03/02/2015

Reboxetine:ANovelAntidepressantKadheNG,ChillarAJ,DeshmukhYAJPostgradMed

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DRUGREVIEW
Year:2003|Volume:49|Issue:4|Page:373375
Reboxetine:ANovelAntidepressant
NGKadhe,AJChillar,YADeshmukh
T.N.MedicalCollege&B.Y.L.Ch.NairHospital,MumbaiCentral,
Mumbai,India
CorrespondenceAddress:
NGKadhe
DepartmentofPharmacology,T.N.MedicalCollege&B.Y.L.Ch.
NairHospital,MumbaiCentral,Mumbai
India

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::MechanismofAction
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::ADRs
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::ComparisonofEf...
::ComparisonofSa...
::Otherindications
::Conclusion
::References

Howtocitethisarticle:
KadheNG,ChillarAJ,DeshmukhYA.Reboxetine:ANovel
Antidepressant.JPostgradMed200349:3735
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KadheNG,ChillarAJ,DeshmukhYA.Reboxetine:ANovel
Antidepressant.JPostgradMed[serialonline]2003[cited2015Feb
2]49:3735.Availablefrom:http://www.jpgmonline.com/text.asp?
2003/49/4/373/4988
Depressionisacommonanddisablingdisorder.TheWorldHealth
Organisationhasrankeddepressionfourthinalistofthemosturgent

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healthproblemsworldwide.[1]Depressionhasmajoreffectson
economicproductivity,individualwellbeingandsocialfunctioning,
aroundtheglobe.Itisahugeburdenonindividuals,families,and
society.Thelifetimeriskformajordepressionhasbeenestimatedtobe
7%12%formenand20%25%forwomen.[1],[3]
AccordingtotheBiogenicMonoaminetheoryofSchildkraut(1965),
depressionresultsduetoimpairmentordysregulationofaminergic
transmission.[1]Otherssuggestthatthoughnoradrenalineand
serotoninergicsystemsareinvolved,thespecificimpairmentthat
underliesdepressionisunclearandislikelytovaryamongpatients.[4]

Jan
78
2015

Medicaltreatmentfordepressionfavorsprescriptionantidepressant
drugsthatworkbyincreasingneurotransmissionforoneormoreofthe
monoaminesserotonin,norepinephrine,ordopamine.Before1980,
antidepressanttreatmentconsistedprimarilyofthetricyclics
antidepressants(TCADs),monoamineoxidaseinhibitors(MAOI),and
lithium.Theantidepressantpropertiesofthesemedicationsare
attributedtomodulationofnoradrenergicandserotonergicfunction,
buttheyalsohavemanysideeffectsduetobindingtomultiple
unrelatedreceptors.Thetricyclicsantagonizemuscarinic,H1
histaminic,anda1adrenergicreceptorscausingconstipation,urinary
retention,drymouth,sedation,andposturalhypotension.5Inaddition
tothese,themonoamineoxidaseinhibitorshavetheaddedriskof
potentiallyseverehypertensivecrisisduetopressoreffectsofdietary
tyramine,whichrequiresdietaryrestrictions.Thisriskismuchlower
withthenewerreversibleinhibitorsofmonoamineoxidase.Boththe
tricyclicsandthemonoamineoxidaseinhibitorscanbelethalin
overdose,andthemonoamineoxidaseinhibitorsinteractdangerously
withseveraloverthecounterandprescriptiondrugs.
Inthelate1980'saimportantclassofantidepressantwasintroduced,
theselectiveserotoninreuptakeinhibitors(SSRIs),whichincludes
fluvoxamine,fluoxetine,sertraline,paroxetine,andcitalopram.This
classhasbecomeamainstayofantidepressanttreatmentbecauseof
substantialadvantagesoverthetricyclicsandmonoamineoxidase
inhibitorsinsafety,tolerability,andeaseofdosing.TheSSRI'salso
havelimitations,especiallyresponsefailureinmanyofthosemost
severelyaffected.Manypatientsexperiencesideeffectslike
gastrointestinalcomplaints,nervousnessandagitation,sexual
dysfunction,andweightgainwithlongtermuse.[5]
Alltheseleadtodifficultyinlongtermtreatmentandnoncompliance.
Hence,oneofthemostimportantgoalsinthepharmacological
treatmentofdepressionistoprovidethepatientswithhighly
efficaciousdrugsthathavefewsideeffects,lowornotoxicityanda
highleveloftolerability.
Reboxetineisaselectivenoradrenalinereuptakeinhibitor(NaRI),the
firstdrugofnewantidepressantclassintroducedin1997.Reboxetine
isaaariloxybenzylderivativeofmorpholine.

::MechanismofAction
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Reboxetineisaselectiveinhibitorofnoradrenalinereuptake.Itinhibits
noradrenalinereuptakeinvitrotoasimilarextenttothetricyclic
antidepressantdesmethylimipramine.Reboxetinedoesnotaffect
dopamineorserotoninreuptake[5]andithaslowinvivoandinvitro
affinityforadrenergic,cholinergic,histaminergic,dopaminergicand
serotonergicreceptors.[6]

::PharmacokineticProperties

Reboxetineisrapidlyandextensivelyabsorbedfollowingoral
administration.Maximumplasmaconcentrationofreboxetineis
reachedin22.5hoursaftera4mgoraldoseinhealthyvolunteers.
Reboxetinehaslinearpharmacokineticsacrossthenormaldoserange.
[5]Steadystateplasmaconcentrationsarereachedwithin5daysof
startingtherapy.Reboxetineis98%boundtoplasmaproteins,
predominantlythea1acidglycoprotein.[6]Reboxetineismetabolized
bydealkylation,hydroxylationandoxidationfollowedbyglucuronide
orsulphateconjugation.[7]ItismetabolizedbythecytochromeP450
CYPisoenzyme3A4.[1]Compoundsthatdecreasetheactivityofthis
isoenzymearelikelytoincreasetheplasmaconcentrationsof
reboxetine.Reboxetinehasarelativelyshorteliminationhalflifeof
12.5hoursandthereforeisgiventwicedaily.Eliminationismainlyvia
urinewith10%excretedasunchangeddrug.Elderlyindividuals,
patientswithhepaticandrenalinsufficiencyhaveahigherplasma
concentration,alongert1/2,andreducedclearanceofreboxetine.[6]

::Dose

Initialdoseforadultsis4mgtwicedaily.Formostpatientsanincrease
indoseisnotnecessary.However,ifneeded,thedosemaybe
increasedtoatotalof1012mg/dayintwodosesafter3weeks.In
elderlypatientsorthosewithhepaticorrenalimpairment,therapymay
beinitiatedat2mgtwicedailyandincreasedtoamaximumof6
mg/dayintwodosesafter3weeks.[2],[5]

::ADRs

Duetoselectivityofreboxetinefornorepinephrine,itisgenerallywell
toleratedwithabenignsideeffectprofile.Thesideeffectsreportedare
drymouth,constipation,urinaryhesitancyand/orretentionandother
anticholinergicsideeffectsCNSsideeffectslikeagitation,anxiety,
nervouness,daytimesomnolence.Asmallpercentageofpatientshave
reportedsexualdysfunction.[2],[5],[7]

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::DrugInteractions

Clinicaldataoninteractionswithreboxetineislimited,but
concomittantadministrationwithMAOinhibitors,tricyclic
antidepressants,SSRIs,antipychotics,antiarrythmics,cyclosporin,
azoleantifungals,andmacrolideantibiotics[5],[7]shouldbeavoided.

::ComparisonofEfficacywithotherantidepressants

Inclinicaltrials,Reboxetinehasbeenshowntobeatleastaseffective
astricyclicantidepressantsdesipramineandimipramineinthe
treatmentofpatientswithmajordepressivedisorderintheadultand
theelderlypopulationandoffersasignificantadvantageover
imipramineinthetreatmentofmelancholicpatients.[6],[8]
ReboxetineisaseffectiveasSSRIfluoxetine.[8],[9]Reboxetineoffers
significantadvantagesoverfluoxetineintermsofsocialfunctioning.
Certainsymptomswithinthedepressivesyndromerespondbetterto
NaRIs,whereasothersymptomsrespondbettertoSSRIs.
Noradrenergicneuronsareinvolvedinmood,arousal,appetite,reward
anddrives.Dopamineisimportantforpleasure,sex,pychomotor
activitySerotonininregulatorycontrolofaffects,aggression,sleep
andappetite.Norepinephrinedepletionstudiessuggestthatwhile
norepinephrinereuptakeinhibitionmayimproveallcoresymptomsof
depression,norepinephrineregulationmaybemostcloselycorrelated
withpatientimprovementsinenergy,interest,concentration,agitation,
helplessness,andhopelessness.Reboxetine,therefore,throughits
mechanismofactionmaybeusefulfordrivedeficientanergicstates[5]
wherethecapacityforsustainedmotivationislackingformelancholic
depressiveswithapoorabilitytocopewithstress[8]andthosewith
comorbidanxiety[2].Inasubanalysisofpatientswithsevere
depressionindicatedthat,reboxetinehadsuperiorefficacycompared
withfluoxetine.[8],[9],[10]
Remissionratesweresimilarforreboxetine,imipramineand
fluoxetine.Theonsetofaction23weeksissimilartoother
antidepressants.[6]

::ComparisonofSafety&Tolerabilitywithotherantidepressants
Reboxetinehasasignificantlyimprovedadverseeventprofileas
comparedtoTCADs.[8]Whencomparedwithimipramine,inpatients
withseveredepressionandmelancholythefrequencyof
discontinuationduetoadverseeventswaslowerinthereboxetine
treatedandthecumulativeriskofdevelopmentofdrymouth,
hypotensionand/orrelatedsymptomsandtremorwassignificantly
higheronimipraminethanonreboxetine.[11]
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Datafrompatientstreatedwithreboxetineshowthatreboxetinehasno
significantcardiovasculareffects,alowpotentialfordruginteractions,
causesnosignificantimpairmentofcognitiveormotorfunctionandno
increaseinsuicidalideation.Incontrasttocertainserotonergicdrugs,
thereisnoevidenceofanywithdrawalsyndromeuponabrupt
discontinuationortaperingofreboxetinetreatment.Sexualdysfunction
appearsinonlyasmallfractionofthepatientsandmainlywithdoses
higherthan8mgdaily.[12]
Elderlypatientsareparticularlysusceptibletothepotentialsideeffects
ofcurrentantidepressantsduetoagerelatedphysiologicchanges.
Reboxetine4mg/day,increasingto6mg/dayonthebasisofindividual
patienttolerability,maybeconsideredsafedoserangefortestingthe
efficacyandtolerabilityofreboxetineinlongtermcontrolledclinical
trialsinelderlypatientswithdepression.[13]

::Otherindications

Reboxetinehasbeenfoundusefulinnarcolepsy,[14]Panicdisorders,
[1],[15]treatmentofdepressioninpatientswithParkinsonsdisease.
[16]

::Conclusion

Noradrenalinehasamajorimpactonthesymptomatologyof
depression.Itisinvolvedinenhancingvigilance,attention,anddrive.
Thedeterminationofoutcomeoftreatmentofdepressionisimportant
bothforthesymptomsofdepressionandsocialfunctioning.[17]
Hence,noradrenalinereuptakeinhibitorsmayhaveagreaterimpacton
drive,motivation,energyandsocialfunctioning.Acomprehensive
seriesofclinicaltrialshavecomparedtheuniqueselectiveNaRI
reboxetinewithplaceboandwiththeTCADsimipramineand
desipramine,aswellaswiththeSSRIfluoxetine.Reboxetineisclearly
effectiveinboththeshortandthelongtermcomparedwithplacebo.
Againstcomparatorantidepressants,reboxetineisatleastaseffective
inthetreatmentofpatientswithmajordepressivedisorderintheadult
andtheelderlypopulationandoffersasignificantadvantageover
imipramineinthetreatmentofmelancholicpatients.Ithasa
significantlyimprovedadverseeventprofilecomparedwithTCADs.
Inseverelydepressedpatients,reboxetinewassignificantlymore
effectivethanfluoxetine.Reboxetinealsoofferssignificantadvantages
overfluoxetineintermsofsocialfunctioning.[8],[18]
Reboxetine,thefirstselectiveNaRI,withitsselectivemechanismof
action,offeringequivalentorevenbetterefficacyincertainpatient
groupsandacceptabletolerabilityprofileisavaluableadditiontothe
existingarmamentariumofdrugsusedforthetreatmentofdepression.

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::References

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ComprehensiveTextbookofPsychiatry.7thedn.Lippincott
Williams&Wilkins2000.pp.1284440.
2. DeBattistaC,SchatzbergAF.OtherBiologicaland
PharmacologicaltherapiesIn:SadockBJ,SadockVA,editors.
KaplanandSadock'sComprehensiveTextbookofPsychiatry.7th
edn.LippincottWilliams&Wilkins2000.pp.2527.
3. ZydusNeurosciences.Narebox.ProductMonograph.
4. DelgadoPL,MorenoFA.Roleofnorepinephrineindepression.J
ClinPsychiatry200061:512.
5. KentJM.SNaRIs,NaSSAsandNaRIs:newagentsforthe
treatmentofdepression.Lancet2000355:9118.
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6. HolmKJ,SpencerCM.ReboxetineAReviewofitsUsein
Depression.CNSDrugs199912:6583.
7. MartinDale.Thecompletedrugreference.ParfittK,editor.32nd
edn.PharmaceuticalPress1999.pp.307.
8. MontgomerySA.Chairman'soverview.Theplaceofreboxetinein
antidepressanttherapy.JClinPsychiatry199859:269.
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9. MassanaJ,MollerHJ,BurrowsGD,MontenegroRM.Reboxetine:
adoubleblindcomparisonwithfluoxetineinmajordepressive
disorder.IntClinPsychopharmacol199914:7380.
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10. VendittiLN,ArcelusA,BirnbaumH,GreenbergP,BarrCE,
RowlandC,etal.Theimpactofantidepressantuseonsocial
functioning:reboxetineversusfluoxetine.IntClin
Psychopharmacol200015:27989.
11. BerzewskiH,VanMoffaertM,GagianoCA.Efficacyand
tolerabilityofreboxetinecomparedwithimipramineinadouble
blindstudyinpatientssufferingfrommajordepressiveoffsodes.
EurNeuropsychopharmacol1997Suppl1:S3747(discussion
S713).
12. TanumLReboxetine:tolerabilityandsafetyprofileinpatientswith
majordepression.ActaPsychiatrScandSuppl2000402:3740.

13. AndreoliV,CarbogninG,AbatiA,VantiniG.Reboxetineinthe
treatmentofdepressionintheelderly:pilotstudy.JGeriatr
PsychiatryNeurol199912:20610.
14. LarrosaO,delaLlaveY,BarioS,GranizoJJ,GarciaBorreguero
D.Stimulantandanticataplecticeffectsofreboxetineinpatients
withnarcolepsy:apilotstudySleep200124:2825.
15. DannonPN,IancuI,GrunhausL.Theefficacyofreboxetineinthe
treatmentrefractorypatientswithpanicdisorder:anopenlabel
study.HumanPsychopharmacol200217:32933.
16. LemkeMR.EffectofreboxetineondepressioninParkinson's
diseasepatients.JClinPsychiatry200263:3004.
17. HealyD.Reboxetine:itseffectsasmeasuredbytheSocial
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Reboxetine:ANovelAntidepressantKadheNG,ChillarAJ,DeshmukhYAJPostgradMed

adoubleblindcomparisonwithfluoxetineinmajordepressive
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