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Lamotrigine in bipolar depressionvan der Loos, Marcus Lambertus Maria

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Stellingen

1. Detoevoegingvanlamotrigineaanlithiumbijpatiëntenmeteenbipolairestoornisgedurendeeendepressieveepisodeiseffectiefenveilig(ditproefschrift).

2. Verschillendestappenvanadditievanmedicatietijdenseendepressieveepisodevandebipolairestoornisisnietalleen‘careasusual’,hetisookteonderbouwen(ditproefschrift).

3. Onderzoeknaaradditie-strategieënbijdebehandelingvanbipolairestoornissenisnodig,nuttigenmogelijk(ditproefschrift).

4. Hetismogelijkombinnenéénstudiedrieachtereenvolgendestappenindebehandelingvandebipolairestoornisteonderzoeken(ditproefschrift).

5. Dekwaliteitvanhetseparatiebeleidineenpsychiatrischziekenhuisafmetenaaneenverplichtedalingvanhetaantalseparatiesmet10procentisabsurdendoetgeenrechtaandeernstvandesituatievandepatiënt.

6. Deangstvoorsamenwerkingmetdefarmaceutischeindustrieiseenremopkwalitatiefhoogwaardigonderzoeken‘evidencebasedmedicine’.

7. Marketeerszijneringeslaagdmensentedoengelovendatkamperenhetoptimumaanvrijheidenprivacybetekent.

8. Hetbelangvanhethebbenvaneeneigenmeningwordtinhetalgemeenschromelijkoverschat.

9. Gelukkigzijnernogsteedsmensendienietdoenwatzezeggenenvooralnietzeggenwatzedenken.

10.Hysterieisalsdiagnosenietverdwenenomdathetziektebeeldnietmeerbestaatmaaromdatdisproportioneelreagerennormaalisgeworden.

11.‘Socialmedia’iseencontradictiointerminus.

MarcvanderLoos

Lamotrigine in bipolar depression: a randomised placebo-controlled trial on the acute and long-term outcome

of lamotrigine as add-on to lithium with the possibility of the addition of paroxetine

28september2011

LAMOTRIGINEIN BIPOLAR DEPRESSIONa randomised placebo-controlled trial on the acute and long-term outcome of lamotrigine as add-on to lithium with the possibility of the addition of paroxetine

Marc van der Loos

Cover designKoen Kloosterhuis, May 2011

Design and lay-outGoedbezigNaarden, the Netherlands

PrintBrügemann B.V.Hilversum, the Netherlands

ISBN: 978-90-9026249-9

No part of this book may be reproduced in any form without permission of the author.

RIJKSUNIVERSITEIT GRONINGEN

Proefschrift

ter verkrijging van het doctoraat in de Medische Wetenschappen

aan de Rijksuniversiteit Groningen op gezag van de

Rector Magnificus, dr E. Sterken,in het openbaar te verdedigen op woensdag 28 september 2011

om 11.00 uur

Marcus Lambertus Maria van der Loosgeboren op 10 maart 1958

te Amsterdam

LAMOTRIGINEIN BIPOLAR DEPRESSIONa randomised placebo-controlled trial on the acute and long-term outcome of lamotrigine as add-on to lithium

with the possibility of the addition of paroxetine

Promotor: Prof dr W.A. Nolen

Beoordelingscommissie: Prof dr R.A. Schroevers

Prof dr R.W. Kupka

Prof J.R. Calabrese M.D.

Ah, si j’avais pu travailler sans cette sacré maladie! Que de chôses j’aurais fait isolé des

autres selon que le pays m’en dirait. Mais oui - c’est bien fini ce voyage ci.

Ah, if I’d been able to work without this bloody illness! How many things I could have done,

isolated from the others, according to what the land would tell me.

But yes - this journey is well and truly finished

To Theo van Gogh. Saint-Rémy-de-Provence, on or about Thursday, 1 May 1890

Letter 865, Vincent van Gogh

Contents

Chapter1 Introduction.......................................................................... 11

Chapter2 Lamotrigine in bipolar disorder: an overview........................... 25

Chapter3 Efficacy and Safety of Lamotrigine as Add-On Treatment to Lithium in Bipolar Depression: A Multicenter, Double-Blind, Placebo-Controlled Trial......................................................... 47

Chapter4 Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.................................................... 71

Chapter5 Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design............................. 95

Chapter6 Discussion.......................................................................... 115

Summary........................................................................... 135

Samenvatting..................................................................... 145

Curriculum Vitae M.L.M. van der Loos................................... 155

Dankwoord (Acknowledgments)........................................... 161

Introduction

14 Chapter 114

Foreword

Bipolardisorder(manic-depressiveillness)isoneofthegreatandmaybethemostintriguingofpsychiatricdiseases,notonlybecauseofitshighprevalencebutalsobecauseofitsspreadingthroughtimeandcultures.ThechangeofmoodoverashorttimehasalreadybeendescribedbyancientGreeksasadisturbanceoftheequilibriumbetweenyellowandblackbile.Whereanexcessofyellowbilewasresponsiblefor(hypo)manicepisodes,anexcessofblackbilewasacauseofmelancholia.Thetermmanic-depressiveillness(manisch-depressieveIrresein)wasintroducedbyKraepelin(1)in1899.Themoderntermbipolardisorder(whichgivesalsothelesssevere(hypo)manicepisodesaplaceanddifferentiatesbetweenunipolarandbipolardisorders)wasintroducedin1957byLeonard(2).

Thecorecharacteristicofbipolardisorderisthealternationinmoodbetweenhigh,lowand‘normal’.Moreover,therearechangesinenergy,selfesteem,sexualdesire,needofsleep,keepingrelationswithotherpeople.Inthemostseriousformspsychosis,rage,andsuicidecandestroyorevenendlives.InthisthesiswewillusetheclassificationofbipolardisordersaccordingtotheDSM-IV(3)(table1,page18,19,20and21).

Theinstabilityofthecorecharacteristicsofthe‘self’ofpatientsmaybeoneoftheheaviestburdensofthisdisease.“WhoamI?Anenergetic,attractive,confidentoutgoingbigspenderwhorulestheworldortheslow,gloomy,tired,suicidalbunchofmiseryormaybesomethinginbetween?HowcanIrelyonmyself,makeappointments,livetogether,raisechildren,followastudy,findandkeepajob,etceterawhenthereisnostable‘Me’?”Questionsenoughforpatientsbutalsoforrelativesandtreatingphysicians.

Therecanbeagreatdiscrepancybetweenthegoalsofthephysicianandthepatient.Themainproblemisthedefinitionof‘stability’.Whereaspatientsmayperceivestabilityasplainandboring,familymembersanddoctorsmay

1Introduction 15

regardsuchasituationasdesirable.ThefrequentlyusedquestionnairestoassessseverityofillnesssuchastheMontgomery-ÅsbergDepressionRatingScale(MADRS)(4),theHamiltonDepressionRatingScale(HAM-D)(5),andtheYoungManiaRatingScale(YMRS)(6)arealldesignedtomeasurethepresenceandseverity(orabsence)ofsymptoms.Theydon’tsaymuchaboutfunctioningofthepatientorhissatisfactionwithlife.Formanypatientshypomaniaorevenmaniaisthemostsoughtaftersituation.Asonepatientoncestated:“IpreferbeingsecludedonceinafewyearsaslongasIdon’thavetotakelithiumandfeelnothingatall”.

Inoursocietythereisagreatpressureonbeingenthusiastic,active,outgoing,sexualactive,etcetera.Infactthesecharacteristicscanalsoberegardedassymptomsofhypomania.Forthatreasonitisnotsostrangethatdrugslikecocaineandamphetamineswhichcanbringusersinaeuphoric(or“hypomanic”)state,aresopopular.Andeventhedepressionandinsomniawhichcomeaftertheeuphoria,arecomparablewiththedepressiveepisodeswhichcomessooftenaftera(hypo)manicepisode.Inthebeginningthesedrugsweremostlyusedintheglamorousworldofart,filmandfashion.Butalsoinbipolardisorderthereisalwaysahintofromanticismandartistry.In1993KayRedfieldJamesonwrote‘Touchedwithfire’,abookabouttheassociationoftheartistictemperamentwithbipolardisorder.ThefirstsentenceofthisbookisaquotefromLordByron:“Wewritersareallinsane”.Thisromanticviewofdiseaseisinthemedicalworldexclusiveforpsychiatricdiseases;Patientssufferingfromaddictionareviewedas‘bohemien’,schizophrenicpatientsarehiddengeniuses(see:AbeautifulMind(SylviaNasar1998))andlastbutnotleastbipolarpatientsare‘artists’.Especiallyhypomanicepisodeswerehardlyseenaspartofadiseasebutmoreastheholygrailofpsychiatry.Astateofmindwhichgiveswaytoallkindsofartisticeruptions.Theothersideofthishighmood;thedepressionisafarlesssexykindofmooddisorder,aprizetobepaidpreferentiallyinsilence.Thissilenceisbestdemonstratedwith932hitsinPubmed®forthecombinationofthesearchterms‘bipolardepression’and‘randomisedcontrolledtrial’versus13066hitsforthecombination’depression’

16 Chapter 116

and‘randomisedcontrolledtrial’. Inthisthesiswetrytoaddsomeknowledgetothetreatmentofthebipolardepression;anunderstudiedbutverysignificantmedicalproblem.

Stabilizing mood and treatment of depression

Althoughsufferingandalsomortalityduetosuicideishighinbipolardepression,thefocusofresearchintothetreatmentofbipolardisorderhasuntilrecentlybeenmostlyontheacutetreatmentofmanicepisodes(e.g.withantipsychotics)andonmaintenancetreatment(e.g.withlithium).Thetreatmentofbipolardepressionwashardlystudiedasapparentlythesametreatmentswereusedasforunipolar(i.e.non-bipolar)depression:initiallysincethe1940ieselectroconvulsivetherapy(ECT)andsincethe1950iesand1960iestheantidepressants,originallythetricyclicantidepressants(TCAs)andmonoamineoxidaseinhibitors(MAOIs)andlatertheselectiveserotoninreuptakeinhibitors(SSRIs)andotherrelatedcompounds.Onlyafterthe1980iestherebecamesomeinterestforalternativesforthesetreatments,especiallywhenitbecameevidentthattheregularantidepressantsmightalsoinduceaswitchto(hypo)maniaandanincreaseofepisodefrequency;cycleacceleration(7;8).

Withtheintroductionoflithiuminthe1970ies(9)therebecamealsointerestintreatmentsthatwereeffectiveagainstbothpoles(maniaanddepression)oftheillness,notonlytoreducethesymptomsofthemoodepisodes(asacutetreatment)butalsotopreventfurtherepisodes,aslong-termormaintenancetreatment.Forthelatterpurposethequestwasfora‘moodstabilizer’.Themainproblemwiththisconceptisthattheterm‘moodstabilizer’hasmanydefinitions.Themoststringentdefinitionisthatatrue‘moodstabilizer’demonstratesefficacyintheacutetreatmentofbothmanicanddepressiveepisodesandpreventsagainstfurthermanicanddepressiveepisodes(fig1).

1Introduction 17

Figure 1. Whatisamoodstabilizer?

1. Effective in treating acute mania

• Bothacutelyandincontinuation

• Withoutcausingdepression

2.Effectiveintreatingacutebipolardepression

• Bothacutelyandincontinuation

• Withoutcausingmania

3.Effectiveinpreventingrecurrenceofbothmaniaanddepression(prophylaxis)

• (Andalsoinrapidcycling)

Figure 2.Treatments“fromabove”and“frombelow”

Stabilizefrombothsides

Stabilizefromabove

Stabilizefrombelow

Treatfrombelow

Treatfromabove

Symptoms

“Normalcy”

Symptoms

Depression

18 Chapter 118

Theloosestdefinitionrequiresefficacyinonlyonepolewithoutworseningoftheotherpole.Althoughitisinouropinionjustifiedtouseastrictdefinition,itmakessensetodifferentiatebetweenmoodstabilizingfrombelow(i.e.todiminishdepression)andmoodstabilizingfromabove(i.e.todiminishmania)(10).

Untilrecentlylithiumcameclosesttomeetingthestrictestdefinitionasa‘moodstabilizer’.Alsovalproicacid/valproateandcarbamazepineclaimedthistermbutunfortunatelyallthreecompoundswereconsidered(andpartlyalsofound)moreeffectiveintreatingandpreventingmanicepisodesthandepressiveepisodes.Asaresult,bipolardepressedpatientsweremostlytreatedwithantidepressantswhichhadlargelybeentestedonlyinunipolardepression.Asevidencegrewthattheefficacyofantidepressantsislimited(11;12)andthattheremaybetheriskofinductionof(hypo)maniaorcycleacceleration(7;8),thetreatmentofbipolardepressionbecameanunmetneed:foramoodstabilizerfrombelowwithoutinducinga(hypo)manicepisode(fig2).

Lamotrigine

Aftersomecasereportsinthe1990ies(13;14)itbecameclearthatlamotriginemightbesuchadrug.In1999,thefirstrandomized,placebo-controlledtrialshowedefficacyoflamotrigineintheacutetreatmentofbipolardepression,althoughnotontheapriorichosenprimaryoutcomemeasure(theHAM-D)butonlyonsecondaryoutcomemeasures(e.g.theMADRS)(15).However,foursubsequentstudiescouldnotreplicatethisfinding(16).Atthesametimetwootherrandomizedplacebo-controlledtrialsstudyingthelong-termeffectoflamotrigineshowedapreventiveeffectagainstfurtherdepressiveepisodesbutnotagainstmanicepisodes,whileinthesamestudieslithiumwasfoundeffectiveinthepreventionofmanicepisodesbutnotofdepressiveepisodes(17;18).

Thisbroughtustotheideatostartadouble-blindrandomizedplacebo-controlledtrialintotheeffectoflamotrigineasadd-ontoongoingtreatment

1Introduction 19

withlithiuminpatientswithabipolardepression.DuringPhaseIofthatstudylamotrigineorplacebowasaddedtoongoingtreatmentwithlithiumfor8weeks.After8weeksresponderscontinuedtheircombinationofmedicationwhereasparoxetinewasaddedopenlabelinnon-respondersinbothgroups(lithiumpluslamotrigineandlithiumplusplacebo)(PhaseII).At16weeksresponderscontinuedtheirmedicationregimeandwerefolloweduntilanewdepressiveor(hypo)manicrelapseoruntilthemaximumdurationofthestudy(68weeks)(Follow-up).

Outline of this thesis

InchapterIIwewillreviewthepharmacologicalprofileandtheplaceoflamotrigineinbipolardisorder. InchapterIIItheresultsobtainedduringthefirst8weeksofthestudy(phaseI)willbediscussed. InchapterIVtheresultsobtainedduringweek9-16(phaseII)willbediscussed. InchapterVtheresultsobtainedduringfollow-up(until68weeks)ofrespondersatweek16willbediscussed. InchapterVItheoverallresultsofourstudyandmorespecificallytheplaceoflamotrigineamongtheotheroptionsinthetreatmentofbipolardepressionandtheadvantagesanddisadvantagesofthedesignofourstudyincomparisonwithotherlong-termstudiesthathavebeenperformedinbipolardisorderwillbediscussed.Finally,somesuggestionsforfutureresearchwillbepresented.

20 Chapter 120

Bipolar II Disorder-Diagnostic Features

TheessentialfeatureofBipolarIIDisorderisaclinicalcoursethatischaracterizedbytheoccurrenceofoneormoreMajorDepressiveEpisodesaccompaniedbyatleastoneHypomanicEpisode.HypomanicEpisodesshouldnotbeconfusedwiththeseveraldaysofeuthymiathatmayfollowremissionofaMajorDepressiveEpisode.EpisodesofSubstance-InducedMoodDisorder(duetothedirecteffectsofamedication,orothersomatictreatmentsfordepression,adrugofabuse,ortoxinexposure)orofMoodDisorderDuetoaGeneralMedicalConditiondonotcounttowardadiagnosisofBipolarIDisorder.Inaddition,theepisodesarenotbetteraccountedforbySchizoaffectiveDisorderandarenotsuperimposedonSchizophrenia,SchizophreniformDisorder,DelusionalDisorder,orPsychoticDisorderNotOtherwiseSpecified.

Criteria for Major Depressive Episode

A.Five(ormore)ofthefollowingsymptomshavebeenpresentduringthesame2-weekperiodandrepresentachangefrompreviousfunctioning;atleastoneofthesymptomsiseither(1)depressedmoodor(2)lossofinterestorpleasure

Note:Donotincludesymptomsthatareclearlyduetoageneralmedicalcondition,ormood-incongruentdelusionsorhallucinations.

1.depressedmoodmostoftheday,nearlyeveryday,asindicatedbyeithersubjectivereport(e.g.,feelssadorempty)orobservationmadebyothers(e.g.appearstearful).Note:Inchildrenandadolescents,canbeirritablemood.

2.markedlydiminishedinterestorpleasureinall,oralmostall,activitiesmostoftheday,nearlyeveryday(asindicatedbyeithersubjectiveaccountorobservationmadebyothers)

3.significantweightlosswhennotdietingorweightgain(e.g.,achangeofmorethan5%ofbodyweightinamonth),ordecreaseorincreaseinappetitenearlyeveryday.Note:Inchildren,considerfailuretomakeexpectedweightgains.

4.insomniaorhypersomnianearlyeveryday5.psychomotoragitationorretardationnearlyeveryday(observablebyothers,

notmerelysubjectivefeelingsofrestlessnessorbeingsloweddown)6.fatigueorlossofenergynearlyeveryday

Table 1

1Introduction 21

7.feelingsofworthlessnessorexcessiveorinappropriateguilt(whichmaybedelusional)nearlyeveryday(notmerelyself-reproachorguiltaboutbeingsick)

8.diminishedabilitytothinkorconcentrate,orindecisiveness,nearlyeveryday(eitherbysubjectiveaccountorasobservedbyothers)

9.recurrentthoughtsofdeath(notjustfearofdying),recurrentsuicidalideationwithoutaspecificplan,orasuicideattemptoraspecificplanforcommittingsuicide

B.ThesymptomsdonotmeetcriteriaforaMixedEpisode.

C.Thesymptomscauseclinicallysignificantdistressorimpairmentinsocial,occupational,orotherimportantareasoffunctioning.

D.Thesymptomsarenotduetothedirectphysiologicaleffectsofasubstance(e.g.,adrugofabuse,amedication)orageneralmedicalcondition(e.g.,hypothyroidism).

E.Thesymptomsarenotbetteraccountedforbybereavement,i.e.,afterthelossofalovedone,thesymptomspersistforlongerthan2monthsorarecharacterizedbymarkedfunctionalimpairment,morbidpreoccupationwithworthlessness,suicidalideation,psychoticsymptoms,orpsychomotorretardation.

Criteria for Manic Episode

A.Adistinctperiodofabnormallyandpersistentlyelevated,expansive,orirritablemood,lastingatleast1week(oranydurationifhospitalizationisnecessary).

B.Duringtheperiodofmooddisturbance,three(ormore)ofthefollowingsymptomshavepersisted(fourifthemoodisonlyirritable)andhavebeenpresenttoasignificantdegree:1.inflatedself-esteemorgrandiosity2.decreasedneedforsleep(e.g.,feelsrestedafteronly3hoursofsleep)3.moretalkativethanusualorpressuretokeeptalking4.flightofideasorsubjectiveexperiencethatthoughtsareracing5.distractibility(i.e.,attentiontooeasilydrawntounimportantorirrelevant

externalstimuli)

22 Chapter 122

6.increaseingoal-directedactivity(eithersocially,atworkorschool,orsexually)orpsychomotoragitation

7.excessiveinvolvementinpleasurableactivitiesthathaveahighpotentialforpainfulconsequences(e.g.,engaginginunrestrainedbuyingsprees,sexualindiscretions,orfoolishbusinessinvestments)

C.ThesymptomsdonotmeetcriteriaforaMixedEpisode.

D.Themooddisturbanceissufficientlyseveretocausemarkedimpairmentinoccupationalfunctioningorinusualsocialactivitiesorrelationshipswithothers,ortonecessitatehospitalizationtopreventharmtoselforothers,ortherearepsychoticfeatures.

E.Thesymptomsarenotduetothedirectphysiologicaleffectsofasubstance(e.g.,adrugofabuse,amedication,orothertreatments)orageneralmedicalcondition(e.g.,hyperthyroidism).

Note:Manic-likeepisodesthatareclearlycausedbysomaticantidepressanttreatment(e.g.,medication,electroconvulsivetherapy,lighttherapy)shouldnotcounttowardadiagnosisofBipolarIDisorder.

Criteria for Mixed Episode

A.ThecriteriaaremetbothforaManicEpisodeandforaMajorDepressiveEpisode(exceptforduration)nearlyeverydayduringatleasta1-weekperiod.

B.Themooddisturbanceissufficientlyseveretocausemarkedimpairmentinoccupationalfunctioningorinusualsocialactivitiesorrelationshipswithothers,ortonecessitatehospitalizationtopreventharmtoselforothers,ortherearepsychoticfeatures.

C.Thesymptomsarenotduetothedirectphysiologicaleffectsofasubstance(e.g.,adrugofabuse,amedication,orothertreatment)orageneralmedicalcondition(e.g.,hyperthyroidism).

Criteria for Hypomanic Episode

1Introduction 23

A.Adistinctperiodofpersistentlyelevated,expansive,orirritablemood,lastingthroughoutatleast4days,thatisclearlydifferentfromtheusualnondepressedmood.

B.Duringtheperiodofmooddisturbance,three(ormore)ofthefollowingsymptomshavepersisted(fourifthemoodisonlyirritable)andhavebeenpresenttoasignificantdegree:1.inflatedself-esteemorgrandiosity2.decreasedneedforsleep(e.g.,feelsrestedafteronly3hoursofsleep)3.moretalkativethanusualorpressuretokeeptalking4.flightofideasorsubjectiveexperiencethatthoughtsareracing5.distractibility(i.e.,attentiontooeasilydrawntounimportantorirrelevant

externalstimuli)6.increaseingoal-directedactivity(eithersocially,atworkorschool,orsexually)

orpsychomotoragitation7.excessiveinvolvementinpleasurableactivitiesthathaveahighpotentialfor

painfulconsequences(e.g.,engaginginunrestrainedbuyingsprees,sexualindiscretions,orfoolishbusinessinvestments)

C.Theepisodeisassociatedwithanunequivocalchangeinfunctioningthatisuncharacteristicofthepersonwhennotsymptomatic.

D.Thedisturbanceinmoodandthechangeinfunctioningareobservablebyothers.

E.Theepisodeisnotsevereenoughtocausemarkedimpairmentinsocialoroccupationalfunctioning,ortonecessitatehospitalization,andtherearenopsychoticfeatures.

F.Thesymptomsarenotduetothedirectphysiologicaleffectsofasubstance(e.g.,adrugofabuse,amedication,orothertreatment)orageneralmedicalcondition(e.g.,hyperthyroidism).

Note:Hypomanic-likeepisodesthatareclearlycausedbysomaticantidepressanttreatment(e.g.,medication,electroconvulsivetherapy,lighttherapy)shouldnot

counttowardadiagnosisofBipolarIIDisorder.

24 Chapter 124

References

1. E.Kraepelin.Psychiatrie.EinLehrbuchfurStudirendeundAerzte.IIBandSechsteAuflage.Leipzig,VerlagvonJohannAmbrosiusBarth.1899.

2. K.Leonhard.AufteilungderEndogenenPsychosen.Berlin,AcademieVerlag.1957.

3. AmericanPsychiatricAssociation.DiagnosticandStatisticalManualofMentalDisorders,4thEdition(DSM-IV).WashingtonDC,AmericanPsychiatricPress.1994.

4. MontgomerySA,ÅsbergM.Anewdepressionscaledesignedtobesensitivetochange.BrJPsychiatry1979Apr;134:382-9.

5. HAMILTONM.Aratingscalefordepression.JNeurolNeurosurgPsychiatry1960Feb;23:56-62.

6. YoungRC,NysewanderRW,SchreiberMT.Maniascalescores,signs,andsymptomsinfortyinpatients.JClinPsychiatry1983Mar;44(3):98-100.

7. AltshulerLL,PostRM,LeverichGS,MikalauskasK,RosoffA,AckermanL.Antidepressant-inducedmaniaandcycleacceleration:acontroversyrevisited.AmJPsychiatry1995Aug;152(8):1130-8.

8. LichtRW,GijsmanH,NolenWA,AngstJ.Areantidepressantssafeinthetreatmentofbipolardepression?Acriticalevaluationoftheirpotentialrisktoinduceswitchintomaniaorcycleacceleration.ActaPsychiatrScand2008Nov;118(5):337-46.

9. SCHOUM,JUEL-NIELSENN,STROMGRENE,VOLDBYH.Thetreatmentofmanicpsychosesbytheadministrationoflithiumsalts.JNeurolNeurosurgPsychiatry1954Nov;17(4):250-60.

10. KetterTA,CalabreseJR.Stabilizationofmoodfrombelowversusabovebaselineinbipolardisorder:anewnomenclature.JClinPsychiatry2002Feb;63(2):146-51.

11.GhaemiSN,WingoAP,FilkowskiMA,BaldessariniRJ.Long-termantidepressanttreatmentinbipolardisorder:meta-analysesofbenefitsandrisks.ActaPsychiatrScand2008Aug24.

1Introduction 25

12. SachsGS,NierenbergAA,CalabreseJR,MarangellLB,WisniewskiSR,GyulaiL,etal.Effectivenessofadjunctiveantidepressanttreatmentforbipolardepression.NEnglJMed2007Apr26;356(17):1711-22.

13. SmithD,BakerG,DaviesG,DeweyM,ChadwickDW.Outcomesofadd-ontreatmentwithlamotrigineinpartialepilepsy.Epilepsia1993Mar;34(2):312-22.

14.CalabreseJR,FatemiSH,WoyshvilleMJ.Antidepressanteffectsoflamotrigineinrapidcyclingbipolardisorder.AmJPsychiatry1996Sep;153(9):1236.

15.CalabreseJR,BowdenCL,SachsGS,AscherJA,MonaghanE,RuddGD.Adouble-blindplacebo-controlledstudyoflamotriginemonotherapyinoutpatientswithbipolarIdepression.Lamictal602StudyGroup.JClinPsychiatry1999Feb;60(2):79-88.

16.CalabreseJR,HuffmanRF,WhiteRL,EdwardsS,ThompsonTR,AscherJA,etal.Lamotrigineintheacutetreatmentofbipolardepression:resultsoffivedouble-blind,placebo-controlledclinicaltrials.BipolarDisord2008Mar;10(2):323-33.

17.CalabreseJR,BowdenCL,SachsG,YathamLN,BehnkeK,MehtonenOP,etal.Aplacebo-controlled18-monthtrialoflamotrigineandlithiummaintenancetreatmentinrecentlydepressedpatientswithbipolarIdisorder.JClinPsychiatry2003Sep;64(9):1013-24.

18. BowdenCL,CalabreseJR,SachsG,YathamLN,AsgharSA,HomplandM,etal.Aplacebo-controlled18-monthtrialoflamotrigineandlithiummaintenancetreatmentinrecentlymanicorhypomanicpatientswithbipolarIdisorder.ArchGenPsychiatry2003Apr;60(4):392-400.

Lamotrigine in bipolar disorder: an overview

MarcL.M.vanderLoos(1)JosephR.Calabrese,M.D.(2)WillemA.Nolen(3)DavidJ.Muzina,M.D.(4)

1.DepartmentofPsychiatry,IsalaKlinieken,locationSophia,Zwolle,theNetherlands

2.CaseWesternReserveUniversitySchoolofMedicine,UniversityHospitalsofCleveland,Cleveland,Ohio,USA

3.DepartmentofPsychiatry,UniversityMedicalCenterGroningen,UniversityofGroningen,Groningen,theNetherlands

4.DepartmentofPsychiatryandPsychology,ClevelandClinicFoundation,Cleveland,Ohio

Thischapterisanadaptationfrom:Chapter 4 Pharmacological profile and clinical utility of lamotrigine in mood disordersBipolar Psychopharmacotherapy: Caring for the Patient, 2nd EditionHagopS.Akiskal(Editor),MauricioTohen(Editor)Wiley-BlackwellJohnWiley&Sons,Ltd.

28 Chapter 228

Introduction

Thereremainsapressingneedforadditionaltreatmentoptionsformooddisorders,particularlythoserefractoryordifficulttotreatdisorderssuchasbipolardisorder.EstimatesoftheprevalenceofbipolarIdisorderacrossdiverseculturesandethnicgroupsareconsistent,rangingbetween0.4%and1.6%inadults(Weissman1996andRegeer2004).Recentestimatesoftheoverallprevalenceofbipolardisorder(typesIandIIaswellasNOS)suggestthat4-5%suffersfromthisdebilitatingmentaldisorder(Hirschfeld.2003;Regeer2004).Bipolardisorderscarriesahighburden,negativelyaffectinglivesinmanyareas,mostnotablytheperformanceofwork-related,leisure,andinterpersonalactivities(Calabrese2003).Thegreatestneedexistsinthetreatmentofdepressiveepisodesassociatedwithbipolardisordersassymptomsofdepressionaremuchmorecommonlyexperiencedandmoredifficulttotreatthanmanicsymptoms(Post2002;Judd2002andKupka2005). Reportsoflamotrigine’sbeneficialeffectsonmoodinepilepsypatientsledtoitsuseandstudyinaffectivedisorders.Studiesinvolvingbipolarpatientssuggestedthatlamotriginepossessedabroadspectrumoftherapeuticactivityinbipolardisorder,withlaterdescriptionsofgreaterefficacyfordepressivethanformanicsymptoms.Giventhesignificantburden,prevalence,andrecurrentnatureofbipolardisorder-especiallybipolardepression–lamotrigineappearstobegintoaddressanareaofseriousunmetpublichealthneed(Calabrese2003).

Clinical Pharmacology of Lamotrigine

Pharmacodynamics Lamotrigineisanantiepilepticdrugofthephenyltriazineclassthathasdemonstratedefficacyasadd-ontreatmentofpartialseizures(Mikati1989;Matsuo1993)andasmaintenancetreatmentofbipolarIdisordertodelaythetimeofoccurrenceofmoodepisodes(Bowden2003;Calabrese2003).Althoughitsmechanismoftherapeuticactioninhumansisnotdefinitivelyunderstood,lamotrigineisthoughttopossessmodulatoryandprotectiveeffects

onneurotransmissionandintracellularsignaltransductionprocesses. Structurallydistinctfromotherantiepilepticdrugs,lamotrigineinteractspreferentiallyontheslowinactivatedstateofpresynapticneuronalsodiumandcalciumchannelstoprolonginactivationoftheneuronandpromotestabilizationoftheneuronalmembrane(Xie1998).Thiseffectisaugmentedbyause-dependentactioninwhichfurtherinhibitionbythedrugdevelopsduringrapid,repetitivestimulation(i.e.,epileptiformbursts).Consequently,thereleaseoftheexcitatoryaminoacidglutamateisantagonized(Fitton1995,LiandKetter2002).Lamotriginehasalsobeenobservedtoinhibitcorticalandamygdaloidkindling(Gilman1995,Leach1986andXie1995). Lamotriginehasnosubstantialinvitroaffinityforadenosine,adrenergic,dopaminergic,muscarinicandopioidreceptorsatclinicallyapplicableconcentrationsandbindsonlyweaklytoinhibitserotonin5HT3receptors(Leach1991).Lamotriginelacksclinicallymeaningfulactivityatthe5HT1Areceptor,wherechangesin5HT1Areceptor-mediatedcyclicadenosinemonophosphatepathwayhavebeenimplicatedinaffectivedisorders(Shiah1998andVinod2002). Inearlyepilepsystudieswithlamotrigineitwasnotedthatmanypatientsreportedimprovementinmoodandpsychologicalwell-beingindependentfromreductioninseizurefrequency,whichledtoitsinvestigationforuseinaffectivedisorders(Smith1993a;Smith1993b).Significantly,lamotriginehasminimalnegativeeffectsoncognitive,memory,orpsychomotorfunctionandisnotassociatedwithsedativeeffectsorweightgain(Goa1993,Cohen1985andGinsberg2003).

Pharmacokinetics Lamotrigineisextensivelyabsorbeddemonstratinglinearkinetics,resultingin98%bioavailability(Garnett1997).Peakplasmaconcentrationsareattainedafter1-3hourswithmeanplasmaproteinbindingof55-68%(Cohen1987,Ramsay,1991andRambeck1993).Lamotriginereadilycrossestheplacentalbarriercausingfetalbloodconcentrationssimilartomaternallevelsandpassesintobreastmilkreaching40-80%ofthematernallamotrigine

30 Chapter 230

concentration(Ohman,2000andPennell2003). Therate-limitingstepintheeliminationoflamotrigineisN-glucoronidationbytheliverwithaplasmaeliminationhalf-lifeof25+10hours(Cohen1987).Autoinductionofitsownmetabolismdoesnotoccurandtherearenoactivemetabolites.Pregnancyincreaseslamotrigineclearancebymorethan50%earlyduringpregnancyandrevertsquicklyafterdelivery(Tran2002).Clearancemaybereducedintheelderlyandinpatientswithmoderatetoseverehepaticdysfunction.

Drug Interactions Lamotrigineadministrationaffectshardlytheserumconcentrationsofotherdrugs.However,enzyme-inhibitingdrugssuchasdivalproexsodiumincreaselamotrigineconcentrationsbysignificantlycompetingformetabolismthroughglucoronidationeffectivelyincreasingthemeanhalf-lifeoflamotriginetoabout70hours(Yuen1992andAnderson1996).Enzyme-inducingdrugs,suchasphenytoin,carbamazepine,andphenobarbital,reducethelamotrigine’smeaneliminationhalf-lifetoabout12hoursanddecreaselamotrigineconcentrations(Hachad2002).Therearepharmacokineticinteractionsbetweenlamotrigineandanti-conceptivemedication.(Sidhu2005).Theclearanceoflevonogestrelisincreasedwithapossibledecreaseoftheanti-conceptivereliability.Ontheotherhandistheclearanceoflamotrigineenhancedbyanti-conceptivemedication,withaloweringoflamotrigineplasmalevels. Lamotriginedoesnotsignificantlyaffectthepharmacokineticsoflithium(Chen2000).

Lamotrigine and Mood Disorders

Acute treatment of bipolar depression TheobservationsofSmithandcolleagues(Smith1993a,1993b)thatpatientstreatedwithadd-onlamotrigineforpartialseizuresexperiencedimprovedmoodapartfromeffectsonepilepsystimulatedinvestigationsoflamotrigine’sefficacytotreatmooddisorders.Earlycasereportsinvolving

bipolarpatientssuggestedthatlamotriginepossessedabroadspectrumoftherapeuticactivityinbipolardisorder,includingrapidcyclingandmixedstates(Weisler1994,Calabrese1996andWalden1996).Asubsequentopen-labelstudyprovidedpreliminarydatathatlamotriginewaseffectiveforpatientswithrefractorybipolardisorder,with68%ofdepressedpatientsand84%ofmanic/hypomanic/mixedpatientsshowingmoderatetomarkedresponse(Calabrese1999a). Anopennaturalisticstudyoftwenty-twodepressedbipolarpatientswhowererefractorytotreatmentwithacombinationofdivalproexsodiumandanothermoodstabilizerordivalproexsodiumandanantidepressantfor6weeksweretreatedwithadd-onlamotrigine.Sixteenoutof22(72%)respondedbytheendofweek4,suggestingthatlamotriginemaybeusefulinbipolardepression(Kusumakar1997).Inadouble-blindplacebo-controlledstudyoflamotriginemonotherapyinoutpatientswithnonrapid-cyclingbipolarIdepression,treatmentwithlamotrigineover7weeks(50or200mg/day)didnotresultinasignificantdifferenceversusplaceboontheprimaryoutcomemeasure(HAM-D),butdidsoonseveralsecondaryoutcomemeasuresincludingtheMADRS,particularlyinthe200mggroup,comparedwithplacebo(Calabrese1999b).Improvementswereobservedasearlyasweek3. AfterthisfirstpositiveresultforlamotrigineinaRCT,lamotriginewastestedagainstplaceboinfourotherRCT’s(Calabrese2007andGoldsmith2003).NoneoftheseRCT’sdiscriminatedsignificantlybetweenlamotrigineandplaceboontheprimaryoutcomecriteria.Partofthisnegativeresultwasbecauseofahighplaceboresponseinallfourstudies.Nevertheless,ameta-analysisofallfivestudiesshowedasignificantalthoughmodestbenefitforlamotrigine.(Geddes2009) Thirty-onepatientswithrefractorybipolarandunipolarmooddisordersparticipatedinadouble-blind,randomized,crossoverstudyofthree6-weekmonotherapyevaluationsincludinglamotrigine,gabapentin,andplacebo.UsingtheClinicalGlobalImpressionsScaleforBipolarIllness(CGI-BP)astheprimaryoutcomevariable,thisstudyreporteda52%responserate(CGI-BPasmuchorverymuchimproved)forlamotrigine,comparedto26%forgabapentinand23%

32 Chapter 232

forplacebo-treatedpatients(Frye2000). Thefinalstudy(n=410)comparedlamotrigine(doseuptitratedto200mg/day)witholanzapine/fluoxetine(dose6/25,6/50,12/25or12/50mg/day)(Brown.2006)andshowedasmallbutsignificantadvantage(improvementontheMADRSafter7weeksof14.91vs12.92respectivelyp=0.002)fortheolanzapine/fluoxetinecombination.

Acute treatment of mania / mixed states The1999open-labelstudybyCalabreseandcolleaguesobservedarobustresponsetolamotrigine(primarilyasadd-ontherapy)in84%ofmanic/hypomanic/mixedpatients(Calabrese1999a).Inthefirstdouble-blind,randomized,controlledstudyoflamotrigineinacutemanialamotriginetitratedto100mg/dayoverthreeweekswasaseffectiveaslithium800mg/day(meanbloodlevel0.77mmol/L)inreducingmanicsymptoms(Ichim2000).However,lamotriginehasnotshownanti-manicactivityinplacebo-controlledstudies(Bowden2003).Unpublishedstudies(dataonfile,GlaxoSmithKline2003)inpatientswithacutemanicormixedexacerbationsofbipolarIdisorderhavefoundnosignificantdifferencefrombaselineinthe11-itemManiaRatingScale(MRS)betweenlamotrigineandplacebo(Goldsmith2003).

Maintenance therapy Theinitiallamotriginemaintenancestudywasadouble-blind,placebo-controlledstudyinrapidcyclingbipolardisorder(Calabrese2000).Openlabellamotrigineaddedtothetreatmentregimensof324patientsmeetingDSM-IVcriteriaforrapidcyclingbipolardisorderresultedin182stabilizedpatientswhowerethenrandomlyassignedtothedouble-blindmaintenancephaseafterbeingstratifiedforbipolarIorIIdisorder.Otherpsychotropicagentsweretaperedandpatientsrandomlyassignedtoeitherlamotriginemonotherapyorplaceboina1:1ratioforthesix-monthmaintenancephase.Overall49placebopatients(56%)and45lamotrigine-treatedpatients(50%)requiredtreatmentofanemergingmoodepisodewithadditionalpharmacotherapy.Althoughtherewasnostatisticalsignificancebetweenthesetwotreatmentgroupsontheprimary

outcomemeasureoftimetoadditionalpharmacotherapy(medianof12weeksforplaceboversus18weeksforlamotrigine),lamotriginewassignificantlymoreeffectivethanplacebointhesurvivalinstudyanalysis(medianof8weeksforplaceboversus14weeksforlamotrigine).Inthesub-analysisaccordingtodiseasetype,lamotriginewassignificantlymoreeffectivethanplaceboindelayingtimetoadditionalpharmacotherapyforbipolarIIpatientsthanbipolarIpatients.Forty-sixpercentofbipolarIIpatientsonlamotriginemonotherapywerestablewithoutrelapseafter6monthscomparedtoonly18%ofplacebo-treatedbipolarIIpatients.(Calabrese2000).TheseresultswereconfirmedinaposthocanalysisofthesamepatientsamplewiththeLifechartmethod.Measuredwiththelifechartatleastonceweeklypatientstakinglamotriginewere1,8timesmorelikelytoachieveeuthymiathanthosetakingplacebo(Goldberg2008).Inanunpublishedstudy(dataonfile,GlaxoSmithKline2003),thesefindingswerenotreplicated.However,significantlyfewerlamotriginetreatedrapidcyclersrequiredinterventionforadepressiveepisode.Collectively,theseresultssuggestthatlamotriginemaybeausefultreatmentforrapidcyclingbipolarpatients,especiallyfortypeIIandforthepreventionofdepressiverelapses. Two18-monthmaintenancestudies(Bowden2003andCalabrese2003)comparinglamotrigine,lithium,andplaceboprovidedfurthersupportfortheuseoflamotrigineasamoodstabilizerandledtoitsapprovalbytheUSFDAinJune2003asamaintenancetreatmentforbipolarIdisorder.Thesecomplementarystudiesenrolledpatientsinadouble-blindphaseofmaintenancetherapyafterarecentdepressed,hypomanic,ormanicepisoderemitted(CGI-Sscoreof<3for4consecutiveweeks)duringopen-labelstabilizationduringwhichlamotriginewasinitiatedasadjunctiveormonotherapyandotherpsychotropicsdiscontinued.Inbothstudies,50%ofpatientsachievedstabilizationcriteriaallowingforprogressionintodouble-blindedmaintenancetherapywithlamotrigine(50-400mg/day),lithium(0.8-1.1mEq/L),orplacebo.Theprimaryefficacyendpointusedwastimetointerventionforanymoodepisode. Inbothofthesestudies,lamotrigineandlithiumdemonstratedeffectiveprophylaxisagainstanyemergingmoodepisodecomparedwithplacebo.Therewerestatisticallyfewerrelapsingmoodepisodesandlongermediansurvivalin

34 Chapter 234

lamotrigineandlithiumtreatedpatientscomparedwithplacebo.Mediansurvivalbeforeinterventionforanymoodepisodeforlamotrigine-treatedpatientsrangedfrom118-256days,significantlybetterthanplacebo(85-93days).Lithiumalsooutperformedplacebowithamediansurvivalof170-292days.However,therewereimportantdifferencesinthespectraofmaintenanceefficacy. Inbothstudies,lithium,butnotlamotriginewassuperiortoplaceboatdelayingthetimetointerventionforamanicorhypomanicepisode.Intotalforbothstudies123hypomanic/maniceventsemergedduringmaintenance,with25%ofplacebotreatedpatientsexperiencingahypomanic,manic,ormixedepisode(47of188);21%ofthelamotriginegrouprelapsed(58of273),butonly11%ofpatientsinthelithium-treatmentarmhadbreakthroughmaniaorhypomania(18of164).LithiumwasclearlymoreeffectivethanplaceboandlamotrigineinpreventingmanicandhypomanicrelapseinrecentlysymptomaticbipolarIpatients. Incontrast,lamotrigineappearstobemoreeffectivethanlithiuminthepreventionofdepressiverelapseinbipolarIpatients.Inbothstudies,lamotriginebutnotlithium,wassignificantlybetterthanplaceboatprolongingtimetointerventionforadepressivemoodepisode.Therewere209depressiverelapsesinthepatientsobservedinthetwostudies,withahigherrateofrelapseintheplacebo(68of188,or36%)andlithiumtreatmentgroups(56of164,or34%);lamotriginewasbetteratpreventingrecurrenceofdepressionwitha31%rateofdepressiverelapseandalongermediansurvivalbeforetreatmentofdepressionwasnecessary.Thedifferencewasparticularlyevidentinthetreatmentofrecentlymanicorhypomanicpatientsinwhomonly14%ofthosereceivinglamotrigine(8of58)neededinterventionforemergentdepressioncomparedwith23%ofpatientsreceivinglithium(10of44)and30%receivingplacebo(21of69).Inaposthocanalysisofthefirst6monthsofthebipolarIpatients(indexepisodedepression)therewasnoevidenceforagreaterriskformooddestabilization(emergent(hypo)manicsymptoms)inthelamotriginegroupversustheplacebogroup(Goldberg2009).

Safety

Rash Rashesrequiringhospitalizationanddiscontinuationoftreatmenthavebeenreportedwithlamotrigine.Thereportedrashrateis10%inadultpatientswithepilepsytreatedwithadjunctivelamotrigineand7%inbipolarIadultstreatedwithmonotherapy;theplaceborateis5%inbothpopulations(lamotriginepackageinsert).Seriousrashratesareconsiderablylowerat0.8%inpediatricepilepsypatients,0.3%inepilepticadultsasmonotherapyand0.13%asadjunctivetherapy.Aretrospectiveanalysisconductedofratesoflamotrigine-relatedrashin12multicenterstudiesoflamotrigineformooddisorders(n=1955),including1openstudy,7randomizedcontrolledacutetrials,and4randomizedcontrolledmaintenancetrialsfrom1996to2001reportedseriousrashin0%withlamotrigine,0.1%(n=1)withplacebo,and0%withcomparators(Calabrese2002).Acrossallbipolardisorderstudieswith2,272patientsonlamotrigine,seriousrashwasobservedinthreepatientsforanoverallrateof0.1%(lamotriginepackageinsert).OneofthesethreepatientsexperiencedamildStevens-Johnsonsyndromeonadjunctivelamotrigineanddidnotrequirehospitalization. InarandomizedtrialUsualCarePrecautionswerecomparedwithDermatologicPrecautions(UCPplusadditionalspecificprecautionsintendedtodecreasetheriskofrash)for12weeks(Ketter2006).Lamotriginewasadded(targetdose200mg/day)toongoingmedicationwithaslowuptitration.

UsualCareprecautionswere:1.notexceedingtheinitialdoseordose-escalationschedule2.ifarashdevelopedduringthestudythepatientcontactedtheinvestigator

immediately3.lamotriginewasstoppedincaseofrash.PatientsintheDermatologicPrecautionsgroupwere,besidesUCP,advisednotto:4.takenewmedicationsorfoods,usenewcosmetics,deodorants,detergentsor

36 Chapter 236

fabricsofteners5.stimulatetheimmunesystemthroughexcessivesunexposure6.participateinactivitiesthatmightleadtoexposuretopoisonoakorpoisonivy7.receiveanyimmunizations

1175patientswereincluded.Inbothgroupstherewerenoreportsofseriousrash.Therateofnon-seriousrashwaslowforUCPaswellasforDP(8.8%and8.6%respectively,OR0.99).whichiscomparablewithratesofrashinpreviousstudies.Clinicalresponsewas50%with29%remissionoverbothgroups(accordingtotheClinicalGlobalImpressionsBipolarversion). AGermanregistrythatdocumentstheincidencesofseriousrashhasbeeninplacesince1990andascertainshospitalizedcasesofStevens-Johnsonsyndrome(SJS)andtoxicepidermalnecrolysis(TEN)relatedtoantiepilepticdruguse(Rzany1996).Reportedcasesareconfirmedbyaregistryphysicianandreviewedbyadermatologicalexpertcommitteeensuringhighdiagnosticaccuracy.TheincidenceofseriousrashrisingtothelevelofSJS/TENdiagnosisintheGermanregistrywas0.02%from1993-2001(Messenheimer2002). Riskofrashisnotedtobehigherinpediatricpatientsandmaybeincreasedbyco-administrationofdivalproexsodiumorexceedingtherecommendedinitialdoseordoseescalationscheduleforlamotrigine.Womenmaybeatincreasedriskforrashcomparedwithmen,witharelativeriskof1.8(Wong1999).

Other side effects and tolerability Lamotrigineisknowntobegenerallywelltoleratedinthetreatmentofepilepsy(Choi2003).Agreatdealofdatageneratedbythe18-monthlamotriginemaintenancetrials(Bowden2003andCalabrese2003)confirmsclinicalexperienceandepilepsymanagementreportsoflamotrigine’sfavorablesideeffectprofileinthetreatmentofbipolarpatients.In280patientsonmaintenancelamotrigineduringdouble-blindedtreatmentinbothtrialscombined,only23(8.2%)discontinuedstudyparticipationprematurelyduetoanadverseevent;7.9%ofplacebotreatedpatientsexperiencedadverseeventsthatledto

endofstudy(15of191).Overthe18monthsrandomizedphase,lamotriginetreatedpatientsexhibiteda4.9poundmeandecreaseinbodyweight,comparedtoa2.6poundmeanweightgainintheplacebogroup.Inacombinedanalysisofbothstudies,theincidenceofmania/hypomania/mixedepisodesreportedasadverseeventswas5%forpatientstreatedwithlamotrigine,4%forpatientstreatedwithlithium,and7%forpatientstreatedwithplacebo.Ingeneral,lamotrigineexhibitsplacebolevelratesoftreatment-emergentadverseeventsandisbettertoleratedthanlithium(Calabrese2003).Table1liststreatment-emergentadverseeventsforthecombinedmaintenancestudiesduringrandomizedphase.

Table 1. Adverseeventsobservedduringrandomizedphaseoflamotriginemaintenancestudies(inpercent)*

Event Lamotrigine(n=227) Placebo(n=190)

Nausea 14 11

Insomnia 10 6

Somnolence 9 7

Backpain 8 6

Fatigue 8 5

Rhinitis 7 4

Benignrash 7 5

Abdominalpain 6 3

Drymouth 6 4

Constipation 5 2

Vomiting 5 2

Coughexacerbation 5 3

Pharyngitis 5 4

*Adverseeventslistedhadincidence>5%andwerenumericallygreaterthanplacebo.[Bowden2003;Calabrese2003;Dataonfile,GlaxoSmithKline]

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Clinical applications for lamotrigine

Bipolar depression Forthemanagementofacutebipolardepression,theAPAPracticeGuidelinesof2002recommendedlamotrigineasafirst-lineoptionwithmoderateclinicalconfidence(Hirschfeld2002).Sincethenotheroptionshavebecomeavailable,especiallyquetiapineandthecombinationofolanzapineplusfluoxetine.Withthedatathatbecameavailableafterthe2002guideline,lamotriginehasaplaceinthetreatmentofacutebipolardepression,especiallyinpatientsexperiencingadepressiveepisodedespiteadequatetreatmentwithlithium.Inthesepatientslamotriginecanberecommendedasadd-ontherapywithsubstantialclinicalconfidence. Dosingshouldfollowpublishedtitrationschedulestominimizetheriskofrash,withaminimumdoseof50mg/dayandatargetdoseof200mg/dayformostpatients(table2).Thereisnopharmacokineticinteractionwithlithium,However,inbipolarpatientsexperiencingabreakthroughdepressiononcarbamazepineorvalproate,lamotrigineshouldbeaddedwhilekeepinginmindpharmacokineticinteractionsthatmayaffectdosing:doubledoseoflamotrigineincombinationwithcarbamazepine,halfthedoseincombinationwithvalproate.

Table 2. RecommendedLamotriginedosingschedule

Concomitant

medication?

Week5 Week6 Week7

Notondivalproexor

carbamazepine

25mgqd 50mgqd 100mg

Ondivalproex 25mg

25mgqd 50mgqd 100mg

Oncarbamazepine

orphenytoin

50mgqd 100mg

Mania / mixed states LamotriginemonotherapyisnotrecommendedfortheacutemanagementofmaniaormixedstatesassociatedwithbipolarIdisorder.Despitelimitedcasereportsandearlydatasuggestingthatlamotriginemaypossessanti-manicproperties,furtherstudyhasledtotheconclusionthatlamotriginehasonlymildtomoderateefficacyinmaniaandshouldnotbereliablyusedasmonotherapyintheseurgentabovebaselinemooddisturbances.Theadditionoflamotriginetootherfirst-lineantimanicagents,suchaslithium,divalproex,olanzapine,orquetiapinemayhastenorcompleterecoveryfromacutemanicormixedstates.LamotrigineshoulddefinitelybeconsideredasaninitialadjunctivetreatmentforthesebipolarIpatientstoaddresstheneedtopreventfuturemoodepisodesafterrecoveryfromthecurrentmanicormixedepisode.Again,dosingguidelinesshouldbefollowedasindicatedpreviouslyandinthepackageinserttoavoidincreasedriskofrash. InbipolarIIpatientsexperiencingacutehypomania,lamotriginecanbeusedasamonotherapyorinconjunctionwithanothermoodstabilizersuchaslithium.Oneeffectivestrategyistheprescriptionoflamotrigineplusashort-termatypicalantipsychotic

Maintenance therapy LamotrigineisindicatedbytheUSFDAandtheEMEAforthemaintenancetreatmentofbipolarIdisordertodelaythetimetooccurrenceofmoodepisodes.Itshouldthereforebeconsideredinthetreatmentofallbipolarpatientsduetotheinherentnaturaltendencyfortheillnesstobechronicandrecurrent. Maintenancemonotherapywithlamotriginecanbeconsideredinthoseindividualswithnon-bipolarIillness,milderformsofbipolarIIdisorderwithpredominantdepressivecourse,andinotherbipolarspectrumdisorderssuchascyclothymicorhyperthymicpersonalities.Intheory,lamotriginemonotherapycouldalsobeconsideredasamaintenancetherapyaftersuccessfulECTforeitherunipolarorbipolardepression.Inmostpatients,lamotrigineshouldbepartofacombinedpharmacologicalstrategytopreventrelapse.Althoughlamotrigine

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hasbeendemonstratedaneffectivemaintenancetreatmentforbipolarIdisorder,itsabilitytopreventmanicepisodeswasconsiderablylessrobustthanitsantidepressantability.Acomprehensivebipolarmaintenancemedicationtreatmentplanmustaddresspreventionofdepressiveandmanicphases,andlamotrigineisonlymoderatelyeffectiveinthedelayofmanicepisodesnecessitatinguseofothermoodstabilizerswithacomplementaryefficacyprofile,suchaslithium,divalproex.oratypicalantipsychotics.

Use in women Therehavebeenreportsoflamotrigineserumconcentrationsdecreasinginwomenafterstartingoralcontraceptivesandincreasingafteroralcontraceptiveswerediscontinued(Sidhu2005).Dosageadjustmentsmayhavetobemadeinwomentakinglamotrigineduringtimesoforalcontraceptiveinitiationortermination,althoughnoknownlinkexistsbetweenbloodlevelsandtherapeuticeffectsforaffectivedisorders. LamotriginecarriesaCategoryCFDAwarningforuseduringpregnancy.Pregnantwomenmaintainedonlamotrigineduringpregnancyshouldhavebloodlevelsoflamotriginecheckedmonthlyasitsclearanceincreasessignificantlyaspregnancyprogresses.Apreconceptiondeterminationoflamotriginebloodlevelinastablebipolarwomanmayprovideatargetdoserangetomaintainduringpregnancy.Clearanceoflamotriginedropsquicklyafterdelivery,requiringdosagereductioninmostpostpartumpatients.Breast-feedingisnotrecommendedtonursingmothersonlamotriginesincesignificantlevelsoflamotriginearepresentinbreastmilkandlongtermeffectsofexposuretoneonatesisunknown.Althoughtherearesomereportsofanincreasedriskforisolatedcleftpalateorlipdeformityafterexposuretolamotriginemonotherapyduringthefirsttrimesterofpregnancy(Holmes2008)theoverallriskformajorbirthdefectsappeartobesimilartothatofthegeneralpopulation(Cunnington2005).

Summary

Thediscoveryoflamotrigine’spositiveeffectsonmoodinepilepsypatientsledtoitsinvestigationsinandeventualapprovalfortreatingbipolarIdisorder.Althoughtheexactmoodstabilizingmechanismofactionforthisnovelanticonvulsantisunknown,itisthoughttoworkbyinhibitingvoltage-sensitivesodiumcurrents,inthismannerstabilizingneuronalmembranesandasaresultmodulatingthepresynaptictransmitterreleaseofexcitatoryaminoacidssuchasglutamate.Itisapprovedformaintenancetreatmentofbipolardisordertopreventdepressiveepisodes.Inaddition,itdeservesaplaceinthetreatmentofacutebipolardepression,withthestrongestevidenceasadd-ontreatmenttolithium(thisthesis).Lamotrigineiswelltolerated,themajorriskisasevererash,anditrequirescarefuldosemonitoring.

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Holmes,L.B.,BaldwinE.J.,SmithC.R.,HabeckerE.,GlassmanL.,WongS.L.andWyszynskiD.F.(2008),Increasedfrequencyofisolatedcleftpalateininfantsexposedtolamotrigineduringpregnancy,Neurology,70,2152-58

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Judd,L.L.,Akiskal,H.S.,Schettler,P.J.,Endicott,J.,Maser,J.,Solomon,D.A.,Leon,A.C.,Rice,J.A.andKeller,M.B.(2002),Thelong-termnaturalhistoryoftheweeklysymptomaticstatusofbipolarIdisorder,ArchGenPsychiatry,59,530-7.

Kupka,R.W.,Luckenbaugh,D.A,.Post,R.M,Suppes,T.,Altshuler,L.L.,Keck,P.E.,Jr,Frye,M.A.,Denicoff,K.D.,Grunze,H.,Leverich,G.S.,McElroy,S.L.,Walden,J.andNolen,W.A.(2005),Comparisonofrapid-cyclingandnon-rapid-cyclingbipolardisorderbasedonprospectivemoodratingsin539outpatients,Am.JPsychiatry,162,1273-80.

Ketter,T.A.,GreistJ.H.,Graham,J.A.,Roberts,J.N.,Thompson,T.R.andNanry,K.P.,(2006),TheeffectofDermatologicPrecautionsontheIncidenceofRashWithAdditionofLamotrigineintheTreatmentofBipolarIDisorder:ARandomizedTrial,JClin.Psychiatry67,400-6

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Li,X.,Ketter,T.A.andFrye,M.A.(2002),Synaptic,intracellular,andneuroprotectivemechanismsofanticonvulsants:aretheyrelevantforthetreatmentandcourseofbipolardisorders?,JAffectDisord,69,1-14.

Matsuo,F.,Bergen,D.,Faught,E.,Messenheimer,J.A.,Dren,A.T.,Rudd,G.D.andLineberry,C.G.(1993),Placebo-controlledstudyoftheefficacyandsafetyoflamotrigineinpatientswithpartialseizures.U.S.LamotrigineProtocol0.5ClinicalTrialGroup,Neurology,43,2284-91.

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Mikati,M.A.,Schachter,S.C.,Schomer,D.L.,Keally,M.,Osborne-Shafer,P.,Seaman,C.A.,Sheridan,P.H.,Ashworth,M.,Kupferberg,H.,Valakas,A.and(1989),Long-termtolerability,pharmacokineticandpreliminaryefficacystudyoflamotrigineinpatientswithresistantpartialseizures,ClinNeuropharmacol,12,312-21.

Ohman,I.,Vitols,S.andTomson,T.(2000),Lamotrigineinpregnancy:pharmacokineticsduringdelivery,intheneonate,andduringlactation,Epilepsia,41,709-13.

Pennell,P.B.(2003),Antiepilepticdrugpharmacokineticsduringpregnancyandlactation,Neurology,61,S35-42.

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Regeer,E.J.,ten,HaveM.,Rosso,M.L.,Hakkaart-van,RoijenL.,Vollebergh,W.andNolenW.A.(2004),Prevalenceofbipolardisorderinthegeneralpopulation:aReappraisalStudyoftheNetherlandsMentalHealthSurveyandIncidenceStudy.ActaPsychiatr.Scand.110,5374-82.

RzanyB.,Mockenhaupt,M.,Baur,S.,Schroder,W.,Stocker,U.,Mueller,J.,Hollander,N.,Bruppacher,R.andSchopf,E.(1996),Epidemiologyoferythemaexsudativummultiformemajus,Stevens-JohnsonsyndromeandtoxicepidermalnecrolysisinGermany(1990-1992):structureandresultsofapopulation-basedregistry,JClinEpidemiol,49,769-73.

Shiah,I.S.,Yatham,L.N.,Lam,R.W.andZis,A.P.(1998),Effectsoflamotrigineonthe5-HT1Areceptorfunctioninhealthyhumanmales,JAffectDisord,49,157-62.

SidhuJ.,JobS.,SinghS.andPhilipsonR.,Thepharmacokineticandpharmacodynamicconsequencesoftheco-administrationoflamotrigineandacombinedoralcontraceptiveinhealthyfemalesubjects.Br.J.ofClin.Pharmacol.61,191-99

Smith,D.,Baker,G.,Davies,G.,Dewey,M.andChadwick,D.W.(1993),Outcomesofadd-ontreatmentwithlamotrigineinpartialepilepsy,Epilepsia,34,312-22.

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Tran,T.A.,Leppik,I.E.,Blesi,K.,Sathanandan,S.T.andRemmel,R.(2002),Lamotrigineclearanceduringpregnancy,Neurology,59,251-5.

Vinod,K.Y.andSubhash,M.N.(2002),Lamotrigineinducedselectivechangesin5-HT(1A)receptormediatedresponseinratbrain,NeurochemInt,40,315-9.

Walden,J.,Hesslinger,B.,vanCalker,D.andBerger,M.(1996),Additionoflamotriginetovalproatemayenhanceefficacyinthetreatmentofbipolaraffectivedisorder,Pharmacopsychiatry,29,193-5.

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Weissman,M.M.,Bland,R.C.,Canino,G.J.,Faravelli,C.,Greenwald,S.,Hwu,H.G.,Joyce,P.R.,Karam,E.G.,Lee,C.K.,Lellouch,J.,Lepine,J.P.,Newman,S.C.,Rubio-Stipec,M.,Wells,J.E.,Wickramaratne,P.J.,Wittchen,H.andYeh,E.K.(1996),Cross-nationalepidemiologyofmajordepressionandbipolardisorder,Jama,276,293-9.

Wong,I.C.,Mawer,G.E.andSander,J.W.(1999),Factorsinfluencingtheincidenceoflamotrigine-relatedskinrash,AnnPharmacother,33,1037-42.

Xie,X.andHagan,R.M.(1998),Cellularandmolecularactionsoflamotrigine:Possiblemechanismsofefficacyinbipolardisorder,Neuropsychobiology,38,119-30.

Xie,X.,Lancaster,B.,Peakman,T.andGarthwaite,J.(1995),InteractionoftheantiepilepticdruglamotriginewithrecombinantratbraintypeIIANa+channelsandwithnativeNa+channelsinrathippocampalneurones,PflugersArch,430,437-46.

Yuen,A.W.,Land,G.,Weatherley,B.C.andPeck,A.W.(1992),Sodiumvalproateacutelyinhibitslamotriginemetabolism,BrJClinPharmacol,33,511-3.

MarcL.M.vanderLoos,M.D.;PaulG.H.Mulder,Ph.D.;ErwinG.Th.M.Hartong,M.D.,Ph.D.;MarcB.J.Blom,M.D.;AntonC.Vergouwen,M.D.,Ph.D.;HermanJ.U.E.M.deKeyzer,M.D.;PeterJ.H.Notten,M.D.;MarijkeL.Luteijn,M.D.;ManuelaA.Timmermans,M.Sc.;EduardVieta,M.D.,Ph.D.;andWillemA.Nolen,M.D.,Ph.D.,fortheLamLitStudyGroup

FromtheDepartmentofPsychiatry,IsalaKlinieken,locationSophia,Zwolle(Dr.vanderLoos);theDepartmentofEpidemiology&Biostatistics,ErasmusUniversityMedicalCenter,Rotterdam(Dr.Mulder);theDepartmentofPsychiatry,Canisius-WilhelminaHospital,Nijmegen(Dr.Hartong);ParnassiaPsychiatricInstitute,TheHague(Dr.Blom);theDepartmentofPsychiatry,St.LucasAndreasHospital,Amsterdam(Dr.Vergouwen);GroupPractice:BiologicalPsychiatryandPsychotherapy,Retranchement(Dr.deKeyzer);theDepartmentofPsychiatry,St.ElisabethHospital,Tilburg(Dr.Notten);theDepartmentofPsychiatry,AlbertSchweitzerHospital,Dordrecht(Dr.Luteijn);ClinicalOperations,GlaxoSmithKline,Zeist(Ms.Timmermans);BipolarDisordersProgram,DepartmentofPsychiatry,UniversityMedicalCenterGroningen,UniversityofGroningen(Dr.Nolen),theNetherlands;andInstituteofNeuroscience,HospitalClinic,UniversityofBarcelona,IDIBAPS,CIBER-SAM,Catalonia,Spain(Dr.Vieta).

The Journal of Clinical Psychiatry 2009; 70: 223-231

Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial

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Abstract

Objective:Lamotrigineisoneofthepharmacologicoptionsforthetreatmentofbipolardepressionbuthasonlybeenstudiedasmonotherapy.Thisstudycomparedtheacuteeffectsoflamotrigineandplaceboasadd-ontherapytoongoingtreatmentwithlithiuminpatientswithbipolardepression. Method:Outpatients(n=124)aged18yearsandolderwithaDSM-IVbipolarIorIIdisorderandamajordepressiveepisode(Montgomery-ÅsbergDepressionRatingScale[MADRS]score≥18andClinicalGlobalImpressions-BipolarVersion[CGI-BP]severityofdepressionscore≥4)whilereceivinglithiumtreatment(0.6–1.2mmol/L)wererandomlyassignedto8weeksofdouble-blindtreatmentwithlamotrigine(titratedto200mg/d)orplacebo.TheprimaryoutcomemeasurewasmeanchangefrombaselineintotalscoreontheMADRSatweek8.Secondaryoutcomemeasureswereresponse(definedasareductionof≥50%ontheMADRSand/orchangeofdepressionscoreontheCGI-BPof“muchimproved”or“verymuchimproved”comparedtobaseline)andswitchtomaniaorhypomania(definedasaCGI-BPseverityofmaniascoreofatleastmildlyillatanyvisit).PatientswereincludedinthestudybetweenAugust2002(SpainstartedinOctober2003)andMay2005. Results:EndpointmeanchangefrombaselineMADRStotalscorewas–15.38(SE=1.32)pointsforlamotrigineand–11.03(SE=1.36)pointsforplacebo(t=–2.29,df=104,p=.024).SignificantlymorepatientsrespondedtolamotriginethantoplaceboontheMADRS(51.6%vs.31.7%,p=.030),butnotontheCGI-BPchangeofdepression(64.1%vs.49.2%,p=.105).Switchtomaniaorhypomaniaoccurredin5patients(7.8%)receivinglamotrigineand2patients3.3%)receivingplacebo(p=.441). Conclusion:Lamotriginewasfoundeffectiveandsafeasadd-ontreatmenttolithiumintheacutetreatmentofbipolardepression.

Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial 51

Introduction

Patientswithbipolardisorderspendmoretimedepressedthanmanicorhypomanic(1–4),whilemostmoodstabilizers(lithium,valproate,carbamazepine)aremoreeffectiveagainstmanicepisodesthandepressiveepisodes(5–7).Thesameappearstrueforatypicalantipsychotics,althougholanzapine(aloneaswellasincombinationwithfluoxetine(8))andquetiapine(9)havedemonstratedefficacyintheacutetreatmentofbipolardepression. Asaconsequence,manybipolarpatientsalsoreceiveantidepressants,mostlyincombinationwithothertherapies.Thefindingthattheeffectsizeforthecombinationofolanzapinewithfluoxetinewassuperiortotheeffectsizeofolanzapinemonotherapyunderscorestheimportanceofcombinationtherapystudies(10).Whilesomestudiesfoundthatantidepressants,eitherasmonotherapyorcombinationtherapywithmoodstabilizers,areeffectiveinthetreatmentofacutebipolardepression(11),otherstudiesfoundnoeffectoftheadditionofantidepressantstomoodstabilizers(12,13).Inaddition,theirusemaybeassociatedwiththeriskofswitchtomaniaorhypomania(11,14) Theanticonvulsantlamotrigineprovidesanadditionaltreatmentoption.Afterafewcasereportsandsomeopenlabelstudies(15–17),thefirstdouble-blindrandomizedcontrolledtrial(18)ontheefficacyoflamotriginemonotherapyintheacutetreatmentofbipolardepressionfounditmoreeffectivethanplaceboatdosesof50and200mg/dayonseveralsecondaryoutcomemeasures,includingtheMontgomery-ÅsbergDepressionRatingScale(MADRS),butnotontheprimaryoutcomemeasure,i.e.,theHamiltonRatingScaleforDepression(HAM-D).Subsequently,itsefficacyintheacutetreatmentofbipolardepressionwasstudiedin4otherrandomizedcontrolledtrials.Althoughthosestudieswereallnegativeontheprimaryoutcomecriterion(19),ameta-analysisofthe5studiesshowedasmallbutsignificantpositiveresult(20,21).Inanotherstudy,lamotriginewasslightlylesseffectivebutbettertoleratedthanacombinationofolanzapineandfluoxetine(22).Collaborativeresultswerealsoobtainedfromacrossoverstudythatcomparedlamotrigineandgabapentintoplacebo(23).In2long-termstudiesofbipolarIpatientswithacurrent(orrecent)manicor

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depressiveepisode(24,25),lamotrigine(titratedupto200–400mg/day)wasaddedtoongoingtreatmentwithotherpsychotropicdrugsover8to16weeks.Concomitantdrugsweregraduallywithdrawn,afterwhichstabilizedpatientswererandomlyassignedtocontinuationoflamotrigineortolithiumorplacebo(eachasmonotherapy)forupto18months.Inbothstudies,lamotrigineandlithiumwerestatisticallymoreeffectivethanplaceboontheprimaryoutcomemeasure(timefromrandomizationtointerventionforanymoodepisode),butlithiumwaspredominantlyeffectiveagainstmanicepisodesandlamotriginepredominantlyagainstdepressiveepisodes,suggestingthatlithiumandlamotriginehavedifferentialandpotentiallycomplementaryeffects. Inthisarticle,wereporttheresultsofthefirstplacebocontrolledstudyaddressingtheefficacyandsafetyoflamotrigineasadd-ontolithiumintheacutetreatmentofpatientswithbipolardepression.

Method

Study Design Thisstudyisthefirstphaseofaninvestigator-initiated(W.A.N.)randomized,double-blind,placebo-controlledtrial,with23recruitingcenters(of25selected)intheNetherlandsand3recruitingcenters(of5selected)inSpain. RecruitmenttookplacebetweenAugust2002andMay2005(SpainstartedinOctober2003).ThestudywasapprovedbytheethicalreviewboardoftheUniversityMedicalCenterUtrecht,theNetherlands,andbylocalinstitutionalreviewboardsinbothcountries.Allpatientsgavewritteninformedconsentpriortoinitiationofanystudyprocedure.

Patients Outpatients(menorwomen)aged18yearsoroldercouldbeincludediftheymetcriteriaforDSM-IVbipolarIorIIdisorder,currentmajordepressiveepisodeconfirmedbytheMini-InternationalNeuropsychiatricInterviewPlus(MINI-Plus)(26)withascoreof≥18pointsontheMADRS(27)andascoreof≥4(moderatelyill)ontheClinicalGlobalImpressions-BipolarVersion(CGI-BP)

severityofdepressionrating(28).Allpatientshadtobereceivingtreatmentwithlithiumwithastabledose(plasmalevel,0.6–1.2mmol/L)duringatleast2weekspriortothestudy. Exclusioncriteriawerethefollowing:thepresenceofpsychoticfeatures,asevererapidcyclingcoursewith≥10episodesoverthelast12months(rapidcyclingwith4–9episodesintheprevious12monthswasallowed),severesuicidality(scoreof≥5onitem10oftheMADRS),ahistoryofalcoholorsubstanceabusewithin1monthordependencewithin12monthsofenrollment,aseverepersonalitydisordersuggestingnoncompliance,orasevereneurologicorothersomaticillnessandtheuseofsomaticmedicationthatcouldaffectmood.Womenofchild-bearingpotentialwereonlyeligibleforthestudyiftheyhadanegativepregnancytestatscreeningandagreedtoutilizeaneffectivecontraceptivemethod.Exceptforlithium,patientswerenotallowedtohaveusedanantipsychoticoranantidepressantwithin2weeks(fluoxetine,4weeks)ofrandomization.Benzodiazepineswereallowedatamaximumof2-mglorazepamequivalentsperdaythroughoutthestudy,i.e.,forstandingaswellasrescuemedication,foranxiety,agitation,orsleepproblems.

Treatments Afterinclusioninthestudy,patientswererandomlyassigned1:1toeitherlamotrigineorplaceboinblocksof2asadjunctivetreatmenttoongoingtreatmentwithlithiumaccordingtoarandomizationlist.Stratificationwasdonebysite.Thecodeofeachpatientwaskeptinasealedenvelopeatthepharmacyofeachparticipatingcenterandcouldbeopenedbythepharmacistonlyincaseofmedicalemergency.Thestudyblindwaspreserveduntilafterthelastpatientevaluation. Studymedicationwasadministeredoncedailyinthemorning.Lamotriginewasstartedat25mg/dayinweeks1and2andwasincreasedto50mg/dayinweeks3and4,to100mg/dayinweeks5and6,and,finally,to200mg/dayinweeks7and8.Placebowasadministeredbyutilizingtabletsidenticalinappearanceandnumber.Thelithiumdosageremainedstableduringthestudywithmonitoringofplasmalevels(tobekeptat0.6–1.0mmol/L)at

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baselineandweek8. Toestablishmedicationcompliance,apillcountwasdoneateveryvisit.Patientsreturningmorethan30%oftheirprescribedmedicationorreportinganinterruptionofmedicationformorethan3dayswerewithdrawnfromthestudy.Patientswhomissedtheirstudymedicationfor1,2,or(maximum)3daysrestartedatthesamedose.

Outcome Measures Atbaseline,diagnosiswasconfirmedwiththeMINI-Plussectionsdepressiveepisode,manicepisode,hypomanicepisode,alcoholabuseanddependence,andsubstanceabuseanddependence.Inaddition,clinicianscompletedtheClinicalQuestionnaireforBipolarIllness(CQBP-C),withitemsonillnessandtreatmenthistory,asusedbytheformerStanleyFoundationBipolarNetwork(29).Severityofsymptomswasassessedatbaselineandatweeks2,4,6,and8byusingtheMADRSandtheCGI-BPseverityofdepressionandseverityofmania.Adverseeventswereassessedateachvisitbyinquiringaboutanyunpleasantfeelingsincethelastvisitand,ifpresent,ratedmild,moderate,orsevere. TheprotocolaswellasthecaserecordformwerewritteninEnglishbutincludedvalidatedDutchandSpanishtranslationsoftheMADRSandtheCGI-BP.IntheNetherlands,therewere4researchmeetings,includingMADRStrainingsessions;27ratersscoredatleast4patientswithanintraclasscoefficient=0.95.AfterreceivinganinitialMADRStraininginSpain,allSpanishresearchersparticipatedinaresearchmeetingintheNetherlandswithadditionalMADRStraining. TheprimaryoutcomemeasurewasthemeanchangefrombaselineintotalMADRSscoreatweek8.Secondaryoutcomemeasureswereresponse(definedasareductionof≥50%ontheMADRSand/orCGI-BPchangeofdepressionscoreof“muchimproved”or“verymuchimproved”comparedtobaseline)andswitchintomaniaorhypomania(definedasaCGI-BPseverityofmaniascoreofatleastmildlyillatanyvisit).Posthoc,wealsoanalyzedon

whichitemsoftheMADRSthereweresignificantdifferencesbetweenlamotrigineandplaceboatweek8. Switchtomaniaorhypomaniaisanundesirableoutcomeinthetreatmentofbipolardepressionbutcanoccurfollowingrecoveryfromdepression.However,itoftenremainsunclearinpublicationswhetherpatientswhoswitchedwerealsocountedasresponders.Therefore,inaposthocanalysis,weassessedwhetherpatientsreachedthecriteriaforbothresponse(MADRSand/orCGI-BPchangeofdepression)andnoswitchtomaniaorhypomania(CGI-BP),whichistheultimategoalinthetreatmentofbipolardepression. Thestudywasinitiallyaimedatcomparing2groupsof110patientsinordertodetectameandifferenceof4pointsinMADRSscoresbetweenthe2groups,with80%powerandαof.05(2-sided).Thestandarddeviation(SD)oftheMADRSscorewasinitiallysetat11points.Becauseofdifficultiesinrecruitingtheplannednumberofpatients,thesamplesizewasrecalculatedafterinclusionofatotalof43patients.TheMADRSscoresbasedontheseactuallyobservedpatients,whowereevaluatedblindlytooutcome,resultedinanSDof8pointsandacorrespondingrecalculatedsamplesizeof60patientspergroup.

Analysis Mixed-modelanalysisofvariance(ANOVA)forrepeatedmeasureswasprospectivelychosenasmethodofanalysisforMADRSscores.Theindependentvariablesinthisanalysisweretimeandtreatmentandtheirinteraction.TimeascategoricalvariableallowedestimatingandtestingmeandifferencesinMADRSscorebetweenthe2treatmentsatanyvisit,includingtheprimaryefficacymeasure:scorechangefrombaselineatweek8.ForthispurposetherelevantcontrastswerespecifiedinthemodelforwhichtheANOVAproducedtheestimates,SEs,confidenceintervals(CIs),andappropriatettestspervisit.Inordertomakeinferenceaboutanoveralltreatmenteffectoverallvisits,timewasconsideredanumerictrendvariableinthemodel.ThisallowedestimatingandtestingadownwardtrendintimeofthemeanMADRSscoreineithertreatment

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groupandthedifferenceintimetrendbetweenthe2treatmentsasasingleefficacymeasure,forwhichthemixed-modelANOVAproducedtheestimateSE,CI,andappropriatettest.Inaccordancewiththeintent-to-treatprinciple,allrandomlyassignedsubjectscontributedtotheseanalyses,missingvaluesofMADRSbeingproperlyadjustedforbytherestrictedmaximumlikelihoodestimationprocedureusedinthemixed-modelANOVAs.ClinicalGlobalImpression-BipolarVersionseverityscoresweresimilarlyanalyzedbyusingmixed-modelANOVA,withtimeascategoricalvariable.Dichotomousoutcomescores(response,switch,orpresenceofadverseeffects)weremadecompletebyusingthelast-observation-carried-forwardmethodandthenwereanalyzedbycomparingpercentagesbetweenthe2treatmentgroupsusingFisherexacttest.Differencesinthedistributionofcategoricalnominalvariablesbetweenthe2treatmentgroupsweretestedusingFisherexacttest;forcategoricalordinalvariablestheexactχ2trendtestwasused.Foreachtest,a2-sidedpvaluebelow.05wasconsideredtodenotestatisticalsignificance.

Results

Patients and Illness Characteristics Intotal,128patientswererecruited(fig1):mostpatients(n=82)fromthe23centersintheNetherlands,34patientsviaadvertisementsinDutchnewspapers,and12patientsfromthe3centersinSpain.Therangeofincludedpatientspercenterwasbetween1and25. Fourpatientswerenotincludedintheanalysis:atbaseline,1patientappearedtouseanantipsychotic;1patienthadusedanantidepressantinthe2weeksbeforerandomization;1patienthadhypothyroidism;and1patientnevertookanymedication.Thus,124patientswererandomlyassignedandincludedintheanalysis:64patientstolithiumpluslamotrigineand60patientstolithiumplusplacebo.Therewerenostatisticallysignificantdifferencesbetweenthe2groupsinpatientcharacteristicsandillnessseverityatbaseline(table1).

Figure 1. Flowchartofpatientsrandomlyassignedtolamotrogineorplaceboasadd-ontreatmenttolithium

AssessedforEligibility(n=128)

Randomlyassigned(n=124)

Lamotrigine(n=64)

LosttoFollow-Up (n=0)Discontinued (n=12)

Completed (n=52)Analyzed (n=64)

LackofEfficacy (n=2)AdverseEffects (n=4)WithdrawnConsent(n=1)ProtocolViolation (n=2)Noncompliance (n=1)Other (n=2)

LackofEfficacy (n=3)AdverseEffects (n=2)WithdrawnConsent(n=1)ProtocolViolation (n=0)Noncompliance (n=1)Other (n=2)

LosttoFollow-Up (n=1)Discontinued (n=9)

Completed (n=50)Analyzed (n=60)

Placebo(n=60)

Excluded(n=4)NotmeetinginclusionCriteria(n=3)NotTakingStudyMedication (n=1)

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Table 1. Baselinepatientandillnesscharacteristicsinpatientsrandomlyassignedtolamotrogineorplaceboasadd-ontreatmenttolithium

CGI-BP=ClinicalGlobalImpressions-BipolarVersion,MADRS=Montgomery-ÅsbergDespressionRatingScale,MAOI=monoamineoxidaseinhibitor,SSRI=selectiveserotoninreuptakeinhibitor,SNRI=serotonin-norepinephrinereuptakeinhibitor,TCA=tricyclicantidepressant.

Lamotriginen=64

Placebon=60

Totaln=124 Statistic Value df P

Femalegender(n,%) 37 57.8 30 50 67 54.0 Fisher’s - - 0.471Age(years)(mean,SD) 45.2 12.1 47.6 11.6 46.4 11.9 t-test 1.13 122 0.261IlnesscharacteristicsBipolarIdisorder(n,%) 43 67.2 41 68.3 84 67.7 Fisher’s - - 1.000Rapidcyclingcourse–last12months(n,%)

12 18.8 4 6.7 16 12.9 Fisher’s - - 0.061

MADRS(mean,SD) 28.25 5.97 28.82 6.24 28.52 6.08 t-test 0.52 122 0.606CGI-BPdepressionseverity(mean,SD)

4.56 0.64 4.53 0.57 4.55 0.60 ChiSq.trend

0.07 1 0.882

CGI-BPmaniaseverity(mean,SD)

1.03 0.18 1.03 0.18 1.03 0.18 Fisher’s - - 1.000

PrevioustreatmentsforindexdepressiveepisodeLithiumBaselineplasmalevel(mEq)(mean,SD)

0.82 0.16 0.84 0.16 0.83 0.16 t-test 0.48 122 0.634

Durationoftreatmentbeforerandomisation2to4weeks(n,%) 1 1.9 4 8.0 - - Fisher’s - - N.S.1-3months(n,%) 6 11.3 4 8.0 - - Fisher’s - - N.S≥3months(n,%) 46 86.8 42 84.0 - - Fisher’s - - N.S.Unknown/missing(n,%) 11 10

TCA(n,%) 6 9.4 4 6.7 10 8.1 Fisher’s - - 0.745SSRI/SNRI(n,%) 15 23,4 16 26.7 31 25.0 Fisher’s - - 0.836MAO-inhibitor(n,%) 1 1.6 3 5.0 4 3.2 Fisher’s - - 0.353Antipsychotic,typical(n,%)

4 6.3 3 5.0 7 5.6 Fisher’s - - 1.000

Antipsychotic,atypical(n,%)

15 23.4 11 18.3 26 21.0 Fisher’s - - 0.317

Valproicacid(n,%) 5 7.8 2 3.3 7 5.6 Fisher’s - - 0.247Carbamazepine(n,%) 1 1.6 3 5.0 4 3.2 Fisher’s - - 0.285Benzodiazepine(n,%) 44 68.8 35 58.3 79 63.7 Fisher’s - - 0.154Other(n,%) 3 4.7 4 6.7 7 5.6 Fisher’s - - 0.464

Inbothgroups,morethan80%ofthepatientshadbeenreceivinglithiummaintenancetreatmentforatleast3months. Atbaseline,lithiumplasmalevelswerewithinthepredefinedrangefor119patients(0.6–1.2mmol/L),while5patientshadmarginallylowerplasmalevels(allabove0.53mmol/L).Astheselevelswereonlymarginallylowerthantherequiredlevelof0.6mmol/L,adecisiontoincludethesepatientsintheanalysiswasmadepriortobreakingofthetreatmentblind.Therewasnosignificantdifferencebetweenlithiumplasmalevelsintheplacebogroupversusthelamotriginegroupatbaseline(t=0.48,df=122,p=.63;0.84[SD=0.16]mmol/Land0.82[SD=0.16]mmol/L,respectively)norat8weeks(t=1.36,df=100,p=.18;0.80[SD=0.14]mmol/Land0.76[SD=0.16]mmol/L,respectively). Inthelamotriginegroup,52patients(81%)completedthe8-weekstudyperiodversus50patients(83%)intheplacebogroup.Ofthe12patientswhodiscontinuedthetrialinthelamotriginegroup,2discontinuedbecauseoflackofefficacyand4becauseofadverseeffects.Intheplacebogroup,10patientsdiscontinuedthetrial:3becauseoflackofefficacyand2becauseofadverseeffects.Otherreasonsinbothgroupsfordiscontinuingwerewithdrawnconsent,protocolviolation,noncompliance,andlosttofollow-up.

Efficacy ResultsarepresentedinTables2and3.Ontheprimaryoutcomemeasure,changeintheMADRSscorefrombaselinetoweek8,lamotriginewassignificantlymoreeffectivethanplacebo(decreaseof15.38vs.11.03,respectively,p=.024)(table2).ThelamotriginegroupalsohadsignificantlylowerMADRSscoresatweeks6and8comparedtotheplacebogroup(Figure2).Startingfromanoverallaveragebaselinelevelof28.4points,theMADRSscoredecreasedonaverageby3.77pointsper2weeks(95%CI=3.15to4.38;p<.0005)duringthefirst8weeksoftreatmentinthelamotriginegroup.Intheplacebogroup,thedecrementwasonaverage2.59pointsper2weeks(95%CI=1.96to3.22;p<.0005).Hence,themeanMADRSscoreinthelamotriginegroupbecameincreasinglylowerthanthemeanscoreintheplacebo

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groupby,onaverage,1.17pointsper2weeks(95%CI=0.33to2.02;p=.007)duringthefirst8weeksoftreatment.Response,definedasareductionoftheMADRSscoreof≥50%,wasstatisticallygreater(p=.03)inthelamotriginegroup(51.6%)thanintheplacebogroup(31.7%)(table3).ResponseaccordingtoCGI-BPchangeofdepressionscores≤2andresponseaccordingtoeithercriterion(MADRSand/orCGI-BPchangeofdepression)showednosignificantdifferences.

Table 2.EfficacyResults(mixedmodelestimates):severityscales

CGI-BP=ClinicalGlobalImpressions-BipolarVersion,MADRS=Montgomery-ÅsbergDepressionRatingScale.Boldvaluesindicatesignificantlevels<0.05

Lamotrigine(n=64)

Placebo(n=60) Difference

tTest df PMeasure Mean SE Mean SE Mean SEMADRSscorechangefrombaseline(primaryoutcomemeasure)Week2 -5.30 0.87 -3.74 0.91 -1.56 1.26 -1.23 121 .220Week4 -9.22 1.25 -6.24 1.29 -2.98 1.80 -1.66 110 .101Week6 -12.84 1.35 -9.31 1.39 -3.53 1.90 -1.82 104 .071Week8 -15.38 1.32 -11.03 1.36 -4.35 1.90 -2.29 104 .024

MADRSscoreateachvisitBaseline 28.25 0.76 28.82 0.79 -0.57 1.10 -0.52 122 .606Week2 22.95 1.02 25.08 1.06 -2.12 1.47 -1.44 121 .153Week4 19.03 1.28 22.58 1.32 -3.55 1.84 -1.93 113 .056Week6 15.41 1.30 19.50 1.34 -4.09 1.87 -2.19 106 .031Week8 12.87 1.23 17.79 1.27 -4.92 1.77 -2.78 104 .006

CGI-BPseverityofdepressionscoreateachvisitBaseline 4.56 0.08 4.53 0.08 0.03 0.11 0.27 122 0.789Week2 4.14 0.14 4.15 0.14 -0.01 0.20 -0.03 121 0.976Week4 3.69 0.17 3.86 0.18 -0.17 0.24 -0.70 111 0.486Week6 3.07 0.18 3.48 0.19 -0.40 0.27 -1.52 104 0.131Week8 2.63 0.18 3.10 0.19 -0.47 0.26 -1.79 103 0.077

CGI-BPchangeofdepressionscorefrombaselineWeek2 3.49 0.13 3.44 0.14 0.05 0.19 0.27 121 0.788Week4 3.37 0.16 3.46 0.17 -0.09 0.24 -0.37 101 0.710Week6 2.79 0.17 3.21 0.18 -0.42 0.25 -1.68 90 0.097Week8 2.52 0.19 2.96 0.19 -0.44 0.27 -1.65 117 0.101

CGI-BPseverityofmaniascoreateachvisitBaseline 1.03 0.02 1.03 0.02 0.00 0.03 -0.07 122 0.948Week2 1.11 0.04 1.07 0.04 0.04 0.06 0.68 121 0.496Week4 1.13 0.05 1.07 0.05 0.06 0.07 0.92 79 0.360Week6 1.07 0.03 1.07 0.03 0.00 0.05 0.08 54 0.940Week8 1.15 0.06 1.13 0.06 0.02 0.08 0.31 78 0.757

Because12patients(18.8%)receivinglamotrigineversus4patients(6.7%)intheplacebogrouphadbeenrapidcyclersinthepastyear(differenceapproachingstatisticalsignificance[p=.06,Fisherexacttest]),thissubgroupwasthesubjectofaposthocanalysis,revealing8(66.7%)lamotrigineand1(25%)placeborespondersbyMADRSand/orCGI-BPchangeofdepression(p=.26,Fisherexacttest).Fourpatients(25%)ofthe16rapidcyclingpatients(all4receivinglamotrigine)hadamanicorhypomanicepisodeversus3patients(2.8%)of108non–rapidcyclingpatients(1patientreceivinglamotrigine,2patientsreceivingplacebo).Overbothtreatmentconditions,theswitchratetomaniaorhypomaniawassignificantlyhigherintherapidcyclingversusthenon–rapidcyclingpatients(p=.005,Fisherexacttest). OnthedifferentMADRSitems,therewasasignificantdifferenceafter8weeksbetweenlamotrigineandplaceboonapparentsadness,reportedsadness,reducedappetite,lassitude,inabilitytofeel,andsuicidalthoughts.Thesamplesizewastoosmalltodetectthefollowingtreatment-by-subgroupinteractions:bipolarIversusII,rapidcyclingversusnon–rapidcycling,andsevereversuslessseveredepressionatbaseline.Asite-bytreatmentanalysiswasnotdoneasitwasnotforeseenintheprotocol.

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Figure 2. SeverityofdepressionaccordingtothemeanMADRSscoreateachvisitforpatientsreceivingplaceboorlamotrigine

Table 3. Efficacyresults:responseandswitchto(hypo)mania*

Boldvaluesindicatesignificantlevels<0.05*adjustedforgender,bipolarI/II,age,lithiumandrapidcycling**1missing***CGI-BPseverityofmania≥3****ReductionMADRS≥50%and/orCGI-BPchangeofdepression≤2andCGI-BPseverityof

mania<3

Lamotriginen=64

Placebon=60

Statistic PResponse N % N %ReductionMADRS≥50%

33 51.6 19 31.7 fisher 0.030

CGI-BPchangeofdepression≤2

41 64.1 29 49.2** fisher 0.105

Eitherorboth 42 65.6 29 49.2** fisher 0.065Switchto(hypo)mania***

5 7.8 2 3.3 fisher 0.441

Responseandnoswitchto(hypo)mania****

39 60.9 28 46.7 fisher 0.149

MADRS=Montgomery-ÅsbergDepressionRatingScale

*p=.031**p=.006

0Baseline Wk2 Wk4 Wk6 Wk8

PlaceboLamotrigine

Safety

Fivepatientshadaseriousadverseevent(SAE).Onepatientintheplacebogroupexperiencedasevererash.Asthiswasanunexpectedfinding,wecheckedtherandomizationcodeforpossiblemistakesandaskedthelaboratorytocheckthepillsdirectly;bothchecksrevealedthatthemedicationwasindeedplacebo.Sowedecidedthatthiswasachancefinding.FourSAEsoccurredinthelamotriginegroup.Onepatientdevelopedamanicpsychoticepisoderequiringhospitalization.Theepisoderesolvedcompletelyafterstoppingofthestudymedicationandwithadditionaltreatment.The3otherSAEswithlamotrigineinvolved1patientwithseverehypertensionthatwasconsideredtobeunrelatedtostudydrug,1patientwithanonseverelithiumintoxication(lithiumlevel,1.36mmol/L,unexplainedandprobablynottheresultofanautointoxication),and1patientwhohadtobehospitalizedduetodeteriorationofdepressivesymptoms.Studymedicationwascontinuedinthepatientswiththelithiumintoxicationandthehypertensionandwasstoppedintheotherpatients. Otheradverseeventsoccurringinmorethan5%ineithergrouparepresentedintable4.Mostoftheadverseeventsweremildormoderate.Therewerenostatisticallysignificantdifferencesbetweenthe2groupsinoccurrenceofadverseevents.Inparticular,therewasnodifferenceintheincidenceofskinrash(4.7%forlamotriginevs.6.7%forplacebo,p=.71). Asmentionedbefore,1patientinthelamotriginegroupdevelopedamanicepisodewithpsychoticfeaturesforwhichhewashospitalized(SAE).Inadditiontothispatient,4patientsreceivinglamotrigineand2patientsreceivingplacebodevelopedahypomanicepisode(CGI-BPseverityofmania=3).Thenumberofmanicorhypomanicswitcheswasnotstatisticallydifferent.Combinedresponseandnoswitchintomaniaorhypomaniawasobtainedin39patients(60.9%)receivinglamotrigineand28patients(46.7%)receivingplacebo(p=.149).

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Table 4. Adverseeventsoccuringin≥5%ofpatientsinanygroup

Discussion

Toourknowledgethisisthefirstrandomizedcontrolledtrialtoassesstheefficacyoflamotrigineasadd-ontreatmenttoongoinglithiumtherapyinpatientswithbipolardepression.Theresultsshowaclinicallysignificant(>4points)differenceinfavoroflamotrigineontheprimaryoutcomemeasure(changefrombaselineinMADRSscore)andonseveralsecondaryoutcomemeasures,includingMADRSscoresatweeks6and8,thepercentageofMADRSrespondersatendpoint,and6of10itemsontheMADRS,includingcoredepressivesymptomsasapparentsadness,reportedsadness,inabilitytofeel,andsuicidalthoughts.ResultsobtainedwiththeCGI-BPchangeofdepressionwereequivocal,withweeklyscoresandoverallresponseratesnumericallyfavoringlamotriginebutnotreachingstatisticalsignificance.ThiscouldbeduetolimitationsinthesensitivityoftheCGI-BP.Anotherpossibilityisthatthisresultedfromamoreoptimisticimpressionamongthephysicianswhenassessingtheeffectoftreatmentsincestartoftreatment,comparedwiththecross-sectionally–

Lamotrigine(n=64)

Placebo(n=60)

AdverseEvent N % N % PHeadache 12 18.8 9 15.0 0.64Fatigue 9 14.1 7 11.7 0.79Nausea 8 12.5 4 6.7 0.37Flu-likesymptoms 7 10.9 4 6.7 0.52Insomnia 6 9.4 1 1.7 0.12Tremor 5 7.8 1 1.7 0.21Skinproblems/mildrash 5 7.8 1 1.7 0.21Dizziness 1 1.6 5 8.3 0.17Abdominalpain 4 6.3 3 5.0 1.00Rash 3 4.7 4 6.7 0.71Joint/musclepain 2 3.1 4 6.7 0.43Backpain 2 3.1 3 5.0 0.67Agitation 1 1.6 3 5.0 0.35

assessedMADRS.However,previouslamotriginestudiesdidshowsignificantchangeinCGIratingsofdepressedbipolarpatients(23–25). Thisstudyindicatesefficacyforlamotrigineintheacutetreatmentofbipolardepression,whichcomplementssimilarfindingsin2previousstudieswithlamotriginemonotherapy(17,23).However,4subsequentplacebocontrolledtrialswithlamotriginemonotherapywereallnegative,possiblybecauseofhighplaceboresponse(35%–47%asassessedbyMADRSorHAM-D-17)orlackofintrinsicefficacy(20),whileinanotherstudylamotriginewaslesseffectivebutbettertoleratedthanacombinationofolanzapineandfluoxetine(22). Besidesthepossibilityofachanceeffect,thereareseveralpossibleexplanationsforourpositivefindingcomparedwithprevious,mostlynegativestudies.First,thiswasanadd-onstudyinwhichallpatientsreceivedlithium,atreatmentthatappearstohavesomeefficacyonitsowninthetreatmentofbipolardepression(30).Thecombinationoflithiumandlamotriginemayhaveproducedadditiveeffects,ortheefficacyoflamotriginemayhavebeenenhancedbyconcurrentlithiumtreatment.Althoughthismightbespeculative,thepotentiallysynergicactioncouldcomeasaresultofcommonfinaltherapeuticpathwaysinvolvingpresynapticserotoninreleaseandincreasedneuroplasticity(31,32).Apharmacokineticinteractionseemsunlikelyinviewofapreviouslyconducteddruginteractionstudy(33).Ontheotherhand,theadd-ondesigncouldhavereducedthechanceofpositivefindings,since,asageneralrule,thistypeoftrialislesslikelytobesuccessfulinbipolardisorder(34). Second,therelativelylowoveralldropoutrate(17.7%)inthecurrentstudypermittedarobustefficacyassessmentduetofewermissingdata.Thus,itaffirmstheutilityofadd-onstudydesignsinthispatientpopulation.Thelowdropoutratemaybeattributabletovariousreasons.First,allpatientshadtheoptiontogetanantidepressantduringthesecondphaseofthestudy,iftheyshouldnotrespondtothestudydrugattheendofthedouble-blindtrial.Second,thereisadifferenceinhealthcaresystemsinthecountriesinwhichourstudywasconductedcomparedtothehealthcaresystemsinwhichpreviouslamotriginestudies(21)wereconducted.IntheNetherlandsandSpainallinhabitantshaveamandatoryhealthinsuranceprogramthatpaysforthetreatmentofbipolar

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disorder,whereasthisisnotthecaseintheUnitedStates,whereallthenegativeacutetrialswereconducted.Thismeansthatmostpatientscouldstaywiththeirownphysician,evenduringtheirparticipationinthetrial. Theresponsetolamotrigineoccurredratherlate.In2recenttrialscomparingquetiapinewithplaceboinbipolardepressionandinthetrialwiththecombinationofolanzapineplusfluoxetineversusplacebo,therewasaseparationbetweenmedicationandplaceboafter1week(8,9).Inourstudy,thisseparationoccurredat6weeks,whichiscomparablewiththeseparationat5weeksinthepriorpositivestudywithlamotriginemonotherapy(18)Thisdelayedeffectoflamotriginemightbeduetotheslowtitrationoflamotrigine. Switchtomaniaorhypomaniaoccurredin7patients:in5patientswhoweretakinglamotrigineandin2patientstakingplacebo.Changingmoodstatesformthecorefeatureofbipolardisorder;placeboresponseisalwaysafactortoconsider,especiallyinrapidcyclingpatientswhotypicallyhavefrequentepisodesofrelativelyshortduration.Althoughsevererapidcycling(morethan10episodesinthelastyear)wasanexclusioncriterion,nearly13%ofenrolledpatientsmetDSM-IVcriteriaforrapidcycling(4–9episodes),whichiscomparablewiththeoverallfrequency(15%)ofrapidcyclingreportedinpreviousstudies(3).Inthequetiapineversusplacebostudy(9),18.2%ofthepatientswererapidcyclers.Intheolanzapine(plusfluoxetine)versusplacebostudy(8),morethan35%ofthepatientswererapidcyclers.Althoughtherapidcyclingpatientsshowedmoreswitchesthanthenon-rapidcyclingpatients,wedidnotdetectadifferenceinefficacy,unlike2recentstudies(35,36),whichindicatedagreatershort-termresponsetoolanzapineorclozapineinrapidcyclingversusnon-rapidcyclingpatients.However,detectionofanysuchdifferencemayhavebeenhamperedbylackofstatisticalpowerforthissubgroupandconfoundedbyanear-significantdifferenceintheincidenceofrapidcyclingbetweenthelamotrigineandplacebogroups. Inthisstudy,thecombinationoflithiumandlamotriginewaswelltolerated.Therewererelativelyfewseriousadverseeventsforthispopulationandotheradverseeventswereallmildormoderateanddidnotdifferinfrequencyfromplacebo.Therelativelylowrateofskinrashobservedinthis

studymaybeattributabletoslowtitrationoflamotrigineinaccordancewiththemanufacturer’srecommendationsandconfirmsthatlithiumdoesnotincreasetheriskoflamotrigine-inducedrash.Themostimportantlimitationofourstudyistherelativelysmalloverallsamplesize(smallerthaninitiallyplanned),whichdidnotpermitsubgroupanalysesforassessmentofresponsepredictorsandmoderators.Anotherlimitationisthatwehavenoreliabledataregardingthenumberofbipolarpatientsinthestudycenterswhodevelopedadepressiveepisodewhilebeingtreatedwithlithiumandwhowerenotselectedforthestudy.Finally,wehavenosufficientdataonpatients’recenttreatmenthistoriestosuggestwherethecombinationoflithiumandlamotriginemightfitwithintreatmentalgorithms. Becausemanybipolardepressedpatientsdonotrespondadequatelytomonotherapy,thereisanurgentneedforstudiesaddressingtheefficacyofothertreatmentregimens,includingcombinationswithmoodstabilizers.Currentlypublishedplacebo-controlledstudieshaveonlyaddressedthecombinationofanantidepressant(paroxetineorimipramine)withlithium(13),ofolanzapineplusfluoxetine(8)andoftheadditionofanantidepressanttovariousmoodstabilizersand/oratypicalantipsychotics(12).Ourstudyisthefirstplacebo-controlledstudythataddressedthecombinationoflamotrigineandlithiuminbipolardepression.Thiscombinationhasbeenconsideredinteresting,especiallysinceinthe2long-termstudiescomparingbothlamotrigineandlithiumwithplacebo,lithiumwasespeciallyeffectiveinthepreventionofmanicepisodesandlamotrigineespeciallyeffectiveinthepreventionofdepressiveepisodes(24,25). Regardingclinicalconsequences,severalquestionsremainabouttheplaceofthecombinationoflamotrigineandlithiuminthetreatmentofbipolardepression.Antidepressantsremainanotherpossibleoptioninthetreatmentofbipolardepressioninpatientsusinglithium(8,11,37–39). However,theirusemaybeassociatedwiththeriskofaswitchtomaniaorhypomania(8,11,37–39).Furtherstudiesareneededtocomparetheseandotheroptions,suchas(combinationswith)atypicalantipsychotics.Anotherquestioniswhethertheeffectsoflamotrigineandlithiumwillbemaintainedintheresponders;thiswillbeaddressedinthenotyetanalyzed,1-yearcontinuationphaseofthisstudy.

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25. BowdenCL,CalabreseJR,SachsG,etal.Aplacebo-controlled18-monthtrialoflamotrigineandlithiummaintenancetreatmentinrecentlymanicorhypomanicpatientswithbipolarIdisorder.ArchGenPsychiatry2003;60:392–400

26. SheehanDV,LecrubierY,SheehanKH,etal.TheMini-InternationalNeuropsychiatricInterview(M.I.N.I.):thedevelopmentandvalidationofastructureddiagnosticpsychiatricinterviewforDSM-IVandICD-10.JClinPsychiatry1998;59(suppl20):22–33

27.MontgomerySA,ÅsbergM.Anewdepressionscaledesignedtobesensitivetochange.BrJPsychiatry1979;134:382–389

28. SpearingMK,PostRM,LeverichGS,etal.Modificationoftheclinicalglobalimpressions(CGI)scaleforuseinbipolarillness(BP):theCGI-BP.PsychiatryResearch1997;73:159–171

29. LeverichGS,NolenWA,RushAJ,etal.TheStanleyFoundationBipolarTreatmentOutcomeNetwork.I.Longitudinalmethodology.JAffectDisord2001;67(1–3):3344

30. BhagwagarZ,GoodwinGM.Theroleoflithiuminthetreatmentofbipolardepression.ClinNeurosciRes2002;2:222–227

31.ConsoniFT,VitalMA,AndreatiniR.Dualmonoaminemodulationfortheantidepressant-likeeffectoflamotrigineinthemodifiedforcedswimmingtest.EurNeuropsychopharmacol2006;16:451–458

32.CorbellaB,VietaE.Moleculartargetsoflithiumaction.ActaNeuropsychiatrica2003;15:1–25

33.ChenC,VeroneseL,YinY.Theeffectsoflamotrigineonthepharmacokineticsoflithium.BrJClinPharmacol2000;50:193–195

34. VietaE,CarneX.Theuseofplaceboinclinicaltrialsonbipolardisorder:anewapproachforanolddebate.PsychotherPsychosom2005;74:10–16

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39. LeverichGS,AltshulerLL,FryeMA,etal.Riskofswitchinmoodpolaritytohypomaniaormaniainpatientswithbipolardepressionduringacuteandcontinuationtrialsofvenlafaxine,sertraline,andbupropionasadjunctstomoodstabilizers.AmJPsychiatry2006;163:232–239

Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine

M.L.M.vanderLoos1,P.Mulder2,E.G.Th.M.Hartong3,M.B.J.Blom4,A.C.Vergouwen5,M.S.vanNoorden6,M.A.Timmermans7,E.Vieta8,W.A.Nolen9,fortheLamLitStudyGroup.

1 DepartmentofPsychiatry,IsalaKlinieken,LocationSophia,Zwolle,

2 DepartmentofBiostatistics,ErasmusUniversityMedicalCenter,Rotterdam,

3 DepartmentofPsychiatry,Canisius-WilhelminaHospital,Nijmegen,

4 ParnassiaPsychiatricInstitute,TheHague,5 DepartmentofPsychiatrySintLucasAndreasHospital,

Amsterdam,6 DepartmentofPsychiatry,LeidenUniversityMedicalCenter,

Leiden,7 PraktijkondersteuningZuidOostBrabant,Veldhoven,

theNetherlands,8 BipolarDisordersProgram,CIBERSAMInstituteof

Neuroscience,HospitalClinic,UniversityofBarcelona,IDIBAPS,Barcelona,Catalonia,Spainand

9 DepartmentofPsychiatry,UniversityMedicalCenterGroningen,UniversityofGroningen,Groningen,theNetherlands

Acta Psychiatrica Scandinavica 2010; 122: 246-254

74 Chapter 474

Abstract

Objective:Inapreviouspaper,wereportedabouttheefficacyoftheadditionoflamotriginetolithiuminpatientswithbipolardepression.Inthesecondphaseofthisstudyparoxetinewasaddedtoongoingtreatmentinnon-responders. Method:Bipolardepressedpatients(n=124)treatedwithlithiumwererandomizedtoadditionoflamotrigineorplacebo.Innonrespondersafter8weeks,paroxetine20mgwasaddedforanother8weekstoongoingtreatment. Results:After8weekstheimprovementinpatientstreatedwithlamotriginevs.patientstreatedwithplacebowassignificant.Afteradditionofparoxetinethisdifferencedisappearedasaresultofgreaterfurtherimprovementinthenon-responderstoplacebo. Conclusion:Additionoflamotriginetolithiumwasfoundeffectiveinbipolardepressedpatients.Furtheradditionofparoxetineinnonresponderstolithiumpluslamotriginedidnotappeartoprovideadditionalbenefit,whileitappearedtodosoinnon-responderstolithiumplusplacebo.

Significant outcomes

• Additionoflamotrigineismoreeffectivethantheadditionofplaceboinbipolardepressedpatientsalreadyusinglithium.

• Paroxetineadditioninnon-responderstotheformertreatmentappearedtoprovidebenefitfornonresponderstolithiumplusplacebobutnotfornon-responderstolithiumpluslamotrigine.

• Thecombinationoflithiumpluslamotrigineplusparoxetinewaswelltoleratedandsafe.Tremorwastheonlyadverseeventthatseparatedbetweenlamotrigineandplacebo.Therewerenodifferencesbetweenlamotrigineandplaceboinseriousadverseevents.

Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine 75

Limitations

• Thesamplesizeofthenon-responderstolithiumpluslamotrigineorplacebowasrelativelysmall.

• Theadditionofparoxetineinthesecondphaseofthestudywasopenanduncontrolled.

• Thedurationofthisstudywasshortinregardtothelifelongpatternofmoodepisodesinbipolardisorder.Efficacyandsafetyoftwotreatmentalgorithmsinbipolardepression.

Introduction

Since1993casereportsontheeffectivenessoflamotrigineintheacutetreatmentofbipolardepressionhavebeenpublished(1–3).Thefirstplacebo-controlledrandomizedcontrolledtrial(RCT)showingefficacyoflamotriginemonotherapywasnegativeontheprimaryoutcomecriteriontheHamiltonRatingScaleforDepression(HAMD)(4)butpositiveonseveralsecondaryoutcomemeasuresincludingtheMontgomery-ÅsbergDepressionRatingScale(MADRS)(5,6).Fourmonotherapystudiesthereafter(7)(1999–2006)wereallnegativeontheprimaryoutcomecriterion(theMADRS),althoughameta-analysisofallthesefivestudiesshowedasmallbutstatisticallysignificantpositiveresult(8).Paroxetineisaselectiveserotoninre-uptakeinhibitor(SSRI)whichisverybroadlyusedforthetreatmentofmajordepressivedisorder,andwhichhasalsobeentestedinseveralRCTsinbipolardepressionbothasmonotherapyandasadjunctivetherapy(9–13).AlthoughthesestudieswerenotpositiveandSSRIsarecurrentlynotviewedasafirst-linetreatmentoptioninthetreatmentofbipolardepression,theymayplayaroleinpatientswhoareresistanttofirst-linetherapies(14).Inapreviouspaper,wedescribedtheresultsofaplacebo-controlledRCTexaminingtheefficacyandsafetyoftheadditionoflamotrigineduring8weeksinbipolarpatientswithabreak-throughdepressionduringtreatmentwithlithium(15).ChangeinMADRSscorescomparedwithbaselinewassignificantlygreateraftertheadditionoflamotriginetolithiumthanafterthe

76 Chapter 476

additionofplacebo.Responserate(definedasadecreaseofatleast50%oftheinitialMADRSscore)wasalsosignificantlygreaterwithlamotriginecomparedtoplacebo.Inthispaper,wedescribetheresultsoftwodifferenttreatmentalgorithms;treatmentwithlamotrigineaddedtolithiumduringthefirst8weeks(firstphase)followedbyfurtheradditionofparoxetineinnon-respondersduringweeks9–16(secondphase)vs.8weeksoftreatmentwithlithiumplusplacebo(firstphase)alsofollowedbyfurtheradditionofparoxetineinnon-responders(secondphase)duringweeks9–16.

Aims of the study Theaimofthisrandomizedcontrolledtrialwastocomparetheefficacy,safetyandtolerabilityoftwotreatmentalgorithmsinpatientssufferingfromabipolardepression.Patientsusinglithium(firststep)witharelapseorrecurrenceofabipolardepressionwererandomizedtotheadditionoflamotrigineorplacebo(secondstep),20mgparoxetinewassubsequentlyaddedtonon-respondersoftheformer2steps(thirdstep).

Material and methods

Study design Thisarticledescribesthecombinedresultsofboththefirstandsecondphaseofaninvestigatorinitiated(WN)study.Inthefirstphase,124patientswererecruitedin23out-patientcentersintheNetherlands(n=112)and3centersinSpain(n=12)between2002and2005(15).Duringthesecondphaseofthisstudyparoxetine20mgwasopenlabeladdedtonon-respondersatweek8.Lithium(openlabel)andlamotrigineorplacebo(double-blind)wascontinuedatthesamedose.ThestudywasapprovedbytheethicalreviewboardoftheUniversityMedicalCenterUtrecht,Utrecht,theNetherlandsandbylocalinstitutionalreviewboardsintheNetherlandsandinSpain.Allpatientssignedinformedconsentpriortothestartofanystudyprocedures.

Patients Patients(age18–65)wereeligibleforthisstudyiftheysufferedfrombipolardisorderwithamajordepressiveepisodeaccordingtoDSM-IVcriteriaconfirmedbytheMINIplus(16),ascoreof≥18ontheMADRS(6)andaClinicalGlobalImpressionforBipolarIllness(CGI-BP)(17)severityscoreof≥4(moderatelyill).Allpatientswereonlong-termtreatmentwithlithium,withalithiumplasmalevelbetween0.6and1.2mmforatleast2weeksbeforethestartofthestudy.Patientswithpsychoticfeatures,withasevererapidcyclingpattern(morethan10episodesintheprecedingyear)withseveresuicidality(scoreonitem10oftheMADRS≥5)orwithahistoryofalcoholorsubstanceabusewithin1monthpriortothestartofthestudyordependencewithin12months,wereexcluded.Nopatientshadneurologicalorothersomaticillnessesknowntoaffectmood.Femalepatientswerenotpregnant(negativepregnancytestpriortothestudy)andwererequiredtouseaneffectivecontraceptivemethod.Patientswerenotallowedtotakepsychotropicsotherthanstudymedications,exceptforbenzodiazepinesatamaximumof2mglorazepamequivalents⁄day.

Treatments Duringthefirstphaseofthestudy(week0–8)patients(n=124)receiveddouble-blindtreatmentwithlamotrigine(uptitratedto200mg⁄day)orplaceboaddedtoongoingtreatmentwithlithium(119patientshadplasmalevelsbetweenthepredefinedrangeof0.6–1.2mm;fivepatientsbetween0.53and0.6mm.Beforedeblindingitwasdecidedtoacceptthisminorprotocolviolation,thusincludingthesepatientsintheanalysis.Duringthesecondphase(week9–16)openlabelparoxetinewasaddedatafixeddoseof20mg⁄dayinnon-respondersatweek8(CGI-BPchangeof3ormore,i.e.minimallyimproved,unchangedorworsecomparedwithbaseline),whiledosagesoflithiumandlamotrigineorplacebo(stillgivendouble-blind)werekeptstablethroughoutthesecondphase.Respondersattheendofthefirstphasewerealsofollowedandmaintainedtheirsamedosagesoflithiumandlamotrigineorplacebo.

78 Chapter 478

Outcome measures Patientvisitswerescheduledatbaseline(week0)andfromthenonwardevery2weeks.MADRSscoresandtheCGI-BPSeverityofDepressionandManiascoreswereassessedateachvisit.TheprimaryoutcomeforthesecondstudyphasewaschangefrombaselineonthetotalMADRSscoreatweek16.SecondaryoutcomemeasuresweretotalMADRSscoreatweek16orendpoint,CGI-BPseverityofdepressionandofmaniaatweek16orendpointandresponse.ResponsewasdefinedasadecreaseontheMADRSof≥50%and⁄orGCI-BPchangeof1or2(verymuchormuchimproved)comparedwithbaseline.Anadditionaloutcomemeasurewasswitchto(hypo)mania,definedasascoreof≥3(mildlyill)ontheCGI-BPseverityofmaniascale.Posthocwealsoidentifiedpatientswhohadrespondedwithoutaswitchto(hypo)mania.Ateachvisitadverseeventswereassessedandifpresentratedaccordingtotheirseverityasmild,moderateorsevere.

Statistics Mixedmodelanovaforrepeatedmeasures(MMRM)wasprospectivelychosenasmethodofanalysisforMADRSscores.Theindependentvariablesinthisanalysiswere:time,treatmentandtheirinteraction.TimeascategoricalvariableallowedestimatingandtestingmeandifferencesinMADRSbetweenthetwotreatmentsatanyvisit,includingtheprimaryefficacymeasureforthisstudyphase:changefrombaselineatweek16.Forthispurpose,therelevantcontrastswerespecifiedinthemodelforwhichtheanovaproducedtheestimates,SEs,confidenceintervalsandappropriatet-testspervisit.Tomakeinferenceaboutanoveralltreatmenteffectoverallvisitsineitherphaseofthestudy,timewasconsideredanumerictrendvariableinamixedmodelthatallowedatrend-break(‘brokenstick’)atthetransitionfromthefirsttothesecondphase.Inthismodel,adifferenceintimetrendbetweenthetwotreatmentgroupsineitherphaseandchangesintimetrendbetweenthetwophasesineithertreatmentgroupwereestimatedandtested.OnthebasisofthismodelpredictedMADRSscoreswerecalculated(with95%confidenceintervals)andtestedbetweenthetwotreatmentgroupsatweek8(endofphaseI)andatweek16(endofphaseII).In

accordancewiththeintenttotreatprinciple,allrandomizedsubjectscontributedtotheseanalyzes,missingvaluesofMADRSscoresbeingproperlyadjustedforbytherestrictedmaximumlikelihoodestimationprocedureusedinthemixedmodelanova’s. ClinicalGlobalImpressionforBipolarIllnessseverityscoresweresimilarlyanalyzedusingmixedmodelanovawithtimeascategoricalvariable.Dichotomousoutcomescores(response,switchorpresenceofadverseeffects)werecomparedbetweenthetwotreatmentgroupsusingFisher’sexacttestandlastobservationcarriedforwardformissingdata.DifferencesinthedistributionofcategoricalnominalvariablesbetweenthetwotreatmentgroupsweretestedusingFisher’sexacttest,forcategoricalordinalvariablestheexactChi-squaretrendtestwasused.Foreachtestatwo-sidedP-valuebelow0.05wasconsideredtodenotestatisticalsignificance.

Results

Theflowchartofthestudyispresentedinfigure1.Duringthefirstphase64patientsreceivedadd-onlamotrigineand60patientsreceivedadd-onplacebo.Therewerenostatisticalsignificantdifferencesbetweenthetwogroupsinpatientscharacteristicsorillnessseverityatbaseline(15)(table1).Inthelamotriginegroup52patients(81.3%)completedthefirst8weeksofthestudy,37ofthemasrespondersand15asnon-responders.Afterthefirstphase,ninepatients(14.1%)droppedoutleaving43patientswhoagreedtoparticipateinthesecondphase;34respondersand9non-responders.Duringthesecondphaseanotherfourpatientsdroppedout.Intheplacebogroup50patients(83.3%)completedthefirst8weeks,28asrespondersand22asnon-responders.Sixpatients(10%)droppedout,leaving44patients(26respondersand18non-responders)whocontinuedthestudy.Duringthesecondphaseanothersixpatientsdroppedout.

80 Chapter 480

Figure 1. Flowchartofthestudy

Notmeetinginclusioncriteria:3Nottakenstudymedication:1

Responders:34 Responders:26

Assessed:128

Randomised:124

PlusLamotrigine:64

Completed:52

Non-responders:15Responders:37

Continued:34

Completed:31 Completed:8 Completed:14

Continued:26

Completed:24

Plusparoxetine:9 Plusparoxetine:18

Responders:28

PlusPlacebo:60

Completed:50

Non-responders:22

Drop-outs:10

Drop-outs:3

Lackofefficacy:1Withdrawnconsent:1Protocolviolation:1

Drop-outs:4

Drop-outs:12

Drop-outs:2

Lackofefficacy:1Adverseevents:1

Drop-outs:6

Noncompliance:1

Lackofefficacy:2Adverseevents:2

Table 1. Patientandillnesscharacteristics

MADRS=Montgomery-ÅsbergDespressionRatingScale,CGI-BP=ClinicalGlobalImpressionforBipolarIllnes,TCA=tricyclicantidepressant,SSRI=selectiveserotoninre-uptakeinhibitor,SNRI=serotonin-noradrenalinre-uptakeinhibitor,MAO=monoamineoxidaseinhibitor.

Lamotriginen=64

Placebon=60

Totaln=124 Statistic Value df P

Femalegender(n,%)

37 57.8 30 50 67 54.0 Fisher’s - - 0.471

Age(years)(mean,SD)

45.2 12.1 47.6 11.6 46.4 11.9 t-test 1.13 122 0.261

IlnesscharacteristicsBipolarIdisorder(n,%)

43 67.2 41 68.3 84 67.7 Fisher’s - - 1.000

Rapidcyclingcourse–last12months

12 18.8 4 6.7 16 12.9 Fisher’s - - 0.061

MADRS(mean,SD)

28.25 5.97 28.82 6.24 28.52 6.08 t-test 0.52 122 0.606

CGI-BPdepressionseverity(mean,SD)

4.56 0.64 4.53 0.57 4.55 0.60 ChiSq.trend

0.07 1 0.882

1.03 0.18 1.03 0.18 1.03 0.18 Fisher’s - - 1.000

Lithiumplasmalevelatbaseline(mEq)(mean,SD)

0.82 0.16 0.84 0.16 0.83 0.16 t-test 0.48 122 0.634

Previousothertreatmentsforindexdepressiveepisode(n,%)TCA 6 9.4 4 6.7 10 8.1 Fisher’s - - 0.745SSRI/SNRI 15 23,4 16 26.7 31 25.0 Fisher’s - - 0.836MAO-inhibitor 1 1.6 3 5.0 4 3.2 Fisher’s - - 0.353Antipsychotic,typical

4 6.3 3 5.0 7 5.6 Fisher’s - - 1.000

Antipsychotic,atypical

15 23.4 11 18.3 26 21.0 Fisher’s - - 0.317

Valproicacid 5 7.8 2 3.3 7 5.6 Fisher’s - - 0.247Carbamazepine 1 1.6 3 5.0 4 3.2 Fisher’s - - 0.285Benzodiazepine 44 68.8 35 58.3 79 63.7 Fisher’s - - 0.154Other 3 4.7 4 6.7 7 5.6 Fisher’s - - 0.464

82 Chapter 482

Efficacy Theefficacyresultsoverbothstudy-phasesfromamixedmodelanovawithtimeascategoricalvariablearepresentedintable2.After8weeks,thedifferencebetweenlithiumpluslamotriginevs.lithiumplusplacebointhechangeoftheMADRSscoresfrombaselinetoweek8wassignificant(15);15.37vs.11.16(P=0.029).After16weekstherewasnostatisticallysignificantdifferenceinchangeofMADRSscoresfrombaselinetoweek16betweenlithiumpluslamotrigine(plusparoxetineinnon-responders)vs.lithiumplusplacebo(plusparoxetineinnon-responders);17.91vs.15.40(P=0.253).ThedifferencebetweentotalMADRSscoreswasalsonolongersignificantatweek16:10.34vs.13.42(P=0.134)(fig2).The95%confidenceintervalofthemeandifference(lamotrigineminusplacebo)inMADRSscoreatweek16wasfrom7.13to0.97.

Table 2. EfficacyResult:severityscales

MADRS=Montgomery-ÅsbergDepressionRatingScale,CGI-BP=ClinicalGlobalImpressionforBipolarIllness.Boldvaluesindicatesignificantlevels<0.05

Lamotriginen=64

Placebon=60 Difference Statistic Value df P

ChangeinMADRSscorefrombaseline(primaryoutcomemeasure)(mean,SE)Week2 -5.30(0.87) -3.74(0.91) -1.56(1.26) t-test -1.23 121 0.220Week4 -9.22(1.25) -6.20(1.30) -3.02(1.81) t-test -1.67 110 0.098Week6 -12.84(1.35) -9.35(1.40) -3.49(1.95) t-test -1.79 104 0.076Week8 -15.37(1.32) -11.16(1.37) -4.22(1.90) t-test -2.22 104 0.029

Week10 -16.88(1.30) -12.14(1.34) -4.74(1.87) t-test -2.54 101 0.013

Week12 -15.68(1.51) -13.22(1.55) -2.46(2.16) t-test -1.14 90 0.258Week14 -17.04(1.39) -15.96(1.43) -1.08(1.99) t-test -0.54 90 0.588Week16 -17.91(1.53) -15.40(1.56) -2.51(2.19) t-test -1.15 83 0.253MADRSscoreateachvisit(mean,SE)Baseline 28.25(0.76) 28.82(0.79) -0.57(1.10) t-test -0.52 122 0.606Week8 12.88(1.23) 17.66(1.28) -4.78(1.78) t-test -2.69 104 0.008

Week16 10.34(1.42) 13.42(1.45) -3.08(2.03) t-test -1.52 76 0.134CGI-BPseverityofdepressionateachvisit(mean,SE)Baseline 4.56(0.08) 4.53(0.08) 0.03(0.11) t-test 0.27 122 0.789Week8 2.63(0.18) 3.08(0.19) -0.45(0.26) t-test -1,69 103 0.093Week16 2.20(0.18) 2.56(0.19) -0.36(0.26) t-test -1.38 82 0.171CGI-BPchangeofdepressionfrombaseline(mean,SE)Week8 2.34(0.17) 2.69(0.17) -0.35(0.24) t-test -1.45 96 0.151Week16 1.79(0.14) 2.15(0.14) -0.36(0.20) t-test -1.80 70 0.076CGI-BPseverityofmaniaateachvisit(mean,SE)Baseline 1.03(0.02) 1.03(0.02) 0.00(0.03) t-test -0.07 122 0.948Week8 1.15(0.06) 1.14(0.06) 0.01(0.08) t-test 0.11 64 0.914Week16 1.38(0.16) 1.30(0.16) 0.07(0.22) t-test 0.32 7 0.761

84 Chapter 484

Figure 2. SeverityofdepressionaccordingtothemeanMADRSscoreateachvisitforpatientsonplaceboandlamotrigine

Responserateswere68.8%(44outof64patients)tothelithium-lamotrigine-paroxetinealgorithm,and51.7%(31outof60)(P=0.066)tothelithium-placebo-paroxetinealgorithm,whiletheresponseratesamongcompletersofthestudywere87%(34outof39patients)and73%(27outof37patients)respectively(table3).Othersecondaryoutcomecriteria(allCGI-BPoutcomes)alsodidnotrevealsignificantdifferencesatweek16.

*** P<0.05**P<0.01 Additionofparoxetine

0 2 4 6 8 10 12 14 16

PlaceboLamotrigine

Table 3. Efficacyresults:responseandswitchto(hypo)maniaafter8and16weeks

MADRS=Montgomery-ÅsbergDepressionRatingScale;CGI-BP=ClinicalGlobalImpressionforBipolarIllness.Boldvaluesindicatesignificantlevels<0.05*1missing**CGI-BPseverityofmania≥3***ReductionMADRS≥50%and/orCGI-BPchangeofdepression≤2andCGI-BPseverityof

mania<3

Lamotrigine(n=64)

Placebo(n=60) Statistic P

8weeksResponse N % N %ReductionMADRS≥50% 33 (51.6) 19 (31.7) Fisher 0.030

CGI-BPchangeofdepression≤2 41 (64.1) 29 (49.2)* Fisher 0.105Eitherorboth 42 (65.6) 29 (49.2) Fisher 0.065Switchto(hypo)mania** 5 (7.8) 2 (3.3) Fisher 0.441Responseandnoswitchto(hypo)mania***

39 (60.9) 28 (46.7) Fisher 0.149

16weeksResponse N % N %ReductionMADRS≥50% 33 (51.6) 27 (45.0) Fisher 0.478CGI-BPchangeofdepression≤2 43 (67.2) 31 (51.7) Fisher 0.100Eitherorboth 44 (68.8) 31 (51.7) Fisher 0.066Switchto(hypo)mania** 8 (12.5) 5 (8.3) Fisher 0.562Responseandnoswitchto(hypo)mania***

38 (59.4) 29 (48.3) Fisher 0.280

86 Chapter 486

Intable4,theresultsofthepiecewiselinearmodelarepresented.TheestimateddownwardtrendsintimeoftheMADRSscorewhichweresignificantlydifferentbetweentreatmentgroupsinthefirstphase(P=0.009),becamesignificantlylesssteepinthesecondphase(P=0.015intheplacebogroupandP<0.0005inthelamotriginegroup).Inthesecondphase,thedownwardtrendswerenotsignificantlydifferentanymorebetweenthetreatmentgroups(P=0.19).TheMADRSscoresaspredictedbytheestimatedpiecewiselinearmodelinbothtreatmentgroupswassignificantlydifferent(P=0.009)atweek8(endofphase1)andnotsignificantlydifferent(P=0.22)anymoreatweek16(theendofphase2).

Table 4. PredictedMADRSscores(95%CI)atweeks8and16(righttwocolums)andtimetrend(SE)inMADRS-scoreper2weeks(leftfourcolums)accordingtoa‘brokenstick’modelwithatrendbreakatweek8.Theintercept(SE)equals28.23(0.54).

MADRS=Montgomery-ÅsbergDespressionRatingScale

Eightpatients(12.5%)inthelithium-lamotrigine-paroxetinegroupswitchedto(hypo)mania(fivepatients(7.8%)duringthefirst8weeksand3(4.7%)aftertheadditionofparoxetineinnonresponders).Six(9.4%)ofthesepatientshadalsoreachedtheresponsecriterionfordepression.Inthelithium-placebo-paroxetinegroupfivepatients(8.3%)switchedto(hypo)mania(2(3.3%)inthefirstphaseand3(5%)inthesecondphase).Twoofthem(3.3%)hadalsoreachedtheresponsecriterionfordepression(table3).

TimetrendinMADRSscoreper2weeks PredictedMADRSscore

Phase1:0-8weeks

Phase2:8-16weeks

Differencebetweenphases

P-value(testbetweenphases) Atweek8 Atweek16

Placebogroup -2.68(0.31) -1.39(0.31) 1.29(0.52) 0.015 17.5(15.1to19.9) 11.9(9.4to14.5)

Lamotriginegroup -3.81(0.30) -0.82(0.30) 2.99(0.51) <0.0005 13.0(10.7to15.3) 9.7(7.2to12.2)

Differencebetweengroups

-1.12(0.42) 0.57(0.43) –4.5(–7.8to–1.2) –2.2(–5.8to1.3)

P-value(testbetweengroups)

0.009 0.19 0.009 0.22

Safety

Overall16weeksofthestudy,therewere15seriousadverseevents(SAE)involvingeightpatientsinthelithium-lamotrigine-paroxetinegroup(onepatientexperiencedtwoSAEs)andfivepatientsinthelithium-placebo-paroxetinegroup(alsoonepatientwithtwoSAEs).ThefourSAEsoccurringduringthefirstphasehavebeenreportedbefore(15).Duringthesecondphasetherewere11SAEsinvolvingninepatients.Inthelithium-lamotrigine-paroxetinegrouptwopatients(noadditionofparoxetine)developedamanicepisode,onepatientattemptedsuicide(noadditionofparoxetine),onepatientreceivingparoxetineadditiondevelopedseveresuicidalideation,andonepatientwithhighbloodpressureinthefirstphasehadanatrialflutterinthesecondphase(noparoxetineaddition).Inthelithium-placebo-paroxetinegrouptwopatients(noparoxetineaddition)becameseverelydepressed,onepatienthadaninfectionoftheurinarytract(noparoxetineaddition),onepatientwiththeadditionofparoxetinewasadmittedtoapsychiatrichospital(reasonunknown)withco-occurringhyperthyroidism(secondphase).Allpatientsrecovered.Oftheadverseeventsonlytremorshowedadifferencebetweenthelithium-lamotrigine-paroxetineandthelithium-placebo-paroxetinegroup(23.4%vs.5%P=0.042)(table5).

88 Chapter 488

Table 5. Adverseeventsoccurringin≥5%ofpatientsinanygroup(linear-by-linearassociation,twosided)

Boldvaluesindicatesignificantlevels<0.05

Lamotrigine(n=64)

Placebo(n=60)

PN % N %Sexproblems 1 1.6 5 8.3 .106Pulmonaryproblems 4 6.3 0 0 .120Blurredvision 4 6.3 2 3.3 .746Hallucinations 4 6.3 0 0 .120Throatproblems 3 4.7 3 5.0 1.000Headache 32 50.0 18 30.0 .338Obstipation 7 10.9 1 1.7 .179Diarhea 4 6.3 2 3.3 .746Alopecia 4 6.3 1 1.7 .366Fatigue 13 20.3 12 20.0 1.000Nausea 20 31.3 11 18.3 .209Flu-likesymptoms 13 20.3 10 16.7 .728Insomnia 11 17.2 4 6.7 .105Tremor 15 23.4 3 5.0 .042

Skinproblems/mildrash 9 14.1 4 6.7 .426Dizziness 5 7.8 7 11.7 .590Abdominalpain 6 9.4 4 6.7 .493Rash 5 7.8 4 6.7 1.000Joint/musclepain 8 12.5 9 15.0 .843Backpain 6 9.4 5 8.3 1.000Coordinationproblems 4 6.3 0 0 .245Eyeproblems 5 7.8 0 0 .120Polyuria 1 1.6 3 5.0 .488Agitation 1 1.6 5 8.3 .169

Discussion

Althoughthetermtreatmentresistantishardlyoperationalized(18)inbipolardepression,inclinicalpractice‘break-throughdepressions’duringlong-termtreatmentincludinglithium,aremoretherulethantheexception.Thereisadiscrepancybetweenthehighproportionofpatientsreceivingpolypharmacy(byoneestimate80%ofpatientswithbipolardisorder)(19,20)andthescarcenessofresearchdataontheefficacyofpolypharmacy.Toourknowledge,thisisthefirststudyinbipolardisorderinwhichtwodifferenttreatmentalgorithmsconsistingofthreestepswerecompared.Patientswhodevelopedadepressiverelapseorrecurrence(break-throughdepression)duringlong-termlithiumtreatment(thefirststep)receivedadditionoflamotrigineorplaceboasasecondstep(firstphaseofthestudy)for8weeks.Inthethirdstep,non-respondersafterthesecondstepwereofferedfurtheradditionofparoxetineduringanother8weeks(secondphaseofthestudy).Attheendofthesecondstep(week8)therewasaclinicallyandstatisticallysignificantadvantageofchangeinMADRSscoresfrombaseline(theprimaryoutcomecriterion)andonseveralsecondaryoutcomesinfavoroftheadditionoflamotriginecomparedwiththeadditionofplacebo.However,bytheendofthethirdstep(week16)therewerenosignificantdifferencesbetweenthetwotreatmentalgorithmsonprimaryorsecondaryoutcomes.Wehavethreepossibleexplanationsfortheseresults.First,andinourviewmostlikely,theadditionofparoxetineinthethirdstepwasmorebeneficialtopatientsreceivingadditionofplacebointhesecondstepthanitwasforpatientswhohadreceivedadditionoflamotrigine,allowingtheformergroupto‘catchup’toatleastsomeextentwiththelattergroup.Whereasthelamotriginegrouphadplateauedalreadybyweek8–10,theplacebogrouphadmoreroomforimprovement.Inthelamotriginegroup,allpatientsstartedapotentiallyeffectiveadd-ontreatment(lamotrigine)frombaseline,whileintheplacebogroupthenonresponderstolithiumplusplacebostartedapotentiallyeffectiveadd-ontreatment(paroxetine)atweek8.Indeed,asub-analysisshowedagreatereffectofparoxetineinthenon-responderstoplacebothaninthenon-responderstolamotrigine(table4).Aninterestingfinding

90 Chapter 490

inthisrespectisalsothatthesignificancelevelbetweenlamotrigineandplacebowhichwaspresentatweek8,wasevengreateratweek10.Apparently,the‘catchup’effectofparoxetine(intheplacebogroup)occurredafterthefirst2weeksofitsaddition.ThemajorobjectionagainstthisexplanationisthatthereismoreevidenceagainstratherthaninfavoroftheefficacyofparoxetineorotherSSRIsinbipolardepression(9,12,13).Asecondpossibleexplanationfortheseresultsmaybethattheyareareflectionofthenaturalwaxingandwaningcourseofbipolardisorder.However,weconsiderthisasunlikelygiventherelativeshortperiod(week12–16)duringwhichthedifferenceexistingatweek8(andevenmorestronglyatweek10)receded,butithasbeenreportedthatplaceboresponsemayincreaseovertimeinbipolardisorder(21).Athirdpossibleexplanationcouldbethatanadd-onstudydesignreducesthepossibilitytoshowsignificantresults,andthisproblemmayevenincreasewithmultipleadd-onsteps(21).Wedoubthoweverthatthisistheexplanationasthesignificancelevelwasatitsmaximumatweek10,i.e.evenaftermostpatientswhodroppedoutafterthefirstphase,hadalreadyleftthestudy.Inadditiontotheongoingdebateconcerningtheefficacyofantidepressantsinbipolardepression(9,12,22,23),itisinterestingtofurtherhighlightthepossibleefficacyoftheadditionofparoxetineinnon-responderstolithiumplusplacebointhesecondphaseofthestudy.Itisremarkablethatthissuggestionforefficacyofparoxetinewasonlyfoundinpatientswhohadreceivedlithiumplusplacebo,andnotinthepatientswhohadalreadyreceivedlithiumpluslamotrigine.Weconsideritunlikelythatthisresponsetoparoxetinewasaplaceboeffectasallpatientshadalreadyreceivedplacebointhefirstphase.Perhapsparoxetineiseffectiveinpatientswithabreak-throughdepressionduringlong-termtreatmentwithlithium,butnotinpatientsalsoreceivingvariousotherdrugs,suchaslamotrigine(asshowninourstudy)ortreatmentsotherthanlithium,suchasvalproate,carbamazepine,atypicalantipsychoticsand⁄oradditionalpsychotherapy(asintheSTEP-BDadd-onstudyoftheefficacyofadd-ontreatmentwithantidepressantsincludingtheSSRIsertraline)(12)Tofindananswertothisquestion,onemightconsiderathree-armRCTcomparingtheadditionofbothlamotrigineandparoxetinewithplaceboinpatientswithabreak-throughdepressionduringtreatmentwithlithium.

Overallthetoleranceofthecombinationoflithiumwithlamotrigine(orplacebo)andsubsequentlyparoxetinewasverywell.Oftheoriginalsampleof124patients,76patients(61.3%)completedbothstudy-phases,whilesevenpatients(10.9%)inthelithium-lamotrigine-paroxetinegroupand5(8.3%)inthelithium-placebo-paroxetinegroupdroppedoutasaresultofadverseevents.Exceptforonepatientwhowaslosttofollow-up,allpatientswithSAEsrecovereduneventfully.RegardingSAEstherewasnostatisticaldifferencebetweenthelithium-lamotrigineparoxetinegroupandthelithium-placebo-paroxetinegroup.ItisdifficulttodiscernwhethersomeoftheSAEs(e.g.suicidalideation,mania)wereaneffectofthetreatmentorpartofthenaturalcourseoftheillness,butarelationshiptodrugtreatmentcannotberuledout.Onlytremorwasreportedmorefrequentlyinthelithium-lamotrigine-paroxetinegroupthaninthelithium-placebo-paroxetinegroup. Amajorlimitationofthestudywastheoverallrelativelylimitedsamplesize,andmorespecificallytherelativesmallnumberofpatientsmovingfromphase1tophase2.Withthesignificantdifferenceafterphase1butnotafterphase2,wecannotconcludethatthealgorithmwithlamotrigineisonlyeffectiveat8weeksandnotaftertheadditionofparoxetineat16weeks.Itremainspossiblethatwithalargersamplesize,thedifferencewouldalsohavebecamesignificantatweek16.Moreover,asaconsequenceofthedesignwithopenlabeladditionofparoxetine,thestudywasnotcapableofmeasuringtheindividualcontributionofparoxetineinthetreatmentofbipolardepressioninpatientsnotrespondingtolithiumpluslamotrigineorlithiumplusplacebo.Toevaluatetheefficacyofparoxetine,itwouldhavebeennecessarytocompareitwithplaceboandtore-randomizepatientsafterphase1.However,forsuchastudythesamplesizeofourtrialwasmuchtoosmall.Finally,thedurationofthisstudy,althoughlongbycurrentclinicaltrialstandards,doesnotprovidedatahowtocontinuefurthertreatmentinresponders.Thiswillbeaddressedinanotherpaperinwhichwewilldescribetheresultsofa1yearfollow-upinrespondersofbothphase1andphase2. Inconclusion,thepresentresultsshowsthatinpatientswithabreak-throughdepressionduringlong-termtreatmentwithlithium,theadditionof

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lamotrigineiseffective(firstphaseofthisstudy)whilefurtheradditionofparoxetineinnonresponderstolamotrigine(secondphase)doesnotappeartoprovidemuchextrabenefit.Ontheotherhand,thefindingfromthesecondphaseofanincreasedresponsetoparoxetineinnonresponderstotheadditionofplacebosupportsthenotionthattheadditionofparoxetine,andperhapsotherSSRIs,maybereasonablechoicesforthetreatmentofpatientswithabipolardepressiondespitetreatmentwithlithium.Clearlymorestudiesemployingdifferenttreatmentalgorithmsareneededtohelpdiscernthemostoptimalformsofpolypharmacyforbipolardisorder.

References

1. SpornJ,SachsG.Theanticonvulsantlamotrigineintreatment-resistantmanic-depressiveillness.JClinPsychopharmacol1997;17:185–189.

2. KusumakarV,YathamLN.Anopenstudyoflamotrigineinrefractorybipolardepression.PsychiatryRes1997;72:145–148.

3. CalabreseJR,FatemiSH,WoyshvilleMJ.Antidepressanteffectsoflamotrigineinrapidcyclingbipolardisorder.AmJPsychiatry1996;153:1236.

4. HamiltonM.Aratingscalefordepression.JNeurolNeurosurgPsychiatry1960;23:56–62.

5. CalabreseJR,BowdenCL,SachsGS,AscherJA,MonaghanE,RuddGD.Adouble-blindplacebo-controlledstudyoflamotriginemonotherapyinoutpatientswithbipolarIdepression.Lamictal602StudyGroup.JClinPsychiatry1999;60:79–88.

6. MontgomerySA,ÅsbergM.Anewdepressionscaledesignedtobesensitivetochange.BrJPsychiatry1979;134:382–389.

7. CalabreseJR,HuffmanRF,WhiteRLetal.Lamotrigineintheacutetreatmentofbipolardepression:resultsoffivedouble-blind,placebo-controlledclinicaltrials.BipolarDisord2008;10:323–333.

8. GeddesJ,HuffmanRF,PaskaW,EvoniukG,LeadbetterR.Lamotrigineforacutetreatmentofbipolardepression:additionalclinicaltrialdataandaretrospectivepooledanalysisofresponseratesacrossallrandomizedtrialsconductedbyGSK.BipolarDisord2007;8(Suppl.1):32.

9. NemeroffCB,EvansDL,GyulaiLetal.Double-blind,placebo-controlledcomparisonofimipramineandparoxetineinthetreatmentofbipolardepression.AmJPsychiatry2001;158:906–912.

10. SheltonRC,StahlSM.Risperidoneandparoxetinegivensinglyandincombinationforbipolardepression.JClinPsychiatry2004;65:1715–1719.

11. VietaE,Martinez-AranA,GoikoleaJMetal.Arandomizedtrialcomparingparoxetineandvenlafaxineinthetreatmentofbipolardepressedpatientstakingmoodstabilizers.JClinPsychiatry2002;63:508–512.

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12. SachsGS,NierenbergAA,CalabreseJRetal.Effectivenessofadjunctiveantidepressanttreatmentforbipolardepression.NEnglJMed2007;356:1711–1722.

13.McElroySL,ChangW,NordenhemA,PaulssonB,BrecherM,YoungAH.Adouble-blind,placebo-controlledstudywithacuteandcontinuationphaseofquetiapineinadultswithbipolardepression(emboldenII).27-1-2008.3rdbiennialconferenceoftheinternationalsocietyforbipolardisorders.Delhi,India27–28January2008.

14.GoodwinGM,AndersonI,ArangoCetal.ECNPconsensusmeeting.Bipolardepression.Nice,March2007.EurNeuropsychopharmacol2008;18:535–549.

15. vanderLoosML,MulderPG,HartongEGetal.Efficacyandsafetyoflamotrigineasadd-ontreatmenttolithiuminbipolardepression:amulticenter,double-blind,placebocontrolledtrial.JClinPsychiatry2009;70:223–231.

16. SheehanDV,LecrubierY,SheehanKHetal.TheMini-International NeuropsychiatricInterview(M.I.N.I.):thedevelopmentandvalidationofastructureddiagnosticpsychiatricinterviewforDSM-IVandICD-10.JClinPsychiatry1998;59(Suppl.20):22–33.

17. SpearingMK,PostRM,LeverichG,BrandtD,NolenWA.Modificationoftheclinicalglobalimpressions(CGI)scaleforuseinbipolarillness(BP):theCGI-BP.PsychiatryRes1997;73:159–171.

18. PacchiarottiI,MazzariniL,ColomFetal.Treatmentresistantbipolardepression:towardsanewdefinition.ActaPsychiatrScand2009;120:429–440.

19.GhaemiSN,HsuDJ,ThaseMEetal.Pharmacologicaltreatmentpatternsatstudyentryforthefirst500STEPBDparticipants.PsychiatrServ2006;57:660–665.

20. SimonNM,OttoMW,WeissRDetal.Pharmacotherapyforbipolardisorderandcomorbidconditions:baselinedatafromSTEP-BD.JClinPsychopharmacol2004;24:512–520.

21. VietaE,CarneX.Theuseofplaceboinclinicaltrialsonbipolardisorder:anewapproachforanolddebate.PsychotherPsychosom2005;74:10–16.

22.GijsmanHJ,GeddesJR,RendellJM,NolenWA,GoodwinGM.Antidepressantsforbipolardepression:asystematicreviewofrandomized,controlledtrials.AmJPsychiatry2004;161:1537–1547.

23. LichtRW,GijsmanH,NolenWA,AngstJ.Areantidepressantssafeinthetreatmentofbipolardepression?AcriticalevaluationoftheirpotentialrisktoinduceswitchintomaniaorcycleaccelerationActaPsychiatrScand2008;118:337–346.

MarcLMvanderLoosa,PaulMulderb,ErwinGThMHartongc,MarcBJBlomd,AntonCVergouwene,MartijnSvanNoordenf,ManuelaATimmermansg,EduardVietahandWillemANolenifortheLamLitStudyGroup*

aDepartmentofPsychiatry,IsalaKliniekenLocationSophia,Zwolle,bDepartmentofBiostatistics,ErasmusUniversityMedicalCenter,Rotterdam,cDepartmentofPsychiatry,Canisius-WilhelminaHospital,Nijmegen,dParnassiaPsychiatricInstitute,TheHague,eDepartmentofPsychiatry,SintLucasAndreasHospital,Amsterdam,fDepartmentofPsychiatry,LeidenUniversityMedicalCenter,Leiden,gPraktijkondersteuningZuidOostBrabant,Veldhoven,TheNetherlands,hBipolarDisordersProgram,CIBERSAMInstituteofNeuroscience,HospitalClinic,UniversityofBarcelona,IDIBAPS,Barcelona,Catalonia,Spain,iDepartmentofPsychiatry,UniversityMedicalCenterGroningen,UniversityofGroningen,Groningen,TheNetherlands

Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design

98 Chapter 598

Abstract

Objective:Intwopreviousmanuscripts,wedescribedtheefficacyoflamotrigineversusplaceboasadd-ontolithium(followedbytheadditionofparoxetineinnonresponders)intheshort-termtreatmentofbipolardepression.Inthispaperwedescribethelong-term(68weeks)outcomeofthatstudy. Methods:Atotalof124bipolardepressedpatientsreceivinglithiumwererandomizedtoadditionoflamotrigineorplacebo.Aftereightweeks,paroxetinewasaddedtononrespondersforanothereightweeks.Responderscontinuedmedicationandwerefollowedforupto68weeksoruntilarelapseorrecurrenceofadepressiveormanicepisode. Results:Aftereightweeks,theadditionoflamotriginetolithiumwassignificantlymoreefficaciousthanadditionofplacebo,whileafteradditionofparoxetineinnonrespondersbothgroupsfurtherimprovedwithnosignificantdifferencebetweengroupsatweek16.Duringfollow-uptheefficacyoflamotriginewasmaintained:timetorelapseorrecurrencewaslongerforthelamotriginegroup(mediantime10.0months(confidenceinterval:1.1–18.8)versustheplacebogroup3.5months(confidenceinterval:0.7–7.0)). Conclusion:Inpatientswithbipolardepression,despitecontinueduseoflithium,additionoflamotriginerevealedacontinuedbenefitcomparedtoplacebothroughouttheentirestudy.

Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design 99

Introduction

Bipolardisordersarecharacterizedbyrecurrentmoodepisodes.While98%ofpatientsachievesyndromaticrecoveryfromanacutemanicordepressiveepisodewithintwoyears(1),80–90%ofpatientssufferfromnewepisodesthereafter(1–3).Despitetheuseofmoodstabilizerssuchaslithiumorvalproate,especiallydepressiveepisodesanddayswithdepressivesymptomsarefrequentandmayprovedifficulttotreat(2,4,5).Lithiumandperhapstoalesserextentvalproatehavesomebutlimitedefficacyinthetreatmentandpreventionofdepressiveepisodes(6–8).Thereisacontroversyregardingtheuseofantidepressants,bothinthetreatmentofacutedepressiveepisodes(9,10)aswellasinlong-termtreatmentofbipolardisorder(11–13).Oftheatypicalantipsychotics,onlyquetiapine(14–17)andolanzapine(especiallyincombinationwithfluoxetine)(18)demonstratedefficacyinacutebipolardepression.Moreover,olanzapine(19)andquetiapine(asadd-ontolithiumorvalproate)(20,21)werefoundeffectiveinthepreventionofdepressiverecurrences. Anothertreatmentoptionforbipolardepressionislamotrigine.Theresultsfromtheacutestudiesinbipolardepressionarecontradictory.Thefirstrandomized,controlledtrial(RCT)foundasignificantdifferencebetweenlamotrigineandplaceboinfavouroflamotrigine,althoughonlyonsecondaryoutcomemeasures(22).FouradditionalRCTsthereafterfoundnodifferencebetweenlamotriginemonotherapyandplacebo,probablybecauseofahighplaceboresponseinthesestudies(23,24).Nevertheless,inameta-analysisofallfivestudies,lamotriginewasmoreeffectivethanplacebo(25).Inaddition,lamotriginehasbeencomparedwithplaceboandlithiuminlong-termtreatmentofbipolardisorder. Intwostudies(26,27)lamotriginewasfoundeffectiveinpreventingdepressiverecurrences,whilelithiumwaseffectiveinpreventingmanicrecurrences. Intwopreviouspapers,wedescribedtheshort-termresultsofaplacebo-controlledRCTinvestigatingtheeffectsoftheadditionoflamotriginetolithium

100 Chapter 5100

inpatientswithbipolardepressiondespitelong-termtreatmentwithlithium.Inthefirstphaseofthatstudy(weeks1–8),lamotriginewasfoundtobemoreeffectivethanplacebo(28);inthesecondphase(weeks9–16),furtheradditionofparoxetineinnonresponderstoeitherlamotrigineorplacebo(pluslithium)wasassociatedwithfurtherimprovementinbothgroups,whilethedifferencebetweenlamotrigineandplacebowasnolongersignificantatweek16(29).Inthispaper,wedescribetheresultsofthelong-termoutcomeofthatstudy.

Methods

Study design Inthispaper,wedescribethefollow-upofaninvestigator(WAN)-initiated,randomized,double-blind,placebo-controlledtrialwiththreephases.Thedesignofthestudyisshowninfigure1andhasbeendescribedindetailelsewhere(28,29). Duringthefirsteightweeksofthestudy(phase1),124patientswithabipolarIorIIdisorderandadepressiveepisodewith≥18pointsontheMontgomery-ÅsbergDepressionRatingScale(MADRS)(30)despitelong-termtreatmentwithlithiumreceivedlamotrigineorplaceboinadditiontoongoingtreatmentwithlithium(28).Non-responders(n=37)totheadditionofeitherlamotrigineorplaceboatweek8wereofferedtheopportunitytoreceivefurtheradditionofparoxetine(openlabel)incombinationwithongoinglithiumpluslamotrigineorplaceboduringweeks9–16(phase2)(29). Respondersat8or16weekswerefolloweduntilmaximallyweek68(phase3)oruntiltheyreachedtheprimaryendpoint(adepressiveormanicrelapseorrecurrence).Themedicationregime(lithium,double-blindlamotrigineorplacebo,andinsomepatientsparoxetineaswell)waskeptstableduringtheentirefollow-up.Patientswholeftthestudywithoutarelapseorrecurrencewereconsidereddropouts;reasonsfordropoutwererecorded. ThestudywasapprovedbytheethicalreviewboardoftheUniversityMedicalCenterUtrecht,TheNetherlands,andbylocalinstitutionalreviewboardsinbothcountries.Allpatientsgavewritteninformedconsentpriortoinitiationofanystudyprocedure.

Figure 1. Designofthestudy

Treatments Allpatientswerealreadyreceivinglithium,whichwasmaintainedataplasmalevelof0.6–1.2mmol⁄Lthroughoutthestudy.Duringphase1,lamotrigine(orplaceboinidenticaltablets)wasup-titratedto200mg⁄dayatweek6andmaintainedatthisdosethroughoutthestudy.Innonresponders,atweek8paroxetinewasstartedat20mg⁄dayandalsomaintainedatthisdosethroughoutthestudy.Inadditiontothestudymedication(lithium,lamotrigineorplacebo,andparoxetine)patientswerenotallowedtotakeotherpsychotropicdrugs,withtheexceptionofbenzodiazepinesatamaximumof2mglorazepamequivalents⁄day.

Assessments and outcome measures Afterbaseline,patientswereseeneverytwoweeksuntiltheendofphase2(week16).Duringfollowup(phase3),patientswereassessedatweek20andthereaftereverytwomonths.Duringallvisits,patientswerescoredontheMADRSandtheClinicalGlobalImpression–Bipolarversion(CGIBP)(31);adverseevents

Lithium+Lamotrigine+Paroxetineinnon-reponders

Lithium

+Lamotrigine

+Placebo

Phase 1 Phase 2 Follow-up of respondersPhase 3

Lithium+Placebo+Paroxetineinnon-responders

Week 0 8 16 68

Responders

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andstudymedicationcompliancewerealsoassessed.Lithiumplasmalevelsweremeasuredeveryfourmonths. Responseduringphase1and2leadingtofollow-upwasdefinedasascoreof1or2(verymuchormuchimproved)accordingtotheCGI-BPimprovementofdepressionscale.Outcomeofthestudywastherelapseorrecurrenceofamanicordepressiveepisodedefinedasascore≥4(atleastmoderatesymptoms)ontheCGI-BPseverityofdepressionormaniascale.Inaddition,itwasinvestigatedhowlongtheMADRSscorewasmaintainedat<50%ofitsbaselinevalueafterpatientsreachedthislevelforthefirsttimeduringphase1or2.

Statistics Allanalysesconcerningefficacyduringfollow-up(phase3)havetobeconsideredinadescriptivesensewithoutstatisticaltesting.Thisisbecausethegroupsenteringfollow-upwereselectedbythetreatment-dependentoutcome(very)muchimprovementofdepressionontheCGI-BPandconsequentlyhadbecomeformallyincomparableatthisstage. Theevolutionofnosymptomsoronlymildsymptoms(bothCGI-BPmaniaanddepressionseverityscore<4)duringthewholestudywasdescribedbycalculatingpercentageswithnooronlymildsymptomsoftheoriginalgroupsizesateachvisit.Inaddition,thesustainabilityofaMADRSscore<50%ofbaselineafterthefirstattainmentofthislevelwascomparedbetweenthetwotreatmentgroupsusingaKaplan–Meiersurvivalanalysis. Thefrequenciesofthevarioustypesofadverseeventsoccurringinmorethan5%ofthepatientsduringthecontinuationphasewerecomparedbetweenthetwotreatmentgroupsusingachi-squaretrendtest.

Results

Patientcharacteristicsatbaselinearepresentedintable1.Treatmentgroupswerebalancedatbaseline,consideringtheuniformdistributionofp-valuesovertheinterval(0.1).Theflowchartofthestudy,includingreasonsfordroppingoutduringthethreephases,ispresentedinfigure2.

Table 1. Patientandillnesscharacteristicsatstudyentry

Lamotrigine(n=64)

Placebo(n=60)

Total(n=124) Statistic Value df P-value

Femalegender(n,%) 37 57.8 30 50 67 54.0 Fisher’s - - 0.471

Age(years)(mean,SD) 45.2 12.1 47.6 11.6 46.4 11.9 t-test 1.13 122 0.261

Ilnesscharacteristics

BipolarIdisorder(n,%) 43 67.2 41 68.3 84 67.7 Fisher’s - - 1.000

Rapidcyclingcourse–last12months

12 18.8 4 6.7 16 12.9 Fisher’s - - 0.061

MADRS(mean,SD) 28.25 5.97 28.82 6.24 28.52 6.08 t-test 0.52 122 0.606

CGI-BPdepressionseverity(mean,SD)

4.56 0.64 4.53 0.57 4.55 0.60 ChiSq.trend

0.07 1 0.882

1.03 0.18 1.03 0.18 1.03 0.18 Fisher’s - - 1.000

Lithiumplasmalevelatbaseline(mEq)(mean,SD)

0.82 0.16 0.84 0.16 0.83 0.16 t-test 0.48 122 0.634

Previousothertreatmentsforindexdepressiveepisode(n,%)

TCA 6 9.4 4 6.7 10 8.1 Fisher’s - - 0.745

SSRI/SNRI 15 23,4 16 26.7 31 25.0 Fisher’s - - 0.836

MAO-inhibitor 1 1.6 3 5.0 4 3.2 Fisher’s - - 0.353

Antipsychotic,typical 4 6.3 3 5.0 7 5.6 Fisher’s - - 1.000

Antipsychotic,atypical 15 23.4 11 18.3 26 21.0 Fisher’s - - 0.317

Valproicacid 5 7.8 2 3.3 7 5.6 Fisher’s - - 0.247

Carbamazepine 1 1.6 3 5.0 4 3.2 Fisher’s - - 0.285

Benzodiazepine 44 68.8 35 58.3 79 63.7 Fisher’s - - 0.154

Other 3 4.7 4 6.7 7 5.6 Fisher’s - - 0.464

MADRS=Montgomery-ÅsbergDespressionRatingScale,CGI-BP=ClinicalGlobalImpressionforBipolarIllnes,TCA=tricyclicantidepressant,SSRI=selectiveserotoninre-uptakeinhibitor,SNRI=serotonin-noradrenalinre-uptakeinhibitor,MAO=monoamineoxidaseinhibitor.

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Randomized:124

Pluslamotrigine:64 Plusplacebo:60

Completed:52 Completed:50

Drop-outs:10Drop-outs:12

Nonresponders:15 Nonresponders:22Responders:37 Responders:28

Drop-outs:6

Drop-out:1

Drop-out:3

Drop-outs:3 Drop-outs:2

Drop-outs:2

Drop-out:1

Drop-outs:4

Drop-outs:2

Plusparoxetine:9 Plusparoxetine:18Continued:34 Continued:26

Completed:8

Responders:5 Responders:8Remainedresponders:29

Remainedresponders:20

Startfollow-up:30 Startfollow-up:25Phase3

Figure 2. Flowchartofthestudy

Inphase1,atotalof124patientswererandomizedtolamotrigine(n=64)orplacebo(n=60);102completedthisphase.Aftereightweeks,thedifferenceinchangeofMADRSscore(theprimaryoutcomecriterionduringphase1)wassignificant(15.37versus11.16,respectivelyp=0.029)(28).

Inphase2,nonresponderstolamotrigine(n=9)orplacebo(n=18)receivedadditionofparoxetine(phase2).Attheendofphase2,bothgroupswerefurtherimproved,whilethedifferencebetweengroupsinchangeofMADRSscorewasnolongersignificant(17.91forthelithium–lamotrigine–paroxetinealgorithmversus15.40(p=0.253)forthelithium–placebo–paroxetinealgorithm)(29).

Lithiumplasmalevelsweremeasuredatbaselineandatweeks8,16,32,48,and64.Theoverallvariationinmeanplasmalevelswas0.73–0.82mmol⁄Lforthelamotriginegroupversus0.72–0.83mmol⁄Lfortheplacebogroup.

Long-term efficacy Responders,accordingtotheCGI-BP,duringeitherphase1orphase2wereeligibleforfollowup.Ateachvisitduringfollow-up,thenumberofpatientswhomaintainedresponderstatus(CGIBPseverityofdepressionormaniascore<4)wascalculatedaspercentageofthegroupwhostartedwitheitherlamotrigineorplaceboinphase1.Thesepercentagesmaintainedhigherlevelsinthelamotriginegroupthanintheplacebogroupthroughoutthestudy(fig3).Noformalstatisticaltestwasdoneherebecauseoftheselectedgroupforfollow-up(seeMethods).Thedropinpercentagebetweenweeks16and20iscausedbythetreatment-dependentselectionofpatientsenteringfollow-up. WealsocalculatedtimetofirstrelapseorrecurrencebasedontheMADRSscoreafterhavingachievedresponderstatusaccordingtotheMADRS(i.e.,<50%ofbaseline)forthefirsttimeduringphase1orphase2.Inthisanalysis,patientswholeftthestudyforanyreasonwerecensored. Thetimetorelapseorrecurrencewaslongerforthelamotriginegroupthanfortheplacebogroup:mediantime10.0months(95%confidenceinterval(CI):1.1–18.8)versus3.5months(95%CI:0.7–7.0),respectively(seefig4).Noformalstatisticaltestwasperformed. Attheendofthestudy(68weeks),18patients(28.1%)fromthelamotriginegroupwerestillinthestudyversus14patientsfromtheplacebogroup(23.3%).

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Figure 3. Responders(ClinicalGlobalImpression–Bipolarversionimprovementofdepressionscoreof1or2)aspercentageoftheinitialgroup(n=124;lamotriginen=64,placebon=60)throughoutallthreephasesofthestudy.

PlaceboLamotrigine

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

Figure 4. Probabilityofmaintainingresponse(score<50%ofMontgomery-ÅsbergDepressionRatingScale(MADRS)scoreatbaseline)withoutrecurrence(score≥50%ofinitialMADRS)afterhavingachievedresponderstatusforthefirsttimeduringphase1orphase2.Mediantimetorelapseorrecurrenceforthelamotriginegroupwas10.0months(95%confidenceinterval:1.1–18.8)versus3.5months(95%confidenceinterval:0.7–7.0)fortheplacebogroup.

Safety

Occurrenceofsevereadverseevents(SAEs)andanyadverseevents(AEs)duringthefirst16weeksofthisstudyweredescribedindetailpreviously(28,29).Duringfollow-up,5SAEswereobserved:2inthelamotriginegroup(1patientdevelopedanatrialflutterand1hadhighbloodpressure),and3intheplacebogroup(2patientshadaseveredepressiverecurrenceand1anurinarytractinfection).NoneoftheSAEswereconsideredtoberelatedtostudymedicationandallpatientsrecovered.TheAEsoccurringinmorethan5%ofanygrouparelistedintable2.Therewasnodifferencebetweenlamotrigineandplacebointhepreva-lenceofanyAE.ThetotalamountofAEsinbothgroupswasremarkablylowfora68-weekfollow-up.

Months

PlaceboLamotrigine

0 3 6 9 12 15 18

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Fivepatientsinthelamotriginegroupand8patientsintheplacebogroupdevelopeda(hypo)manicepisodeduringfollow-up.

Table 2. Adverseeventsoccuringin≥5%ofpatientsinanygroup(linear-by-linearassociation,two-sided)

Discussion

Inthispaper,wedescribethelong-termfollow-upofanRCTconsistingofthreephases.Withthisquitenoveldesignwewereabletocomparetwodifferenttreatmentalgorithms,onewithlamotrigineaddedtolithiumandonewithplaceboaddedtolithium(phase1),bothfollowedbyadditionofparoxetineinnonresponders(phase2)andasubsequentfollow-upinrespondersafterphase1or2(phase3).Wefoundthatthealgorithmwithlamotrigineadditionwasnotonlymoreeffectivethanthealgorithmwithplaceboadditionintheacutetreatmentofbipolardepressionbutalsoappearedtoretainitsefficacythroughouttheentirestudy.Thepercentageofrespondersaswellasthetimetorelapseafter

Lamotrigine(n=30)

Placebo(n=25)

PN % N %Pulmonaryproblems 3 10.0 0 0 .242Blurredvision 2 6.7 0 0 .495Hallucinations 2 6.7 0 0 .495Throatproblems 3 10.0 2 8.0 .383Joint/musclepain 2 6.7 3 12.0 .1000Headache 3 10.0 2 8.0 .383Nausea 4 13.3 1 4.0 .301Flu-likesymptoms 3 10.0 1 4.0 .492Insomnia 3 10.0 2 8.0 .745Abdominalpain 3 10.0 0 0 .242Hypertension 2 6.7 0 0 .495Backpain 1 3.3 2 8.0 .585Coordinationproblems 2 6.7 0 0 .495Eyeproblems 2 6.7 0 0 .495

initialresponsewasfavourableforthelamotriginegroupversustheplacebogroup. Inouropinion,thedesignofourstudyhasseveraladvantagesanddisadvantages.Thefirstadvantageisthattheadd-ondesigncloselyresemblesreallife,inwhichmanybipolardisorderpatientsreceivemultiplemedicationsratherthanmonotherapy(32–34).InadditiontotheusualdesignofanRCTcomparinglamotrigineorplaceboaddedtolithium,wealsocouldprovidedataontheadditionofathirddrug(paroxetine)tolithiumandlamotrigine(orplacebo)andonthelong-termfollow-up.Thus,ourstudyprovidesusefulinformationontheefficacyandsafetyofadjunctivelamotriginecomparedtoplacebointheacuteaswellasthelong-termtreatmentofbipolardepression. Asecondadvantageisthatnonrespondersafterphase1couldreceiveactivemedication(paroxetine)inphase2,thusincreasingthefeasibilityofthestudy.Wehypothesizethatitmayalsopartlyexplaintherelativelowdropoutrateinourstudy(only38%duringthefirsttwophasesand74%overtheentirestudyof68weeks),whichismuchlowerthaninthetwopreviouslong-termtrialswithlamotrigine(26,27).Inthesestudies,98%and85%ofthosewhowererandomizedtolamotrigineorplacebo,respectively,weredropoutsafter68weeks. Themaindisadvantageofthisdesignisthattheselectionofnonrespondersforreceivingparoxetineafterphase1andtheselectionofrespondersafterphase1and2forcontinuationofthestudyledtoanunequalnumberofpatientsleavingthestudyatthesedecisionpoints.Thiseventuallyhamperedpossibilitiesforananalysiswithstatisticaltestingoftheresultsofphase3. Themainlimitationofourstudyistherelativelysmallsamplesize.Thiswasalreadyaproblemintheanalysisofphase1,inwhich124patientsparticipatedwhilethestudywasoriginallyplannedtorecruit220patients,anditdefinitelyhamperedstatisticalanalysisafterphase2.Thus,ourfindingsmustbeinterpretedwithsomecaution. Nevertheless,weconcludethatlamotriginewasmoreeffectivethanplaceboasadd-ontreatmenttolithiuminpatientswithbreakthroughbipolar

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depressionandwaswelltoleratedincombinationwithlithium.Moreover,lamotriginecouldsafelybecombinednotonlywithlithiumbutalsowithparoxetineandappearedtoretainitsefficacyandgoodtolerabilitythroughoutfollow-up.

References

1. TohenM,ZarateCAJr,HennenJetal.TheMcLean-HarvardFirst-EpisodeManiaStudy:predictionofrecoveryandfirstrecurrence.AmJPsychiatry2003;160:2099–2107.

2. KupkaRW,LuckenbaughDA,PostRMetal.Comparisonofrapid-cyclingandnon-rapid-cyclingbipolardisorderbasedonprospectivemoodratingsin539outpatients.AmJPsychiatry2005;162:1273–1280.

3. GoodwinFK,JamisonKR.Courseandoutcome.In:ManicDepressiveIllness;BipolarDisordersandRecurrentDepression,2ndedn.NewYork:OxfordUniversityPress,2007:119–154.

4. JuddLL,AkiskalHS,SchettlerPJetal.Thelong-termnaturalhistoryoftheweeklysymptomaticstatusofbipolarIdisorder.ArchGenPsychiatry2002;59:530–537.

5. JuddLL,AkiskalHS,SchettlerPJetal.Aprospectiveinvestigationofthenaturalhistoryofthelong-termweeklysymptomaticstatusofbipolarIIdisorder.ArchGenPsychiatry2003;60:261–269.

6. GeddesJR,BurgessS,HawtonK,JamisonK,GoodwinGM.Long-termlithiumtherapyforbipolardisorder:systematicreviewandmeta-analysisofrandomizedcon-trolledtrials.AmJPsychiatry2004;161:217–222.

7. BowdenCL,CalabreseJR,McElroySLetal.Arandomized,placebo-controlled12-monthtrialofdivalproexandlithiumintreatmentofoutpatientswithbipolarIdisorder.DivalproexMaintenanceStudyGroup.ArchGenPsychiatry2000;57:481–489.

8. GeddesJR,GoodwinGM,RendellJetal.LithiumplusvalproatecombinationtherapyversusmonotherapyforrelapsepreventioninbipolarIdisorder(BALANCE):arandomisedopen-labeltrial.Lancet2010;375:385–395.

9. GijsmanHJ,GeddesJR,RendellJM,NolenWA,GoodwinGM.Antidepressantsforbipolardepression:asystematicreviewofrandomized,controlledtrials.AmJPsychiatry2004;161:1537–1547.

10. SachsGS,NierenbergAA,CalabreseJRetal.Effectivenessofadjunctiveantidepressanttreatmentforbipolardepression.NEnglJMed2007;356:1711–1722.

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11. LichtRW,GijsmanH,NolenWA,AngstJ.Areantidepressantssafeinthetreatmentofbipolardepression?Acriticalevaluationoftheirpotentialrisktoinduceswitchintomaniaorcycleacceleration.ActaPsychiatrScand2008;118:337–346.

12.GhaemiSN,WingoAP,FilkowskiMA,BaldessariniRJ.Long-termantidepressanttreatmentinbipolardisorder:meta-analysesofbenefitsandrisks.ActaPsychiatrScand2008;118:347–356.

13. VietaE.Antidepressantsinbipolardepression.ActaPsychiatrScand2008;118:335–336.

14.CalabreseJR,KeckPEJr,MacfaddenWetal.Arandomized,double-blind,placebo-controlledtrialofquetiapineinthetreatmentofbipolarIorIIdepression.AmJPsychiatry2005;162:1351–1360.

15. ThaseME,MacfaddenW,WeislerRHetal.EfficacyofquetiapinemonotherapyinbipolarIandIIdepression:adouble-blind,placebo-controlledstudy(theBOLDERIIstudy).JClinPsychopharmacol2006;26:600–609.

16. YoungAH,McElroySL,BauerMetal.Adouble-blind,placebo-controlledstudyofquetiapineandlithiummonotherapyinadultsintheacutephaseofbipolardepression(EMBOLDENI).JClinPsychiatry2010;71:150–162.

17.McElroySL,WeislerRH,ChangWetal.Adouble-blind,placebo-controlledstudyofquetiapineandparoxetineasmonotherapyinadultswithbipolardepression(EMBOLDENII).JClinPsychiatry2010;71:163–174.

18. TohenM,VietaE,CalabreseJetal.Efficacyofolanzapineandolanzapine-fluoxetinecombinationinthetreatmentofbipolarIdepression.ArchGenPsychiatry2003;60:1079–1088.

19. TohenM,CalabreseJR,SachsGSetal.Randomized,placebo-controlledtrialofolanzapineasmaintenancetherapyinpatientswithbipolarIdisorderrespondingtoacutetreatmentwitholanzapine.AmJPsychiatry2006;163:247–256.

20. SuppesT,VietaE,LiuS,BrecherM,PaulssonB.MaintenancetreatmentforpatientswithbipolarIdisorder:resultsfromaNorthAmericanstudyofquetiapineincombinationwithlithiumordivalproex(Trial127).AmJPsychiatry2009;166:476–488.

21. VietaE,SuppesT,EggensI,PerssonI,PaulssonB,BrecherM.Efficacyandsafetyofquetiapineincombina-tionwithlithiumordivalproexformaintenanceofpatientswithbipolarIdisorder(InternationalTrial126).JAffectDisord2008;109:251–263.

22.CalabreseJR,BowdenCL,SachsGS,AscherJA,MonaghanE,RuddGD.Adouble-blindplacebo-controlledstudyoflamotriginemonotherapyinoutpatientswithbipolarIdepression.Lamictal602StudyGroup.JClinPsychiatry1999;60:79–88.

23.CalabreseJR,HuffmanRF,WhiteRLetal.Lamotrigineintheacutetreatmentofbipolardepression:resultsoffivedouble-blind,placebo-controlledclinicaltrials.BipolarDisord2008;10:323–333.

24.GeddesJ,HuffmanR,PaskaW,EvoniukG,LeadbetterR.Lamotrigineforacutetreatmentofbipolardepression:additionalclinicaltrialdataandaretrospectivepooledanalysisofresponseratesacrossallrandomizedtrialsconductedbyGSK.BipolarDisord2006;8(Suppl.1):32.

25.GeddesJR,CalabreseJR,GoodwinGM.Lamotriginefortreatmentofbipolardepression:independentmeta-analysisandmeta-regressionofindividualpatientdatafromfiverandomisedtrials.BrJPsychiatry2009;194:4–9.

26. BowdenCL,CalabreseJR,SachsGetal.Aplacebo-controlled18-monthtrialoflamotrigineandlithiummaintenancetreatmentinrecentlymanicorhypomanicpatientswithbipolarIdisorder.ArchGenPsychiatry2003;60:392–400.

27.CalabreseJR,BowdenCL,SachsGetal.Aplacebo-controlled18-monthtrialoflamotrigineandlithiummaintenancetreatmentinrecentlydepressedpatientswithbipolarIdisorder.JClinPsychiatry2003;64:1013–1024.

28. vanderLoosML,MulderPG,HartongEGetal.Efficacyandsafetyoflamotrigineasadd-ontreatmenttolithiuminbipolardepression:amulticenter,double-blind,placebo-controlledtrial.JClinPsychiatry2009;70:223–231.

29. vanderLoosML,MulderP,HartongEGetal.Efficacyandsafetyoftwotreatmentalgorithmsinbipolardepressionconsistingofacombinationoflithium,lamotrigineorplaceboandparoxetine.ActaPsychiatrScand2010;122:246–254.

30.MontgomerySA,ÅsbergM.Anewdepressionscaledesignedtobesensitivetochange.BrJPsychiatry1979;134:382–389.

31. SpearingMK,PostRM,LeverichG,BrandtD,NolenWA.Modificationoftheclinicalglobalimpressions(CGI)scaleforuseinbipolarillness(BP):theCGI-BP.PsychiatryRes1997;73:159–171.

32.GhaemiSN,HsuDJ,ThaseMEetal.Pharmacologicaltreatmentpatternsatstudyentryforthefirst500STEP-BDparticipants.PsychiatrServ2006;57:660–665.

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33. SimonNM,OttoMW,WeissRDetal.Pharmacotherapyforbipolardisorderandcomorbidconditions:baselinedatafromSTEP-BD.JClinPsychopharmacol2004;24:512–520.

34.GoldbergJF,BrooksJOIII,KuritaKetal.Depressiveillnessburdenassociatedwithcomplexpolypharmacyinpatientswithbipolardisorder:findingsfromtheSTEP-BD.JClinPsychiatry2009;70:155–162.

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Discussion

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Introduction

Bipolardisorderisacommonanddebilitatingdisorderwithalifetimeprevalenceofaround2%(1)Althoughthereisconvincingevidencethatpatientsaremoreoftenandlongerdepressedthanmanic(2-4),therewasuntilrecentlynoapproveddrugforthetreatmentofbipolardepression.Currentlyonlyquetiapine(bothinEuropeendeUS)andthecombinationofolanzapinewithfluoxetine(intheUS)havebeenapprovedfortheacutetreatmentofbipolardepression,whilelamotrigine(bothinEuropeandintheUS)hasbeenapprovedforlong-termtreatment,specificallytopreventdepressiveepisodes. Theunderpinningofexistingguidelines,whichalsoadvocatesothertreatmentsincludingantidepressants,isconfinedduetothefactthatresearchinthisfieldislimited.Aslongasthehigheststandardofevidenceinresearch,i.e.randomizedplacebo-controlledtrials,dependsmostlyonfundingfrompharmaceuticalcompaniesandtherewas,withafewexceptions(seeabove),notmuchinterestamongthesecompaniestoapplyforaspecificindication‘bipolardepression’,thefutureofnewrandomizedcontrolledtrialsinbipolardepressionisbleak(5).Inadditiontotheadd-ontrialwithlamotrigineaspresentedinthisthesisandtheotherlamotriginemonotherapytrials,onlyafewothertreatmentshavebeeninvestigatedindouble-blind,randomizedtrialswithsometimesseveremethodologicalproblems.

Antidepressants

Noneofthemorethan20availableantidepressantshasspecificallybeenstudiedanddevelopedbypharmaceuticalcompaniesfortheindication‘bipolardepression’.Asaresult,thereisanalmostcompletelackof(large)randomizedplacebo-controlledtrialsontheefficacyofantidepressantsasmonotherapyinbipolardepression(6;7).Nextwewillbrieflyreviewavailableevidencefromtherandomizedplacebo-controlledtrials. In1980Mendlewiczetal.comparedL-deprenil(MAO-B-inhibitor)incombinationwithL-5-hydroxytryptophantoplaceboin58depressedpatients

Discussion 119

(bothunipolarandbipolar)(8).Thecombinationoutperformedplaceboinclinicalimprovement. In1982Himmelhochetal.comparedtranylcyprominewithplaceboin59anergicmajordepressedpatients(9).Althoughthepatientswerenotformallydiagnosedasbipolar,theauthorsstatedthat‘anergicmajordepressionmosttypicallyoccursinprimarybipolarillnesses’.Theyreportedthattranylcypromineshowedsuperiorityoverplacebobytheendofthefirstweek,andthisimprovementincreasedinsignificanceateachsuccessivevisituntilweek6. In1989Cohnetal.comparedfluoxetine,imipramineandplaceboina6-weekstudyinvolving89patientsofwhom22werealreadyusinglithium(10).Responsetofluoxetinewasgreaterthantoimipramineorplacebowhileresponsetoimipraminewasalsogreaterthantoplacebo.Duetosmallnumbers,thedifferenceswerehowevernotsignificant. In2001Nemeroffetal.comparedtheadditionofparoxetine,imipramineandplaceboasadditiontolithiumin117bipolardepressedpatients(11).Therewasnosignificantdifferencebetweenthethreegroupsinefficacy.However,inapost-hocanalysisbothantidepressantsweresuperiorinasubgroupwithlithiumbloodserumlevelsbelow0.8mmol/l. In2007Sachsetal.publishedthelargestandperhapsalsomostinfluentialstudyofantidepressantsinbipolardepression:theSTEP-BDstudywithatotalof366patients.(12).Inthisdouble-blindtrialbupropion,paroxetineorplacebowereaddedtoongoingtreatment.Allpatientswereonlithium,valproateoracombinationofthesetwowiththenotionthat27%ofthepatientsreceivedaninadequatedoseoflithiumorvalproate.Later,wheninclusionbecameaproblem,alsootherFDAapprovedantimanicagents(especiallyatypicalantipsychoticssuchasolanzapineandquetiapine)wereallowed.Otherantidepressantshadtobetaperedoffbeforeorduringthefirstweekofthetrial.Othermedicationscouldalsobestartedduringthestudy.Besidesparticipatinginthismedicationtrial69%ofthepatientswereatthesametimeincludedinarandomizedpsychotherapytrialcomparingcognitivebehavioraltherapy,interpersonalpsychotherapyandfamilyfocusedtherapywithpsychoeducation.Themainfindingofthestudyisthattheantidepressantshadnoadditionaleffect

120 Chapter 6120

overplacebo.However,duetothemajorlimitationsitisobviousthatwiththechosendesignthewidelydrawnconclusionfromthisstudythatantidepressantsareineffectiveinbipolardepression,isnotwarranted. In2010McElroyetal.reporteda8weeksstudyinwhichshecompared300mg.and600mgquetiapinetoparoxetine20mg(n=122)andplacebo(n=126)inbipolardepression(13).Bothdosesofquetiapineweremoreefficaciousthanplacebobuttherewasnodifferencebetweenparoxetineandplaceboinresponseorremission. Asaconsequenceofthe(almost)lackofrandomizedplacebo-controlledtrials,andespeciallyofwellpoweredmonotherapytrialswithantidepressants,thereisstillmuchdiscussionabouttheuseofantidepressantsinbipolardepression.Someargueorevenconcludethattheyareineffectiveinbipolardepression(12)whileothersstillconsiderthemas(potential)effective,althoughwithasmallriskofswitchingto(hypo)maniaandcycleaccelerationinsomeantidepressants(14;15).Inaddition,someconsiderthemasunsafeastheycancauseaswitchto(hypo)maniaandcycleacceleration(15),whileothersclaimthatthereisnogoodproofforthis(16).Nevertheless,accordingtoanotherSTEP-BDstudyupto60%ofthebipolarpatientsuseantidepressants(12),whileinyetanotherstudytheusageofantidepressantsinbipolardisorderintheU.S.wasfoundevenhigher:79,33%versus63,57%inEurope(17).

Lithium, valproate and carbamazepine

Althoughlithiumhasbeenthegoldenstandardfortreatmentofbipolardisordersformorethan50years,theproofforefficacyinthetreatmentoftheacutebipolardepressionislimited.In1993areviewof9studieswaspublishedwithatotalof163patients(18).Allstudieswere(mostlypartial)cross-overdesignswithmostlyunknownplasmalevelsoflithiumandwithvariousdurationsofthestudiesupto43days.In8outof9studieslithiumwasreportedtobesuperiortoplacebo.However,duetomethodologicallimitations,thereisnorealproofofefficacyinthesestudies.Subsequently,lithiumhasonlybeencomparedinonestudywithplaceboandquetiapine300mgor600mg/day(19).While

Discussion 121

bothdosesofquetiapineweremoreefficaciousthanplacebo,lithium(n=136,dosebetween600-1800mg/day)wasnotdifferentfromplacebo(n=129).Inconclusion,thereisnoevidencefortheefficacyoflithiumintheacutetreatmentofbipolardepression. Twometa-analysesoffoursmallplacebo-controlledtrialswithvalproateinacutebipolardepression(totaln=142)werepublishedin2010(20;21).Whileinonlyoneoftheseindividualstudiesvalproatewasmoreeffectivethanplacebo,thepooledresultsshowedsuperiorityofvalproateoverplaceboinmeandepressionscoresaswellasinresponserateswithanestimatednumberneededtotreatof5. Carbamazepinewascomparedtoplaceboinonestudy(n=124)withathirdarmwithcarbamazepineincombinationwithaherbalmedicinecalled‘Freeandeasywandererplus’(FEWP)(22).Carbamazepinemonotherapyhadahigherclinicalresponserateatendpointthanplacebo,buttheadditionofFEWPproducedanevenhigherresponseratethancarbamazepinemonotherapy.

Atypical antipsychotics

Thecombinationofolanzapinewithfluoxtinehasbeeninvestigatedin2003byTohen(23).Olanzapinemonotherapywassignificantmoreefficaciousthanplacebobutthecombinationofolanzapinewithfluoxetinewassuperiortoplaceboandtoolanzapinemonotherapy.BasedonthisstudythecombinationbecamethefirstFDAapprovedtreatmentofbipolardepressionintheU.S. Subsequentlyalsoquetiapinehasbeentestedinseveralstudies(13;19;24;25).Inallstudiestherewasarobustdifferencebetweenquetiapineandplaceboinfavorofquetiapine.Nowadaysquetiapinehasbeenapprovedfortheacutetreatmentofbipolardepression(andalsofortheacutetreatmentofmaniaandformaintenancetreatment)intheU.S.andinEurope. Finally,aripiprazolhasbeenstudiedinbipolardepression,butsurprisinglyitwasnotfoundefficaciousincomparisontoplaceboinseveralstudies(7).

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Lamotrigine

Inthisthesiswereportastudyontheefficacyoflamotrigineinthetreatmentofbipolardepression.Whenourstudystartedtheclassicalmoodstabilizerlithiumwasconsideredthegoldstandardinthelong-termtreatmentofbipolardisorderwitha(presumed)strongereffectinthepreventionofmanicepisodesthanofdepressiveepisodes(26).Moreover,theanticonvulsantsvalproateandcarbamazepineappearedtohaveasimilarprofile. Atthesametime,therewassomeevidencethatlamotriginemightbeeffectiveasmonotherapyinthetreatmentofacutebipolardepression(27),whileitalsohadbeenfoundeffectiveaslong-termtreatmentinthepreventionofdepressiveepisodes(28;29).(seealsochapter2)Oneotherstudycomparedlamotrigineandolanzapine/fluoxetine(30):therewasaslightdifferenceinefficacyinfavorofthecombination,butthedrop-outrateduetoadverseeffectswaslowerforlamotrigine.Thisbroughtustothefundamentalideaofourstudy:theadditionoflamotriginetolithiummightprovideabetterefficacyinthetreatmentofacutebipolardepressionandmightprovideagreaterstabilitythereafterduringlong-termfollow-up. Thestudywasdesignedasanadditionstrategycomparablewithtreatmentdecisionsmadeinreallifeclinicalpractice.Weselectedbipolarpatientswhodespitelong-termmaintenancetreatmentwithlithiumhaddevelopedadepressiveepisode.Twodifferenttreatmentalgorithmswerecompared;onetreatmentarmwithadditionoflamotriginetoongoingtreatmentwithlithiumandonetreatmentarmwithadditionofplacebotolithium(phaseI). After8weeksparoxetinewasaddedinnon-respondersinbothgroups(phaseII).Respondersinbothgroupswerefolloweduntilarelapse,arecurrenceoruntilendofstudyat68weeks(phaseIII).

Results Phase I (chapter 3)

Themainfindingofourstudyisagreaterefficacyoftheadditionoflamotriginetolithiumat8weeksthantheadditionofplacebotolithium

Discussion 123

inpatientswithabipolardepression.Assuch,itisthefirststudytoprovidestatisticalsignificantevidencefortheefficacyoflamotrigineasaddontolithiuminbipolardepressedpatients.Afterfivemonotherapystudieswithonlylimitedpositiveresults,thispositivetrialaddsprovetoanothertreatmentoptioninbipolardepressioninadditiontoquetiapine,olanzapine(especiallyincombinationwithfluoxetine)andtosomeextendtheantidepressants. Thequestionremainswhythistrialhadapositiveoutcomeincontrastwiththepreviousfivemonotherapytrials.Themaindifferencebetweenourstudyandthepreviousstudiesistherelativelowresponserateofplaceboinourstudy(31,7%).Theplaceboresponserateofthefirststudy(whichwaspositiveonsecondaryoutcomecriteria)was29%(27)buttheplaceboresponserateofthefourfollowingstudieswasintherangeof40-50%.(32)Aboutthereasonsforsuchahighplaceboresponsewecanonlyhypothesize.ThepreviousstudieswereallcarriedoutintheU.S.withlotsofpatientswithouthealthinsurance.Forthesepatientseverytreatment,evenanexperimentaltreatment,maybeanimprovementcomparedtoregularcare.Asresponseisoftenrequestedforfurthercontinuationinastudy(andthusreceivingtreatment)theremayalsobeahighpressureonpatientstobecomearesponder.Aseverypatientinourstudyhadaninsurance,suchapressurewasnotthecaseinourpatients,whichmay(inpart?)explainthedifference. Anotherremarkabledifferenceisthemuchlowerdropoutrateinourstudy(17,7%after8weeks)comparedtothepreviousstudies(varyingbetween29%and41%).Apossibleexplanationforthisisthatalmostallourinvestigatorswerealsothetreatingphysiciansofthepatients.This‘personalized’approachmayhaveaddedtothereliabilityandstabilityoftheresults. Afinalreasonmightbethatallourpatientswereusinglithiumandthereforetheywereusedtolaboratorycheckseveryfewmonths.Wehypothesizethatthismayhaveaddedtotreatmentadherencealsofortheothermedications(lamotrigine,placeboandparoxetine)inourstudy.

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Results Phase II (chapter 4)

InphaseIIweadded20mg.paroxetinetoongoingtreatmentwithlithiumandplaceboorlamotrigineinnon-respondersafter8weeks.Althoughbothgroupsimprovedfurtherbetweenweek8and16,thestatisticaldifferencebetweenbothgroupsdisappeared. Thereareafewpossibleexplanationsforthiseffect.FirstthetotalamountofpatientswasfurtherdiminishedduringphaseII.Toremainstatisticalsignificantthedifferenceinoutcomebetweenthetwogroupsshouldhaveincreasedasthenumberofpatientshaddecreased.Giventhetendencyofregressiontothemeanafteralongerperiodoftime,thechanceforsuchanoutcomewassmall. Anotherexplanationisthatithastodowithanantidepressanteffectofparoxetineinthesebipolarpatients.Asthereweremorenon-respondersintheplacebogroupafter8weeks,moreplacebopatientsreceivedparoxetineinphaseII,resultingina‘catchup’ofthenon-respondersintheplacebogroup.However,thisdoesnottakeintoaccountthatpreviousstudieswithparoxetinedidnotfoundparoxetineeffectiveinbipolardepression(11-13).

Results Phase III (chapter 5)

After16weeksallpatientswhowerestillonlithiumwithadditionoflamotrigineorplaceboduringphaseIandwiththepartialadditionofparoxetineinphaseIIandwhohadreachedresponderstatusatweek16,remainedinthestudyandwerefolloweduntilamanicordepressiverelapseoruntiltheendofthestudyat68weeks. Overall68weeksthedifferencebetweenthetreatmentalgorithmwithlamotrigineversusthetreatmentalgorithmwithplaceboappearedtoremainstable.Survivalwithoutrelapseorrecurrencewaslongerforthealgorithmwithlamotriginethanforthealgorithmwithplacebo.Moreover,throughoutthestudytolerabilityingeneralwasgoodasreflectedbyalowdrop-outrateduetoadverseeffectsandtheoveralllowamountofseriousandnon-seriousadverseevents.

Discussion 125

Design of the study: advantages and disadvantages

Thedesignofourstudyhadadvantagesanddisadvantages.Themainadvantageofthisstudyisthecomparabilitywithclinicalpracticeinwhichmanypatientswithbipolardisorderreceivecombinationtherapyratherthanmonotherapy.Therefore,theresultsappearapplicabletoreallifepatients.Moreover,weconsideradesignwithaplaceboarmduringthefirst8weeks(phaseI)followedbytheadditionofanactivetreatmenttonon-responderstoeithertheinvestigationaldrugorplaceboduringthefollowing8weeks(phaseII),anadvantagefortheparticipatingpatients,resultinginagreaterchancetoobtaininformedconsentfrompatientstoparticipateinatrialinwhichtheyhaveachancetoreceiveplacebo.Nevertheless,inclusionwasaproblemandthenumberof124includedpatientswaslowerthantheoriginallyplanned220patients.Thislimitedthepowerofthestudy. Disadvantages/limitationsofthedesignarethatwedidnotrandomizeagainatweek8(afterphaseI),thatnotallpatientsparticipatedinphaseIIandthatnotallpatientsenteredfollow-upafterweek16(phaseIII)whichseriouslyhamperedthepossibilitiesforformalstatisticaltesting.Therefore,wehadtousedescriptivestatisticsfortheanalysisofthefollow-upperiod. Nevertheless,weconcludethatwehaveprovedthefeasibilityofperformingaplacebo-controlledeffectivenessstudywithmultipleadditionsandalongfollow-up.Inouropinion,thisopensthewaytootheradditiontrials.

Clinical implications

Aspolypharmacyisthemainstayinthetreatmentofbipolardisorder,weconsidertheresultsofourstudyclinicallyimportantasweprovedthattheadditionoflamotriginetolithiumisindeedanoptioninthetreatmentofbipolardepressedpatients:itwasnotonlyfoundeffectiveasacutetreatmentbutalsoappearedtosustainit’sefficacyduringfollowup.Sofartheapprovedarmoryforthetreatmentofbipolardepressionwaslimitedtoquetiapine,olanzapinein

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combinationwithfluoxteineandlamotrigine(forlong-termtreatment).Besideslithium,valproateandantidepressantsmightbeconsideredaspotentialoptions.Whentheresultsofourstudywouldbeconfirmedinfuturestudies,thereshoulddefinitelybeaplaceforlamotrigineintheacutetreatmentofbipolardepression,atleastincombinationwithlithium. Animportantadvantageoflamotrigineisitsbenignadverseeffectprofilewithnoweightgain,sedationormetabolicsyndrome.Theonlyseriousriskisasevererash,butwithcarefuldosingthechanceforsucharashislimitedandextremelyrare.

The long-term efficacy of drugs in the maintenance treatment of bipolar disorder

Inbipolardisordersthefocusshouldalwaysbeonmaintenancetreatment:thepreventionagainstnewepisodesusingmedicationwithapositivebenefit(effectiveness)/risk(adverseeffects)profile. Maybethebiggestprobleminlong-termstudiesistochoosetherightdesign,whichinpracticeisalwaysacompromisebetweenpossibilitiesandimpossibilities.Thereisadelicatebalancebetween‘hardcore’randomizedplacebo-controlledefficacytrialswithhighlyselectedpatients,and‘realpractice’effectivenesstrialswithadesignwhichfocusesmoreongeneralizability.Itisquestionablewhethertheusualstandardforefficacystudies(therandomizedplacebo-controlledmonotherapytrial)isthebestwaytofindnewstrategiesforthelong-termtreatmentofbipolardisorder. Forregistrationpurposes,double-blindplacebo-controlledefficacytrialsarerequestedbytheauthorities.ThemainideabehindRCT’sistomakeequalandcomparablegroupsallowingacomparisonbetweentheinvestigatedcompoundandplacebo(orothercontroltreatments),whichisessentialinefficacystudies.Inacutetreatmentstudies(ofmaniaordepression)patientsaredirectlyrandomizedtostartwiththeinvestigationaldrugorplacebo(withthepossibilityofathirdarmwithadrugwithprovenefficacy,thesocalledstandardtreatment). Forlong-termtrialstherearehoweverafewdesignoptionswith

Discussion 127

advantagesanddisadvantages.Mostlong-termstudiesuseso-calledenricheddesigns(35).Inthesestudiesallpatientsstartopenlabelwiththeinvestigationaldrug,forinstanceastreatmentofanacutemanicordepressiveepisode.Thereafter,responderstotreatmentarerandomizedtocontinuationoftheinvestigationaldrugortoswitchtoplacebo(againwiththepossibilityofathirdarmwithadrugwithprovenefficacy,thesocalledstandardtreatment).Goodexamplesofthisarethetwolong-termlamotriginestudies(28;29)inwhichmanicordepressedpatientsfirstreceivedopenlabeltreatmentwithlamotrigine.Responderstolamotriginewererandomizedtocontinuewithlamotrigineortoswitchtoplaceboortolithium(thestandardtreatment).Thisenricheddesignalsohasitslimitations.Itfavorstheinvestigationaldrug(intheexamplelamotrigine)overthestandardcomparisondrug(intheexamplelithium)asonlyresponderswhoalsotoleratedtheinvestigationaldrugentertherandomizedphase. AnexampleofanotherdesignistheBALANCEstudy(36).Inthisstudycomparingtheprophylacticeffectoflithium,valproateendthecombinationofboth,patientsenteredthestudyduringanepisodefowhichtheyweretreatedwiththecombinationofbothdrugs.Stabilizedpatientswererandomizedtocontinuetreatmentwitheitherlithium(monotherapy),valproate(monotherapy)ortocontinuewiththecombinationofboth.Thisisalsoanenricheddesignwithaselectiononresponseandtolerancetolithiumandvalproate,butwithoutfavoringoneofthecompounds. AthirdexampleofmaintenancetrialsisreflectedbythreestudiesbyGreiletal(37),Hartongetal.(38)andLichtetal.(39)Inthesestudieslithiumwascomparedtocarbamazepine(Greil/Hartong)orvalproate(Licht).Patientsenteredthestudyduringorafteranacutemanicordepressedepisodethatwastreatedwithmedicationsotherthantheinvestigationaldrugs(lithiumandcarbamazepineorvalproate).Afterrecoveryfromtheepisodepatientswererandomizedtothestudydrugsandsimultaneouslytheotherdrugsweretaperedoff.Subsequentlypatientswerefolloweduntiltherecurrenceofanewepisodeoruntilendoffollow-up. Inourstudyweusedanextensiondesignwithextendedblindfollow-upafterashort-termdouble-blindrandomizedtrial(phaseI)inwhichpatients

128 Chapter 6128

receivedadditionofeitherlamotrigineorplacebo.Aftertheacutetrial(phaseIandphaseII)wefollowedtherespondersupto68weekswithoutnewrandomizationafterrecovery,butwithkeepingthetreatments(lamotrigineofplacebo)blindedthroughoutfollow-up.Assuch,ourstudydoesnotprovethatlamotriginehasaprophylacticeffect.Forthatpurposeweshouldhavere-randomizedallresponderstolamotrigineafterphaseItocontinuedouble-blindwithlamotrigineortoswitchtoplacebo(asinthefirstexampleabovewiththeenricheddesign).Besidesthatwedidnotaimforthatgoal,wealsohadtoofewpatientsforsuchastudy.Forrandomizingtwiceduringonestudy,manymorepatientsshouldhavebeenrequired.Moreover,itcanleadtoanoverpoweredfirstpartofthestudyoranunderpoweredsecondpartofthestudy(andnottomentiontheextraproblemswiththeadditionofparoxetineinnon-respondersafter8weeks).Therefore,wechooseforanaturalistic,blindfollow-upinresponders.

Limitation of the add-on design

Alimitationofourstudyisthatweonlygatheredinformationonaddingnewmedication(s).Wehavenoinformationonhowtocontinuetreatment.Wouldithavebeenpossibletotaperofflithiumorlamotrigine,andwhattodowithparoxetine?Thisproblemisuntilnowanalmostunmetneed.Moststudiessofararedesignedtogatherinformationonshort-andlong-termefficacyandtolerabilityofstartingnewcompoundsandcombinations,buthardlyonhowtheymightbestopped.Thisisprobablypartlyrelatedtothefactthatsponsoringofatrialinvestigatingstoppingofmedicationisnotinterestingforpharmaceuticalcompanies.Moreover,thelong-termmaintenancestudies(withenricheddesigns)aresetuptoproofefficacy(andtolerability)butnottofindoutwhichpatientsareinneedoflong-termtreatmentandwhichpatientsarenot.Medicationsareoftenaddedtotheineffective(oronlypartiallyeffective)treatment,withoutknowingwhetheritwouldalsohavebeenanoptiontoswitchfromthe(partially)ineffectivetreatmenttoanotherdrug.I.e.woulditalsobepossibletostopthefirstdrug(inourstudylithium)insteadofaddingnewmedicationtothefirstdrug.

Discussion 129

Patientscanbereluctanttostopmedicationorcombinationsofmedications.Atleastsomepatientswanttocontinuemedicationiftheybelievethatthesedrugskeptthemstableoveralongtime.Thisisunderpinnedbyanintendedstudyinwhichbipolardepressedresponderstotheadditionofanantidepressant(toongoingtreatmentwithmoodstabilizers)(40)wereaskedtoconsenttoberandomizedtodouble-blindcontinuingorstoppingoftheaddedantidepressant.Itprovedalmostimpossibletofindpatientswhoacceptedtoberandomizedafterasuccessfullytreateddepressiveepisode.Somepatientsonlywantedtokeeptheirmedication,buttherewerealsopatientswhowerereluctanttocontinuetheirmedication,forinstancebecauseofadverseeffects,orbecausetheywereill-affectedtotake(toomany)drugs.Finallythestudywascompletedbycomparingtwonon-randomizedgroupsofpatientswhothemselveshaddecidedtostoptheantidepressantortocontinuetheantidepressantwithquestionableresults. Theonlyrandomizeddiscontinuationtrialwithantidepressantsinbipolardepression(41)showednosignificantbenefitfromcontinuingantidepressantsinthelong-termtreatmentofbipolarpatientsontheprimaryoutcome(meanchangeonthedepressivesubscaleoftheCMF).Onlytimetoafirstnewdepressiveepisodewassignificantlylongerforthegroupthatcontinuedwiththeantidepressant.However,alsotheseresultsarequestionable,giverthefactthatthiswasafollow-upstudyoftheSTEP-BDtrialwithallit’smethodologicallimitationsdescribedabove.

Conclusion

Inourstudytheadditionoflamotriginetoongoingtreatmentwithlithiumwasmoreeffectivethantheadditionofplacebointhetreatmentofacutebipolardepression.Moreover,wefoundafterfurthercontinuationoftreatment,thatlamotrigineappearedtomaintainitseffect.Duetothefactthatwedidnotre-randomizepatientsafterthefirst8(or16)weeksoftreatment,theresultsofthefollow-upphasecannotbeconsideredasevidenceforthelong-termeffectivenessoflamotrigine.However,thereissuchevidencefromtwootherstudies,inwhich

130 Chapter 6130

responderstolamotriginewererandomizedtocontinuewithlamotrigineortoswitchtoplacebo(orlithium)(28;29). Furtherresearchonthetreatmentofbipolardepressionshouldbedirectedtofind(other)long-termtreatment(s)withmaximumeffectivenessandwithminimaladverseeffects.Inaddition,futureresearchshouldnotonlybedirectedtotheeffectivenessandsafetyofstartingmedication(s)butalsototherisksandbenefitsofstoppingmedication(s).Moreover,theoptimalbalancebetweenefficacyandadverseeffectsisdifferentforeachindividualandthereforeachallengetothecooperationbetweendoctorandpatient.Psychoeducationisnotamatterofconvincingpatientstoacceptadverseeffects,itismoreaquesttofindtherightmedicationorcombinationofmedicationsfitfortheindividualpatientwithoptimalfunctioninginallaspectsofhumanlife.

Discussion 131

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Discussion 133

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24.CalabreseJR,KeckPE,Jr.,MacfaddenW,MinkwitzM,KetterTA,WeislerRH,etal.ARandomized,Double-Blind,Placebo-ControlledTrialofQuetiapineintheTreatmentofBipolarIorIIDepression.AmJPsychiatry2005Jul;162(7):1351-60.

25. ThaseME,MacfaddenW,WeislerRH,ChangW,PaulssonB,KhanA,etal.EfficacyofquetiapinemonotherapyinbipolarIandIIdepression:adouble-blind,placebo-controlledstudy(theBOLDERIIstudy).JClinPsychopharmacol2006Dec;26(6):600-9.

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134 Chapter 6134

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Summary

138138

Design of the study

Inthisthesiswedescribeaninvestigator(W.A.Nolen)initiateddouble-blindrandomizedplacebo-controlledtrial(RCT)comparingtwodifferenttreatmentalgorithmswithafollow-upuntilamaximumof68weeks. Inbipolaroutpatients(menorwomenagedatleast18years),withadepressiondespitelong-termtreatmentwithlithium(atserumlevelsof0.6-1.2mmol/l)lamotrigineorplacebowasaddedtoongoingtreatmentwithlithium.Innon-respondersafter8weeksparoxetinewasopen-labeladdedtoongoingtreatmentwithlithiumpluslamotrigineorplacebo.Respondersafter8or16weekswerefolloweduntilarelapseorrecurrenceoruntilthemaximumdurationofthestudy;68weeks(fig1).

Figure 1. Designofthestudy

ThestudywasapprovedbytheethicalreviewboardoftheUniversityMedicalCenterUtrecht,theNetherlandsandbylocalinstitutionalreviewboardsintheNetherlandsandinSpain.Allpatientsgavewritteninformedconsent.

Lithium

+Lamotrigine

+Placebo

Phase 1 Phase 2 Follow-up of respondersPhase 3

Week 0 8 16 68

Responders

139Summary 139

Results

Figure 2.Flowchartofthestudy

124Patientswererandomised,112intheNetherlandsand12inSpain.

Phase 1: week 1-8 (chapter 3) Ofthe64patientswhostartedinthelamotriginegroup(fig2),52patients(81%)completedthefirst8weeksversus50(83%)ofthe60patientsintheplacebogroup.Ontheprimaryoutcomemeasure(changeinMADRSscorefrombaselinetoweek8;-15.38vs.-11.03respectively;P=0.024)aswellasonsomesecondaryoutcomemeasureslamotriginewassignificantlymoreefficaciousthanplacebo(fig3).

Randomized:124

Drop-outs:6

Drop-out:1

Drop-out:3

Drop-outs:2

Drop-out:1

Drop-outs:4

Drop-outs:2

Completed:8

140140

Figure 3. SeverityofdepressionaccordingtothemeanMADRSscoreateachvisitforpatientsonplaceboandlamotrigine

Phase 2: week 9-16 (chapter 4) After8weeksresponderstothelithium-lamotrigineandthelithium-placebocombinationcontinuedthestudywithlithiumand(stilldouble-blind)lamotrigineorplacebo,whileopen-labelparoxetinewasaddedinnon-responders.Althoughbothgroupsimprovedfurther,thedifferenceafter16weeksbetweenlithiumpluslamotrigine(plusparoxetineinnon-responders)versuslithiumplusplacebo(plusparoxetineinnonresponders)wasnotstatisticallysignificantanymore(changeinMADRSscorefrombaselinetoweek16-17.91versus-15.40respectively;p=0.253).Othersecondaryoutcomecriteriaalsodidnotrevealsignificantdifferencesatweek16(fig4).

*p=.031**p=.006

PlaceboLamotrigine

141Summary 141

Figure 4. SeverityofdepressionaccordingtothemeanMADRSscoreateachvisitforpatientsonplaceboandlamotrigine(plusadditionofparoxetineinnon-respondersatweek8)

Phase 3: week 17-68 (chapter 5) Duringfollow-uprespondersafter8or16weeksweremaintainedonstudymedicationsuntilamanicordepressiveepisodeoruntilthemaximumdurationofthestudy,i.e.untilweek68.Descriptivestatisticsshowedthatthedifference(aspercentageofrespondersoftheinitialgroup)betweenthelamotriginegroupversustheplacebogroupremainedstablethroughoutthefollow-upperiod(fig5and6).

*** P<0.05**P<0.01 Additionofparoxetine

0 2 4 6 8 10 12 14 16

PlaceboLamotrigine

142142

Figure 5. Responders(CGI-BPimprovementofdepressionscoreof1or2)aspercentageoftheinitialgroup(n=124,lamotriginen=64,placebon=60)throughoutallthreephasesofthestudy

Alsotimefromfirstresponse(score<50%ofMADRSscoreatbaseline)torecurrence(score≥50%ofinitialMADRS)showedasimilarpatterninfavourofthelamotriginegroup. Themediansurvivaltimeforrespondersofthelamotriginegroupwas10.0months(95%CI:1.1-18.8)versus3.5months(CI:0.7–7.0)fortherespondersintheplacebogroup.

PlaceboLamotrigine

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

143Summary 143

Figure 6. Probabilityofmaintainingresponse(score<50%ofMADRSscoreatbaseline;n=79;lamotrigine:n=41;placebo:n=38)withoutrecurrence(score≥50%ofinitialMADRS)sincehavingachievedresponderstatusduringphase1orphase2

Safety and Adverse Events

Duringthe68weeksofthestudytherewere20SeriousAdverseEvents(SAE),15duringthefirst16weeksand5thereafter.10patientsinthelamotriginegroup(2patientshad2SAEs)groupversus8patientsintheplacebogroupexperiencedaSAE.MostSAEsconcernedseriousmoodswingsascouldbeexpectedinatrialwith124bipolarpatients.Statisticallytherewerenodifferencesbetweenlamotrigineandplacebo.Theonlystatisticaldifferencebetweenlamotrigineandplaceboinadverseeventswastremorat16weekswhichoccurredmoreofteninthelamotriginegroupversustheplacebogroup.So,wecanconcludethattheadditionoflamotriginetolithium(withfurtheradditionofparoxetineinnon-responders)wassafeandhadanadverseeventsprofilecomparabletotheadditionofplacebotolithium.

Months

PlaceboLamotrigine

0 3 6 9 12 15 18

144144

Conclusions

Afterthisstudyseveralconclusionsconsideringthetreatmentandfutureresearchofpatientswithabipolardepressioncanbedrawn.

1. Theadditionoflamotriginetolithiuminpatientswithbipolardepressionisefficaciousandoverallwelltolerated.

2. Afterthefurtheradditionofparoxetineinnon-responderstothecombinationoflithiumpluslamotrigineorplacebothestatisticalsignificancebetweenthetreatmentarmwithlamotriginegroupandthetreatmentarmwithplacebogroupdisappearedwithongoingimprovementinbothgroups.However,thetreatmentarmwithlamotrigineremainednumericallymoreeffective,alsoduringfollow-upuptooneyear.

3. Thesefindingsindicatethatlamotrigine-inadditiontoitsuseinthelong-termpreventionofdepressiveepisodes-alsodeservesaplaceintheacutetreatmentofbipolardepression.

4. Thegapbetweenscientificresearchwithrandomizedplacebo-controlledtrialsandclinicalpracticecanbebridgedbydesigningstudiescomparingcombinationsofmedications.

145Summary 145

146146

Samenvatting

148148

Design van de studie

InditproefschriftbeschrijvenwijeendoorW.A.Nolengeinitialiseerddubbelblindplacebogecontroleerdonderzoekwaarintweebehandelingalgoritmesvergelekenwerdenmeteenvervolgtoteenmaximumvan68weken.Bijbipolairedepressievepatiënten(manofvrouw,ouderdan18jaar)meteenbipolairedepressieondankslangdurigebehandelingmetlithium(bloedspiegels0.6-1.2mmol/lwerdlamotrigineofplacebotoegevoegd. Naachtwekenkregennon-respondersinbeidegroepen(lithium+lamotrigineoflithium+placebo)‘openlabel’paroxetine(20mg)extratoegevoegd.Respondersna8of16wekenwerdengevolgdtoteenterugvalineendepressieveof(hypo)manischeepisodeoftotheteindvandestudiena68weken.

Figuur 1. Ontwerpvandestudie

VoorafgaandaandestudiewastoestemmingverleenddoordemedischethischetoetsingscommissievanhetUMCUtrechtendoorde

Lithium

+Lamotrigine

+Placebo

Fase 1 Fase 2 Follow-up of respondersFase 3

Week 0 8 16 68

Responders

149Samenvatting 149

lokaletoetsingscommissiesinNederlandeninSpanje.Allepatiëntengavenvoorafgaandaandestudie‘informedconsent’.

Results

Figuur 2. ‘FlowChart’vandestudie

124patiëntenwerdengerandomiseerd,112inNederlanden12inSpanje.

Fase I: week 1-8 (hoofdstuk 3) 52vande64patiënten(81%)indelamotriginegroepdieindestudiestarttenvoltooidendeeerste8wekenvanhetonderzoekversus50vande60patiënten(83%)indeplacebogroep(fig2).Opdeprimaireuitkomstmaat;de

Randomized:124

Drop-outs:6

Drop-out:1

Drop-out:3

Drop-outs:2

Drop-out:1

Drop-outs:4

Drop-outs:2

Completed:8

150150

veranderinggemetenvan‘baseline’totenmetweek8opdeMontgomery-ÅsbergDepressionRatingScale(MADRS)(enopsommigesecundaireuitkomstmaten)bleekdetoevoegingvanlamotrigineaanlithiumstatistischsignificant(-15,38versus-11.03p=0.024)effectieverdandetoevoegingvanplaceboaanlithium(fig3).

Figuur 3.ErnstvandedepressiegemetenalsgemiddeldeMADRSscoretijdenselkevisitevoorpatiëntenoplamotrigineenplacebo

Fase II: week 9-16 (hoofdstuk 4) Na8wekenvervolgdenrespondersopzoweldelithiumlamotriginecombinatiealsderespondersopdelithiumplacebocombinatiedestudiemetdezelfde(nogsteedsdubbelblinde)medicatie.Bijnon-respondersinbeidegroepenwerd‘openlabel’20mgparoxetinetoegevoegd. Beidegroepenverbeterdenverder,maarhetverschiltussendegroepmetlithium+lamotrigine+paroxetine(vanaf8wekeninnon-responders)versusdegroepmetlithium+placebo+paroxetine(vanaf8wekeninnon-responders)wasnietlangerstatistischsignificant(-17.91versus-15.40p=0.253)(fig4).Ookanderesecundaireuitkomstmatenwarennietstatistischsignificant.

*p=.031**p=.006

PlaceboLamotrigine

151Samenvatting 151

Figuur 4. ErnstvandedepressievolgensdeMADRSopelkebezoekvoorpatiëntenmetlamotrigineenplacebotoevoegingaanlithium(plusadditievanparoxetinena8wekenbijnon-respons)

Fase III: week 17-68 (hoofdstuk 5) Respondersna8of16wekenwerdenverdergevolgdmetbehoudvandezelfde(deelsdubbelblinde)medicatietoteennieuwedepressieveof(hypo)manischeepisodeoftotheteindvandestudiena68weken.Uitbeschrijvendestatistiekbleekdathetverschiltussendelamotriginegroependeplacebogroep(gemetenalspercentagerespondersvande2oorspronkelijkegroepen)stabielbleefgedurendede‘follow-up’(fig5en6).

*** P<0.05**P<0.01 Plusadditievanparoxetine

0 2 4 6 8 10 12 14 16

PlaceboLamotrigine

152152

Figuur 5. Responders(volgensdeCGI-BPverbeteringdepressiescore1of2)alspercentagevandeoorspronkelijkegroep(n=124,n=64voorlamotrigineenn=60voorplacebo)gedurendealledriedefasesvandestudie

Ookdetijdvanafdeeerstekeerdateenpatiëntresponderswas(MADRSscore<50%vandeinitiëlescore)totterugval(MADRSscore≥50%vandeinitiëlescore)liethetzelfdepatroonzien.Degemiddeldetijdalsrespondervoordelamotriginegroepwas10.0maanden(95%CI:1.1-18.8)versus3.5maanden(95%CI0.7-7.0)voorderespondersindeplacebogroep.

PlaceboLamotrigine

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

153Samenvatting 153

Figuur 6. Kansomresponderteblijven(score<50%ofMADRSscoreopbaseline;n=79;lamotrigine:n=41;placebo:n=38)zonderterugval(score≥50%vandeoorspronkelijkeMADRS)nadatmenrespondergewordenisgedurendefase1offase2

Veiligheid en bijwerkingen

Gedurendede68wekenvandezestudiewarener20SAE’s(SeriousAdverseEvents),15gedurendedeeerste16wekenen5daarna.10patiëntenindelamotriginegroep(2patiëntenhadden2SAE’s)versus8patiëntenindeplacebogroepkregeneenSAE.DemeesteSAE’swarenheftigestemmingswisselingen.Ditwasnietonverwachtineengroepvan124bipolairepatiënten.Overdegeheleperiodewaseralleenna16wekenvoorwatbetreft.tremoreenstatistischverschiltussenlamotrigineenplacebotengunstevanplacebo.Voorderestwasergeenenkelstatistischsignificantverschiltussenlamotrigineenplacebooverdegehelestudie. Concluderendkunnenwestellendatdetoevoegingvanlamotrigineaanlithium(metdaarnadetoevoegingvanparoxetinebijnon-respons)veiligwasen

Maanden

ijnlij

PlaceboLamotrigine

0 3 6 9 12 15 18

154154

datdebijwerkingenvandetoevoegingvanlamotrigineaanlithiumvergelijkbaarwarenmetdetoevoegingvanplaceboaanlithium.

Conclusies

Nadezestudiekunnenweeenaantalconclusiestrekkenoverdebehandelingentoekomstigonderzoekbijpatiëntenmeteenbipolairestoornisgedurendeeendepressievefase.

1. Detoevoegingvanlamotrigineaanlithiumbijpatiëntenmeteenbipolairestoornisgedurendeeendepressievefaseiseffectiefenveilig.

2. Nadetoevoegingvanparoxetineop8wekenbijnon-respondersverdweenhetstatistischsignificanteverschiltussendebehandelingmetlamotrigineenlithiumversusdebehandelingmetplaceboenlithium.Beidegroepenverbeterdennogwelverdertussende8en16weken.Ooktijdenshetvervolgtot68wekenbleefdebehandelarmmetlamotrigineinaantaleffectieverdandebehandelarmmetplacebo.

3. Dezeresultatenlatenziendatlamotrigine-intoevoegingaanhetgebruikvoordepreventieopdelangetermijnvannieuwedepressieveepisoden-ookeenplaatsverdientindeacutebehandelingvandebipolairedepressie.

4. Deklooftussenwetenschappelijkonderzoekendedagelijksebehandelpraktijkkanoverbrugdwordendoorhetontwerpenvanstudiesdiekijkennaarcombinatiesvanmedicatie.

155Samenvatting 155

156156

Curriculum VitaeM.L.M. van der Loos

158158

Curriculum Vitae

MarcvanderLooswerdop10maart1958geboreninAmsterdam.NadeafrondingvanhetVWOstarttehijaandeAmsterdamseAcademievoorLichamelijkOefeningdeopleidingtotgymnastiekleraar.AansluitendstudeerdehijgeneeskundeaandeUniversiteitvanAmsterdam. IndezelfdeperiodewerktehijalsslowmotionredacteurenlateralsregisseurbijNOSStudioSport. DespecialisatiepsychiatriewerdgevolgdbijhetHaags-LeidsOpleidingsConsortiummetProf.HGM.Rooijmansalsopleider. Sinds1997ishijwerkzaamalspsychiaterbijdeIsalaKliniekenlok.SophiainZwolle.

Publicaties

Lamotrigine bij de behandeling van bipolaire stoornissen.TijdschriftvoorPsychiatrie49(2007)2,95-103M.L.M.vanderLoos,P.Kölling,E.A.M.Knoppert-vanderKlein,W.A.Nolen

Efficacy and safety of lamotrigine as add-on to lithium in the treatment of bipolar depression: a multi-center, double-blind, placebo-controlled trial J.ClinPsychiatryvol70;223-31MarcL.M.vanderLoosMD1;PaulMulderPhD2;ErwinG.Th.M.HartongMDPhD3;MarcB.J.BlomMD4;AntonC.Vergouwen,MDPhD5;HermanJ.U.E.MdeKeyzerMD6;PeterJ.H.NottenMD7;MarijkeL.LuteijnMD8;ManuelaA.TimmermansM.Sc9;EduardVietaMDPhD10;WillemA.Nolen,MDPhD11andtheLamLitStudyGroup*

Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.ActaPsychiatrScand.2010;122:246-54.

159159Curriculum Vitae M.L.M. van der Loos

MarcL.M.vanderLoosMD1;PaulMulderPhD2;ErwinG.Th.M.HartongMDPhD3;MarcB.J.BlomMD4;AntonC.Vergouwen,MDPhD5;MartijnSvanNoorden6;ManuelaA.TimmermansM.Sc7;EduardVietaMDPhD8;WillemA.Nolen,MDPhD9;fortheLamLitStudyGroup*

Treatment of Unipolar Psychotic DepressionA randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapineActaPsychiatricaScandinavica;2010Mar.121(3);190-200JaapWijkstra,HuibertBurger,WalterW.vandenBroek,TomK.Birkenhager,JoostG.E.Janzing,MarcoP.M.Boks,JanA.Bruijn,MarcL.M.vanderLoos,LeonieM.T.Breteler,GuillaumeM.G.I.Ramaekers,RobbertJ.Verkes,WillemA.Nolen,

Long term response to successfull acute pharmacological treatment of psychotic depressionJournalofaffectivedisorders;2010Jun;123(1-3);238-42JaapWijkstra,HuibertBurger,WalterW.vandenBroek,TomK.Birkenhager,JoostG.E.Janzing,MarcoP.M.Boks,JanA.Bruijn,MarcL.M.vanderLoos,LeonieM.T.Breteler,RobbertJ.Verkes,WillemA.Nolen,

Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design.BipolarDisord.2011;13:111-7vanderLoosML,MulderP,HartongEG,BlomMB,VergouwenAC,vanNoordenMS,etal.

160160

Voordrachten

Lamotrigine as add-on to lithium in bipolar depression5-10-2006Barcelona,InternationalSocietyofBipolarDepressionStanleyConferencemeeting,presentation

Lamotrigine as add-on to lithium in bipolar depression followed by open label paroxetine addition in non-responders26-10-2007Kopenhagen,DUAGsymposiumPresentation

Workshop; ‘Farmacologische behandeling bipolaire depressie’15-10-2009,Apeldoorn:Nationaalfarmacotherapiecongres

Presentatie: Farmacotherapie in de onderhoudsfase10-11-2009Utrecht:NajaarssymposiumBipolairestoornissen

Posters

Verhoogde plasma vasopressine spiegels bij opgenomen patienten met een depressie21eVoorjaarscongres,NedelandseVerenigingvoorPsychiatrie,Lunteren1994LondenL.van,LoosMLMvander,GoekoopJG,KempenGMJvan,DeWiedD,RooijmansHGM

Lamotrigine as add-on to lithium in bipolar depressionMLMvanderLoos,EVieta,WANolen28-5-2007SanDiego,AmericanPsychiatricAssociation

161161Curriculum Vitae M.L.M. van der Loos

Lamotrigine as add-on to lithium in bipolar depression followed by open label paroxetine addition in non-respondersMLMvanderLoos,EVieta,WANolen8-6-2007Pittsburg,InternationalSocietyofBipolarDisorders

Boekhoofdstukken

Handboek Bipolaire StoornissenRed:.RalphKupka,EliseKnoppert-vanderKlein,WillemNolenUitgeverijdeTijdstroomHoofdstuk14AnticonvulsivaErwinHartong,MarcvanderLoos,WillemNolen

Bipolar Psychopharmacotherapy; Caring for the patient, second editionRed.HagopS.Akiskal,MauricioTohenChapter4:PharmalogicalprofileandclinicalutilityoflamotrigineinmooddisordersM.L.M.vanderLoos,JosephR.Calabrese,WillemA.Nolen,DavidJ.Muzina

The essentials of psychopharmacology, third edition (in press)Red:Dr.SchatzbergandDr.NemeroffChapter:LamotrigineDavidE.Kemp,MarcvanderLoos,KemingGao,JosephR.Calabrese

Dankwoord

164164

Dankwoord (Acknowledgments)

Nanegenjaarishetmoeilijkomiedereenpersoonlijktebedankendieaanditprojecthebbenmeegewerkt.Vandaardatditdankwoordeerdereensamenvattinggenoemdmoetworden.

WillemNolenwasdegenedieaandewiegvanditonderzoekheeftgestaan.Toenikin2002solliciteerdenaardefunctievan‘hoofdonderzoeker’voorzaghijtweemogelijkeproblemen.Demogelijkheidvangeenofonvoldoenderesultatendoortegeringeinclusiewasheteerstemogelijkeobstakel.Doordesamenwerking,betrokkenheidenhetenthousiasmevanzowelpatiëntenalslokaleonderzoekersluktehetechternietalleenomvoldoendepatiëntenteincluderen,maarookomhetaantaluitvallersopmerkelijklaagtehouden.Mijnwaarderingvoormetnamedepatiëntendievaak68wekenlangaanallestudieproceduresmeewerktenisgroot. HettweedemogelijkeprobleemschoolvolgensWillemNoleninmijnonervarenheidalsonderzoekerenschrijvervanartikelen.DitprobleembleekechtermaarvangeringbelangtezijnomdatWillemnietalleeneenuitmuntendonderzoekerismaaromdathijinhetbespreken,corrigerenenuitleggeneenprofessorindewarezinvanhetwoordbleektezijn.Willem,hetiseenzeldzameengrotekwaliteitvanjouomstevigekritiektekunnenleverenzonderooitontmoedigendtezijn,meweer30jaarjongertelatenvoelenalsstudentzonderpatriarchaaltezijnenveeltebegeleidenzonderhetovertenemen.NooitreedikteruguitGroningenzondernieuwenthousiasmeeneengoedhumeur. DaaromWillem,zeerbedanktvoorjebegeleiding,steun,hulpenloyaliteit.Ditproefschrifthadernietzozeerandersuitgezienzonderjouwbegeleiding,hethadnooitbestaan.

HetwerkdatdoorManuelaTimmermansisgedaanverdiendzekermijngrotedank.WerkendvoorGSKzorgdejijvoordeorganisatievanhetprotocol,

165165Dankwoord

afsprakenmetonderzoekers,controleerdedata,organiseerde‘investigatormeetings’etc.Manuela,doorjouwhulpisditonderzoekvoormijgeenlogistiekenachtmerriegeworden.

PaulMulder,jouwilikgraagbedankenvoorhetgrotegeduldwaarmeejijmijdebasalestatistiekvoordezestudiewistuitteleggenzonderdatikeniginzichtindebenodigdecomputerprogramma’shad.Jouwgebrekaanopgewondenheidoverresultatenplaatstezowelmee-alstegenvallersvandeuitkomstendirectineengeheelanderlicht.Meestalineenwatgedemptereschakering.

DefinanciëleenorganisatorischesteunvanGSKmaaktedezestudiemogelijk.OoknahetaflopenvanhetpatentoplamotriginebleefGSKondersteuningbieden.Hiermeeisduidelijkgemaaktdatineengoedesamenwerkingtussenpatiënten,onderzoekersendefarmaceutischeindustrieervooriedereenvoordeelvalttebehalen.

DedirectievandeIsalaKliniekengafmijtijdvoorditprojectwaardoorhetmogelijkbleekomnaasthet‘gewonewerk’dezestudieopeengoedeentochnog‘socialewijze’afteronden.

DenauwkeurigheidenvolhardingwaarmeeJaapJansenenHenkHallie(UMCG)deenormehoeveelheiddataindedatabaseinvoerdenverdiendgrotedank.

Veelwaarderinggaatuitnaarmijntweecollega’sJanPieterSmitenDouweKromdijk.TemiddenvanbijtijdenwijleheftigeberoeringishetonstotnutoegeluktomonzegezamenlijkevisieopdeplaatsvandeziekenhuispsychiatrieindeIsalaKliniekenvormtegeven.Ikhoopvanhartedathetonsookindekomendejarenzalblijvenlukken.

166166

Inhetbeginvanmijndankwoordnoemdeikaldelokalemede-onderzoekers.Zijvormdenderuggengraatvandeze‘multicentretrial’enikwilgraagmijndankwoordeindigenmethunallenhiertenoemen:

R.W.J.Baas,MD,P.R.Bakker,MD,M.B.J.Blom,MD,W.Brouwer,MD,P.H.M.vanDongen,MD,D.M.H.vanHyfte,MD,K.Geling,MD,G.Glas,MDPhD,E.G.Th.M.Hartong,MDPhD,O.Habekotté,MD,A.Keegan,MD,H.deKeyzer,E.deJong,MD,E.A.M.Knoppert-vanderKlein,MDPhD,P.Kölling,MD,D.Koning,MD,A.G.Kunst,MD,R.W.Kupka,MDPhD,G.Kuut,MD,J.J.vanLieshout,MD,D.H.Kromdijk,MD,F.R.Kruisdijk,MD,E.vanLeeuwen,MD,M.deMaat,MD,M.vanNoorden,MD,P.J.H.Notten,MD,M.L.Luteijn,MD,P.Schoof,MD,J.M.J.F.Offermans,MD,D.Bloemkolk,MD,R.R.Ploeger,MD,J.Segeren,MD,S.Smit,MD,D.H.Postma,MD,M.J.W.T.Scherders,MD,A.C.M.Vergouwen,MDPhD,T.Vos,MD,J.vanZaane,MDinNederlandenEVieta,MDPhD,R.Arce,MD,L.Livianos,MD,A.González-Pinto,MDPhD,E.Álvarez,MDPhDinSpanje.

167167Dankwoord

university of groningen lamotrigine in bipolar depression ... · bipolar disorder (manic-depressive...

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