Theabilityoffolatesupplementationtopotentiatetheeffectsofantidepressantsinadultswith

majordepressivedisorders
Introduction
Folate,otherwiseknownasvitaminB9,isessentialforawidearrayofbodilyfunctionssuchas,
proteinmetabolism,theformationofredbloodcells,thepreventionofneuraltubedefects,the
preventionofanemia,andotherhealthrelatedproblems.Thehumanbodycannotsynthesize
folate,andthereforefolatemustbeobtainedthroughtheconsumptionof,vegetables,grains,
beans,andotherfoods.However,folicacid,whichisthesyntheticformoffolatefoundinmany
fortifiedfoods,is1.7xmorebioavailablethannaturallyoccurringfolate;andistheforminwhich
themajorityofindividualsobtaintheirrecommended400mcgDFE/dailyfrom.Folatedeficiency
hasdecreasedwithtimeintheUnitedStatesduetoanabundanceoffortifiedfoods,howeverit
doesstillexist.Interestinglyenough,manystudiesovertimehaveobservedthatasubsectionof
individualswhoareinclinedtowardsbeingfolatedeficient,areindividualswithmajordepressive
disorders.Thecorrelationbetweenfolatedeficiencyanddepressionmostlikelyliesin5
methyltetrahydrofolate,whichactsastheactivemetaboliteoffolate.5MTHFplaysacrucialrole
intheremethylationofhomocysteinetomethionine,eventuallycreatingSAMe,whichisthen
involvedinmanymethyldonatingreactions,suchasthecreationofneurotransmittersinthe
centralnervoussystem1.Individualswhoarefolatedeficienthavedecreasedlevelsof
neurotransmitterssuchasdopamineandserotoninintheircerebrospinalfluid,andthereforeare
moreinclinedtowardsdevelopingdepressivedisorders.Sincefolatedeficiencyisnottheonly
contributingfactortowardsdevelopingdepression,folatesupplementationalonewouldnotbean
adequatetreatment.Currently,selectiveserotoninreuptakeinhibitors(SSRIs),whichmostly
likelyfunctionbyincreasingthelevelofserotoninavailableforbindingtothepostsynaptic
receptorinthepostsynapticcleft,arethemajorclassofdrugsprescribedfortreatingdepressive

disorders,howevertheyarenotalwayssuccessful.Thepurposeofthispaperistodetermineifthe
combinationofanantidepressantandafolatesupplementwillpotentiatethepositiveeffectsof
thedrug.
Methods
TheresearchforthispaperwasconductedprimarilythroughtheusageoftheUniversityofNorth
Floridaslibraryssearchengine.Searchtermsthatwereincludedinordertofindsupporting
evidencethisresearchpaperincluded,folate,supplementation,depression,antidepressants,folic
acid,SSRIs,anddeficiency.PubMed,EBSCO,andScienceDirectwerethemaindatabasesthat
providedforthesourcesofthisresearchpaper.Thestudydesignsincludedinthisresearchpaper
wereallexperimentalinnatureandinvolvedtheassessmentofarandomlyassigned
intervention/treatment,andmostofthestudiesinvolvedaplaceboaswell.Onlyoneofthestudies
includedinthisresearchpaperinvolvedanimals,andtherestofthestudieswereconsensually
conductedonindividualswithahistoryofmajordepressivedisorders.
MainFindings
Thefirstsetofevidencepresentedtodeterminewhetherornotfolicacidsupplementationin
combinationwithanantidepressantwouldenhancetheeffectivenessoftheantidepressant,was
providedbyananimalstudyconductedby,Brocardoetal.Undertheprecedencethatprevious
studieshaveshownthatfolicacidhasaroleinthephysiologicalresponsesofdepression,the
researchteamusedmaleandfemale,3040g,Swissmiceinordertodeterminetheeffectfolic
acidhadondepressionwhen,administeredorally,viai.c.vroute,andincombinationwithan
antidepressant.Inordertoassesstheeffectivenessofacombinationofanantidepressantandan
effectivedosageoffolicacid,theresearchteamconductedaforcedswimmingtestaswellasa
tailsuspensiontest,bothofwhicharepredictivemodelsforantidepressantactivityinmice.The
miceorallyreceived10mgoffolicacidincombinationwith10mgoffluoxetine(anSSRIdrug)

andafter60minutestheywereassessedintheforcedswimmingtest.AtwowayANOVA
presentedsignificantdifferencesforthefolicacidtreatment,fluoxetinetreatment,andfolicacid
incombinationwithfluoxetinetreatment.Analysesoftheseresults,providedfortheobservation
ofenhancedantidepressanteffectsresultswhenfluoxetinewascombinedwithfolicacid
supplementation2.Duetotheseeminglysynergisticeffectsmeasuredthroughoutthecourseofthe
experiment,researchersproposedthatthemechanismofactioncouldbecontributedtothefact
thatbothfluoxetineandfolicacid,increase5HT(serotoninreceptors)inthesynapticcleft 2.
AstudyconductedbyPapakostasetal,wasundertakeninordertoexaminetheeffectivenessof
Lmethylfolate(abiologicallyactiveformoffolicacid)supplementationonpatientswithmajor
depressivedisorderswhohavepreviouslyhadpartialresponseornoresponsetoSSRIs.148
patientswereenrolledintwo,30daytrialswheretheywererandomlyassignedtoreceiveL
methylfolatefor60days(7.5mg/dayfor30daysfollowedby15mg/dayfor30days),placebo
for30daysfollowedbylmethylfolate(7.5mg/day)for30days,orplacebofor60days.The
resultsofthefirst30daytrial,whichincludedtheusageof7.5mgoflmethylfolatein
conjunctionwithSSRIs,foundthattherewasnosignificantdifferencebetweenthegroupthat
receivedtheSSRIplusthefolicacidsupplementincomparisontothegroupthatreceivedthe
SSRIandtheplacebo3.However,researcherswitnessedthat,duringthesecond30daytrail,the
15mg/dayoflmethylfolateinconjunctionwithcontinuedSSRItherapyprovedtobemore
effectivethantheSSRI/placebocombinationwhenresponserate,degreeofdepressionsymptom
score,andsymptomseverityweremeasured3.Theresultsofthisstudyimplicatethatpatientswho
havepreviouslyhadlittletonoresponsetoSSRIsmightfinditbeneficialto
supplement15mg/dayoflmethylfolateinordertotreatsymptomsofdepression.
127Patientswhowerestratifiedbysex,andwhometboththeDSMIIIcriteriaformajor
depressionandhadaHamiltonRatingscalescoreof20ormorepartookinastudyconductedby,

BaileyandCoppen,inordertoassesstheantidepressantactionoffluoxetinewhenadministered
withfolicacid.Thesubjectswereallrandomlyassignedtoreceive500goffolicacidora
placebo,inadditiontoreceiving20mgoffluoxetinedaily.Patientssymptomsofdepression
wereassessedusingtheHamiltonratingscale,andtheyweremeasuredatbaselineandthenagain
aftertwo,four,six,andtenweeksoftreatment.Otherfactorsthatwereassessedincluded,sex,
plasmafolatelevels,andhomocysteinelevels.HRSscoreswerecalculatedinordertoassess
patientsresponsivenesstotreatment.Interestingly,theresultsofthisstudyconcludedthatonlyin
femalepatientsdoestheadministrationoffolicacidenhancetheefficacyoffluoxetine,where
72.7%ofwomenwhoweretreatedwithfluoxetineandfolicacidrecoveredincomparisontoa
47.2%recoverywitnessedintheplacebogroup4.Researchersrelatedthedifferenceinthe
effectivenessofthetreatmentmechanisminmenwhencomparedtowomentothereduced
increaseinplasmafolate,whichwasinsufficienttoalterhomocysteinelevels,whichthey
attributedtothewitnessedreductionofdepressivesymptomsinwomen.Implicationsofthis
experimentresultedintheresearchersconcludingthatfolicacidsupplementationinconjunction
withanantidepressantcouldbegroundbreakingforthetreatmentofdepression,especiallyin
women.
InastudyconductedbyGinsbergetal,SSRIaswellasSNRI(serotoninnorepinephrinereuptake
inhibitors)monotherapywascomparedtoSSRI/SNRIplustheadditionofeither7.5mgor15mg
ofmethylfolatetodeterminewhichmechanismwasbetteratprovidingtreatmentforpatientswith
depressionattheinitiationoftreatment.Thisexperimentincluded242patientsbetweentheages
of1870,whohadahistoryofmajordepressivedisorderandscoreda45ontheCGISscale.
Subjectswereassignedtobeontheirrespectivemedicationsfor60days,andtheprimary
measureofoutcomewasdeterminedbyimprovementinCGISscores.Theresearchersofthis
studyconcludedthatafter60days,SNRI/SSRIplusmethylfolateismoreeffectiveattreating

majordepressivedisordersthanmonotherapyalone,withan18.5%improvementindepressive
symptomsincomparisonto7.04%5.Theresearchersalsonotedthat,the
antidepressant/methylfolatecombinationgroupshowedstricteradherencetotheirtherapywhen
comparedtothemonotherapygroup5.Thiswasnotedbyasignificantreductioninthenumberof
patientsdroppingoutoftheexperimentduetoadverseeffects.Ultimately,theresearchers
concludedthatantidepressanttherapyincombinationwithlmethylfolatesupplementationproved
tobenotonlyamorerapidtreatmentmethodfordepressionthanantidepressantsalone,butalsoa
moretoleratedmethod.
Conclusion
AlargenumberofadultsintheUnitedStatessufferfromdepression,andmanyoftheseadultsdo
notrespondwelltoSSRIsandotherdepressionmedications,ortheydiscontinueusingthemdue
topoorsideeffects.Thepooreffectivenessofdrugtreatmentcausedresearcherstoseek
alternativeformsoftherapy,whichleadtothediscoverythatmanydepressedindividualsare
folatedeficient.Althoughresearchinthisareaisstillfairlyyoung,evidencesupportingthe
combinationofafolatesupplementandanantidepressantasamoreeffectivemeanstotreat
majordepressivedisordersisdefinitelypresent.Amechanismofactionprovidedbytheabove
mentionedresearchdemonstratesthat,thecoupledpositiveeffectoffolicacidand
antidepressantsmaybeattributedto,bothcompoundsinhibiting5HTuptakethusincreasing5
HTlevelsinthesynapticcleft2;thisultimatelyincreasestheefficacyofSSRIdrugs.Researchin
thisfieldalsoindicatesthat,toincreasetheeffectivenessofantidepressants,menmayneedlarger
dosesoffolicacidthanwomendo.Thislineofevidencecomesfromthemechanismofaction
wherebyfolicacidsexertssynergisticeffectswhencoupledwithantidepressantsbyincreasing
plasmafolateenoughtoincreaseplasmahomocysteineanimportantmetaboliteinmonoamine
neurotransmitters4.Althoughthemechanismsofactionareonlypostulatedasofnow,folicacid

supplementationdoesappeartoincreasetheeffectivenessofantidepressantsmorerapidlyand
withfewersideeffectsthanwhenantidepressantsareadministeredalone.However,more
researchintheareaneedstobedoneinordertodeterminetheexactpositiverelationshipthat
thesetwocompoundsmayhave,andtheadequatedosageneededinordertomaximizetheir
synergisticeffects.

References
1. MillerA.Themethylation,neurotransmitter,andantioxidantconnectionsbetweenfolate
anddepression.AltMedicineRev[serialonline].September2008;13(3):216226.
Availablefrom:AcademicSearchComplete,Ipswich,MA.AccessedApril1,2016.
2. BrocardoP,BudniJ,KasterM,SantosA,RodriguesA.Folicacidadministration
producesanantidepressantlikeeffectinmice:Evidencefortheinvolvementofthe
serotonergicandnoradrenergicsystems.Neuropharmacology[serialonline].January1,
2008;54:464473.Availablefrom:ScienceDirect,Ipswich,MA.AccessedApril1,2016.
3. PapakostasG,SheltonR,FavaM,etal.lMethylfolateasAdjunctiveTherapyforSSRI
ResistantMajorDepression:ResultsofTwoRandomized,DoubleBlind,Parallel
SequentialTrials.AmericanJournalOfPsychiatry[serialonline].December
2012;169(12):126712748p.Availablefrom:CINAHLPluswithFullText,Ipswich,
MA.AccessedApril1,2016.
4. CoppenA,BaileyJ.Enhancementoftheantidepressantactionoffluoxetinebyfolicacid:
Arandomised,placebocontrolledtrial.JournalOfAffectiveDisorders[serialonline].
November2000;60(2):121130.Availablefrom:PsycINFO,Ipswich,MA.Accessed
April1,2016.
5. GinsbergL,OubreA,DaoudY.Lmethylfolateplusssriorsnrifromtreatmentinitiation
comparedtossriorsnrimonotherapyinamajordepressiveepisode.InnovationsIn
ClinicalNeuroscience[serialonline].January2011;8(1):192810p.Availablefrom:
CINAHLPluswithFullText,Ipswich,MA.AccessedApril1,2016.