tw]) AND (sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms]))) AND ((randomized controlled

trial[pt] OR controlled clinical trial[pt] OR randomized[tiab]

OR placebo[tiab] OR “drug therapy”[Subheading] OR

randomly[tiab] OR trial[tiab] OR groups[tiab]) NOT

(“animals”[MeSH Terms] NOT “humans”[MeSH Terms]))

AND (English[la] AND (“2006/10/01”[PDAT] :

“3000/12/31”[PDAT]) NOT (Comment[pt] OR Editorial[pt] OR

News[pt] OR Newspaper Article[pt] OR Letter[pt] OR Case

Reports[pt] OR Review[pt])))) NOT (((((circadian rhythm sleep

disorders[tw] OR circadian rhythm sleep disorder[tw] OR

“Sleep Disorders, Circadian Rhythm”[Mesh:noexp] OR

“chronobiology disorders”[tw] OR “Chronobiology

Disorders”[Mesh:noexp] OR hypernychthemeral[tw] OR

circadian misalignment[tw] OR circadian dysregulation[tw]))

OR (((irregular[tw] OR non 24 hour[tw]) AND (sleep wake[tw]

OR sleep-wake[tw]))) OR (((advanced[tw] OR delayed[tw])

AND (sleep phase[tw]))) OR ((idiopathic[tw] AND chronic[tw]

AND (sleep-onset[tw] OR sleep onset[tw]) AND insomnia[tw]))

OR (((nonentrained[tw] OR non-entrained[tw]) AND (sleep[tw]

OR “sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms]))) OR

(((DSPS[tw] OR ASPS[tw] OR phase advance* OR phase delay*

OR phase shift*) AND (sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms]))) OR (((free running[tw] AND

(disorder[tw] OR rhythm[tw])) AND (sleep[tw] OR

“sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms]))) OR

(((dark therapy[tw] OR light therapy[tw] OR amber lenses[tw]

OR Blue light[tw] OR bright light[tw] OR eyewear[tw] OR

Phototherapy[tw] OR “Phototherapy”[Mesh]) AND (sleep[tw]

OR “sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms]))) OR

((Sleep Phase Chronotherapy[Mesh])) OR (((chronotherapy[tw]

OR “Chronotherapy”[Mesh:noexp]) AND (sleep[tw] OR

“sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms]))) OR

(((melatonin receptor agonists[tw] OR melatonin receptor

agonist[tw] OR melatonin agonist[tw] OR melatonin

agonists[tw] OR melatonin receptor antagonists[tw] OR

melatonin receptor antagonist[tw] OR melatonin antagonist[tw]

OR melatonin antagonists[tw] OR melatonin receptor

inhibitor[tw] OR melatonin receptor inhibitors[tw] OR

melatonin inhibitor[tw] OR melatonin inhibitors[tw] OR

“Receptors, Melatonin/drug effects”[Mesh] OR “Receptors,

Melatonin/agonists”[Mesh] OR “Receptors, Melatonin/

antagonists and inhibitors”[Mesh]) AND (sleep[tw] OR

“sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms]))) OR

(((melatonin[tw] OR “melatonin”[MeSH Terms] OR

ramelteon[tw] OR “ramelteon”[Substance] OR tasimelteon[tw]

OR “tasimelteon”[Supplementary Concept] OR

agomelatine[tw] OR “S 20098”[Supplementary Concept])

AND (sleep[tw] OR “sleep”[mesh] OR “Sleep

1229

Journal of Clinical Sleep Medicine, Vol. 11, No. 10, 2015

Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms]))) OR (((dim light melatonin onset[tw]

OR DLMO[tw]) AND (sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms]))) OR (((Blindness[tw] OR

“Blindness”[Mesh] OR nonsighted[tw] OR (visual impair*) OR

(visually impaired[tw])) AND (sleep[tw] OR “sleep”[mesh] OR

“Sleep Disorders”[Mesh:noexp] OR circadian[tw] OR

“Circadian Rhythm”[MeSH Terms]))) OR (((“dementia”[MeSH

Terms] OR dementia[tw] OR “alzheimer disease”[MeSH

Terms] OR alzheimer[tw] OR alzheimers’s[tw]) AND (sleep[tw]

OR “sleep”[mesh] OR “Sleep Disorders”[Mesh:noexp] OR

circadian[tw] OR “Circadian Rhythm”[MeSH Terms]))) OR

(((owl[tw] OR owls[tw] OR lark[tw] OR larks[tw] OR

morningness[tw] OR eveningness[tw] OR morning types[tw]

OR morning type[tw] OR evening types[tw] OR evening

type[tw]) AND (sleep[tw] OR “sleep”[mesh] OR “Sleep

Disorders”[Mesh:noexp] OR circadian[tw] OR “Circadian

Rhythm”[MeSH Terms]))))) AND ((randomized controlled

trial[pt] OR controlled clinical trial[pt] OR randomized[tiab]

OR placebo[tiab] OR “drug therapy”[Subheading] OR

randomly[tiab] OR trial[tiab] OR groups[tiab]) NOT

(“animals”[MeSH Terms] NOT “humans”[MeSH Terms]))

AND (English[la] AND (“2006/10/01”[PDAT] :

“3000/12/31”[PDAT]) NOT (Comment[pt] OR Editorial[pt] OR

News[pt] OR Newspaper Article[pt] OR Letter[pt] OR Case

Reports[pt] OR Review[pt])))

Terms for the Literature Search #2 in Embase Database

(‘circadian rhythm sleep disorders’:de,ab,ti OR ‘circadian

rhythm sleep disorder’:de,ab,ti OR ‘circadian rhythm

sleep disorder’/exp OR ‘chronobiology disorders’:de,ab,ti

OR ‘hypernychthemeral’:de,ab,ti OR ‘circadian

misalignment’:de,ab,ti OR ‘circadian dysregulation’:de,ab,ti)

OR((‘advanced’:de,ab,ti OR ‘delayed’:de,ab,ti) AND

(‘sleep phase’:de,ab,ti)) OR ((‘irregular’:de,ab,ti OR

‘non 24 hour’:de,ab,ti) AND (‘sleep wake’:de,ab,ti

OR ‘sleep-wake’:de,ab,ti)) OR ((‘idiopathic’:de,ab,ti

AND ‘chronic’:de,ab,ti AND (‘sleep-onset’:de,ab,ti

OR ‘sleep onset’:de,ab,ti) AND ‘insomnia’:de,ab,ti)) OR

((‘nonentrained’:de,ab,ti OR ‘non-entrained’:de,ab,ti)

AND (‘sleep’:de,ab,ti OR ‘sleep’/exp OR ‘sleep disorder’/

de OR ‘circadian’:de,ab,ti OR ‘circadian rhythm’/exp)) OR

((‘DSPS’:de,ab,ti OR ‘ASPS’:de,ab,ti OR ‘early morning

awakening’:de,ab,ti OR phase advance* OR phase delay* OR

phase shift*) AND (‘sleep’:de,ab,ti OR ‘sleep’/exp OR ‘sleep

disorder’/de OR ‘circadian’:de,ab,ti OR ‘circadian rhythm’/

exp)) OR (((‘free running’:de,ab,ti AND (‘disorder’:de,ab,ti

OR ‘rhythm’:de,ab,ti)) AND (‘sleep’:de,ab,ti OR ‘sleep’/

exp OR ‘sleep disorder’/de OR ‘circadian’:de,ab,ti OR

‘circadian rhythm’/exp))) OR ((‘dark therapy’:de,ab,ti

OR ‘light therapy’:de,ab,ti OR ‘amber lenses’:de,ab,ti OR

‘blue blocker’:de,ab,ti OR ‘blue-blocker’:de,ab,ti OR ‘blue

blockers’:de,ab,ti OR ‘blue-blockers’:de,ab,ti OR ‘Blue

light’:de,ab,ti OR ‘bright light’:de,ab,ti OR ‘eyewear’:de,ab,ti

OR ‘Phototherapy’:de,ab,ti OR ‘phototherapy’/exp) AND

(‘sleep’:de,ab,ti OR ‘sleep’/exp OR ‘sleep disorder’/de

OR ‘circadian’:de,ab,ti OR ‘circadian rhythm’/exp)) OR

((‘chronotherapy’:de,ab,ti OR ‘chronotype’:de,ab,ti OR

‘chronotherapy’/exp) AND (‘sleep’:de,ab,ti OR ‘sleep’/exp

OR ‘sleep disorder’/de OR ‘circadian’:de,ab,ti OR ‘circadian

rhythm’/exp OR ‘sleep therapy’/exp)) OR ((‘melatonin receptor

agonists’:de,ab,ti OR ‘melatonin receptor agonist’:de,ab,ti

OR ‘melatonin agonist’:de,ab,ti OR ‘melatonin

agonists’:de,ab,ti OR ‘melatonin receptor antagonists’:de,ab,ti

OR ‘melatonin receptor antagonist’:de,ab,ti OR ‘melatonin

antagonist’:de,ab,ti OR ‘melatonin antagonists’:de,ab,ti

OR ‘melatonin receptor inhibitor’:de,ab,ti OR ‘melatonin

receptor inhibitors’:de,ab,ti OR ‘melatonin inhibitor’:de,ab,ti

OR ‘melatonin inhibitors’:de,ab,ti OR ‘melatonin

receptor’/exp/dd_dt OR (‘melatonin receptor’/exp

AND ‘agonist’/exp)) AND (‘sleep’:de,ab,ti OR ‘sleep’/

exp OR ‘sleep disorder’/de OR ‘circadian’:de,ab,ti OR

‘circadian rhythm’/exp)) OR ((‘melatonin’:de,ab,ti OR

‘melatonin’/exp OR ‘ramelteon’:de,ab,ti OR ‘ramelteon’/

exp OR ‘tasimelteon’:de,ab,ti OR ‘tasimelteon’/exp

OR ‘agomelatine’:de,ab,ti OR ‘agomelatine’/exp) AND

(‘sleep’:de,ab,ti OR ‘sleep’/exp OR ‘sleep disorder’/de

OR ‘circadian’:de,ab,ti OR ‘circadian rhythm’/exp)) OR

((‘dim light melatonin onset’:de,ab,ti OR ‘DLMO’:de,ab,ti)

AND (‘sleep’:de,ab,ti OR ‘sleep’/exp OR ‘sleep disorder’/

de OR ‘circadian’:de,ab,ti OR ‘circadian rhythm’/

exp)) OR ((‘Blindness’:de,ab,ti OR ‘blindness’/exp

OR ‘blind person’:de,ab,ti OR ‘blind people’:de,ab,ti

OR ‘blind subject’:de,ab,ti OR ‘blind subjects’:de,ab,ti

OR ‘blind patient’:de,ab,ti OR ‘blind patients’:de,ab,ti

OR ‘enucleated’:de,ab,ti OR ‘nonsighted’:de,ab,ti OR

(visual AND impair*) OR (‘visually impaired’:de,ab,ti))

AND (‘sleep’:de,ab,ti OR ‘sleep’/exp OR ‘sleep disorder’/

de OR ‘circadian’:de,ab,ti OR ‘circadian rhythm’/exp)) OR

((‘dementia’/exp OR ‘dementia’:de,ab,ti OR ‘Alzheimer

disease’/exp OR ‘alzheimer’:de,ab,ti OR alzheimer*)

AND (‘sleep’:de,ab,ti OR ‘sleep’/exp OR ‘sleep disorder’/

de OR ‘circadian’:de,ab,ti OR ‘circadian rhythm’/exp))

OR ((‘owl’:de,ab,ti OR ‘owls’:de,ab,ti OR ‘lark’:de,ab,ti

OR ‘larks’:de,ab,ti OR ‘morningness’:de,ab,ti OR

‘eveningness’:de,ab,ti OR ‘morning types’:de,ab,ti OR

‘morning type’:de,ab,ti OR ‘evening types’:de,ab,ti OR

‘evening type’:de,ab,ti) AND (‘sleep’:de,ab,ti OR ‘sleep’/exp

OR ‘sleep disorder’/de OR ‘circadian’:de,ab,ti OR ‘circadian

rhythm’/exp)) AND ((random* OR factorial* OR crossover*

OR cross NEXT/1 over* OR cross-over* OR placebo* OR

doubl* NEXT/1 blind* OR singl* NEXT/1 blind* OR assign*

OR allocat* OR volunteer* OR ‘crossover procedure’/de OR

‘double blind procedure’/de OR ‘randomized controlled trial’/

de OR ‘single blind procedure’/de) OR (‘clinical trial’/exp

OR ‘counterbalance’:de,ab,ti OR ‘counterbalanced’:de,ab,ti

OR ‘crossover’:de,ab,ti OR ‘trial’:de,ab,ti)) AND ((AND

[english]/lim AND [2006-2012]/py AND [embase]/lim NOT

[medline]/lim NOT (‘editorial’:it OR ‘conference review’:it

OR ‘conference paper’:it OR ‘note’:it OR ‘conference

abstract’:it OR ‘letter’:it OR ‘review’:it) NOT ([animals]/lim

NOT [humans]/lim))

Terms for the Literature Search # 2 in PsychInfo

Database

((TI “circadian rhythm sleep disorders” or TI “circadian

rhythm sleep disorder” or AB “circadian rhythm sleep

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RR Auger, HJ Burgess, JS Emens et al.

disorders” or AB “circadian rhythm sleep disorder” or

TI “chronobiology disorders” or AB “chronobiology

disorders” OR TI “chronobiology disorder” or AB

“chronobiology disorder” or TI “hypernychthemeral” or AB

“hypernychthemeral” or TI “circadian misalignment” or AB

“circadian misalignment” or TI “circadian dysregulation” or

AB “circadian dysregulation”)) OR ((TI “advanced” or AB

“advanced” or TI “delayed” or AB “delayed”) and (TI “sleep

phase” or AB “sleep phase”)) OR ((TI “irregular” or AB

“irregular” or TI “non 24 hour” or AB “non 24 hour”) AND

(TI “sleep wake” or AB “sleep wake” or TI “sleep-wake” or

AB “sleep-wake”)) OR ((TI “idiopathic” or AB “idiopathic”)

and (TI “chronic” or AB “chronic” ) and (TI “sleep-onset” or

AB “sleep-onset” or TI “sleep onset” or AB “sleep onset”)

and (DE “Insomnia” or TI “insomnia” or AB “insomnia”))

OR ((TI “nonentrained” or AB “nonentrained” OR TI “non-

entrained” OR AB “non-entrained”) AND (TI “sleep” or

AB “sleep” or DE “Sleep” or DE “Sleep Disorders” or TI

“circadian” or AB “circadian” or DE “Human Biological

Rhythms” or DE “Sleep Wake Cycle”)) OR ((TI “DSPS”

or AB “DSPS” or TI “ASPS” or AB “ASPS” or TI “early

morning awakening” or AB “early morning awakening” or

TI “phase advance*” or AB “phase advance*” or TI “phase

delay*” or AB “phase delay*” or TI “phase shift*” or AB

“phase shift*”) and (TI “sleep” or AB “sleep” or DE “Sleep”

or DE “Sleep Disorders” or TI “circadian” or AB “circadian”

or DE “Human Biological Rhythms” or DE “Sleep Wake

Cycle”)) OR (((TI “free running” or AB “free running”)

and (TI “disorder” or AB “disorder” or TI “rhythm” or AB

“rhythm”)) and (TI “sleep” or AB “sleep” or DE “Sleep” or

DE “Sleep Disorders” or TI “circadian” or AB “circadian”

or DE “Human Biological Rhythms” or DE “Sleep Wake

Cycle”))) OR ((TI “dark therapy” or AB “dark therapy” or

TI “light therapy” or AB “light therapy” or TI “amber lenses”

or AB “amber lenses” or TI “blue blocker” or AB “blue

blocker” or TI “blue-blocker” or AB “blue-blocker” or TI

“blue blockers” or AB “blue blockers” or TI “blue-blockers”

or AB “blue-blockers” or TI “Blue light” or AB “Blue light”

or TI “bright light” or AB “bright light” or TI “eyewear” or

AB “eyewear” or DE “Optical Aids” or TI “Phototherapy”

or AB “Phototherapy” or DE “Phototherapy”) and (TI

“sleep” or AB “sleep” or DE “Sleep” or DE “Sleep Disorders”

or TI “circadian” or AB “circadian” or DE “Human

Biological Rhythms” or DE “Sleep Wake Cycle”)) OR ((TI

“chronotherapy” or AB “chronotherapy” or TI “chronotype”

or AB “chronotypes” or TI “chronotypes” or AB

“chronotypes” or TI “chronotherapy” or AB “chronotherapy”)

AND (TI “sleep” or AB “sleep” or DE “Sleep” or DE “Sleep

Disorders” or TI “circadian” or AB “circadian” or DE

“Human Biological Rhythms” or DE “Sleep Wake Cycle”))

OR ((TI “melatonin receptor agonists” or AB “melatonin

receptor agonists” or TI “melatonin receptor agonist” or AB

“melatonin receptor agonist” or TI “melatonin agonist” or

AB “melatonin agonist” or TI “melatonin agonists” or AB

“melatonin agonists” OR TI “melatonin receptor antagonists”

or AB “melatonin receptor antagonists” or TI “melatonin

receptor antagonist” or AB “melatonin receptor antagonist”

or TI “melatonin antagonist” or AB “melatonin antagonist” or

TI “melatonin antagonists” or AB “melatonin antagonists” or

TI “melatonin receptor inhibitor” or AB “melatonin receptor

inhibitor” or TI “melatonin receptor inhibitors” or AB

“melatonin receptor inhibitors” or TI “melatonin inhibitor”

or AB “melatonin inhibitor” or TI “melatonin inhibitors” or

AB “melatonin inhibitors”) AND (TI “sleep” or AB “sleep”

or DE “Sleep” or DE “Sleep Disorders” or TI “circadian”

or AB “circadian” or DE “Human Biological Rhythms” or

DE “Sleep Wake Cycle”)) OR ((TI “melatonin” OR AB

“melatonin” or DE “melatonin” OR TI “ramelteon” OR AB

“ramelteon” OR TI “tasimelteon” OR AB “tasimelteon” OR

TI “agomelatine” OR AB “agomelatine”) AND (TI “sleep”

or AB “sleep” or DE “Sleep” or DE “Sleep Disorders” or

TI “circadian” or AB “circadian” or DE “Human Biological

Rhythms” or DE “Sleep Wake Cycle”)) OR ((TI “dim light

melatonin onset” or AB “dim light melatonin onset” or TI

“DLMO” or AB “DLMO”) and (TI “sleep” or AB “sleep”

or DE “Sleep” or DE “Sleep Disorders” or TI “circadian”

or AB “circadian” or DE “Human Biological Rhythms”

or DE “Sleep Wake Cycle”)) OR ((TI “Blindness” or AB

“blindness” or TI “blind person” or AB “blind person” or

TI “blind people” or AB “blind people” or TI “blind subject”

or AB “blind subject” or TI “blind subjects” or AB “blind

subjects” or TI “blind patient” or AB “blind patient” or TI

“blind patients” or AB “blind patients” or TI “enucleated”

or AB “enucleated” or TI “nonsighted” or AB “nonsighted”

or (TI “visual” and TI “impair*”) or (AB “visual” and

TI “impair*”) or TI “visually impaired” or AB “visually

impaired” or DE “Vision Disorders” or DE “Balint’s

Syndrome” or DE “Blind” or DE “Eye Disorders” or DE

“Hemianopia”) and (TI “sleep” or AB “sleep” or DE “Sleep”

or DE “Sleep Disorders” or TI “circadian” or AB “circadian”

or DE “Human Biological Rhythms” or DE “Sleep Wake

Cycle”)) OR ((DE “Dementia” OR DE “AIDS Dementia

Complex” OR DE “Dementia with Lewy Bodies” OR DE

“Presenile Dementia” OR DE “Semantic Dementia” OR

DE “Senile Dementia” OR DE “Vascular Dementia” or DE

“Alzheimer’s Disease” OR TI “dementia” or AB “dementia”

or TI “Alzheimer*” or AB “Alzheimer*”) AND (TI “sleep”

or AB “sleep” or DE “Sleep” or DE “Sleep Disorders” or

TI “circadian” or AB “circadian” or DE “Human Biological

Rhythms” or DE “Sleep Wake Cycle”)) OR ((TI “owl” or AB

“owl” OR TI “owls” or AB “owls” or TI “lark” or AB “lark”

OR TI “larks” or AB “larks” or TI “morningness” or AB

“morningness” or TI “eveningness” or AB “eveningness” or

TI “morning types” or AB “morning types” or TI “morning

type” or AB “morning type” or TI “evening types” or AB

“evening types” or TI “evening type” or AB “evening type”

or TM “Horne and Ostberg Morningness-Eveningness

Questionnaire”) and (TI “sleep” or AB “sleep” or DE “Sleep”

or DE “Sleep Disorders” or TI “circadian” or AB “circadian”

or DE “Human Biological Rhythms” or DE “Sleep Wake

Cycle”)) AND ((randomized controlled trial[pt] OR controlled

clinical trial[pt] OR randomized[tiab] OR placebo[tiab]

OR “drug therapy”[Subheading] OR randomly[tiab] OR

trial[tiab] OR groups[tiab]) NOT (“animals”[MeSH Terms]

NOT “humans”[MeSH Terms])) AND ((English[la] AND

(“2006/10/01”[PDAT] : “3000/12/31”[PDAT]) NOT (Comment

[pt] OR Editorial [pt] OR News [pt] OR Newspaper Article

[pt] OR Letter [pt] OR Case Reports [pt] OR Review [pt]))

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

Terms for the Literature Search for Harms/Adverse

Effects of light Treatment (Pubmed Database)

(harm* OR “side effect*” OR “adverse effect*”) and (Light*

OR “light therapy*” OR “light exposure*” OR “Light

treatment*”) and “sleep”

Terms for the Literature Search for Harms/Adverse

Effects of Treatment with Hypnotics (Pubmed

Database)

(harm* OR “side effect*” OR “adverse effect*”) and

(hypnotic*)

Terms for the Literature Search for Harms/Adverse

Effects of Melatonin Treatment (Pubmed Database)

(harm* OR “side effect*” OR “adverse effect*”) and

(melatonin*)

Limits Used for the Searches of Harms/Adverse

Effects of Treatments

Article types: meta-analysis, systematic review

Species: humans

Languages: English

Table S1—Light treatment compared to placebo for ASWPD in adults.

Bibliography:

Palmer et al., 2003;

Campbell et al., 1993.

CI of the absolute effect crosses the clinical signicance threshold (dened by the TF) on both

sides of the “no effect” line.

CI of the absolute effect crosses the clinical signicance threshold dened by the TF.

CI of the absolute effect crosses the clinical

signicance threshold (dened by the TF) and the “no effect” line. aMT6, 6-sulfatoxymelatonin (urinary metabolite of melatonin); TST, total sleep time; ISL,

initial sleep latency; SOT, sleep onset time; SOffT, sleep offset time; CBT

Min

, core body temperature minimum; CI, condence interval; min, minutes; PSG,

polysomnography; TF, task force.

Summary of Findings Tables (Tables S1–S12)

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Table S2—Melatonin treatment compared to placebo for DSWPD in adults with and without depression.

Bibliography:

Kayumov et al., 2001;

Mundey et al., 2005;

Rahman et al., 2010.

In studies with crossover design, where more than one measurements

were taken on the same patients, all calculations were made based on the number of measurements.

High level of heterogeneity.

CI of the absolute

effect crosses the clinical signicance threshold dened by the TF.

CI of the absolute effect crosses the clinical signicance threshold (dened by the TF)

and the “no effect” line.

CI of the absolute effect crosses the clinical signicance threshold (dened by the TF) on both sides of the “no effect” line. TST,

total sleep time; ISL, initial sleep latency; DLMO, dim light melatonin onset; SOT, sleep onset time; SOffT, sleep offset time; CI, condence interval; PSG,

polysomnography; TF, task force; min, minutes.

Table S3 —Melatonin treatment compared to placebo for DSWPD in children/adolescents with no comorbidities.

Bibliography: van Geijlswijk et al., 2010.

CI of the absolute effect crosses the clinical signicance threshold dened by the TF on both sides of the “no effect”

line.

CI of the absolute effect crosses the clinical signicance threshold (dened by the TF) and the “no effect” line.

CI of the absolute effect crosses the

clinical signicance threshold dened by the TF. DLMO, dim light melatonin onset; ISL, initial sleep latency; SOT, sleep onset time; CI, condence interval;

mg, milligrams; min, minutes; kg, kilograms; TF, task force.

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Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders

Table S4—Melatonin treatment compared to placebo for DSWPD in children/adolescents comorbid with psychiatric conditions.

Bibliography:

Smits et al., 2001;

van der Heijden et al., 2007.

CI of the absolute effect crosses the “no effect” line and the clinical signicance threshold

dened by the TF.

CI of the absolute effect crosses the clinical signicance threshold dened by the TF.

CI of the absolute effect crosses the clinical

signicance threshold (dened by the TF) on both sides of the “no effect” line. TST, total sleep time; ISL, initial sleep latency; DLMO, dim light melatonin

onset; SOT, sleep onset time; SOffT, sleep offset time; CI, condence interval; TF, task force; min, minutes.

Table S5—Vitamin B12 compared to placebo for DSWPD in adults.

Bibliography: Okawa et al., 1997.

CI of the absolute effect crosses the clinical signicance threshold dened by the TF. TST, total sleep time; SOT, sleep

onset time; CI, condence interval; TF, task force; min, minutes.

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Table S6 —Light/combination treatment compared to controls for DSWPD in adults.

Bibliography:

Cole et al., 2002;

Lack, Bramwell et al., 2007.

This is a short paper with lack of detail in methods and results; a lot of information is missing.

Condence interval of the absolute effect crosses the clinical signicance threshold (dened by the TF) on both sides of the “no effect line.”

Condence

interval of the absolute effect crosses the “no effect” line.

Condence interval of the absolute effect crosses the clinical signicance threshold dened by

the TF. TST, total sleep time; SOT, sleep onset time; SOffT, sleep offset time; aMT6, 6-sulfatoxymelatonin (urinary metabolite of melatonin); CI, condence

interval; TF, task force; min, minutes.

Table S7—Light/combination treatment (multicomponent behavioral interventions + light) compared to controls for DSWPD in

children/adolescents.

Bibliography: Gradisar et al., 2011.

Study was not blinded, and an intention to treat analysis was NOT utilized.

CI of the absolute effect does not reach

clinical signicance threshold dened by the TF. TST, total sleep time; ISL, initial sleep latency; SOT, sleep onset time; SOffT, sleep offset time; CI,

condence interval; TF, task force; min, minutes.

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Table S8 —Melatonin treatment compared to placebo for N24SWD in blind adults.

Bibliography: Lockley et al., 2000; Sack et al., 2000; Hack et al., 2003. CI, condence interval; OR, odds ratio.

Table S9 —Light treatment compared to placebo for ISWRD in elderly with dementia.

Bibliography:

Dowling et al., 2008;

Mishima et al., 1994.

A. No intention-to-treat principle: only completed cases were analyzed. B. Selective reporting:

dropouts are not described and some actigraphy variables are not reported (sleep onset, offset, sleep efciency etc.).

CI of the absolute value crosses the

clinical signicance threshold (dened by the TF) on both sides of the “no effect” line.

A. No blinding, B. No intention-to-treat principle observed. C. Role

of control group is vaguely described.

CI of the absolute effect crosses the clinical signicance threshold (dened by the TF) on both side of the “no effect”

line. TST, total sleep time; CI, condence interval; TF, task force; min, minutes.

Table S10—Melatonin treatment compared to placebo for ISWRD in elderly with dementia.

Bibliography: Serfaty et al., 2002.

CI of the absolute effect crosses the clinical signicance threshold (dened by the TF) on both sides of “no effect” line.

TST, total sleep time; CI, condence interval; TF, task force; min, minute.

Table S11—Melatonin treatment compared to placebo for ISWRD in children/adolescents with neurologic disorders.

Bibliography: Wright et al., 2011.

CI of the absolute effect crosses the clinical signicance threshold dened by the TF. TST, total sleep time; ISL, initial

sleep latency; CI, condence interval; TF, task force; min, minutes.

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Table S12—Comparison of combination of light therapy and melatonin/placebo for ISWRD in elderly with dementia.

Bibliography: Dowling et al., 2008.

A. No intention-to-treat principle: only completed cases were analyzed. B. Selective reporting: dropouts are not

described and some actigraphy variables are not reported (sleep onset,/offset, etc.).

CI of the absolute effect crosses the clinical signicance threshold

(dened by the TF) on both sides of the “no effect” line. PSWS, prescribed sleep-wake scheduling; TST, total sleep time; CI, condence interval; TF, task

force; min, minutes.