SalinanterjemahanCRSWD Intrinsic

7/25/2019 SalinanterjemahanCRSWD Intrinsic

1/71

pii: jc-00358-15 http://dx.doi.org/10.5664/jcsm.5100

Pedoman Praktek Kinis !nt!k Pengo"atan intrinsik

#ircadian $h%thm &angg!an 'id!r-(ake: )anj!tan

tid!r-Phase (ake *isorder +,(P* 'ert!nda tid!r-"ang!n 'ahap *isorder +*(P* on-4-2o!r eep-

(ake $h%thm *isorder +4(* dan tidak terat!r

eep-(ake $h%thm *isorder +($*. pdate 015

,n ,merican ,cadem% o eep edicine #inica

Practice &!ideineR. Robert Auger, MD1; Helen J. Burgess, PhD2; Jonathan S. Emens, MD3; Lum!la ". Der!#, PhD$; Sherene M. %homas, PhD$;

&ather!ne M. Shar'e#, MD, PhD( 1Ma#o Pusat Slee) Me!*!ne, Ro*hester, M+; 2Rush n!-ers!t# Me!*al enter, h!*ago, /L;

3Portlan "A Me!*al enter, Portlan, 0R; $Amer!*an A*aem# o Slee) Me!*!ne, Dar!en, /L; (Bron n!-ers!t#,

Pro-!en*e, R/

$ingkasan

TF. TF dikembangkan hasil berbasis konsensus yang relevan, dinilai kepentingan relatif mereka, dan ditentukan

batas signifikansi klinis. Data diekstrak dikumpulkan di studi Tujuan

untuk setiap ukuran hasil sesuai dengan pertanyaan

PICO, Dokumen ini menggantikan update !meri" sebelumnya

dan berdasarkan diagnosis C#$%D, desain

penelitian, pop pasien dapat !&ademy of $leep 'edi&ine Parameter (!!$') Praktek

modulasi , hasil dari bunga, dan metode derivasi.

$tatistik yang berkaitan dengan C#$%Ds intrinsik (yaitu, !$%PD, D$%PD,

analisis vertikal dilakukan dengan menggunakan

perangkat lunak khusus, dan *+$%D, dan I$%#D). Pengobatan tersisa C#$%Ds

meta"analisis diselesaikan ketika berlaku. The

-#!D tidak ditangani.

(-rading Penilaian #ekomendasi, Pengembangan, dan valuasi) Pendekatan yang digunakan untuk

mengembangkan'etodologirekomendasi

laporan seperti dan untuk menentukan arah dan

kekuatan dari The !!$' menugaskan $atuan Tugas (TF) dari anggota

rekomendasi ini berdasarkan pada penilaian

komposit dengan keahlian di bidang C#$%Ds, menunjuk De/an

kualitas bukti, keuntungan versus kerugian

analisis, dan Direksi pasien (0OD) penghubung, dan diberi $ains dan #esear&h.

nilai"nilaidan preferensi !nggota staf

departemen untuk mengelola proyek. PICO (Pa" ra/at, Penduduk atau masalah, Intervensi, Perbandingan, dan


2/71

Temuan 1asil) pertanyaan yang dikembangkan

oleh TF dan disetujui

data yang tersedia memungkinkan untuk

disahkan positif (pada detik" oleh Direksi. Pen&arian literatur luas dilakukan untuk

O*D"tier tingkat keper&ayaan) dari melatonin

strategis /aktunya mengidentifikasi artikel yang menarik, dan data yang relevan diekstraksi oleh

(untuk pengobatan D$%PD, orang de/asa buta dengan *+$%D, dan

a#TI23 214$4$

Sebuah tinjauan literatur sistematis dan meta-analisis (jika perlu) dilakukan dan pendekatan GRADE digunakan

untuk memperbarui American Academy sebelumnya Parameter Sleep Medicine Praktek pada pengbatan ritme

sirkadian gangguan tidur-bangun intrinsik! Data yang tersedia memungkinkan untuk disahkan psiti" (pada derajat

kedua-tier kepercayaan) dari melatnin strategis berjangka #aktu (untuk pengbatan DS$PD% rang de#asa buta

dengan &'S$D% dan anak-anak remaja dengan *S$RD dan gangguan neurlgis kmrbiditas)% dan terapi

cahaya dengan atau tanpa disertai inter+ensi perilaku (rang de#asa dengan AS$PD% anak-anak remaja dengan

DS$PD% dan lansia dengan demensia)! Rekmendasi terhadap penggunaan melatnin dan diskrit bat tidur-

memprmsikan disediakan untuk pasien usia lanjut gila% pada

11 Journal o l!n!*al Slee) Me!*!ne, "ol. 11, +o. 14, 241(

derajat kedua dan pertama-tier kepercayaan masing-masing! ,idak ada rekmendasi yang diberikan untuk sisa

pera#atan ppulasi% karena data baik tidak cukup atau tidak ada! Area dimana penelitian lebih lanjut diperlukan

dibahas! ata kunci. ritme sirkadian% DS$PD% AS$PD% &'S$D% *S$RD /itatin. Auger RR% 0urgess 12% Emens

2S% Deriy 34% ,hmas SM% Sharkey M! Praktek klinis pedman untuk pengbatan ritme sirkadian gangguan tidur-

bangun intrinsik. gangguan "ase tidur-bangun canggih (AS$PD)% tertunda tidur-bangun gangguan "ase (DS$PD)%

nn-'-jam tidur-bangun gangguan irama (&'S$D)% dan tidak teratur tidur-bangun gangguan irama (*S$RD)!

5pdate untuk '678! 2 /lin Sleep Med '6789 77 (76). 77:: -7';


3/71

RR Auger% 12 0urgess% 2S Emens et altanpa!!

anak remaja dengan I$%#D dan komorbiditas neurologi" kal gangguan), dan terapi &ahaya dengan atau

a&&ompany" ing intervensi perilaku (orang de/asa dengan !$%PD, anak"anak remaja dengan D$%PD, dan lanjut

usia dengan demensia dan I$%#D). #ekomendasi terhadap penggunaan melatonin dan diskrit obat tidur"

mempromosikan disediakan untuk pasien usia lanjut mented de", di tingkat kedua dan pertama"tier keper&ayaanmasing"masing. Tidak ada rekomendasi yang diberikan untuk sisa pera/atan populasi, karena data baik tidak

&ukup atau tidak ada.

$ekomendasi adaah se"agai engik!ti

!$%PD 5.6.a TF menunjukkan bah/a dokter mengobati pasien !$%PD de/asa dengan terapi &ahaya malam

(versus tidak ada pera/atan). 73'!1 4*T428

D$%PD 5.+.9.6a TF menunjukkan bah/a dokter mengobati D$%PD pada orang de/asa dengan dan tanpa depresi

dengan melatonin strategis berjangka /aktu (versus tidak ada pera/atan). 73'!1 4*T428

5.+.9.+.6a TF menunjukkan bah/a dokter memperlakukan anak"anak dan remaja dengan D$%PD (dan tidak ada

komorbiditas) dengan melatonin strategis berjangka /aktu (versus tidak ada pera/atan). 73'!1 4*T428

5.+.9.+.+a TF menunjukkan bah/a dokter memperlakukan anak"anak dan remaja dengan D$%PD komorbiditasdengan kondisi keji/aan dengan melatonin strategis berjangka /aktu (versus tidak ada pera/atan). 73'!1

4*T428

5.+.:.+a TF menunjukkan bah/a dokter memperlakukan anak"anak dan remaja dengan D$%PD dengan terapi

&ahaya pas&a"kebangkitan dalam hubungannya dengan perilaku pera/atan (versus tidak ada pera/atan). 73'!1

4*T428

*+$%D 5.;.9.6a TF menunjukkan bah/a dokter menggunakan melatonin strategis /aktunya untuk pengobatan

*+$%D pada orang de/asa yang buta (versus tidak ada pera/atan). 73'!1 4*T428

I$%#D 5..a TF menunjukkan bah/a dokter mengobati I$%#D pada pasien usia lanjut dengan demensia dengan

terapi &ahaya (versus tidak ada pera/atan). 73'!1 4*T428

5..5a TF merekomendasikan bah/a dokter menghindari penggunaan obat tidur"mempromosikan untuk mengobatipasien tua gila dengan I$%#D (versus tidak ada pera/atan). 724!T '3!%!*8

5..9.6a TF menunjukkan bah/a dokter menghindari penggunaan melatonin sebagai pengobatan untuk I$%#D

pada orang yang lebih tua dengan demensia (versus tidak ada pera/atan). 73'!1 T#1!D!P8


5..9.+a TF menunjukkan bah/a dokter menggunakan strategis /aktunya melatonin sebagai pengobatan untuk

I$%#D pada anak"anak remaja dengan gangguan neurologis (versus tidak ada pera/atan). 73'!1 4*T428

5..:.6a TF menunjukkan bah/a dokter menghindari penggunaan pengobatan kombinasi yang terdiri dari terapi

&ahaya dalam kombinasi dengan melatonin di gila, pasien usia lanjut dengan I$%#D (versus tidak ada pera/atan).

73'!1 T#1!D!P8

Kesimp!an

Penggunaan sistem -#!D untuk Pedoman Ti&e ini diperbarui Clini&al"praktek merupakan perubahan besar.

Pembaruan ini harus menyediakan dokter dengan keyakinan yang meningkat sehubungan dengan resep pilih

pera/atan dan, sama"sama penting, harus berfungsi sebagai peta jalan untuk studi masa depan yang akan

mendorong kualitas yang lebih tinggi, terapi yang lebih &anggih untuk C#$%Ds intrinsik.


4/71

Pengbatan Gangguan intrinsik /ircadian Rhythm Sleep-$ake

1.0

P*D!1434!*!meri&an !&ademy of $leep 'edi&ine (!!$') pro diproduksi Parameter pertama Pra&ti&e

(dan terkait ulasan) untuk evaluasi dan pengobatan ritme sirkadian gangguan tidur"bangun (C#$%Ds) di +


5/71

The C#$%Ds intrinsik se&ara singkat di&irikan sebagai berikut. D$%PD bermanifestasi sebagai penundaan

episode tidur utama sehubungan dengan /aktu pasien diinginkan atau /aktu yang diperlukan untuk menghadiri

sosial, pendidikan, dan atau tuntutan pekerjaan. Pasien melaporkan kesulitan ekstrim baik dengan jatuh tertidur

pada /aktu tidur"dianggap khas di antara rekan"rekan mereka, dan dengan bangun pada /aktu yang diperlukan atau

diinginkan, tetapi kualitas tidur biasanya re" porting seperti biasa ketika individu tidur pada /aktu yang tertunda.

$ebaliknya, uang muka episode tidur utama sehubungan dengan pasien yang diinginkan atau dibutuhkan kali tidur"

bangun karakter"iBes !$%PD. Pasien !$%PD melaporkan kesulitan ekstrim tetap terjaga selama jam malam dan

sering perhatikan jatuh tertidur sebelum menyelesaikan pekerjaan yang bersangkutan, sosial, atau ke/ajiban

keluarga. $elain itu, bangun /aktu tidak diinginkan a/al, dan dianggap atypi" kal dibandingkan dengan rekan"

rekan. 4ntuk kedua kondisi, gejala harus hadir untuk setidaknya ; bulan dan jad/al harus didokumentasikan dengan

buku harian tidur dan atau pergelangan a&tigraphy untuk jangka /aktu minimal = hari.

*+$%D didiagnosis ketika pasien gagal naik kereta api ke +" terang"gelap jam siklus dan jam kali. Dengan

demikian, pasien menunjukkan pola tidur"bangun yang menunjukkan penundaan progresif (biasanya) atau uang

muka, tergantung pada panjang periode (tau) dari en" ritme sirkadian dogenous mereka. $elama periode gejala, saat

ke&enderungan tidur tinggi se&ara bertahap bergeser, sehingga pasien mengalami siang hipersomnolen dan insomnia

malam hari. 2ebanyakan pasien dengan *+$%D yang benar"benar buta, tapi gangguan ini juga terjadi di antara

individu terlihat. 0erbeda dengan C#$%Ds lainnya, diagnosis *+$%D membutuhkan setidaknya 6 hari

umentation"ajaran dari semakin menggeser kali tidur"bangun dengan buku harian tidur dan atau a&tigraphy.

Pasien dengan I$%#D kekurangan pola sirkadian yang jelas dari perilaku bangun tidur". Dengan demikian,

individu yang menderita mengalami pro merindukan periode terjaga selama episode tidur malam yang khas di

samping kantuk yang berlebihan dan serangan tidur berkepanjangan selama siang hari. Tidur terfragmentasi dan

sering tidak &ukup. I$%#D diamati lebih umum di antara pasien dengan gangguan tive perkembangan saraf atau

neurodegenera", dan dapat menimbulkan tantangan khusus untuk ers &aregiv". Dokumentasi (buku harian tidur dan

atau a&tigraphy) dari beberapa serangan tidur"bangun non"sirkadian untuk jangka /aktu minimal = hari diperlukan

untuk diagnosis.



6/71

RR Auger% 12 0urgess% 2S Emens et al!

,abel 7-P*/= parameter pertanyaan!

Pend!d!k nter9ensi Per"andingan 2asi

Pasien yang didiagnsis dengan /RS$Ds intrinsik (AS$PD% DS$PD% &'S$D% *S$RD)

Intervensi untuk C#$%Ds dapat dikategorikan sebagai terendah follo/> (6) /aktu yang ditentukan tidur"bangun

dan atau aktivitas fisik olahraga, (+) penerimaan strategis dan atau menghindari &ahaya, (;) penggunaan obat

dan atau suplemen untuk phase shift dan atau untuk mempromosikan tidur atau terjaga, dan () intervensi

alternatif yang mengerahkan dampak bagi dengan mengubah fungsi tubuh berdampak tidur bangun perilaku (yaitu,

intervensi somatik).

Cahaya yang strategis /aktunya sesuai dengan kurva respon fase (P#C$)

membina hubungan anak, dan ditugaskan seorang staf !!$' $ains dan Departemen #iset untuk mengelola proyek.

$ebelum diangkat, para ahli konten diminta untuk mengungkapkan semua potensi konflik kepentingan sesuai

dengan kebijakan !!$'. Tak satu pun dinyatakan. TF dilakukan tinjauan luas dari literatur ilmiah dan menilai bukti

yang mempekerjakan metodologi kedokteran berbasis bukti (khusus, meta"analisis dan -rading Penilaian

#ekomendasi, Development dan sistem evaluasi, atau -#!D) untuk meran&ang rekomendasi"rekomendasi.

Tulisan ini telah disetujui oleh !!$' 0OD dan) mengarah ke fase penundaan, dan &ahaya /aktunya setelah C0T"


7/71

menggantikan sebelumnya Praktek Parameters.6 !!$' mengharapkan

diamati menit

di pagi hari dengan lead intensitas yang lebih besar untuk phase advan&es.65 &ahaya dan lebih besar efek lagi durasi

pedomanini untuk memiliki dampak positif pada pengambilan keputusan klinis dan hasil pasien. #ekomendasi ini

men&erminkan &ahaya, tetapi kenaikan ini nonlinear.69,6= $elain itu, ulang

keadaan pengetahuan pada saat publikasi dan

akan tanggapan terhadap &ahaya diubah oleh paparan sebelum &ahaya atau ?&ahaya

direvisi ketika ketersediaan informasi baru

membutuhkan. sejarah, ?6,6: sehingga sejarah paparan kurang &ahaya mengarah ke respon yang lebih besar

terhadap &ahaya. $ama seperti paparan &ahaya dapat menggeser &ir&a"

;,+ PICO Pertanyaan /aktu dian, sehingga juga

bisa menghindari strategis atau pengurangan

Delapan PICO (Pasien, Penduduk atau

masalah, Intervensi, light.+


8/71

Penjelasan rekomendasi Pra&ti&e Parameter

reEuir" dipublikasikan). $elain fase efek pergeseran, melatonin dapat

ing revisi, dan juga dibantu dengan

penyempurnaan lebih lanjut dari juga memiliki efek obat tidur langsung, terutama pada dosis yang lebih tinggi.

Pertanyaan PICO. Pen&arian literatur berikutnya (G +) ditargetkan uji perlakuan yang melibatkan C#$%Ds intrinsik

yang ditujukan minimal

30 '*

satu pertanyaan PICO. Pen&arian ini dimanfaatkan database Pub'ed, mbase, dan Psy&I*FO.

$etidaknya dua anggota TF hati"hati menilai

abstrak ;.6 Apert Task For&e

setiap artikel diambil (n +



9/71

Pengbatan intrinsik /ircadian Rhythm Gangguan ,idur-$ake

,abel hasil '-R*,*S dan ,C-dide"inisikan ambang signi"ikansi klinis mereka!

#inica igniikansi ,m"ang "atas #ircadian 'ahap *iagnosis

+per!"ahan menit

6. Diagnosis atau tidak pengobatan +. Tidak C#$%D ;. C#$%D Tidak intrinsik (shift kerja atau gangguan jet"lag)

. $alah jenis publikasi (revie/, editorial, dll) 5. Tidak subyek manusia 9. studi mekanistik atau metodologis =. $tudi

itu diterbitkan sebelum Oktober +


10/71

untuk *+$%D, yang statusnya entrainment (yaitu, apakah jam biologis yang disinkronkan dengan hari + jam)

semata"mata dimanfaatkan sebagai ukuran hasil 2#ITI$, karena mendefinisikan C#$%D ini fisiologis (lihat bagian

5.; di ini kertas).

3.5 kstraksi "!kti

Data kuantitatif berkaitan dengan hasil yang menarik serta informasi yang diperlukan untuk evaluasi yang

sistematis dan grading bukti yang diambil dari artikel diterima menggunakan spreadsheet berdedikasi. !rtikel

bertekad untuk kekurangan data kuantitatif atau dengan data yang disajikan dalam format ketidak"&o&okan dengan

analisis statistik yang diinginkan ditolak pada tahap ini, tapi digunakan se&ara selektif untuk diskusi lebih lanjut.

Dalam kasus di mana data yang diinginkan yang tersedia tetapi tidak disajikan dalam gelaran untuk" diinginkan,

penulis dihubungi, dan data mentah diperoleh jika memungkinkan. Data dikumpulkan seluruh studi untuk setiap

ukuran hasil sesuai dengan pertanyaan PICO dan berdasarkan diagnosis, desain penelitian, populasi pasien, hasil

klinis yang menarik, dan metode derivasi (misalnya, P$- berasal Data dianalisis se&ara terpisah dari data yang

berasal dari a&tigraphy atau buku harian tidur).

3.6 anaisis statistik

'eta"analisis diselesaikan (dalam beberapa kasus memung" kinkan) menggunakan model efek a&ak. $emua

perhitungan yang dilakukan menggunakan 4lasan soft/are 'anager, +9 dan termasuk perhitungan dari perbedaan

rata"rata ('D) standar deviasi ($D) untuk hasil 2#ITI$. *ilai dianalisis dengan &ara ini akan ditampilkan ke

tempat seratus. Demografi usia dan informasi mengenai dosis melatonin disajikan dalam format yang disediakan

oleh studi terkait (mean $D jika tersedia) tetapi, dalam upaya untuk menjaga konsistensi, ditampilkan hanya untuk

tempat persepuluh dalam kasus di mana penulis pro vided nilai"nilai dengan nilai tempat numerik dari hirarki yang

lebih rendah. 1asil meta"analisis yang digambarkan dalam angka dalam



11/71


Gambar 7-Panduan untuk interpretasi signi"ikansi klinis dari hasil!

,

7

#

signi"ikansi klinis

signi"ikansi klinis

ambang batas signi"ikansi

klinis dide"inisikan leh ,C

ambangdide"inisikan leh ,C

ambang batas yang ditetapkan leh,C

/nthdari (A) peningkatan yang signi"ikan secara klinis9 (0) @serius@ ketidaktepatan% kelas satu tingkat ke ba#ah9

(/) @sangat serius@ ketidaktepatan% kelas dua tingkat ke ba#ah!

Teks, berkaitan dengan ?ren&ana hutan.? #ingkasan temuan tabel untuk semua investigasi disajikan dalam 3ampiran.

2etika studi yang terdapat kelompok plasebo kontrol, asi evalu" efek pengobatan dilakukan dengan

perbandingan pas&a"pera/atan rata"rata dan rata"rata post"pla&ebo kontrol nilai"nilai kelompok, terlepas dari

pendekatan penulis @. Dalam studi dengan Crossover atau ?sebelum"sesudah? desain di mana tidak ada kelompok

plasebo kontrol, nilai"nilai pas&a"pera/atan dibandingkan dengan nilai"nilai dasar. 2ami menggunakan metodologi

ini kadang"kadang pro" hasil yang diinduksi yang berbeda dari yang dilaporkan dalam publikasi asli (eg+="+:).

3.< nterpretasi igniikansi kinis 2asi

Interpretasi signifikansi klinis dipastikan melalui perbandingan dengan batas yang telah ditetapkan (lihat Tabel +

dan -ambar 6 ). 4ntuk meta"analisis, yang dikumpulkan 'D (diamond hitam) dari ?plot hutan? menggambarkan

respon rata"rata atau besarnya efek di semua studi, lebar berlian me/akili terkait :5J &onfiden&e interval (CI), dan

?tidak ada ef " fe&t ?garis me/akili manfaat nihil dari intervensi. The dot ted garis pada sisi kiri dan kanan (berjarak

sama dari garis ?tidak berpengaruh?) merupakan ambang batas keputusan klinis didefinisikan oleh TF (!ngka 6!,

60, dan 6C). $isi kanan merupakan peningkatan dalam ukuran hasil, sementara sebelah kiri me/akili penurunan.

Peningkatan dalam beberapa ukuran hasil, seperti T$T, me/akili peningkatan. Hika berlian hitam data T$T terletak

di luar batas signifikansi klinis di sisi kanan, hasil dari pengobatan ditafsirkan sebagai perbaikan klinis yang

signifikan (-ambar 6!). *amun, jika berlian terletak di sebelah kiri garis ?signifikansi klinis?, penurunan ini

dianggap sebagai hasil yang tidak diinginkan yang signifikan se&ara klinis, dan pengobatan yang dianggap

kontraindikasi. 2etika peningkatan ditandai dengan penurunan ukuran hasil (misalnya, I$3), yang interpretasi

dibalik.

2etika interval keper&ayaan melintasi batas signifikansi klinis di satu sisi, bukti tersebut dinilai satu tingkat ke

ba/ah (-ambar 60) untuk ?ketidaktepatan serius.? 2etika interval keyakinan mengenai melintasi batas signifikansi

klinis

dikedua sisi garis tidak berpengaruh, bukti tersebut dinilai dua lev" els turun untuk ?ketidaktepatan yang sangat

serius? (-ambar 6C). 2arena perangkat lunak 4lasan 'anager tidak beroperasi dengan batas signifikansi klinis,

garis"garis putus"putus tidak digambarkan dalam angka yang terkait dengan data aktual. . Penafsiran signifikansi

klinis dari hasil penelitian individu di&apai dengan &ara yang sama, tapi plot hutan tidak di&iptakan

38 K!aitas 7!kti

Pendekatan -#!D digunakan untuk penilaian 2ualitas kepemilikan eviden&e;


12/71

///.grade/orkinggroup. org publikasi HCKseries.htm). 0erbeda dengan ods meth" lainnya, perkiraan efek

yang dihasilkan untuk hasil penting di studi, sebagai la/an evaluasi dari studi yang dilakukan individu. 0eberapa

aspek kualitas bukti yang dinilai, dengan penurunan tingkat bukti yang berlaku (lihat Tabel ;).

-#!D memberikan kualitas tinggi untuk bukti dari per&obaan terkontrol a&ak sementara bukti dari studi

observasional dianggap kualitas rendah. *amun, bukti kualitas tinggi dapat dinilai turun, dan bukti kualitas rendah

dapat dinilai up, berdasarkan faktor di ba/ah ini (lihat Tabel ;). !nalisis risiko bias meliputi peninjauan kehadiran tiadanya menyilaukan, alokasi penyembunyian, mangkir, atau hasil selektif pelaporan. Indire&tness terjadi ketika

pertanyaan yang ditujukan berbeda dari bukti yang tersedia dalam hal populasi, intervensi, pembanding, atau hasil.

!da inkonsistensi ketika ada heterogenitas dijelaskan hasil. 2etidaktepatan dijelaskan dalam detik" tion ;,= dalam

makalah iniTinggi>..

Pada -#!D, ada kategori khusus untuk menilai kualitas tubuh bukti

$esuai dengan tingkat kepastian yang tinggi bah/ayangbenar

efek terletak dekat dengan yang dari perkiraan efeknya. 'oderat> sesuai dengan tingkat moderat kepastian

dalamestimasi efekL efek yang benar adalah mungkin dekat dengan perkiraan efek, tetapi ada kemungkinan bah/a

hal itu se&ara substansial berbeda.

124$ Journal o l!n!*al Slee) Me!*!ne, "ol. 11, +o. 14, 241(


13/71

Pengbatan intrinsik /ircadian Rhythm Gangguan ,idur-$ake

,abel ;-Ringkasan pendekatan GRADE kualitas #isata#an bukti (dari Guyatt et al!;6)!

nitia =!ait% dari *esaint!di

'!"!h 7!kti *o>ngrade jika 'ingkatkan jika =!ait% o a 7od% o 9idence

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 ublication bias 1 Serious 2 Very serious

3o/> &orresponds to a lo/ level of &ertainty in the effe&t estimateL the true effe&t may be substantially different from

the estimate of the effe&t. Mery lo/> &orresponds to very little &ertainty in the effe&t estimateL the true effe&t is likely

to be substantially different from the estimate of effe&t. The body of eviden&e for ea&h out&ome /as assessed and

graded, taking into a&&ount Euality &onsiderations based on the Euantitative analysis and other major fa&tors

des&ribed above. C#ITIC!3 out&ome results are presented as summary of findings tables organiBed by PICOEuestion and patient pop" ulation (see !ppendiA, Tables $6N$6+).

! &umulative Euality grade for a parti&ular PICO Euestion and patient population is predi&ated upon the lo/est

level of eviden&e assigned to one of the C#ITIC!3 out&omes. Thus, if a re&ommendation /as based upon t/o

out&omes, one of mod" erate and one of lo/ Euality, the overall grade /ould be lo/.

3.? trength o $ecommendations

The TF developed re&ommendation statements and deter" mined the strengths of these re&ommendations based on

the balan&e of the follo/ing major fa&tors>

6. 3evel of eviden&ebased on an assessment of the

Euality of eviden&e using -#!D &riteria (see Table ;), the TF &ategoriBed the eviden&e as>

a. 1igh b. 'oderate &. 3o/ d. Mery 3o/ +. 0enefits vs. 1armsbased upon C#ITIC!3 out&omes and analysis of

any harmsside effe&ts, the TF assessed /hether>

a. 0enefits out/eighed harms b. 0enefits eEualed harms &. 1arms out/eighed benefits d. The balan&e bet/een

benefits and harms /as un&lear ;. Patient values and preferen&esbased on the &lini&al

eApertise of the TF and relevant published data,

3arge e""ect

7 3arge ' 4ery large Dse respnse

7 E+idence " a

gradient All plausible residual cn"unding

7 $uld reduce

a demnstrated e""ect 7 $uld suggest

a spurius e""ect i" n e""ect #as bser+ed

High !four plus" ####$

%oderate !three plus" ###&$

'bser(ational studies )o* )o* !t*o plus" ##&&$

Very )o* !one plus" #&&&$


14/71

in&luding dis&ussion in the referen&ed papers about tolerability, &omplian&e, and patients@ eAperien&es /ith the

treatments in Euestion, the TF judged /hether>

a. The vast majority of /ell"informed patients ( :


15/71


,able FDe"initins " AASM strengths " recmmendatins!

,, trength o $ecommendation xampe #haracteristics &!iding $ecommendation

,here is a high degree " clinical certainty in the net bene"its " this patient-care strategy!

S,R=&G

,he +ast majrity " #ell-in"rmed patients #uld mst likely chse this patient-care strategy% cmpared t

alternati+e patient-care strategies r n treatment!

C=R

,here is a l#er degree " clinical certainty in the balance bet#een bene"its +s! harms (eg% net bene"its) "

$EA

this patient-care strategy!

,he majrity " #ell-in"rmed patients #uld mst likely chse this patient-care strategy% cmpared t alternati+e

patient-care strategies r n treatment!

AGA*&S,

4.0 2,$ ,* ,*@$ ;;#'

4.1 )ight 'herap%

*o studiesrevie/s /ere identified that spe&ifi&ally ad" dressed potential harms among patients /ith C#$%Ds. In

their Co&hrane $ystemati& #evie/ for the treatment of non" seasonal depression, Tuunainen and &olleagues; found

that hypomania /as the sole side effe&t that /as more &ommon among patients re&eiving light therapy versus

&ontrols (#ela" tive #isk .:6 7CI 6.99N.98). *evertheless, light treatment has been safely used for the treatment of

bipolar depression, /ith &areful monitoring.;:

Other &ommonly des&ribed side effe&ts in&lude eyestrain, nausea, and agitation, albeit /ith predominant

spontaneous remission. Treatment"emergent heada&hes also &ommonly re" mit,< but light therapy &an indu&e

migraines in approAimately one"third of those sus&eptible.6

Finally, although &ommer&ially available produ&ts do not emit ultraviolet light, patients /ith eye disease andor

those using photosensitiBing medi&ations should only use light therapy /ith periodi& ophthalmologi&al andor

dermatologi" &al monitoring of the underlying &ondition.


16/71

S,R=&G

,here is a high degree " clinical certainty in the net harms " this patient-care strategy!

,he +ast majrity " #ell-in"rmed patients #uld mst likely nt chse this patient-care strategy% cmpared t

alternati+e patient-care strategies r n treatment!

associated *ith a lack of reported serious ad(erse e+ects,--.-/ 0 re(ie* by the ational

0cademy of Sciences stated that short term use of 3 14 mg5daily !higher than typicalchronobiotic doses$ appears to be safe in healthy adults but recommended caution in

children5adolescents and *omen of reproducti(e age !see further belo*$, 0d(erse e+ects

such as headaches6 somnolence6 hypotension6 hypertension6 gastrointestinal up set6 and

e7acerbation of alopecia areata ha(e been reported at higher melatonin doses in healthy

adults6 and the same e+ects ha(e been reported at lo*er doses among those *ith rele(ant

pree7isting conditions, %elatonin has also been asso ciated *ith an increase in depressi(e

symptoms6-8 and caution is ad(ised *hen prescribing to patients taking *arfarin and to

patients *ith epilepsy6 as a result of (arious case reports sub mitted to the 9orld Health

'rganization,-: 0 recent publica tion described impairment in glucose tolerance among

healthy *omen:4 subse;uent to acute melatonin administration,

Studies that address longterm e+ects are scarce6 as are stud ies that speci 14 studies6 o(er 244 sub=ects$ used for 3 ?

months6 there *ere fe* reports of ad(erse e(ents,-/

! long"term follo/"up study of pediatri& patients /ith D$%PD attention defi&it hypera&tivity disorder (!D1D)

/ho utiliBed melatonin doses up to 6< mg (mean follo/"up time of approAimately years) dete&ted no serious

adverse events as a result of serial intervie/s /ith the &hildren@s parents, and 95J of parti&ipants &ontinued to use

the medi&ation daily.5+ ! follo/"up open"label prospe&tive study of subje&ts /ith neu" rodevelopmental disabilities&omorbid /ith D$%PD /ho re" &eived &ontrolled"release melatonin (maA dosage 65 mg) up to ;. years similarly

des&ribed no adverse events.5;,5 Patients and



17/71

,reatment " *ntrinsic /ircadian Rhythm Sleep-$ake Disrders

&aregivers are nevertheless freEuently /ary to use this supple" ment, due to &on&erns related to potential adverse

effe&ts on gro/th hormone regulation (6< mg dose),55 and on reprodu&tive fun&tiondevelopment (; mg dose).59

Possibly relevant to the latter &on&ern, Tanner stages /ere assessed serially in a Eues" tionnaire"based study

involving &hildrenadoles&ents (mean du" ration ; years), in an effort to &ompare pubertal development amongthose using melatonin (mean dose ; mg) during pre" puberty to non"melatonin users in the general Dut&h

population (&ontrols).5= *o signifi&ant group differen&es /ere dete&ted.

4.3 2%pnotics

-eneral adversities attributed to sedative"hypnoti&s (though not spe&ifi&ally among patients /ith C#$%Ds)

in&lude in" &reased risks for falls, heada&hes, nausea, medi&ation"med" i&ation intera&tions, and drug

dependen&e,5,5: /ith elderly patients at spe&ifi& high risk.9


18/71

OPTIO* in the +


19/71


,able 8F=+er+ie# " AASM recmmendatin status "r *ntrinsic /RS$D treatments

'reatment ,(P* *(P* 4(* ($*

Prescribed scheduling

sleep-#ake

& Recmmendatin & Recmmendatin & Recmmendatin & Recmmendatin

,imed physical acti+ity eHercise

& Recmmendatin & Recmmendatin & Recmmendatin & Recmmendatin

Strategic a+idance " light & Recmmendatin & Recmmendatin & Recmmendatin & Recmmendatin

3ight therapy 8!7!a $EA C=R (adults) & Recmmendatin & Recmmendatin

8!!a $EA C=R (elderly #ith dementia)

Sleep-prmting medicatins

respect to most prede8!'!

8!!

8!!


20/71

=ther smatic inter+entins & Recmmendatin & Recmmendatin & Recmmendatin & Recmmendatin

/mbinatin treatments & Recmmendatin

& Recmmendatin (adults)

8!'!:!'a $EA C=R (light therapy multicmpnent beha+iral inter+entins "r childrenadlescents)

5.4.?.1a (,K ,&,' o $ecommendation

(cmbinatin treatment " light and melatnin "r demented% elderly patients)

years). The light sour&e &onsisted of t/o light boAes (proAim" ity to sour&e not spe&ified), and therapy /as for +

hours in duration, bet/een +


21/71


,able

8!'!

cnditins #ith strategically timed melatnin (+ersus n treatment)

$EA C=R 3=$ 5ncertainty in the estimates " bene"its harms

,he majrity " patients #uld use this treatment% #ith apprpriate in"rmed cnsent "rm the patient and caregi+er!

8!'!: /mbinatin ,reatments

8!'!:!'a ,he ,C suggests that clinicians treat childrenadlescents #ith DS$PD #ith pst- a#akening light therapy in

cnjunctin #ith beha+iral treatments (+ersus n treatment)

$EA C=R 3=$ 0ene"its

ut#eigh harms

,he majrity " patients #uld use this treatment% particularly #ith acti+e caregi+er supprt!

on-4-2o!r eep-(ake $h%thm *isorder +4(*

8!;!< ,imed ral administratin " melatnin r agnists (P*/= Iuestin


22/71

ut#eigh harms

,he majrity " patients #uld use this treatment!

rreg!ar eep-(ake $h%thm *isorder +($*

8!! 3ight ,herapy (P*/= Iuestin )

8!!a ,he ,C suggests that clinicians treat *S$RD in elderly patients #ith dementia #ith light therapy (+ersus n

treatment)

$EA C=R 4ER 3=$ 0ene"its

clsely balanced #ith harms

,he majrity " #ell- in"rmed patients andr caregi+ers " #uld elect t use this treatment!

8!!8 Sleep- prmting medicatins (P*/= Iuestin 8)

8!!8a ,he ,C recmmends that clinicians a+id the use " sleep-prmting medicatins t treat demented elderly

patients #ith *S$RD (+ersus n treatment)

S,R=&G AGA*&S,

&=&EJ 1arms

ut#eigh bene"its

,he +ast majrity " #ell- in"rmed patients andr caregi+ers #uld &=, elect t use this treatment!

8!!< ,imed ral administratin " melatnin r agnists (P*/= Iuestin dementia (+ersus n treatment)

$EA AGA*&S, 3=$ 1arms

ut#eigh bene"its

,he majrity " patients andr caregi+ers #uld &=, elect t use this treatment!

8!!


23/71


$%&a The T' suggests that clinicians treat adult ASWPD patients with evening light therap" (versus no

treatment) WA* '+,

$ummary> *o treatment trials of light therapy in !$%PD have been published sin&e the +


24/71

reported as normal.5

5.2.1 Prescribed Sleep-Wake Scheduling for Patients with DSWPD

The previous re&ommendation /as designated as an OP" TIO* (spe&ifi&ally /ith respe&t to &hronotherapy, a

pres&ribed progressive delay of the sleep/ake s&hedule until the desired s&hedule is rea&hed), based upon t/o

studies /ith adult parti&i" pants.=5,=9 The 6::; study by Ito and &olleagues,=5 revie/ed pre" viously, /as not

in&luded in the &urrent analysis, as it did not investigate dis&rete sleep out&omes, but instead in&orporated subje&tiveassessments of global fun&tioning. The 6:6 study by CBeisler and &olleagues=9 /as eA&luded due to a lo/ number

of subje&ts (n 5). There is one report of an adult D$%PD patient /ho developed free"running &ir&adian rhythms

after engaging in this treatment.==

!lthough ineligible for &urrent analyses, ; studies /ere published subseEuent to availability of the previous

Pra&ti&e Parameters that may bear relevan&e to the use of pres&ribed sleep"/ake s&heduling (other than

&hronotherapy) as a ther" apy for adoles&ent patients.=N< T/o groups=:,< des&ribed potentially meaningful

out&omes, but the parameters of inter" est /ere different from those spe&ifi&ally defined by the TF, and, in the &ase

of the de $ousa study,< all parti&ipants /ere healthy adoles&ents (ie, not affli&ted /ith D$%PD). $imilarly, the

$harkey group (+


25/71


amber glasses that blocked *a(elengths 3 :?4 nm E,,,from sun do*n until bedtime e(ery

e(ening6F for a minimum of ? hours6 and for a period of 2 *eeks, @oncomitant instructions

included the use of only Goor and table lamps !ie6 a(oidance of o(erhead lights$ during the

e(ening, If a participant a*oke during the night6 he5she *as instructed to don the glassesprior to light e7posure, In addition6 sub=ects *ere gi(en speci

three revie/ed investigations provide &ontradi&tory information regarding sleep&ir&adian"related effe&ts of

melatonin among adults /ith D$%PD. 3evel of re" vie/ed eviden&e> 3O% (!ppendiA, Table $+).


26/71

In a randomiBed double"blinded pla&ebo"&ontrolled study (parallel design, n 66, mean age +.+ 5.= years+=),

'undey and &olleagues utiliBed either


27/71


Cigure 'FMeta-analysis " data "r PSG determined ,S, in respnse t melatnin treatment "

adult patients #ith DS$PD and cmrbid depressin!

Cigure ;FMeta-analysis " data "r PSG determined *S3 in respnse t melatnin treatment "

adult patients #ith DS$PD and cmrbid depressin!

$ummary> The previously published re&ommendation /as designated as a -4ID3I*. The overall Euality of

eviden&e from the analyses of the three a&&eptedrevie/ed studies+=,:

*o studies /ere previously revie/ed /hi&h dire&tly ad" dressed the pediatri&adoles&ent population. $trategi&ally

timed melatonin at the dose spe&ified belo/ is effe&tive for &hildrenadoles&ents /ith D$%PD. 3evel of revie/ed

evi" den&e> 'OD#!T (!ppendiA, Table $;).

One randomiBed, pla&ebo"&ontrolled double"blinded study /as revie/ed (unpublished ra/ data provided &ourtesy

of au" thor).+: Parti&ipants ranged in age from 9N6+ years. The three a&tive treatment groups re&eived melatonin at

dosages of


28/71

with strategicall" timed melatonin (versus no treatment) WA* '+,



29/71


Cigure FMeta-analysis " data "r D3M= in respnse t melatnin treatment "

childrenadlescents #ith DS$PD and cmrbid psychiatric cnditins!

Cigure 8FMeta-analysis " data "r actigraphically-determined S=, in respnse t melatnin

treatment " children adlescents #ith DS$PD and cmrbid psychiatric cnditins!

$ummary> This is a ne/ re&ommendation in &omparison to the prior Pra&ti&e Parameter, as no studies /ere

previously re" vie/ed /hi&h dire&tly addressed the pediatri&adoles&ent pop" ulation. The level of revie/ed eviden&e

from a singular study+: /as 'OD#!T (!ppendiA, Table $;). Optimal results /ere obtained /ith a dose of

3O% (!ppendiA, Table $) T/o randomiBed, pla&ebo"&ontrolled studies by the same group eAamined the use of

melatonin for D$%PD among &hil" drenadoles&ents /ith various psy&hiatri& &omorbidities (all /ere diagnosed

/ith !D1D).:5,:9 Parti&ipants aged 9N6+ years re&eived fast"release melatonin (one of several instan&es /here

melatonin formulation /as spe&ified) for /eeks at dosages of ; or 5 mg, at either 6>


30/71

$./..a The T' suggests that clinicians treat children and adolescents with DSWPD comorbid with

ps"chiatric conditions with strategicall" timed melatonin (versus no treatment) WA* '+,



31/71


$ummary> This is a ne/ re&ommendation in &omparison to the previous Pra&ti&e Parameters, as no studies

spe&ifi&ally ad" dressed this patient population. The overall Euality of eviden&e from the analyses of the t/o

revie/ed studies:5,:9 /as 3O% (see Figures and 5 and !ppendiA, Table $). ! fast"release formulation of

melatonin /as utiliBed, /ith dosages ranging from ;N5 mg, taken bet/een 6> M#S 3O% (!ppendiA, Table $5).

In a multi&enter study:= that &ontained predominantly adult D$%PD patients (n 5


32/71

&losed eyelids (about 5= luA at the &ornea) for a period of +9 days, and &ompared it to an ina&tive &ondition ( 2? and n >

226 respecti(ely6 used as a measure to di(ide groups by the degree to *hich they *ere

physiologically delayed$6 signi


33/71


! separate group5 performed a randomiBed &ontrolled trial of = days duration (n 6, mean age +.+ 6 3O% (!ppendiA, Table $=).

This is a ne/ re&ommendation, based both upon the novel &ohort (solely

&hildrenadoles&ents) and lightbehavioral multi&omponent interventions.

'ne nonblinded randomized controlled trial14- *as identi -4$6 composed of

adolescents aged 1?.1/ !mean ages 1-,L P 1,L and 1-,L P 1,/ years in the acti(e and

control groups6 respecti(ely$, Ahe minority of participants !24O$ had mental health

comorbidities6 and *as spread e(enly across the t*o groups, '(er a period of / *eeks6

acti(e sub=ects !n > 2?$ *ere e7posed to either posta*akening natural sunlight !*hen a(ail

able$ or a broad spectrum lamp !Q1444 lu76 pro7imity to source not speci


34/71

ad(ised, @oncomitant multicomponent beha(ioral education5inter(entions !includ ing

instructions to Ereduce e(ening lightF$ *ere pro(ided in si7 -:.B4 minute sessions !*ith

parental in(ol(ement$6 either *eekly !


35/71


spectrum lamp !Q1444 lu76 pro7imity to source not speci


36/71

5.&.& Strategic A"oidance of 'ight for Patients with 2(SWD

There is one &ase report that in&ludes strategi& avoidan&e of light, and it is in&luded belo/ in the &ombination

treatments se&tion.66+ The previous Pra&ti&e Parameters6 provided no per" tinent re&ommendations.

There is no evidence to support the use of strategic avoid- ance of light (as monotherap") in patients with

!.&SWD !o recommendation

5.&.( 'ight Therap! for Patients with 2(SWD

The previous Pra&ti&e Parameters re&ommended this treat" ment at an OPTIO* level (for sighted individuals), based

on 5 &ase seriesreports,66+N669 all &omposed of 6N+ subje&ts. The small numbers of study parti&ipants prevented

in&lusion for the present report, and no studies have been published subseEuently. There is some eAperimental

eviden&e that light is &apable of resetting the &ir&adian pa&emaker in the absen&e of &ons&ious light per&eption,66=

and most blind individuals /ho retain su&h photi& input to the &ir&adian pa&emaker /ould not be eApe&ted to have

*+$%D. 1o/ever, some su&h individuals may have insuffi&ient eAposure to light to maintain entrainment and

therefore timed light eAposure may be a potential therapeu" ti& intervention in a subset of blind individuals /ith

*+$%D. 1o/ever, as noted, there have been no studies that eAamined this Euestion.

There is insufficient evidence to support the use of light therap" in patients with !.&SWD (versus no

treatment) !o recommendation5.&.5 Sleep-Prooting )edications for Patients with 2(SWD

The previous Pra&ti&e Parameters did not make any re&" ommendation for the use of sleep"promoting medi&ations

in *+$%D, and no ne/ studies /ere identified.

There is no evidence to support the use of sleep- promoting medications in patients with !.&SWD !o

recommendation

5.&.* Tied +ral Adinistration of )elatonin or Agonists for Patients with 2(SWD

8!;!


37/71


Cigure This re&ommendation /as designated at the -4ID3I* level (for the blind) in the previous Pra&ti&e

Pa" rameters.6 Only ; studies6++N6+ met in&lusion &riteria for the present analysis and the level of eviden&e from

these small trials /as 3O% (Figure 9 and !ppendiA, Table $). Doses ranged bet/een

There is insufficient evidence to support the use of melatonin among sighted patients with !.&SWD

(versus no treatment) !o recommendation

5.&., Wakefulness-Prooting )edications for Patients with 2(SWD

The previous Pra&ti&e Parameters did not make any per" tinent re&ommendations regarding the use of

/akefulness" promoting medi&ations in *+$%D, and no ne/ studies /ere identified.

!s noted above, both sleep and a&tivity have the potential to reset the &ir&adian pa&emaker and therefore it is

reasonable to think that medi&ations that promote either sleep or /akeful" ness might be useful in the treatment of

this disorder, either by entrainment of the biologi&al &lo&k or by improving alertness and sleep /hen individuals are

sleeping out of syn&hrony /ith the &ir&adian pa&emaker. $imilar to sleep"/ake s&heduling and physi&al a&tivity

ho/ever, there have not been any studies of either of these approa&hes in *+$%D.

There is no evidence to support the use of wakefulness- promoting medications in patients with !.&SWD

!o recommendation


38/71

5.&. +ther Soatic nter"entions for Patients with 2(SWD

The previous Pra&ti&e Parameters &ited Qinsuffi&ient evi" den&eR to support the use of oral vitamin 06+ for use in

sighted individuals /ith *+$%D (OPTIO*), based on + open"label &ase reports.6;;,6; *o studies have sin&e

been published per" taining to the use of vitamin 06+ (or other alternate somati& interventions) for *+$%D.

There is insufficient evidence to support the use of oral vitamin 0%. (and no evidence to support alternate

somatic interventions) among patients with !.&SWD (versus no treatment) !o recommendation

5.&./ 0obination Treatents for Patients with 2(SWD

The previous Pra&ti&e Parameters did not dis&uss the use of &ombination treatments in *+$%D. There are

un&ontrolled &ase reports involving a &ombination of treatments in sighted individuals /ith

*+$%D.66+,669,6;5,6;9 1o/ever, these studies did not meet in&lusion &riteria for the present revie/.



39/71


There is insufficient evidence to support the use of combination treatments in patients with !.&SWD

(versus no treatment) !o recommendation

5.4 $ecommendations or the 'reatment o ($*

I$%#D is diagnosed /hen patients eAhibit no &lear &ir" &adian pattern of sleep"/ake behavior. !ffli&ted

individuals demonstrate /akefulness during &onventional sleeping hours and bouts of sleep during the day.5 The

&ondition is observed most &ommonly among patients /ith neurodevelopmental or neurodegenerative disorders, and

&an pose parti&ular &hal" lenges for &aregivers.

5.(.1 Prescribed Sleep-Wake Scheduling for Patients with SWD

There /as no re&ommendation in the previous Pra&ti&e Parameters regarding pres&ribed sleep"/ake s&heduling as

a stand"alone treatment for patients /ith I$%#D, and no ne/ studies /ere identified. 1o/ever, pres&ribed

s&hedules have been tested in &ombination /ith other modalities (see se&tion 5..:, QCombination TreatmentsR).

There is no evidence to support the use of prescribed sleep-wake scheduling as a stand-alone treatment for

patients with 7SW,D !o recommendation

5.(.2 Tied Ph!sical Acti"it!#$%ercise for Patients with SWD

There /as no re&ommendation in the previous Pra&ti&e Pa" rameters regarding timed physi&al a&tivityeAer&ise as

a sole treatment for patients /ith I$%#D, and no ne/ studies /ere identified. 1o/ever, s&heduled a&tivity has been

used in &om" bination /ith other modalities (see se&tion 5..:, QCombination TreatmentsR).

There is no evidence to support the use of timed ph"sical activit" or e#ercise as a stand-alone treatment for

patients with 7SW,D !o recommendation

5.(.& Strategic A"oidance of 'ight for Patients with SWD

There /as no re&ommendation in the previous Pra&ti&e Pa" rameters regarding strategi& avoidan&e of light as a

treatment for patients /ith I$%#D, and no ne/ studies /ere identified.

There is no evidence to support the use of strategic avoid- ance of light as a treatment for patients with7SW,D !o recommendation

5.(.( 'ight Therap! for SWD in $lderl! Patients with Deentia

In &ontrast to the present revie/, the +


40/71

T$T did not differ bet/een a&tive and &ontrol groups. ! se&ond open"label study tested light therapy of + hours du"

ration bet/een This re&ommendation /as designated as an OPTIO* in the +


41/71


luA (6 meter from parti&ipants), 6N+ hours in duration, be" t/een ith ($*

8!!

In the +


42/71

/ell" designed trial also failed to sho/ an improvement in T$T /ith either dose of melatonin &ompared to pla&ebo.

#iemersma van der 3ek and &olleagues6= published another potentially relevant &ombination study among

dementia patients in assisted living in /hom I$%#D /as not spe&ifi&ally identified. In &ontrast to the other studies,

the melatonin"only arm (+.5 mg immediate"release formulation administered approAimately one hour before bed"

time) demonstrated de&reased a&tigraphi& I$3 and in&reased T$T &ompared to pla&ebo. 1o/ever, detrimental effe&ts

of melatonin on mood and daytime fun&tioning /ere also observed.

$&/%a The T' suggests that clinicians avoid the use of melatonin as a treatment for 7SW,D in older people

with dementia (versus no treatment) WA* A8A7!ST

$ummary> 'elatonin /as deemed Qnot indi&atedR for the treatment of I$%#D in older people /ith dementia

(OPTIO*) in the previous Pra&ti&e Parameters. The present re&ommen" dation against melatonin treatment is based

on one revie/ed study that failed to sho/ benefit /ith respe&t to the C#ITIC!3 out&ome of T$T (3evel of

eviden&e> 3O% (!ppendiA, Table $6

an insuffi&ient num" ber of parti&ipants or grouping of parti&ipants /ith different C#$%Ds. One ne/ eligible study

/as identified,65= and mela" tonin /as sho/n to improve sele&t predefined C#ITIC!3 out" &omes (T$T, I$3),

although the &onfiden&e interval asso&iated /ith both values &rossed the threshold of the predetermined &lini&ally

signifi&ant minimal &hange (see Table +). The level of revie/ed eviden&e /as 'OD#!T (!ppendiA, Table $66).

%right and &olleagues65= performed a double"blind, ran" domiBed, &ontrolled, &rossover trial in 69 &hildren

(mean age : +.: years) /ith autism spe&trum disorder. The proto&ol



43/71


consisted of 1month baseline6 ?months melatonin (s, placebo6 1month *ashout6 ?

months melatonin (s, placebo !cross o(er$6 and 1month medication free, %elatonin dosing

!using a Estandard releaseF formulation administered ?4.-4 minutes before planned

bedtime$ started at 2 mg6 and parents *ere gi(en the option of increasing the dose by 2 mge(ery ? days6 until :4O or more impro(ement in sleep *as obser(ed6 up to 14 mg, Ahe

a(erage This re&ommendation /as designated as an OP" TIO* in the +


44/71

7SW,D !o recommendation

5.(./ 0obination Treatents in Deented $lderl! Adults with SWD

This re&ommendation /as designated as a -4ID3I* in the previous Pra&ti&e Parameters,6 based upon t/o

stud" ies, neither of /hi&h /ere in&luded in the present analysis, ei" ther be&ause parti&ipants did not &learly have a

diagnosis of I$%#D65 or be&ause predefined C#ITIC!3 out&omes /ere not measured.65: One randomiBed

&ontrolled trial pertaining to the treatment of demented elderly patients /ith I$%#D69 /as published subseEuentto +


45/71


studies did not measure out&omes defined by the TF, the multi" modal interventions signifi&antly improved daytime

fun&tion" ing and amplitude of rest"a&tivity rhythms. The investigations /ere restri&ted by &onstraints inherent to the

nursing home environment (eg, high dropout rate, inability to blind raters to &ondition), yet both had relatively large

sample siBes. !n additional &aveat is that many more parti&ipants /ere s&reened than /ere eligible for parti&ipation,su&h that the results may not generaliBe to all patients /ith dementia.

$&4%a The T' suggests that clinicians avoid the use of combined treatments consisting of light therap" in

combination with melatonin in demented1 elderl" patients with 7SW,D (versus no treatment) WA*

A8A7!ST

$ummary> This re&ommendation /as designated as a -4ID3I* in the previous Pra&ti&e Parameters. One rel"

evant randomiBed &ontrolled trial69 /as published subseEuent to +


46/71

the results of light therapy studies that address sleep maintenan&eearly"morning a/ak" ening diffi&ulties are

appli&able to the treatment of !$%PD, and un&ertainty /ill remain unless stri&t terminology are used. Others have

raised &on&erns about the freEuen&y at /hi&h one a&tually en&ounters patients /ith this &ondition in the &lini&al

arena,69; a topi& that is beyond the s&ope of this dis&ussion. !s for I$%#D, the term is rarely used in the medi&al

literature, presumably be&ause the &omorbid disorders that freEuently overlap (eg, dementia, developmental

disabilities) tend to overshado/ the C#$%D. *evertheless, sleep disturban&es are among the most onerous of

diffi&ulties for &aregivers of these patients. Thus, la&k of &onsideration of the formal diagnosis of I$%#D in studies

of sleep in these populations makes it dif" fi&ult to identify effe&tive treatments for this important &lini&al problem.

'ore spe&ifi&ally, future studies &ould advan&e the field by in&luding detailed therapeuti& information, su&h as the

method and means of treatment delivery (eg, prote&tive eye/ear vs. vo" litional avoidan&e of light, light therapy

intensity/avelength proAimity, &ontinuous versus pulsed light administration 7in" &luding gradually versus abruptly

&hanging illumination698, melatonin formulation, et&.), relationship of treatment timing /ith respe&t to a defined

physiologi& &ir&adian phase marker or other sleep parameter, in&lusioneA&lusion of pres&ribed sleep /ake

s&hedules or other behavioral interventions, and study en" vironment (laboratory vs. non"laboratory). #egarding the

latter fa&tor, field"based studies are sorely needed, and one must be &autious not to let tightly &ontrolled ben&h

resear&h prema" turely di&tate &lini&al treatment. !s a prime eAample, there are &urrently no data to support devi&es

that solely deliver blue short /avelength light in the treatment of C#$%Ds, and t/o laboratory"based studies that

des&ribe no additional benefit /ith blue"enri&hed bright light,+,+5 despite the fa&t that these /avelengths have beenidentified as espe&ially important for &ir&adian phase resetting in non"&lini&al eAperiments.+ 'ore importantly,

&omplian&e /ith post"a/akening Qlight boAesR in the field is very poor,: and studies that eAamine the bypassing of

this &omplian&e barrier are parti&ularly intriguing.+,::,695,699



47/71


Future resear&h should address QdoseR of light in&luding luA level and duration,6= and should also &onsider

season69= and other environmental fa&tors that affe&t overall light eAposure history.6: Finally, more su&h studies

spe&ifi&ally targeting C#$%D populations are desired.

From the standpoint of out&omes, similar &lini&ally relevant sleep"related measures /ill be reEuired for inter"study &om" parative purposes (P$- vs. a&tigraphy vs. subje&tive reports, physiologi& or nonphysiologi& &ir&adian

marker), along /ith systemati& measures of treatment &omplian&e, to a&&urately inform &lini&al pra&ti&e. In the

instan&e of I$%#D, it should be determined /hether separate out&ome measures (eg, &ir&a" dian amplitude, rest"

a&tivity &y&le variations) may be superior indi&ators of treatment effi&a&y. For all C#$%Ds, measures of daytime

fun&tioningalertness &ould enhan&e &lini&al relevan&e.

Inter"study medi&ation &omparisons /ill reEuire eEuivalent dosing (analyBed melatonin study doses ranged from

entrainment o&&urred in +


48/71

engender studies that aim to eAplore demonstrable benefits of phase as" sessments in the &lini&al setting, /hi&h in

turn &ould serve to delineate relative &hronobioti& versus hypnoti& effe&ts of medi" &ationssupplements. $ome of the

revie/ed interventions dem" onstrated su&&essful sleep"related out&omes /ithout &hanges in the &ir&adian phase

marker and vi&e versa. In the instan&e that the importan&e of &ir&adian TO! is demonstrated, it /ill be ne&essary to

determine light and melatonin phase P#Cs for adult populations affli&ted /ith C#$%Ds (as they may dif" fer from

normal populations65,6=+) and to determine the same for both affli&ted and healthy pediatri&adoles&ent popula"

tions. Compli&ating matters, alterations in phase relationships bet/een the &ir&adian timing system and the timing of

sleep among those /ith C#$%Ds &ould impa&t the ability of inter" ventions to eAert benefits, even /ith kno/ledge

of the P#C. For eAample, longer intervals from various endogenous mela" tonin Euently parameters6=; been

des&ribed and C0T

among min

6=N6=9 adult to patients sleep offset /ith have D$%PD fre"

as &ompared to &ontrols. 1o/ever, this finding has not been demonstrated among proto&ols in /hi&h subje&ts are

for&ed to maintain a more &onventional sleep/ake s&hedule,+=,6==,6= sug" gesting that this observation may

simply be a &onseEuen&e of longer habitual T$T. -reater elu&idation is reEuired. On a sep" arate note, effe&tive

treatments may need to address &on&omi" tant impairment of homeostati& sleep pro&esses in C#$%Ds, as has been

demonstrated in D$%PD and among adoles&ents in general.6=:,6< %hether hypnoti&s have a role in this settingdeserves to be further eAplored.:

Present guidelines predominantly refle&t biologi&al under" pinnings asso&iated /ith C#$%Ds. $tudies are needed

to investigate and understand predominant eAogenous and en" dogenous &ontributors to the development and

perpetuation of C#$%Ds, so that different subtypes (and possibly differ" ent treatmentprophyla&ti& regimens) &an

be identified. In the &ase of adoles&entsyoung adults (and, to a lesser degree, other adults66), numerous eAogenous

fa&tors, su&h as in&reased auton" omy /ith respe&t to sleep time, employment, and involvement in eAtra&urri&ular

a&tivities have been identified as variables &ontributing to the generally observed delay in sleep/ake pat" terns,6+

but have not been studied among adoles&ent D$%PD &ohorts spe&ifi&ally.6;,6 !dditionally, repeated eAposure

to


49/71


frustrations at not being able to fall asleep at a desired time &an lead to the development of a &on&omitant

&onditioned in" somnia, /hi&h &an perpetuate sleep diffi&ulties. Aposure to indoor lighting during evening

hours65N6 andor delays in /eekend /ake times6:N6:6 have also been impli&ated as &on" tributors to

persistently delayed sleep/ake times, but have not been spe&ifi&ally impli&ated in adoles&ent D$%PD.6:+ $omehave urged that s&hool lighting environments be optimiBed for maAimal &ir&adian benefits.6:; In the &ase of

*+$%D, it may be that the eAogenous and endogenous &ontributors to the dis" order differ bet/een blind and

sighted individuals and that this may similarly ne&essitate different treatment regimens. Iden" tifi&ation and

manipulation of eAogenous variables in trials of C#$%Ds may prove fruitful.

The asso&iated development of &lini&al profiles /ould en" able &lini&ians to better as&ertain /hi&h patients might

respond to suggested treatments, and related resear&h is en&ouraged. In the -radisar study involving adoles&ents

/ith D$%PD,6


50/71

$;$#

7! Mrgenthaler ,*% 3ee-/hing ,% Alessi /% et al! Practice parameters "r the clinical e+aluatin and treatment "

circadian rhythm sleep disrders! An American Academy " Sleep Medicine reprt! Sleep '669;6.78N8:! '! Sack

R3% Auckley D% Auger RR% et al! /ircadian rhythm sleep disrders. part *% basic principles% shi"t #rk and jet lag

disrders! An American Academy " Sleep Medicine re+ie#! Sleep '669;6.7

7:B'97.7:8N'6! ! Mre R% Eichler 40! 3ss " a circadian adrenal crticsterne rhythm

"ll#ing suprachiasmatic lesins in the rat! 0rain Res 7:'9'.'67N

in drinking beha+ir and lcmtr acti+ity " rats are eliminated by hypthalamic lesins! Prc &atl Acad Sci 5SA

7:'9nucleus determines circadian perid! Science 7::69'.:8NB! 76! $elsh D% 3gthetis DE% Meister M% Reppert

SM! *ndi+idual neurns dissciated "rm rat suprachiasmatic nucleus eHpress independently phased circadian "iring

rhythms! &eurn 7::897.

tau in an ultradian light-dark cycle! 2 0il

Rhythms '66B9';.;N

Sinauer Assciates% *nc!% '66! 7! 3e#y A2% $ehr ,A% Gd#in C% &e#sme DA% Markey SP! 3ight suppresses

melatnin secretin in humans! Science 7:B69'76.7'

phase resetting and suppressin! 2 Physil '66698'< Pt ;.


51/71


'6! 0uHtn =M% 31ermite-0aleriauH M% ,urek C$% +an /auter E! Daytime naps in darkness phase shi"t the human

circadian rhythms " melatnin and thyrtrpin secretin! Am 2 Physil Regul *ntegr /mp Physil '6669'B.R;;N

B'! '7! 0urgess 12% Mlina ,A! 1me lighting be"re usual bedtime impacts circadian

timing. a "ield study! Phtchem Phtbil '679:6.';N

'66798;8.'Re+Man 8!'! ,he &rdic /chrane /enter% ,he /chrane /llabratin!

/penhagen% '67'! '! Mundey % 0enluci" S% 1arsanyi % Dubc+ich M3% Oee P/! Phase-

dependent treatment " delayed sleep phase syndrme #ith melatnin! Sleep '6689'B.7'7NB! 'B! /le R2% Smith

2S% Alcala /% Ellitt 2A% ripke DC! 0right-light mask treatment

" delayed sleep phase syndrme! 2 0il Rhythms '66'97.B:N767! ':! +an Geijls#ijk *M% +an der 1eijden 0%

Egberts A/% rKilius 1P% Smits MG! Dse "inding " melatnin "r chrnic idipathic childhd sleep nset insmnia.

an R/,! Psychpharmaclgy '6769'7'.;:N:7! ;6! Guyatt G% =Hman AD% Akl EA% et al! GRADE guidelines. 7!

*ntrductin-

GRADE e+idence pr"iles and summary " "indings tables! 2 /lin Epidemil '6779

guidelines. ! Rating the Quality

" e+idence--study limitatins (risk " bias)! 2 /lin Epidemil '6779

guidelines. ! Rating the Quality

" e+idence--incnsistency! 2 /lin Epidemil '6779guidelines. B! Rating the Quality

" e+idence--indirectness! 2 /lin Epidemil '6779

seasnal depressin!

/chrane Database System Re+ '66./D66686! ;:! Dauphinais DR% Rsenthal 2O% ,erman M% DiCeb 1M%

,uggle /% Rsenthal &E! /ntrlled trial " sa"ety and e""icacy " bright light therapy +s! negati+e air ins in patients

#ith biplar depressin! Psychiatry Res '67'97:


52/71

/chrane Database Systematic Re+ '66'./D6678'6!

receptr agnists. ne# ptins

"r insmnia and depressin treatment! /&S &eursci ,her '67797.;;N7! ! /mmittee n the Crame#rk "r

E+aluating the Sa"ety " the Dietary Supplements Ca&0% 0ard n 3i"e Sciences% *nstitute " Medicine and &atinal

Research /uncil " the &atinal Academies! Dietary supplements. a "rame#rk "r e+aluating sa"ety! $ashingtn%

D/. ,he &atinal Academies Press% '668! B! 0uscemi &% 4andermeer 0% 1tn &% et al! ,he e""icacy and sa"ety "

eHgenus melatnin "r primary sleep disrders! Sebuah meta-analisis! 2 Gen *ntern Med '6689'6.7787NB!

122$ Journal o l!n!*al Slee) Me!*!ne, "ol. 11, +o. 14, 241(

:! $erneke 5% ,urner ,% Priebe S! /mplementary medicines in psychiatry.

re+ie# " e""ecti+eness and sa"ety! 0r 2 Psychiatry '66

rhnen M2% et al! Pre+alence " cncmitant use " alchl and sedati+e-hypntic drugs in middle and lder aged

persns. a systematic re+ie#! Ann Pharmacther '67;9.'8N

phase syndrme by phase ad+ance chrntherapy! Sleep 7:B


53/71

ripke DC% Sa+age 1/ 2r!% /indrich 3A% 3+ing R,% Ellitt 2A! E""icacy " enhanced e+ening light "r ad+anced sleep

phase syndrme! 0eha+ Sleep Med '66;97.'7;N'


54/71


8! *t A% And % 1ayaka#a ,% et al! 3ng-term curse " adult patients #ith delayed sleep phase syndrme! 2pn 2

Psychiatry &eurl 7::;9.8circadian clcks " patients #ith delayed sleep phase insmnia! Sleep 7:B79.7N'7! ! =ren DA% $ehr ,A!

1ypernycthemeral syndrme a"ter chrntherapy "r

delayed sleep phase syndrme! & Engl 2 Med 7::'9;'.7

7::798.7

issues in the use " the hrmne melatnin in

paediatrics! 2 Paediatr /hild 1ealth '678987.8BN:! :8! 4an der 1eijden 0% Smits MG% 4an Smeren E2%

Ridderinkh" R% Gunning $0! E""ect " melatnin n sleep% beha+ir% and cgnitin in AD1D and chrnic sleep-

nset insmnia! 2 Am Acad /hild Adlesc Psychiatry '669

766! Re+ell 43% 0urgess 12% GaKda /2% Smith MR% Cgg 3C% Eastman /*! Ad+ancing human circadian rhythms #ith


55/71

a"ternn melatnin and mrning intermittent bright light! 2 /lin Endcrinl Metab '66

in ttally blind peple. incidence and clinical signi"icance! 2 /lin Endcrinl Metab 7::'98.7'N;! 76

Shanahan ,3% lerman E0% et al! Suppressin " melatnin secretin in sme blind patients by eHpsure t bright

light! & Engl 2 Med 7::89;;'.

a"ter entrainment t a '-hur schedule in a "ree-running man! Psychneurendcrinlgy 7::9''.;:N8'! 77;!

1ban ,M% Sack R3% 3e#y A2% Miller 3S% Singer /M! Entrainment " a "ree-

running human #ith bright light /hrnbil *nt 7:B:9

absence " cnscius +isin! 2 0il Rhythms '66'97.8BN88! 77B! Arendt 2% Aldhus M% $right 2! Synchrnisatin "

a disturbed sleep-#ake

cycle in a blind man by melatnin treatment! 3ancet 7:BB97.'N;! 77:! Clkard S% Arendt 2% Aldhus M% ennett

1! Melatnin stabilises sleep nset time in a blind man #ithut entrainment " crtisl r temperature rhythms!

&eursci 3ett 7::6977;.7:;NB! 7'6! 3apierre =% Dumnt M! Melatnin treatment " a nn-'-hur sleep-#ake

cycle in a blind retarded child! 0il Psychiatry 7::89;B.77:N''! 7'7! ,Kischinsky =% Pal *% Epstein R% Dagan % 3a+ie

P! ,he imprtance " timing in

melatnin administratin in a blind man! 2 Pineal Res 7::'97'.768NB! 7''! 3ckley S$% Skene D2% 2ames % ,hapan

% $right 2% Arendt 2! Melatnin

administratin can entrain the "ree-running circadian system " blind subjects! 2 Endcrinl '66697

/apturing the circadian rhythms " "ree-running blind peple #ith 6!8 mg melatnin! 0rain Res '6679:7B.:

122( Journal o l!n!*al Slee) Me!*!ne, "ol. 11, +o. 14, 241(


56/71


7'! 3e#y A2% Emens 2S% Sack R3% 1asler 0P% 0ernert RA! 3#% but nt high%

dses " melatnin entrained a "ree-running blind persn #ith a lng circadian perid! /hrnbil *nt '66'97:.

1% Creund 12! ,herapeutic entrainment " circadian

rhythm disrder by melatnin in a nn-blind patient! 2 &eurl 7::B9'8.;'NB! 7;7! amei % 1ayaka#a ,% 5rata

2% et al! Melatnin treatment "r circadian rhythm

sleep disrders! Psychiatry /lin &eursci '66698.;B7N'! 7;'! McArthur A2% 3e#y A2% Sack R3! &n-'-hur

sleep-#ake syndrme in a

sighted man. circadian rhythm studies and e""icacy " melatnin treatment! Sleep 7::

treatment "r a patient #ith

hypernychthermal syndrme! Sleep Res 7:B.

Smeren E2% essler A% Mirmiran M% S#aab DC! *ndirect bright light impr+es circadian rest-acti+ity rhythm

disturbances in demented patients! 0il Psychiatry 7::97.:88NA% 4licer 3% Rss 4% 1erK 3% /ampbell S! 0right light treatment " beha+iral and sleep disturbances in patients #ith

AlKheimers disease! Am 2 Psychiatry 7::'97:.76'BN;'! 7

Melatnin and bright-light treatment "r rest-acti+ity disruptin in institutinaliKed patients #ith AlKheimers disease! 2

Am Geriatr Sc '66B98

use

and hip "ractures in nursing hme residents! 2AMA *ntern Med '67;97;.8N


57/71

78'! Singer /% ,ractenberg RE% aye 2% et al! A multicenter% placeb-cntrlled trial

" melatnin "r sleep disturbance in AlKheimers disease! Sleep '66;9'treatment! De+ Med /hild &eurl 7::B96.7B

88! 7


58/71


7

rhythm in delayed sleep phase syndrme and nn-'-hur sleep-#ake syndrme in humans! &eursci 3ett

'6669':.767N! 7! $yatt 2% Stepanski E2% irkby 2! /ircadian phase in delayed sleep phase

syndrme. predictrs and tempral stability acrss multiple assessments! Sleep '66

schl

day delays dim light melatnin nset (D3M=) in middle schl students! &eurendcrinl 3ett '6769;7.:'N

Dagan % Abadi 2! Sleep-#ake schedule disrder disability. a li"elng untreatable pathlgy " the circadian time

structure! /hrnbil *nt '66797B.767:N'! 7:8! Miller &3% ,+aryanas AP% Shattuck 3G! Accmmdating adlescent

sleep-#ake

patterns. the e""ects " shi"ting the timing " sleep n training e""ecti+eness! Sleep '67'9;8.77';N;

schl start times! &AASP 0ull '66'9B


59/71

,he prickly plitics " schl starting times! Phi Delta appa

7:::9B6.;N!

,#K()*&'

,he authrs ackn#ledge Dr! *lene Rsen "r ser+ing as a bard liaisn "r this prject and assuring that the

guideline adhered t the standards set "rth by the 0ard " Directrs " American Academy " Sleep Medicine! ,he

authrs als ackn#ledge the cntributins " the "ll#ing indi+iduals. /hristine Stepanski% MS% "r per"rmingliterature searches U7 and U'9 and Michelle M! ,angredi% PhD% "r managing the prject at the initial steps! ,he

authrs are grate"ul t the rganiKa- tins and indi+iduals #h pr+ided their insights and suggestins during the

public cmment perid! E+ery cmment #as internally dcumented and addressed% and

decisins regarding crrespnding amendments in the teHt #ere le"t t the ,Cs discretin! ,he prject #as "unded by

the American Academy " Sleep Medicine!

7 B #$$P*# ;$,'

Submitted "r publicatin August% '678 Accepted "r publicatin August% '678 Address crrespndence t. R! Rbert

Auger% MD% May /enter "r Sleep Medicine% Rchester% M&9 Email. researchVaasmnet!rg

*#)$ ',''

,his #as nt an industry supprted study! ,he authrs ha+e indicated n "inancial cn"licts " interest! Drs! Deriyand ,hmas are emplyed by the American Acad- emy " Sleep Medicine!

,PP*C

$ear&h Terms and 'e$1 4sed in the 3iterature $ear&h G6 $leep disorders, &ir&adian rhythmR7'e$1 Terms8 O#

(QsleepR7!ll Fields8 !*D QdisordersR7!ll Fields8 !*D Q&ir&adianR7!ll Fields8 !*D QrhythmR7!ll Fields8)

O# Q&ir&adian rhythm sleep disordersR7!ll Fields8 O# (Q&ir&adianR7!ll Fields8 !*D QrhythmR7!ll Fields8 !*D

QsleepR7!ll Fields8 !*D QdisorderR7!ll Fields8) O# Q&ir&adian rhythm sleep disorderR7!ll Fields8 O# (free7!ll

Fields8 !*D QrunningR7!ll Fields8 !*D QdisorderR7!ll Fields8) O# (irregular7!ll Fields8 !*D sleep"/ake7!ll

Fields8 !*D rhythm7!ll Fields8) O# (non7!ll Fields8 !*D +"hour7!ll Fields8 !*D (Qsleep disordersR7'e$1

Terms8 O# (QsleepR7!ll Fields8 !*D QdisordersR7!ll Fields8) O# Qsleep disordersR7!ll Fields8 O# (QsleepR7!ll

Fields8 !*D QdisorderR7!ll Fields8) O# Qsleep disorderR7!ll Fields8)) O#((Q0lindnessR7'esh8 O# (QblindnessR7'e$1 Terms8 O# QblindnessR7!ll Fields8 O# nonsighted7!ll Fields8)) !*D

(Qsleep disordersR7'e$1 Terms8 O# (QsleepR7!ll Fields8 !*D QdisordersR7!ll Fields8) O# Qsleep disordersR7!ll

Fields8)) !*D ('eta"!nalysis7ptyp8 O# Pra&ti&e -uideline7ptyp8 O# systemati&7sb8).

Terms for the 3iterature $ear&h G+ in Pubmed Database ((((&ir&adian rhythm sleep disorders7t/8 O# &ir&adian

rhythm sleep disorder7t/8 O# Q$leep Disorders, Cir&adian #hythmR7'esh>noeAp8 O# Q&hronobiology

disordersR7t/8 O# QChronobiology DisordersR7'esh>noeAp8 O#

hyperny&hthemeral7t/8 O# &ir&adian misalignment7t/8 O# &ir&adian dysregulation7t/8) O# ((irregular7t/8 O# non

+ hour7t/8) !*D (sleep /ake7t/8 O# sleep"/ake7t/8)) O# ((advan&ed7t/8 O# delayed7t/8) !*D sleep

phase7t/8) O# (idiopathi&7t/8 !*D &hroni&7t/8 !*D (sleep"onset7t/8 O# sleep onset7t/8) !*D insomnia7t/8) O#

((nonentrained7t/8 O# non"entrained7t/8) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8

O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O# ((D$P$7t/8 O# !$P$7t/8 O# early morning

a/akening7t/8 O# (phase advan&e7!ll Fields8 O# phase advan&edelay7!ll Fields8 O# phase advan&ed7!ll Fields8

O# phase advan&ement7!ll Fields8



60/71


O# phase advan&ements7!ll Fields8 O# phase advan&es7!ll Fields8) O# (phase delay7!ll Fields8 O# phase

delayarrest7!ll Fields8 O# phase delayed7!ll Fields8 O# phase delaying7!ll Fields8 O# phase delays7!ll Fields8)

O# (phase shift7!ll Fields8 O# phase shifted7!ll Fields8 O# phase shifter7!ll Fields8 O# phase

shiftermodulator7!ll Fields8 O# phase shifters7!ll Fields8 O# phase shifting7!ll Fields8 O# phase shiftkeying7!llFields8 O# phase shiftmeasurement7!ll Fields8 O# phase shifts7!ll Fields8)) !*D (sleep7t/8 O# QsleepR7mesh8 O#

Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O# ((free running7t/8

!*D (disorder7t/8 O# rhythm7t/8)) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O# ((dark therapy7t/8 O# light therapy7t/8 O# amber

lenses7t/8 O# 0lue light7t/8 O# bright light7t/8 !*D blue blo&kers7t/8 O# blue"blo&ker7t/8 O# blue blo&ker7t/8

O# blue"blo&ker7t/8 O# eye/ear7t/8 O# Phototherapy7t/8 O# QPhototherapyR7'esh8) !*D (sleep7t/8 O#

QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O#

Qsleep phase

&hronotherapyR7'e$1 Terms8 O# ((&hronotherapy7t/8 O# &hronotype7t/8 O# QChronotherapyR7'esh>noeAp8)

!*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian

#hythmR7'e$1 Terms8)) O# ((melatonin re&eptor agonists7t/8 O# melatonin re&eptor agonist7t/8 O# melatoninagonist7t/8 O# melatonin agonists7t/8 O# melatonin re&eptor antagonists7t/8 O# melatonin re&eptor

antagonist7t/8 O# melatonin antagonist7t/8 O# melatonin antagonists7t/8 O# Q#e&eptors, 'elatonindrug

effe&tsR7'esh8 O# Q#e&eptors,

'elatoninagonistsR7'esh8 O# Q#e&eptors, 'elatonin antagonists and inhibitorsR7'esh8) !*D (sleep7t/8 O#

QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O# ((melatonin7t/8 O# QmelatoninR7'e$1 Terms8 O#

ramelteon7t/8 O# QramelteonR7$ubstan&e8 O# tasimelteon7t/8 O# QtasimelteonR7$upplementary Con&ept8 O#

agomelatine7t/8 O# Q$ +noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O# ((0lindness7t/8 O# blind person7t/8 O# blindpeople7t/8 O# blind subje&t7t/8 O# blind subje&ts7t/8 O# blind patient7t/8 O# blind patients7t/8 O# QMisually

Impaired PersonsR7'esh8 O# enu&leated7t/8 O# Q0lindnessR7'esh8 O# nonsighted7t/8 O# (visual

impairement7!ll Fields8 O# visual impairment7!ll Fields8 O# visual impairmentblindness7!ll Fields8 O# visual

impairments7!ll Fields8) O# visually impaired7t/8) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep

DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O# ((QdementiaR7'e$1

Terms8 O# dementia7t/8 O# QalBheimer diseaseR7'e$1 Terms8 O# alBheimer7t/8 O# alBheimers@s7t/8) !*D

(sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)) O#

((o/l7t/8 O# o/ls7t/8 O# lark7t/8 O# larks7t/8 O# morningness7t/8 O# eveningness7t/8 O# morning types7t/8

O# morning type7t/8 O# evening types7t/8 O# evening type7t/8) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leepDisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) !*D ((randomiBed &ontrolled

trial7pt8 O# &ontrolled &lini&al trial7pt8 O# randomiBed7tiab8 O# pla&ebo7tiab8 O# Qdrug therapyR7$ubheading8 O#

randomly7tiab8 O# trial7tiab8 O# groups7tiab8) *OT (QanimalsR7'e$1 Terms8 *OT QhumansR7'e$1 Terms8))

!*D (nglish7la8 !*D (Q+


61/71

DisordersR7'esh>noeAp8 O# hyperny&hthemeral7t/8 O# &ir&adian misalignment7t/8 O# &ir&adian

dysregulation7t/8)) O# (((irregular7t/8 O# non + hour7t/8) !*D (sleep /ake7t/8 O# sleep"/ake7t/8))) O#

(((advan&ed7t/8 O# delayed7t/8) !*D (sleep phase7t/8))) O# ((idiopathi&7t/8 !*D &hroni&7t/8 !*D (sleep"

onset7t/8 O# sleep onset7t/8) !*D insomnia7t/8)) O# (((nonentrained7t/8 O# non"entrained7t/8) !*D (sleep7t/8

O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)))

O# (((D$P$7t/8 O# !$P$7t/8 O# phase advan&eX O# phase delayX O# phase shiftX) !*D (sleep7t/8 O#

QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) O#

(((free running7t/8 !*D (disorder7t/8 O# rhythm7t/8)) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep

DisordersR7'esh>noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) O# (((dark therapy7t/8 O# light therapy7t/8 O# amber

lenses7t/8 O# 0lue light7t/8 O# bright light7t/8 O# eye/ear7t/8 O# Phototherapy7t/8 O# QPhototherapyR7'esh8)

!*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian

#hythmR7'e$1 Terms8))) O# (($leep Phase Chronotherapy7'esh8)) O# (((&hronotherapy7t/8 O#

QChronotherapyR7'esh>noeAp8) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) O# (((melatonin re&eptor agonists7t/8 O# melatonin

re&eptor agonist7t/8 O# melatonin agonist7t/8 O# melatonin agonists7t/8 O# melatonin re&eptor antagonists7t/8

O# melatonin re&eptor antagonist7t/8 O# melatonin antagonist7t/8 O# melatonin antagonists7t/8 O# melatonin

re&eptor inhibitor7t/8 O# melatonin re&eptor inhibitors7t/8 O# melatonin inhibitor7t/8 O# melatonin inhibitors7t/8

O# Q#e&eptors, 'elatonindrug effe&tsR7'esh8 O# Q#e&eptors,

'elatoninagonistsR7'esh8 O# Q#e&eptors, 'elatonin antagonists and inhibitorsR7'esh8) !*D (sleep7t/8 O#

QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) O# (((melatonin7t/8 O# QmelatoninR7'e$1 Terms8 O#

ramelteon7t/8 O# QramelteonR7$ubstan&e8 O# tasimelteon7t/8 O# QtasimelteonR7$upplementary Con&ept8 O#

agomelatine7t/8 O# Q$ +


62/71


DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) O# (((dim light melatonin

onset7t/8 O# D3'O7t/8) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O#

&ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) O# (((0lindness7t/8 O# Q0lindnessR7'esh8 O#

nonsighted7t/8 O# (visual impairX) O# (visually impaired7t/8)) !*D (sleep7t/8 O# QsleepR7mesh8 O# Q$leepDisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8))) O# (((QdementiaR7'e$1

Terms8 O# dementia7t/8 O# QalBheimer diseaseR7'e$1 Terms8 O# alBheimer7t/8 O# alBheimers@s7t/8) !*D

(sleep7t/8 O# QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1

Terms8))) O# (((o/l7t/8 O# o/ls7t/8 O# lark7t/8 O# larks7t/8 O# morningness7t/8 O# eveningness7t/8 O#

morning types7t/8 O# morning type7t/8 O# evening types7t/8 O# evening type7t/8) !*D (sleep7t/8 O#

QsleepR7mesh8 O# Q$leep DisordersR7'esh>noeAp8 O# &ir&adian7t/8 O# QCir&adian #hythmR7'e$1 Terms8)))))

!*D ((randomiBed &ontrolled trial7pt8 O# &ontrolled &lini&al trial7pt8 O# randomiBed7tiab8 O# pla&ebo7tiab8 O#

Qdrug therapyR7$ubheading8 O# randomly7tiab8 O# trial7tiab8 O# groups7tiab8) *OT (QanimalsR7'e$1 Terms8

*OT QhumansR7'e$1 Terms8)) !*D (nglish7la8 !*D (Q+de,ab,ti)

O#((@advan&ed@>de,ab,ti O# @delayed@>de,ab,ti) !*D (@sleep phase@>de,ab,ti)) O# ((@irregular@>de,ab,ti O# @non +

hour@>de,ab,ti) !*D (@sleep /ake@>de,ab,ti

O# @sleep"/ake@>de,ab,ti)) O# ((@idiopathi&@>de,ab,ti !*D @&hroni&@>de,ab,ti !*D (@sleep"onset@>de,ab,ti O# @sleep

onset@>de,ab,ti) !*D @insomnia@>de,ab,ti)) O# ((@nonentrained@>de,ab,ti O# @non"entrained@>de,ab,ti) !*D

(@sleep@>de,ab,ti O# @sleep@eAp O# @sleep disorder@ de O# @&ir&adian@>de,ab,ti O# @&ir&adian rhythm@eAp)) O#

((@D$P$@>de,ab,ti O# @!$P$@>de,ab,ti O# @early morning a/akening@>de,ab,ti O# phase advan&eX O# phase delayX

O# phase shiftX) !*D (@sleep@>de,ab,ti O# @sleep@eAp O# @sleep disorder@de O# @&ir&adian@>de,ab,ti O# @&ir&adian

rhythm@ eAp)) O# (((@free running@>de,ab,ti !*D (@disorder@>de,ab,ti O# @rhythm@>de,ab,ti)) !*D (@sleep@>de,ab,ti O#@sleep@ eAp O# @sleep disorder@de O# @&ir&adian@>de,ab,ti O# @&ir&adian rhythm@eAp))) O# ((@dark therapy@>de,ab,ti

O# @light therapy@>de,ab,ti O# @amber lenses@>de,ab,ti O# @blue blo&ker@>de,ab,ti O# @blue"blo&ker@>de,ab,ti O# @blue

blo&kers@>de,ab,ti O# @blue"blo&kers@>de,ab,ti O# @0lue light@>de,ab,ti O# @bright light@>de,ab,ti O# @eye/ear@>de,ab,ti

O# @Phototherapy@>de,ab,ti O# @phototherapy@eAp) !*D (@sleep@>de,ab,ti O# @sleep@eAp O# @sleep disorder@de O#

@&ir&adian@>de,ab,ti O# @&ir&adian rhythm@eAp)) O# ((@&hronotherapy@>de,ab,ti O# @&hronotype@>de,ab,ti O#

@&hronotherapy@eAp) !*D (@sleep@>de,ab,ti O# @sleep@eAp

O# @sleep disorder@de O# @&ir&adian@>de,ab,ti O# @&ir&adian rhythm@eAp O# @sleep therapy@eAp)) O# ((@melatonin

re&eptor agonists@>de,ab,ti O# @melatonin re&eptor agonist@>de,ab,ti O# @melatonin agonist@>de,ab,ti O# @melatonin

agonists@>de,ab,ti O# @melatonin re&eptor antagonists@>de,ab,ti O# @melatonin re&eptor antagonist@>de,ab,ti O#

@melatonin antagonist@>de,ab,ti O# @melatonin antagonists@>de,ab,ti O# @melatonin re&eptor inhibitor@>de,ab,ti O#@melatonin re&eptor inhibitors@>de,ab,ti O# @melatonin inhibitor@>de,ab,ti O# @melatonin inhibitors@>de,ab,ti O#

@melatonin re&eptor@eApddKdt O# (@melatonin re&eptor@eAp !*D @agonist@eAp)) !*D (@sleep@>de,ab,ti O# @sleep@

eAp O# @sleep disorder@de O# @&ir&adian@>de,ab,ti O# @&ir&adian rhythm@eAp)) O

Documents

SalinanterjemahanCRSWD Intrinsic