Emerging Anti-Insomnia Drugs: Tackling Sleeplessness and The

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Hmas sped apprximatey e-third f their ifetimeseepig, bt we sti kw reatiey itte abt why thisprcess is s critica fr eery iig aima. Crretthikig sggests that wakig actiity is reatieydyamic i terms f sig the bdys resrces: breakigdw prteis, gatherig ifrmati ad expedigeergy. Seep is the perid f csidati: prcessigthe ifrmati gathered drig the day, sythesizigew prteis frm triets igested, ad heaig wearad tear f the bdys msces ad tisses.

Athgh the bdy is reatiey iactie drig seep,the brai is sti ery actie, ad cyces thrgh a mberf stages that ca be mitred sig eectrecepha-gram eectrdes. These chages ca be brke dw itrapid eye memet (REM) ad -REM actiity. Iprimates ad feies, -REM seep is characterized byw freqecy ad graday higher ampitde eectrica

actiity; it icdes ight seep (as referred t as Stage1 r 2) ad deep seep (as referred t as Stage 3 r 4)(BOX 1). This deep stage f seep, fte caed sw-waeseep (SWS), is thght t be imprtat fr the csi-dati f memries. REM seep, characterized by highfreqecy, w-ampitde eectrica actiity, has as beeimpicated i this prcess1. I this mde the brai appearst be as actie as drig wake perids ad dreamigccrs, which might represet the repayig f eetst be ecded t memry. Recet stdies hae dem-strated the cgitie cseqeces f REM ad SWSdisrpti, ad hae as shw that differet stages fseep affect differet types f memry csidati2,3.

Ismia is defied as difficty i iitiatig ad/rmaitaiig seep. The icidece f ismia i the ge-era ppati is betwee 1030%, ad apprximatey50% f the cases cmpai f seris daytime cse-qeces, sch as iabiity t ccetrate, redced eergyad memry prbems. Whe this persists fr mretha 1 mth, witht a assciated meta disrderr physica prbem, it is cassified as primary insomnia.Trasiet ismia is say assciated with specificeets sch as perids f stress r axiety, ad ism-ia is fte iked t ther psychgica r physicaprbems sch as depressi r chric pai.

Ismia treatmet cties t be dmiated bybezdiazepies ad reated cmpds, which arepwerf sedatives that ehace the ihibitry acti fGABA (-amibtyric acid) i the brai. Bt they areas assciated with the deepmet ftolerance ad

depedece, amesia ad withdrawa prbems, partic-ary after prged se r i edery patiets4,5. We wderstad i detai hw bezdiazepies affect GABA

A

receptr fcti. Hweer, whe it cmes t ikigtheir acti t seep mechaisms, there is sti mcht ear. T impre r kwedge f seep fctiad dysfcti, ad deep impred therapetics, itwi be crcia t derstad hw mdatrs f GABA

A

receptrs affect seep, the impact that ther ertras-mitter systems hae seep ad the deepy igraiedcircadia ctr er the seepwake cyce.

The deepmet f try e therapies, hweer,des t sey reqire isight it seep mechaisms

*Eli Lilly UK, Erl Wood

Manor, Windlesham,

Surrey GU20 6PH, UK.H. Lundbeck, Ottiliavej 9,

2500 Valby, Denmark.

Correspondence to B.E.

e-mail: [email protected]

doi:10.1038/nrd2464Published online23 May 2008

Primary insomniaPatients who suffer fromsleeplessness for at least1 month that cannot be

attributed to a medical,psychiatric or an environmentalcause (such as drug abuse ormedications).

SedativeA substance that depressesthe central nervous system,resulting in calmness,relaxation, reduction ofanxiety and sleepiness.

ToleranceReduced drug responsivenesswith repeated exposure to aconstant drug dose.

Emerging anti-insomnia drugs:tackling sleeplessness and thequality of wake timeKeith A. Wafford* and Bjarke Ebert

Abstract | Sleep is essential for our physical and mental well being. However, when novel

hypnotic drugs are developed, the focus tends to be on the marginal and statistically

significant increase in minutes slept during the night instead of the effects on the qualityof wakefulness. Recent research on the mechanisms underlying sleep and the control of

the sleepwake cycle has the potential to aid the development of novel hypnotic drugs;

however, this potential has not yet been realized. Here, we review the current

understanding of how hypnotic drugs act, and discuss how new, more effective drugs and

treatment strategies for insomnia might be achieved by taking into consideration the

daytime consequences of disrupted sleep.

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530 | junE 2008 | voluME 7 www.a.m/w/
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Stage 1

Awake

Time (h)

REM

Stage 4

Stage 3

Stage 2

Awake

Stage 1

Stage 2

Stage 3

Stage 4

a

b

Hypnotic drugsA class of drug that inducessleep; used for the treatmentof insomnia and to induceanaesthesia.

ad drg acti. A crrety aaiabe hypnoticdrugshae bee deeped with the fcs e particarpatiet ppati: the primary ismiacs. Thispatiet ppati is characterized by haig prbemsi iitiatig ad/r maitaiig seep ad cmpaitsabt daytime perfrmace, bt as witht ay c-mrbidities ad thereby with few, r ess seere, daytimecseqeces. As the crret regatry eirmetfr e hyptic drgs has fcsed techica

parameters sch as seep idcti ad maiteacef seep i primary ismiacs, the rea chaege, thatis, t impre the qaity f wake time f pepe sfferigfrm ismia, seems t be egected. By sig primaryismiacs as the patiet ppati fr the deep-met f hyptics, we hae imited rsees frmthe pprtities f demstratig psitie effects daytime perfrmace. There is, therefre, a strg eedfr ew thikig, bth by drg deepers ad frmregatry athrities.

Here, we reiew the crret derstadig f seepmechaisms, briefy discss existig therapeticagets, ad the highight emergig therapies, targets

ad strategies fr their ciica eaati. Tgetherthese might ead t the deepmet f ew drgs thataddress the imitatis f existig es.

Understanding sleep mechanisms

The discery f specific pathways ied i gerigseep has greaty impred r derstadig f seepfcti ad the differeces i brai actiity whie weare aseep r awake. A mber f key cei i the brai-

stem ad hypthaams hae bee prpsed t frma seep circit. The arsa cetres, sch as the csceres, drsa raphe ad tbermamiary cesprect t the crtex ia the hypthaams. others,sch as the pedcptie ces ad aterdrsategmeta cei, prect thrgh the thaams (FIG. 1).I tr, ihibiti f these arsa cetres cmes frmcei i the hypthaams, sch as the etraterapreptic ces (vlPo) ad media preptic ces.These cei frm a mta ihibitryexcitatry p,with arsa cetres actie drig wake ad ihibitrycetres actie drig seep. The atre f this circitpredispses it t a fipfp switch mechaism, beig

Box 1 | Sleep parameters and measures

The way in which sleep is quantified and described is critical for determining deficiencies in patients with insomnia and

has contributed useful metrics for demonstrating the efficacy of hypnotics. Both objective and subjective measures of

total sleep time, latency to sleep onset and number of awakenings during sleep, among others, give a good measure

of sleep efficiency. The use of polysomnography or electroencephalography has enabled researchers to measure

electrical activity in the brain over the course of the night. This activity can be classified into different stages as shown

below. During the night, in primates and felines, activity proceeds from waking, through rapid eye movement (REM) and

the four stages of non-REM sleep several times, giving a characteristic pattern known as the sleep cycle. Total REM sleeptime, the number of non-REM sleep bouts and the time to reach these states are among the variables that can be

measured. When combined, these measures allow a detailed picture of an individual or animals sleep cycle.

The awake stage is characterized by high frequency activity with variable amplitude, combined with active

electromyography (EMG). The REM stage is characterized by high frequency activity with high amplitude and no active

EMG. Non-REM sleep consists of four stages:

Stage 1: light or drowsy sleep, dominated by theta frequency (47 Hz).

Stage 2: unconsciousness, lower EMG, EEG contains sleep spindles (1215 Hz events).

Stage 3: deep sleep, slow-wave sleep (0.5-4 Hz) occurs less than 50% of time.

Stage 4: deep sleep, slow-wave sleep occurs more than 50% of the time.

In rodents, sleep stages are usually divided into REM and non-REM sleep. Non-REM sleep is often subdivided into

SWS-1 and SWS-2, mimicking Stages 12 and 34, respectively.

Image modified with permission from Nature Reviews NeuroscienceREF. 80 (2002) Macmillan Publishers Ltd.

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nATuRE REvIEWS |drug discovery voluME 7 | junE 2008 |531


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Sleep debtThe cumulative effect on thebody of not getting sufficientsleep.

Sleep driveThe homeostatic mechanismthat produces an increasedtendency to fall asleep.

NarcolepsyA sleep disorder that usuallypresents in young adulthood,consisting of recurring

episodes of sleep during theday and often disruptednocturnal sleep. Narcolepsyaffects more than 100,000people in the United Statesalone and seems to have agenetic basis.

Rotation adaptation taskA task in which subjects reachfor visual targets using ahand-held cursor whileunconsciously adapting tosystematic rotations imposedon the perceived cursortrajectory.

i either e state r the ther, with a ery rapid trasi-ti state6. This rapid trasiti state is highy cseredacrss species ad is a imprtat sria mechaism.

The mechaisms that ctr this circit, ad thefactrs that ifece it, hae bee the tpic f csider-abe research, pridig ew isights ad pprti-ties fr treatig seep-reated disrders. Tw differetfactrs hae a mar impact the seepwake cyce.First, eirmeta, r hmestatic ifeces, schas the accmati fsleep debt fwig prgedwakefess ad/r axiety, ad secd, the edgescircadia rhythm, which prdces the 24-hr cyce adgers may bigica prcesses.

Homeostatic control. Depriig ay aima f seep hasprfd physigica effects ad, i additi t redcedcgitie fcti, the imme system becmes weak-eed ad metabism becmes swer7,8. It was thghtthat the icreased prpesity t seep after depriatimight be de t the accmati f extracear ade-sie, the ed prdct f ATP degradati, i the basa

frebrai. Adesie is geeray a seep-prmtig tras-mitter, ad the atagist effects f caffeie ca prmtewakefess. By actig A

1receptrs, adesie has

bee prpsed t ihibit the wake-prmtig ers ithis area9. Recet data hae qestied this hypthesis,as A

1receptr kckt mice sti accmated seep

debt10. Mreer, esi f chiergic ers i thebasa frebrai abished the bid p f adesie ithis area bt did t affect sleep drive after prgedwakig11. I additi t the A

1receptrs, stdies with

seectie agists ad atagists12,13 idicate that A2A

receptrs are imprtat mediatrs f the hyptic actiityf adesie. A

2Areceptr agists might icrease the

actiity f seep-actie vlPo ers, thereby icreas-ig seep drie13. other ptetia mediatrs f the effectsf seep depriati are the cytkie itereki 1 (Il-1),prstagadi 2A ad itric xide. Iterestigy, iec-ti f seectie ihibitrs f the tw frms f itric xidesythase (noS), idcibe ad era, it the basafrebrai drig seep depriati, shwed that idcibenoS was reqired fr -REM seep recery, whereasera noS was reqired fr REM seep recery14.

The discery f rexis (as caed hypcretis)ad their ik with narcolepsy has ed t the prpsathat these peptide trasmitters, which rigiate frm agrp f ers i the atera hypthaams, are impr-tat regatrs f the seep cyce15. orexiergic ers

prect t may f the ascedig excitatry pathwaysad are actie drig perids f wake ad siet drigseep16. orexi ifsi ehaces era actiity adicreases arsa17. orexi ers rigiatig i thehypthaams hae widespread prectis, ad haew as bee impicated i appetite ad reward ear-ig18. Seectie rexi receptr atagists ehaceseep bth i aimas ad hmas19, ad frther stdieswith sch cmpds might pride e therapeticcadidates t mdate the seep circit.

The recet appicati f micrarray techgy tthe fied f seep has beg t make a impact i thisarea. A stdy iestigatig gees assciated with seep

depriati ad recery highighted seera immediateeary gees ad heat-shck prteis that were preg-ated drig seep depriati ad recery i mice adrats2022(TABLE 1). Frthermre, a stdy that cmparedthe acti f tw widey sed hyptic bezdiazepies,triazam ad zpidem, with seep recery fwigdepriati fd that y a sbset f the gees ass-ciated with seep recery were eeated with hyptictreatmet23. This sggests that crret therapies d tpride the f beefits affrded by atra seep. Thesestdies are the first t address the mechaisms that mightderie ismia ad sggest pssibe targets fr drgtherapy. Tgether with prtemic techgy, sch stdiesshd hep t ecidate the chages brght abt byseep ad hw differet hyptic therapies cmpare withrma seep recery.

The circadian process. Hmestatic seep drie per-ates er a backgrd f circadia rhythmicity, whichcsists f a mber f prcesses der the eractr f the sprachiasmatic ces (SCn). ners

i the SCn exhibit a pacemaker actiity that is sesi-tie t eirmeta ipts ad tpts i the frmf hrma ad eectrica sigas. The circadia bi-chemistry has bee widey iestigated ad is reiewedesewhere24. Imprtaty, seera gees that ifecead regate the circadia cck, ad cseqetyseepwake actiity, hae bee idetified. May fthese gees hae iertebrate hmges that affectseepwake actiity i isects. Ideed, recet stdies haeshw that mtatis i the Shaker ptassim chaegee (Sh) ad assciated Hyperkietic gee (Hk) resti redced seep ad impaired memry fcti iDrosophila melanogaster25,26. Actiati f the epidermagrwth factr receptr (EGFR) ad extracear siga-regated kiase (ERK) by the membrae prtease rhm-bid (rh) hae as bee shw t icrease seep iD. melanogaster27. As the mammaia eqiaet f rh isas imprtat fr ctrig circadia rhythms, stdiesf eqiaet gees i ertebrates are ikey t pe pe areas f exprati.

Mammaia gees that are kw t ifece cir-cadia actiity icde PER13, CRY1/2, BMAL1 (askw asARNTL) ad CLOCK. These are regated bykiases ad phsphatases, icdig casei kiase 1(CK1)/CK1, CK2, prtei phsphatase 1 (PP1) adPP2 (REF. 24). Fctia abrmaities i these geesrest i chages i the circadia rhythm ad hae bee

impicated i a mber f hma seep disrders. Frexampe, famiia adaced seep phase sydrme hasbee assciated with the S662G mtati i the Per2gee ad the T44A mtati i Ck1. The Per2 mta-ti i mice recapitates the hma cditi f earywakig ad eary seepig28.

osciatis i the ees f the hrme prkietici 2(PK2) i the SCn, are as imprtat fr -REM seepad fr esrig seep cmpesati after depriati29.

Slow-wave sleep. Seera stdies hae iked SWS, cgi-ti ad syaptic pasticity. learig f a mtr crdi-ati task, sch as the rotation adaptation task, was fd

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VLPO

SCN

BF

LHDMH

PeF

VPAG

LDT

PPTRaphe

LC

TMN

Thalamus

Cerebellum

Pons

a

VLPO

SCN

BF

PeF

VPAGDMH

Pin

LDT

PPT

Raphe

LCPC/PB

TMN

Thalamus

Cerebellum

Pons SLD

b

t trigger a ca icrease i sw-wae actiity i thecrtex, crrespdig with a impred perfrmace ithe assciated task the fwig mrig30. Cersey,if syaptic actiity is frciby depressed, by arm imm-biizati, sw-wae actiity was redced i a regi

f the smatsesry crtex drig sbseqet seep31.These experimets demstrate a direct ik betweesyaptic actiity ad caized seep regati.

Frther stdies hae w shw that the degree fexpressi f the pasticity-reated grwth factr brai-deried ertrphic factr (BDnF), is directy iked tthe amt f expratry actiity drig the preisday ad the drati f sbseqet SWS actiity32.As,the imprtace f SWS fr cgitie fcti was dem-strated by presetig dr ces that had preisy beesed i the ctext f a earig task drig either SWSr REM seep33. oy presetati drig SWS icreaseddecaratie memry csidati i the sbseqet seep

perid. These stdies idicate that seep has a imprtatre i memry csidati ad earig, ad that SWSis imprtat t y fr a gd ights seep, bt asfr prdcig adeqate cgitie fcti the fw-ig day34. The deepmet f therapies that specificay

icrease SWS may hae sigificat beefits er thse thatare beig sed at preset.

Sleep and other neurotransmitters. The erpeptidegaai (GAl) is c-expressed i the vlPo withiGABAergic ers ad has bee demstrated ticrease bth REM seep ad SWS whe iecteditraesy35. Grehi (GHRl) ad erpeptide Y(nPY) hae as bee shw t prmte seep adshw cear iks t icreases i grwth hrme (GH)ad grwth-hrme reeasig hrme (GHRH),which themsees icrease -REM seep36. Atherhrme demstrated t hae a re i seepwake

Figure 1 | sp a aa ma

ba. a | Artistic rendering of the human brain in the

awake state illustrating important arousal and sleep

centres and pathways of neurotransmission. Cholinergic

input (orange) from the laterodorsal tegmental (LDT)

and pedunculopontine (PPT) nuclei project through the

thalamus and facilitate thalamocortical transmission of

arousal signals. A second pathway projects through

the hypothalamus to cortical centres and facilitates theprocessing of thalamocortical inputs arising from

midbrain centres including the noradrenergic (blue)

locus coeruleus (LC); the serotonergic (purple) dorsal

raphe (Raphe); the histaminergic (pink) tubero-

mammillary nucleus (TMN); and the dopaminergic

(yellow) ventral periaqueductal grey matter (VPAG).

This pathway also receives input from the cholinergic

(orange) basal forebrain (BF) and the peptidergic

neurons of the lateral hypothalamus (LH) and

perifornical neurons (PeF), which contain orexin or

melanin-concentrating hormone (light green).

The melatonergic (red) neural network affects arousal

and sleep through regulation of circadian rhythms.

This internal biological clock originates in the

suprachiasmatic nucleus (SCN), projects through thedorsomedial hypothalamus (DMH) sending inhibitory

signals to the GABA (-aminobutyric acid)ergic (grey)ventrolateral preoptic nucleus of the hypothalamus

(VLPO). b | Artistic rendering of the human brain in the

sleeping state illustrating important sleep and arousal

centres and pathways of neurotransmission. The VLPO

of the hypothalamus sends descending GABAergic

(grey) inhibitory signals to the midbrain arousal centres

including the PeF, TMN, VPAG, Raphe, LDT and PPT, and

LC. During the early hours of dark periods the pineal

gland (Pin) releases melatonin (red), which has inhibitory

effects on the SCN and DMH of the melatonergic

system. Nuclei that control neural activity during rapid

eye movement (REM) sleep have been identified in the

pontine midbrain. The pericoeruleus (PC) andparabranchial (PB) nuclei send glutaminergic (green)

projections through the BF to affect cortical activity

during REM sleep, and projections from the

sublaterodorsal nucleus (SLD) send glutamatergic

signals through the spinal cord to induce atonia that is

characteristic of REM sleep.

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Sleep hygieneSleep habits that promotehealthy sleep such as fixedbedtime and awakening time,avoiding naps, blocking outnoise and light, and avoidingcaffeine and alcohol beforesleep.

ctr is meai-ccetratig hrme (MCH). Arecet stdy described the wake-prmtig effects f aMCH1 atagist that decreased the drati f bthSWS ad REM seep37.

uti recety, it was thght that dpamie hada mir re i the regati f seepwake actiity;hweer, seera stdies hae reeaed a critica re frdpamie D

2receptrs i the ctr f REM seep.

Experimets i hyperdpamiergic mice shwed thatthey exhibit a haperid-sesitie REM-ike actiitydrig wake-time, ad dpamie-depeted aimas shwcmpete sppressi f REM seep, which is recerabewith dpamie agists38. This stdy as demstrateda ik t the seep distrbaces experieced by patietswith Parkiss disease, sch as excessie daytimeseepiess ad distrbed seep architectre. Atherstdy shwed icreased brst firig f dpamiergicers i the etra tegmeta area drig REM seep,a actiity kw t reease dpamie39.

Despite sme mar adaces i derstadigseep mechaisms i the past few years (BOX 2), there

has bee itte prgress i derstadig ismia adits aetigy. There are cear iks betwee ismiaad psychiatric disrders, sch as axiety ad depres-si, ad gaiig frther isights it these ad therseep disrders wi icrease r abiity t deep mreapprpriate treatmets.

Currently used medications and their limitations

Benzodiazepine receptor agonists. Bezdiazepiesmdate GABA receptrs igad-gated i chaesthat mediate the effects f the ihibitry ertrasmitterGABA. The first bezdiazepie sedatie, chrdiaze-pxide, was deeped ad ached the market i1960 as librim. The mre ptet diazepam vaim f-wed i 1963, ad may ther reated bezdiazepieswere sbseqety ached. This cass f cmpdwas mre ptet tha preisy sed sedaties, schas barbitrates, ad did t hae the assciated txicityprbems r iabiities erdse; recrd mbers fprescriptis were issed i the 1970s ad 1980s4. Theterace ad abse ptetia see with barbitrateswas sti preset, athgh sighty redced, i bezdi-azepies40. Hweer, whie they are effectie fr treatigismia, bezdiazepie receptr agists fte pr-dce ext-day sedati, ataxia, ad memry ad cgi-tie impairmet41,42. As a rest, the se f these drgshas becme imited i recet years, despite them beig

effectie ad fast-actig drgs fr shrt-term se.There are aris sbtypes f GABA

Areceptrs,

which differ i distribti, pharmacgy ad biphysicaprperties43. oe f the mre recety deeped bez-diazepie receptr agists, zpidem, demstratesa degree f seectiity fr the 1-sbit-ctaiigsbtype ad is reatiey mre effectie as a hypticaget tha a axiytic44,45. Zpidem has becme ef the eadig crret therapies fr ismia ad simiars-caed bezdiazepie receptr agists, sch aszaep, zpice, eszpice ad idip (crretyder reiew by the uS Fd ad Drg Admiistrati),as hae a sma degree f1-seectiity46,47. Geetic

mse mdes hae recety idetified the 1-sbtypeas haig a imprtat re i the sedatie prperties fbezdiazepies; hweer, it is sti cear whether themdest in vitro seectiity f these types f cmpdsprides ay adatage in vivo r whether they casefewer side effects48.

Melatonin. The hrme meati, which is reeasedfrm the piea gad drig the ight, is itrisic t thectr f circadia rhythm i the brai. lw ees fmeati hae bee iked t ismia, ad admiis-trati f meati is thght t be seep-prmtig49.The mid hyptic prperties f meati, ad itsaaiabiity i sme ctries as a atra sppemet,hae ed t its widespread se fr ismia50. Hweer,eidece f the efficacy f meati is based imitedciica-tria data. Frthermre, the shrt haf-ife adhigh first-pass metabism f meati ted t imitits sefess as a ra aget. The meati receptragist ramete is w appred fr ismia, adathgh head-t-head reprts with ther agets

hae bee pbished, ciica data sggest that its efficacymight be reatiey mdest cmpared with that f therismia therapetics51.

Antihistamines and antidepressants. Mid ismia caas be treated sig atihistamies, which prdce smedegree f sedati. There are may er-the-ctertreatmets ctaiig diphehydramie r hydrxyziethat ca gie temprary reief fr seep prbems52. Theseagets ted t case daytime drwsiess ad are trecmmeded fr ctis se as they as exhibitterace53.

I the past few years, seera f the serti-mdat-ig atidepressats sch as trazde ad efazde,which i additi t their md-stabiizig effects ashae sedatie effects, hae bee prescribed fr ism-ia, especiay i depressi-reated ismia54,55. Thesedrgs are reatiey safe, with isses regardig teracer abse ptetia, ad prbaby exert their effects byihibitig serti ad histamie receptrs.

Cognitive behavioural therapy. A ateratie t phar-mactherapy fr seep disrders is cgitie behairatherapy (CBT). CBT is say taired t the specificprbems f the patiet ad ca be sed i cmbiatiwith sleep hygiene traiig, reaxati exercises adbifeedback (ctrig breathig ad heart rate).

Cgitie ctr ad psychtherapy ca fte hep tercme daiy axieties r wrries abt gettig t seep.I ciica trias, CBT ca be as effectie, if t better,tha pharmactherapy, with fewer ccers regardigreapse ad terace effects56,57. This frm f treatmetis i may respects der-tiized as it ies freqet

isits t seep speciaists, f which there are crretyery few.

Novel approaches to the treatment of insomnia

Adaces i the derstadig f seep mechaismshae idicated pssibe appraches fr discerig ehyptic drgs. Here, we wi fcs ptetia ew

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Polysomnographic variablesPhysiological variables that

are captured during electro-encephalography sleepanalysis, for example, brainelectrical rhythms, eyemovements, muscle activityor skeletal muscle activation,heart rhythm and breathingfunction or respiratory effortduring sleep. These alsoinclude variables such as sleeplatency and maintenance,duration of rapid eyemovement (REM) and non-REM sleep.

Sleep latency

The time it takes to go from fullwakefulness to being asleep.

Scheduled statusA controlled drug for whichuse and distribution is tightlyregulated owing to its abusepotential or risk. Classified bythe US Food and DrugAdministration from I to V withSchedule I drugs exhibitingthe highest risk. Most benzo-diazepines are Schedule IVmeaning that they can onlybe supplied and produced bythose authorized to do so.

therapies that ehace SWS, sch as gabxad (whichseectiey actiates -ctaiig GABA

Areceptrs);

5-hydrxytryptamie 2A (5-HT2A

) receptr atagists,sch as MDl 100907; sedatie atidepressats; meatireceptr agists, sch as ramete; ad rexi receptratagists (TABLE 2).

Enhancing SWS. uti recety, it seemed that theGABA

Areceptr fied wd ffer e appraches

fr the treatmet f ismia. Gabxad, a GABAA

receptr agist with fctia seectiity fr theextrasyaptic GABA

Areceptrs, which are tched

by the bezdiazepies, was i Phase III ciica triasbefre ciica deepmet was disctied. uikebezdiazepie receptr agists, gabxad sigifi-caty ehaced SWS actiity ad the drati f seepad, reatie t zpidem, it had mdest bt sigificateffects the idcti f seep. Gabxad was fdt seectiey actiate the 42-ctaiig GABA

A

receptr sbtype cated extrasyapticay ers ithe etrbasa thaams58. Treatmet with this sbtype-seectie cmpd impred seep qaity48,59,60 ad hadpsitie effects daytime perfrmace i primaryismiacs61. Hweer, stdies were cdcted ipatiets with seere impairmets i either SWS actiity rdaytime perfrmace, s it is sti qestiabe whetherGABAergic cmpds that ehace SWS actiity wihae sperir beefits er cassica hyptics.

I this ctext, cmpds actig as 5-HT2A

/5-HT2C

receptr atagists are iterestig. Ritaseri hasbee fd t icrease the amt f SWS i heathy

teers ad i yg, pr seepers62,63. Ketaseri,

ather 5-HT2A

/5-HT2C

receptr atagist, has asbee demstrated t prmte SWS, athgh t aesser extet tha ritaseri64, ad a icrease i thember f REM-seep episdes has bee bseredfwig admiistrati f this aget i rats65. It istewrthy that t date pbished data exist dem-stratig impremets assciated with these SWS-prmtig agets traditia polysomnographicvariables, sch as sleep latency r ctiity. Ciicastdies with cmpds ike ritaseri ad keta-seri (ad thers sch as praseri, epiaseri,

iaseri ad pimaaseri) are eagery awaited.These cmpds appear t be we terated ad asthis cass f cmpds ack abse ptetia i theatipsychtic area, it is ikey that, if appred, theywi retai the scheduled status that is assciated withbezdiazepies. Preciica data sggest that they wibe targeted twards imprig seep maiteace adqaity rather tha atecy.

Ather cass f cmpds that hae bee fdt icrease SWS actiity are the cacim chae 2-

sbit mdatrs reated t gabapeti. Pregabaiehaced SWS ad sigificaty impred seep i ahma tria66. Cseqety, seera aages are wi deepmet fr the treatmet f ismia, icdigPD-200390, which is i Phase II trias. The qestiregardig scheded stats with these cmpds ist as cear pregabai was cassified as Schede vi the uited States.

Modulation of circadian rhythms. As metied abe,seep distrbaces may be a cseqece f disrptedcircadia rhythmicity. The hrme meati seresas a seep-aticipatig ce i hmas, ad seera std-ies hae idicated a redced prdcti f meatii patiets wh are edery r depressed. Meatireceptr agists represet a e apprach i thetherapetic maagemet f ismia. There are twmeati-bidig sites: MT1 is a high-affiity sitead is fd i the SCn ad cardiac esses; MT2 isa w-affiity site that as appears t hae a re ithe mdati f circadia rhythms67,68.As meatiexerts its effects by bidig t MT1 ad MT2, high-affiity MT1/MT2 agists with a ger haf-ife thameati (haf-ife f 12 hrs cmpared with the


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Subjective sleep parametersUsing questionnaires, patientsrate their feelings of time tosleep, time awake and numberof awakenings during the nightin addition to the quality ofsleep and feeling refreshedin the morning.

Phase-shiftAn induced temporal shift ofthe normal circadian rhythm.

f meati r circadia-rhythm disrders. Whetherthe effects sbectie seep parameters wi trasateit a impremet i the qaity f ife f patiets whsffer frm depressi r ther types f disrders is stikw. Gie the reatiey weak effects i actestdies, patiet ppatis ther tha primary ism-iacs (with shrt-term cmpaits) might experiecegreater beefits frm this type f cmpd.

Ramete, a MT1/ MT2 agist, has bee themarket i the uited States sice 2005. I ie withthe fidigs with meati, this cmpd is abet idce seep; hweer, sbectie measres f seepqaity were t impred51. This sggests that eithera types f meati receptrs shd be targeted rthat seecti f the reeat patiet ppati is para-mt fr drgs that iteract with the meati-receptr

system. The mar chaege fr these cmpds is thattheir seep idcti ad maiteace prperties wibe cmpared with bezdiazepie receptr agists,which are effectie er a brad rage f idicatis. Ir pii, this cass f cmpds wi fid its ichei patiet ppatis i which circadia rhythmicityderies the seep distrbaces ad t primary ism-ia, i which era meati ees are qite simiart -ismiacs.

Combination therapy. The deepmet f agmeatie,a cmbied 5-HT

2Creceptr atagist ad a meati

receptr agist, fr depressi71 might hd great

ptetia i the treatmet f ismia. Wi agmeatie,which has bee abe t phase-shift hmas ad icrease-REM seep72, hae additia effects imprigseep parameters? Wi the 5-HT

2ceffect act syergisti-

cay with the meatergic effect? It cd be that the5-HT

2creceptr atagism f this cmpd i cm-

biati with seectie serti reptake ihibitrs,fr exampe, cd icrease the set f atidepressatacti. The meatergic prperties f agmeatiemight aeiate the seep distrbaces that are assciatedwith depressi ad hep preet reapse, which is fteiked t seep prbems.

The ik t atidepressats is frther spprted bythe deepmet f w-dse dxepi fr ismia73. Aswe as beig a mscariic atagist, dxepi is a hista-mie H

1/H

2receptr atagist, which might expai

its hyptic prfie. This cmpd is i Phase III cii-ca trias ad is aticipated t reach the marketpace i2008. A cmbied histamie H

1ad 5-HT

2Aatagist

(Hyp-10275) is as i deepmet by Ei liy ( pb-ished data are crrety aaiabe); the cmbied effects

f simtaes actiity at these tw targets might pret be highy efficacis.

Orexinergics. I ight f the wake-prmtig effectsf the edges peptide rexi, the deepmet frexi receptr atagists actig seectiey at oX

1r

oX2, r seectiey, is t expected. The effects

f e f these cmpds (ACT-078573), which isi Phase III ciica deepmet, idicate that thesetypes f cmpds might prmte REM ad -REM seep19. Hweer, as i the case with meatiad ther seep-reated ertrasmitters, a imprtatqesti is whether hyperfcti f the rexiergicsystem i the geera ismiac ppati actayctribtes t their pr seep, r whether this yreates t a specific sbppati. A recet stdy hasdemstrated hyperarsa ad eeated rexi A i thehypthaams f materay depried rats, sggestigthat eeated rexis cd ctribte t ismia ithis mde74.

Benzodiazepine receptor agonists. Despite the mberf bezdiazepie receptr agists that are crrety the market, there are sti seera i deepmet.nG-2-73 is described as a 3-sbtype-seectie partiaagist ad is crrety i Phase II trias. Etec ashas a partia agist (EvT-201) i Phase II trias fr

ismia. It is t crrety kw what adatagesthese cmpds might ffer er simiar drgs thatare aready the market.

Other emerging targets. The discery f ew geesad pathways ied i the ctr f seep hasreeaed a mber f ptetia ew drg targets.Thse ied i ctrig circadia rhythms, schas PK2 (REF. 29), hae aready beg t be stdied, adthe geerati f e igads wi t y ctribtet the derstadig f these pathways, bt mightas ead t the discery f mre efficacis ciicatherapetics.

Box 2 | Techniques in sleep research

Different approaches have been taken to

explore the mechanism and function of

sleep. Electrophysiological measures

such as electroencephalography (EEG)

are vital for providing insight into the

activity of the brain during this process.

More recently, functional imaging hasalso shed light on this activity, by using

positron-emission tomography (PET)

scanning and functional magnetic resonance imaging (fMRI) techniques81. Although at

an early stage, these studies are providing a way to identify in more detail the regions

of the brain that are involved in sleep and the importance of this activity for cognitive

function. For example, sleep deprivation has been associated with declines in cerebral

metabolism, particularly in the frontoparietal cortex and in the thalamus82,83. The fMRI

images above show a marginal activation of the auditory cortex (left image) upon

acoustic stimulation in a healthy sleeping subject during non-rapid eye movement

(REM) sleep. During REM sleep, however, the brain is hardly stimulated by external

stimuli, but shows independently generated activity in many brain areas, which is

thought to be indicative of dreaming (right image).

Advances in genetics have enabled the identification of genes involved in the sleep

process (TABLE 1). Several studies using microarray technology have identified genes

that are associated with sleep deprivation and recovery, as well as the action ofhypnotic drugs. The fruitfly Drosophila melanogaster, which is amenable to rapid

genetic manipulation, is also revealing novel genes and pathways involved in sleep.

These studies identify new avenues, which can be followed up in mammalian systems.

The genetic manipulation of mice also provides a tool for investigating the role of

novel genes and proteins in sleep function. Combining these approaches with direct

measures, such as EEG, creates a powerful means for understanding more about the

function of sleep and identifying new ways to develop sleep therapeutics.

This image is reproduced with permission from REF. 84 (2007) Blackwell Publishing.

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Challenges for novel insomnia therapies

The deepmet f hyptic drgs has aways fcsed the idcti ad maiteace f seep. I ppatiswith seere seep-idcti prbems, the highy sedbezdiazepie receptr agists redce the time it takest fa aseep by apprximatey 30 mites ad icreasethe time spet seepig thrgh the ight by 1020 mi-tes, ths imprig the tta seep i a stadard ight byapprximatey 40 mites.

Hweer, few stdies hae ked at the fctiacseqeces fr the daiy iig f dsig with hypt-ics75. Drg cmpaies ad regatry agecies seemt hae fcsed heaiy the metrics f seep adegected the qaity-f-ife aspect i the defiiti f

ismia i the Diagstic ad Statistica Maa f

Meta Disrders, 4th editi as: casig ciicaysigificat distress r impairmet i scia, ccpatiar ther imprtat areas f fctiig.

Sme stdies hae characterized the daytime cse-qeces f disrpted seep ad estabished crreatisbetwee disrpted seep ad a mber f c-mrbidities.Ths, seep distrbaces appear t be iheret t symp-tm cmpexes describig depressi ad axiety76,Azheimers disease77, ad chric pai78. Despite this,hardy ay hyptic cmpds hae adeqatey beedescribed i these highy reeat ppatis ad, mreimprtaty, ismia drg has bee deeped frthese idicatis. Istead, a cmpds hae bee

Table 2 | Novel insomnia therapeutics in at least Phase II development

d am Pamaaa

cmpa ia dpmpa

Silenor H1/H

2antagonist,

muscarinic antagonistSomaxonPharmaceuticals

Sleep disorders Phase III

Indiplon IR,Indiplon MR

GABAA

BZ-sitemodulator

NeurocrineBiosciences

Sleep disorders Awaitingapproval

Eplivanserin,SR 46349

5-HT2A

receptorantagonist

SanofiAventis Sleep disorders Phase III

Volinanserin,M-100907

5-HT2A

antagonist SanofiAventis Sleep disorders Phase III

VEC-162 Melatonin receptoragonist

VandaPharmaceuticals

Sleep disorders,depression

Phase III

ORG 50081 Noradrenergic,specific serotonergicantidepressant

OrganonInternational

Sleep disorders,hot flushes

Phase III

Agomelatine 5-HT2B

/5-HT2C

antagonist, melatoninagonist

Novartis Depression,sleep disorders

Phase III

Almorexant,

ACT-078573

OX1

and OX2

receptor

antagonist

Actelion Sleep disorders Phase III

PD-6735 Melatonin receptoragonist

Phase 2 Discovery Sleep disorders Phase II

Pruvanserin,EMD 281014

5-HT2A

antagonist Eli Lilly Sleep disorders Phase II

APD125 5-HT2A

inverse agonist Arena Sleep disorders Phase II

ACP-103 5-HT2A

receptor inverseagonist, dopamineD

2/D

3receptor partial

agonist, acetylcholineM

1receptor agonist

AcadiaPharmaceuticals

Sleep disorders,antipsychotic-induced side effects,Parkinsons disease

Phase II

PD 200-390 2calcium channelblocker

Pfizer Sleep disorders Phase II

HY10275 5-HT2A and H1 receptorinverse antagonist

Eli Lilly Sleep disorders Phase II

GW649868 Orexin receptorantagonist

GlaxoSmithKline Sleep disorders Phase II

Adipiplon, NG-2-73 GABAA

BZ-sitemodulator

Neurogen Sleep disorders Phase II

EVT-201 GABAA

BZ-sitemodulator

Evotec Sleep disorders Phase II

5-HT2A

/5-HT2B

/5-HT2C

, 5-hydroxytryptamine (serotonin) receptor 2A/2B/2C; BZ, benzodiazepine; D2/D

3, dopamine receptor 2/3;

GABAA, -aminobutyric acid receptor A; H

1/H

2, histamine receptor 1/2; M

1, muscarinic receptor 1; OX

1/OX

2, orexin receptor 1/2.

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Montgomerysbergdepression rating scaleAn 11-item clinician-administered questionnairethat is used to rate the severityof a patients depression.

Sheehan disability scaleA patient self-reporting tooldeveloped to assess functionalimpairment in work/school,social and family life. It usesa series of 10-point visualanalogue scales.

deeped i primary ismiacs, wh sffer frmdisrpted seep bt hae psychiatric c-mrbiditiesad, therefre, daytime fcti is ess impaired. I mstseep stdies that are cdcted i primary ismiacs,daytime fcti is measred. Hweer, sedm dthese daytime fcti parameters idicate aythigbt absece f impairmet, ad this is prbaby det the seected patiet ppati stdied. I additi,pr daytime fcti deries the secdary effects,icdig a arge prprti f rad traffic accidets adwrk-reated accidets that ccr de t ismia.

It is srprisig that cmpds are deeped i theprimary ismia ppati ad the extrapated itpatiet ppatis wh hae c-mrbidities. nrmay,at the time f ach f these cmpds, stdieshae bee cdcted i the reeat patiet ppatis,ad ths, kwedge tside f primary ismia isackig. oe might expect that the idicati wd befr primary ismiacs y, bt the uS Fd ad DrgAdmiistrati, ad ti recety as the ErpeaMedicies Agecy, has awed the mch brader idi-

cati ismia, impicity assmig that if cmpdsare actie i primary ismiacs, they wi as be actiei ther types f ismia, sch as thse assciated withther c-mrbidities. This might be the case fr bez-diazepies (i which the geera sppressi f arsasystems ad crtica strctres i the CnS eads t aimpred idcti ad pssiby maiteace f seep)bt whe it cmes t the fctia cseqeces frdaytime iig, itte is kw.

Gideies fr the deepmet f hyptic drgsfcs primary ismia ad the simpe metrics fseep, whereas ther ppatis ad measremetshae bee egected. I rder t refect the ciicamet eeds, it wd be highy reeat ad timeyt pdate these gideies fr hyptics. At preset,daytime perfrmace is csidered as a absece fimpairmet impremet f fcti with bez-diazepies r bezdiazepie receptr agists haseer bee demstrated. We wd arge that mrereeat ppatis shd be chse t demstratebth impremets ad impairmets79. Ather impr-tat isse i this ctext is the appicati f sbectieparameters i the eaati f ciica effects f thehyptics. Perhaps the se f disabiity scaes sch asthe Montgomerysberg depression rating scale r theSheehan disability scale wd be mre sitabe fr ea-atig daytime perfrmace istead f the fte-sed

tests measrig the abiity t recect items r separateights (sch as critica f icker fsi).

Fwig appra fr primary ismia, mst hyp-tics derg eaatis i sma-scae stdies sig therismia ppatis. I mst f these stdies, the fcsis sti the idcti ad maiteace f seep, withmst recety deeped hyptics beig bezdiazepiereceptr agists. It is hardy srprisig that data frmprimary ismia easiy trasates it the same metricsi these ppatis. oy Sepracr has cdcted smereatiey iatie stdies. I the pst-fiig eaatif eszpice i the uited States, eszpice was ea-ated i cmbiati with the atidepressat fxetie,

ad istead f y cectig seep data, by statisticaaaysis it was pssibe t demstrate that eszpicesigificaty impred the atidepressat acti ffxetie ad parameters ther tha seep.

S wi it be pssibe t fcs sbectie seep meas-res ad daytime perfrmace? The Erpea MediciesAgecy has recety appred Circadi (prged-reease meati; nerim Pharmaceticas) the basisf sbectie seep measres. Hweer, the idicati frthis cmpd was arrwed t primary ismia iedery patiets, sggestig that with this cmpd theErpea athrities y reied the ciica stdiescdcted ad did t accept the trasati it thegeera edery ppati. The cseqeces f theappra shd t be derestimated. If appra fe seep cmpds wi be based the ppa-tis icded i the ciica deepmet prgramme,this might ecrage cmpaies t deep cmpdsfr the reeat patiet ppatis ad ths, seect theptima ciica tcme parameters. Hweer, if cmpa-ies ad regatry athrities ctie t fcs the

metrics f seep i easiy defiabe ppatis, sch asprimary ismia, ery itte iati r beefit fr thether patiet sbppatis wi be btaied.

Final comments and future directions

Fr the past fr decades, bezdiazepies r -bezdiazepies hae bee the predmiat hypticdrgs. These cmpds are ery effectie i idc-ig ad maitaiig seep. Hweer, the risk that isassciated with these cmpds after g-term se(depedece, icreased abse ptetia ad t smedegree withdrawa symptms) sggests that eappraches fr the treatmet f ismia are reqired.

Crret research seems t be mig away frm themar ihibitry GABA

Areceptr system ad twards

mdatig mre sbte edges pathways thatctr the seepwake cyce. These appraches mightbe mre adeqate fr hepig particar sbppatissfferig frm ismia, bt at the same time a mberf imitatis are iheret t this apprach. oy specificppatis wi respd t the treatmet, hece the eedfr better diagstic criteria ad a deeper derstadigf ismia. Mdati f the seepwake cyce is erymch a qesti f timig f dsig, s the deep-met f dsage frms, ad appicati systems that caesre dsage at the crrect time, wi be essetia frthis apprach.

The deepmet f cmpds that are actie i theCnS is expesie, ad if they are y t beefit particarpatiet sbppatis, the riskbeefit rati f thesecmpds eeds t be estabished carefy at a earystage f ciica deepmet. This wi demad that theidstry, i cabrati with regatry athritiesad ciica experts, defie ad agree bth the patietppatis ad the types f tcmes, ther tha seepparameters, t be mitred i the reeat ppatis.The cseqeces fr the deepmet f e hypticswi hpefy be that seep prbems wi eetay becsidered as a itegra part f, istead f secdary t,diseases sch as depressi ad Azheimers disease.

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Competing interests statementThe authors declare competing financial interests: see webversion for details.

DATABASESEntrez Gene:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

ARNTL| Hk|rho | Sh

OMIM:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

Alzheimers disease | familial advanced sleep phase

syndrome | Parkinsons disease

UniProtKB:

http://ca.expasy.org/sprot

A1

| A2A

| D2|MCH1 | OX

1| OX

2|PK2|5-HT

2A| 5-HT

2C

All links Are Active in the online PdF

R EV IEW S

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Emerging Anti-Insomnia Drugs: Tackling Sleeplessness and The

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