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Allergy,DepressionandTricyclicAntidepressants
A.Hoffer,M.D.,Ph.D.
INTRODUCTION
Psychiatristshavebeenveryreluctanttoaccepttheideathatdepressions,whichtheyknowsowell,
maybecausedbyallergiestocommonenvironmentalmoleculessuchasfoods,airborneparticles,and
chemicalsinwater.Whenpatientsweredepressedandanxious,andatthesametimesufferedfrom
diseasesacceptedasallergic,psychosomaticexplanationswereused.Thisusuallymeantthata
psychologicalexplanationforthepresenceoftheallergicreactionswasinvoked.Themooddisorder
waslookeduponasanaturalreactiontothediscomfortoftheallergicreaction.Asthmaforalong
timewasoneofthesevenmajorpsychosomaticdiseases.Mostpsychiatristsstillbelieve
schizophrenicpatientscannotbeallergic,atleastnotwhentheyareill,butitwasacceptedthat
schizophreniaandallergicreactionscouldalternate.
Afewphysicianshaveconcludedthatallergicreactionsaremuchmorecommonthanonewould
assumefromthepsychiatricliterature,andthattheallergicreactioncausesavarietyofsymptomsof
whichmooddisorderisone.Thepatientwithasthmaisnotdepressedbecauseitishardtobreathethe
depressionandthedifficultyinbreathingarebothexpressionsofanallergicreactiontooneormore
foreigntypesofmolecules.Manyyearsagoallergistsrecognizedthatitwaspossibletobeallergicto
foodsaswellastopollensordusts,anddescribedthemoodsymptomswhichwerealsopresent.The
depressionandanxietywasrecognizedasareactiontotheallergen,butprimeemphasiswasgivento
thenonpsychiatricsymptoms.Clinicalallergistswhoarenowpractisingclinicalecologywentone
stepfurtherwhentheyrecognizedthatallergicreactionscouldcausedepressionandanxietyasthe
mainsymptomwithminimalsomaticreactions.Dr.T.Randolph(1961,1966)observedalarge
numberofallergicdepressions.Manicdepressivepsychosis,inhisopinion,isacyclicalreactiontoa
numberofallergensrangingfromfoodstoairbornepollutants.Butpsychiatristsareunawareofthe
contributionsmadebyclinicalecologistssuchasRandolph(1965),MandellandScanlon(1979),and
rejecttheobservationsofclinicalpsychiatricecologistssuchasNewbold(1975)andPhilpott(1974,
1979)aswellasSheinkin,SchacterandHutton(1979).
InthiscommunicationIwillsummarizetheevidencewhichsupportstheconclusionthatalarge
fractionofdepressionsareresponsestoenvironmentalmolecules,andthatthetricyclicsareeffective
inmanypatientsbecauseoftheirantihistaminicproperties,notbecausetheyactupontheserotoninor
sympathomimeticaminepathways.
DEPRESSIONISASYMPTOMOFALLERGICREACTIONS
Mostpatientswithsomaticsymptomsofallergyhaveamooddisorder,usuallydepressionand
anxiety.Icannotrecallapatientwithasthma,withasevereallergicitch,orsufferingfromhives,who
washappy.Theyallhaddepressionandanxietyrangingfromslighttoverysevere.Psychosomatic
explanationshavealongandhonourablehistorybutarenomorefirmlyestablishedtodaythanthey
werewhentheyweresopopularthirtyyearsago.Theyhavenopredictivevalue,donotindicate
treatment,andnopatientisbetterbecauseofthem.Thefactthatitmakessensethatdepressionshould
bearesponsetothesomaticsymptomsdoesnotmakethistrue.
Clinicalecologistswhohadlittleinterestinpsychiatrydescribeddepressionasacommonproblemin
allergicreactions.RoweandRowe(1972),pioneersinestablishingfooddeprivationteststolocate
foodswhichwerebeingreactedto,wrotethatsymptomsinclude"lackofenergyandambition,
drowsiness,loginess,depression,inabilitytothinkandconcentrate.Tempertantrumsandemotional
instabilitymaybepresent."
Ibecameinterestedintherelationofallergiestodepressionabouttenyearsago.Ialsoobservedthat
patientswhowerefoundtobeallergicusuallyweredepressed.Apsychiatristwhoneglectedtotakea
historyofallergicreactionswouldhavediagnosedthemasamooddisorder.LaterIobservedthat
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overhalfofallthepatientswhowerereferredtomebecausetheyweredepressed,andwhowerein
factdepressed,hadahistorygoingbackmanyyearsofsomaticallergies.Aschildrentheyhadeczema
orrashes,frequentupperrespiratoryproblems,andasthmaorhayfever.Mostwereawareofthese
symptomswhichhadbeentreatedbytheirphysiciansbutnoneassociatedthehistoryofallergic
reactionswiththeircurrentmooddisorder.Icheckedthiswithacolleaguewhowasknownasa
specialistindepressionbutwhodidnotpractiseorthomolecularpsychiatry.Hetoowasamazedatthe
highincidenceofsomaticallergiesinhisdepressedpatients.Theassociationissohighthatany
psychiatristswillcorroborateitinafewmonthsofobservation.Allthatisrequiredistoinclude
allergiesinthehistoryofthepatient.
Allergicreactionsmaybecomeaddictivereactions.Thisisthebasisforthecravingforsugar,alcohol,
andevenforfoodssuchasmilkormeat.Themostaccuratewayofdiagnosingafoodallergyisto
deprivethepatientoffoodforanumberofdaysusuallyfourbutsometimesmanymorearerequired.
Thisisdonebyfastingthepatientsorplacingthemuponadietoffoodsthattheyhaveusedvery
rarely(Mandell,1979).Deprivationofthefooduntilalltracesaregonefromthegastrointestinaltract
willresultinareductionofallsymptomsorintheircompleteremoval.Patientswhohavefood
allergiesoftenfeelnormaltowardthelatterpartofthefast.WhenIfastedfourdaysaboutsixyears
agoIexpectedtofeelhungryandirritablethewholefourdays.FortwoyearsIhadsufferedfroma
chroniccoldanddifficultyinbreathing.IwasunawareIhadanallergyandfastedforotherreasons
tomysurpriseIwaseuphoricthefourthdayandmycoldwasgone.IsubsequentlydiscoveredIwas
allergictomilkproducts.
Thefirstpartofthefastisgenerallyunpleasantthereisawithdrawalreactionlikethatsufferedbya
heavysmokerwhensmokingisstoppedabruptly,orlike"coldturkey"heroinwithdrawalofwhichthe
addictissofearful.Duringthesefewdays,patientsmisstherepeatedstimulusofthefoodsthey
normallyeattowhichtheyareallergicinafewpatientsthewithdrawalfromthesefoodshasbeen
verysevere.Oneofmypatientsconsumedtwelveglassesofmilkeachdayitkepthergoing.Iwas
theninexperiencedinthetechniqueandresultsoffooddeprivationandIadvisedhertodiscontinue
milkimmediately.WithinfivedaysshewasinadeeppsychoticdepressionandIhadtoadmitherto
hospitaltoprotectherfromkillingherself.SincethenIhavewithdrawnpatientsslowly,overaperiod
ofamonth,iftheyconsumelargequantitiesofanyfoods.Theconsumptionoflargequantitiesof
foodbread,pastry,sugarisaclearindicationtosuspectthesefoodsasoneofthecausesofdepression
andanxiety.
Withdrawaldepressionwillalsoaccountforthediurnalrhythmofdepression.Mostillnessesare
madeworsebyfatigueschizophreniaandphysicalillnessestendtobecomeworseintheeveningas
patientsbecomemoretired.Depression,insharpcontrast,tendstobecomebetteratnight,Itis
commonfordepressedpersonstofeelawfulinthemorningtheyaretired,anxiousanddepressed.As
thedaycontinuestheygraduallyfeelbetteraftersuppertheyoftenfeelalmostnormal.Whatlikely
happensisthis:inthemorningthepatientsaresufferingfromwithdrawal,havinghadnofoodfor12
hoursorsoduringthedayfoodstowhichtheyareallergicareconsumed,andbyeveningthereisno
furtherwithdrawalreaction.Eachdaythecycleisrepeated.
Treatmentoftheallergywill,inmostcases,"cure"thedepression.Ihaveseenthisinseveralhundred
patientsoverthepastsixyearsandcannolongerdoubtthisconclusion.Aboutsixyearsagoachronic
psychoticdepressivepatientwasreferredhehadbeendeeplydepressedforfouryears.Duringthat
timehehadfailedtorespondtoaseriesofECTinapsychiatricward.Hewasmaintainedon
injectabletranquilizerswhichpartiallycontrolledhisanxietybutlefthimincapableofdoingmore
thaneatingandsleepinginashelteredenvironment.Idiagnosedhimasadepressionwith
schizophrenicfeatures.Hedidnotrespondtoorthomolecularvitamintreatment.Afterafourdayfast
hewasnormalandonemonthlaterwasbackatworkasahighschoolteacherhehadnotbeenableto
workforfiveyears.Thefourdayfastandsubsequenttestingshowedhewasallergictocigarette
smoking.
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Subjectswhoarefreeofdepressionwillnoteasuddenresurgencewhentheyeatthosefoodsthey
havebeenavoidingeitherbyaccidentordeliberately.IhavefoundthatJanuarytendstobringbacka
largenumberofmypatientswhowerewellbutwhogavewaytotheholidayfoodssoabundantin
December,primarilyjunkfoodsorfoodartifacts.Ihavereferredtoanumberofassociationswhich
supportthecontentionmanydepressionsaresymptomsofallergicreactions.
1.Clinicalecologistsobservedahighincidenceofdepressionintheirallergicpatients.
2.Iobservedthatalargeproportionofdepressedpatientshadearlierinlifesufferedfromavarietyof
somaticallergies.
3.Removalofoffendingfoodsorothermoleculesresultedinrelieffromdepression.
4.Thetypicaldiurnalpatternofdeepdepressioninthemorningandreliefintheeveningcanbe
explainedbytheovernightwithdrawalfromfoodsoneisallergicto.
5.Depressioniscommonfollowingexposuretoallergicfoodsandmaycomeonwithinafew
minutes.
THETRICYCLICANTIDEPRESSANTS
Thetricyclicantidepressantsarethirdgenerationantihistamines.Thediscoveryoftheantihistamines
wasfollowedbytheiruseastranquilizers.Dr.H.Laborit(Caldwell,1970)waslookingforacentrally
activesedative.AsadirectresultofhisinterestchlorpromazinewasgiventothefirstpatientJanuary
19,1952.ItiscuriousthatourfirstuseoflargedosesofvitaminB3cameonlyafewmonthslater.
ButchlorpromazinewaspatentedandownedbyadrugcompanywhilevitaminB3waspublic
domain.
However,theideaofusingantihistaminesprecededchlorpromazinebyatleastthreeyears,Areport
appearedwhereitwasclaimedthatanantihistamine,benadrylIbelieve,wascombinedwithascorbic
acidandhelpedasmallnumberofschizophrenics.Asubsequentreportfailedtocorroborate,butthe
ideawasalreadyinthemedicalliterature.Failuretocorroborateisveryoftenafunctionoftheintent
ofthepersonwhofailed.
Itwasknownshortlyaftertheearlyantihistaminesbecameavailablethattheyhadsedativeproperties
thesewereundesirable.Thecompanieswantedasubstancewithnosedativepropertiesandmaximum
antihistaminiceffect.Dr.H.Laborit,asurgeon,wantedjusttheopposite.Chlorpromazinerepresented
thefirstmemberofthisnewclassofcompoundswhichhadmuchmorecentralsedativeeffectand
lessantihistaminiceffect.FromFrancethetranquilizersrapidlyspreadintoCanadaandlaterintothe
U.S.A.Dr.H.Lehmann'sreportfirsthittheEnglishliteratureafewmonthsaheadofanAmerican
investigator.
Psychiatristsdidnotreceivetranquilizersgratefully,fortheywererapidlyswingingtotheview
schizophreniawasapsychosocialdiseasewithinsignificantbiochemicalfeatures.Inthistheywere
ledbytheNationalInstituteofMentalHealth.Thisanalyticallyledandinspiredgrouponlybeganto
fundtranquilizerstudiesafterimmensepressurefromalargegroupofsenatorsandcongressmen.
Thisisanearlyexampleoftheuseofpoliticalpressuretoachieveapsychiatricimprovement.
Tranquilizerswereadistinctstepforward.Antihistaminesfatheredthetranquilizersandlaterthe
tricyclicantidepressants.Imipraminewassynthesizedin1948.Itislikeaphenothiazinetranquilizer
withantihistamineproperties.Kuhn(1957)reporteditsantidepressantproperties.Sigg(1968)
summarizeditsproperties:
(a)Itwaslikeaweakphenothiazinetranquilizer.
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(b)Itpotentiatedtheactionofnoradrenalininterferingwithuptakeandbinding.Inthisitresembles
phenothiazinesandantihistamines.
(c)Itaugmentsorprolongsmanyeffectsofamphetaminesandmethamphetaminessuchasmotor
activityandhyperthermia.Phenothiazinesincontrastdecreasedtheseeffects.Imipramineresembled
theantihistamines.
(d)Itcausedptosisasdidantihistamines.
(e)Itinterferedwiththehistaminergicsystem.
Siggdiscussedprevioussuggestionsthattheantidepressantactionofimipraminewasduetocentral
antihistaminepropertieswhilenotingthatcertainantihistamineswereantidepressants.InfactIhave
treatedapatientwhoseaddictiontoantihistamineswasaspowerfulasanyheroinaddiction.Sigg
finallyconcludedthattheantihistamineeffectwasnotafactor"becauseclinicallydemonstrated
antidepressantactionseemsinverselycorrelatedwithantihistaminicpotency."Butthentheconceptof
cerebralallergywasunknown.Thereisnonecessarycorrelationbetweencentralandperipheral
antihistamineactivity.SinceSigg'sreview,antihistamineactivityoftranquilizersandantidepressants
hasbeenmoreorlessignored.
However,anewpotentantidepressanthasappeared.MianserinisdescribedinanissueoftheBritish
JournalofClinicalPharmacology,editedbyPeetandTurner(1978).Itisaseffectivean
antidepressantasimipramineoramitriptylenebuthasfewersideeffects.Itisnotan
anticholinesterase.InthefollowingTableIhavelisteditspropertiesandthesearecomparedwiththe
usuallyacceptedpropertiesofthetricyclicantidepressants.
Itisclearwehaveanewantidepressantwhichdoesnotsharewiththetricyclicantidepressantsthe
usualeffectoncatecholaminesandonserotoninmetabolism.Theyonlyhaveantihistamineproperties.
Imipraminehasbeenusedtotreatanumberofallergicdiseases(AngstandTheobald,1970).Given
intramuscularly,25milligramspartiallyprotectedpatientsagainsthistamineinhalation.Ithasbeen
usedasanadjunctfortreatingasthmaandhasbeenrecommendedforthetreatmentofvariousaspects
ofasthma.Itdecreasesthesizeofhistamineinducedweals.Itisapotentantagonistofhistamineand
bradykinin.Infact,alltricyclicshavemoderatetostrongantihistamineactivity.
Mianserinhasalsobeenusedfortreatingasthma(PeetandBehagel,1978).Asthmaticsgiven
Mianserinhadfewernightattacks.Thisfindingwasnotpursuedbecauseofsideeffects,i.e.centrally
antidepressanteffects.Mianserinisaneffectiveantidepressantwhichdoesnothavethetwomain
characteristicactionsoftricyclicantidepressantsoncatecholaminesandserotonin,butisagood
antihistamine.
TABLE1COMPARISONOFMIANSERINANDTRICYCLICANTIDEPRESSANTS

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TREATMENTOFFOODALLERGYBYTRICYCLICANTIDEPRESSANTS
Patientswhohaveoneortwofoodallergiesareeasilydiagnosedandtreatedafterthefoodsare
identifiedtheyareavoided.Ihaveavoidedallmilkproductsforsixyearswithlittledifficultyand
havenothada"cold"sincethen,butmanypatientshavemultiplefoodallergiesandafewseemto
reacttonearlyeverything.Theyareverydifficulttotreatsuccessfullyandavarietyofprocedures
havebeendeveloped.
SpecialDiets
Ofthesetherotationdietshavebeenmostsuccessful.However,thereisalotofpatientresistance
towardthese,andtheirfamiliesmayalsoresist.Theytendtomakepatientstotallypreoccupiedwith
foodandeating,andoftentheysimplydonotwork.FastinghasbeenusedIhavehadseveralpatients
whoweremuchimprovedbyafourdayfastwhohadnofoodallergiesonsubsequenttests.On
returningtotheirnojunkdietwhichtheyhadbeenonbeforethefasttheyremainedwellforalong
time.Thefastappearedtohaveaclearingfunction.
Vitamins
Someofthevitaminshaveantiallergypropertiesandhaveprovenhelpful.Niacinreleaseshistamine
andlowershistaminelevelsinthebody.Ihaveobservedinmanypatientsthattheyrequiredvery
largedosesofniacin,1to12gramsperdayormore,untiltheyeliminatedthosefoodstheywere
allergicto.Inmanypatients,eliminatingmilkpromptlyreducedtheamountofniacinthatwas
requiredandcouldbetoleratedfrom12to3gramsperday.Ascorbicacidreactswithhistaminein
vitroandpresumablyintheblooditrapidlyinactivatesit.ithasbeenveryhelpfulindealingwith
allergicreactionsassociatedwithinsectbites,rashes,etcetera.
Enzymes
Ideally,foodswhicharecompletelydigestedtotheircomponentaminoacids,sugars,andfattyacids
oughtnottocauseallergicreactions.If,however,largerfragmentsareleft,dipeptidesordisaccharides
orothermorecomplicatedmolecules,thenonewouldexpectmoreallergicreactions.Theselarger
fragmentscaneasilycrossintothebloodandevenintothebrain,acrosstheblood/brainbarrierthis
hasbeenestablishedbytracerstudies.
Perhapstheselargeormacromoleculesareresponsibleforthetoxicreactionstosomefood.
Followingthislineofreasoningitispossibleadeficiencyinthesecretionofdigestiveenzymes,either
fromthepancreasortheintestinalwalls,mightbeafactorfinallyitwouldfollowthatreplacingthese
enzymeswouldbehelpful.SomeofmypatientshavebeenhelpedandIhaveseveralwhoareableto
eatfoodswhichpreviouslymadethemilltheytookpancreaticenzymesbeforeeating.Butothers
werenothelpedandseveralsufferedallergicreactionstotheenzyme,eithertothecapsule,itscolor,
ortothecontents.Butpatientswhohavebeenhelpedremainverygrateful.Werequirecareful,large
scaleclinicaltrialstoexaminethetherapeuticroleofenzymesandnutrientsupplements.
TricyclicAntidepressants
Inarecentpaper(1979)1describedtheuseofanantidepressant,Clomipramine,totreatobsessions
anddepression.ThereIsuggestedthatantihistaminepropertiesoftricyclicantidepressantsplayeda
roleandIreferredtoseveralpatientswhosemultiplefoodallergiescameundercontrolbyusingsmall
dailydosesoftricyclicantidepressants.Isuggesttheseantidepressantsshouldbetriedwhenother
therapeuticmeasureshavefailed.
Imipraminehasbeenusedfortreatingchildren'sallergieseventhoughcliniciansusingitthisway
havebeenunawareoftherelationship.Imipraminehasbeeneffectiveintreatingenuresisinchildren
butnoteverychildresponds.Gerrard(1973)establishedthatenuresisinsomechildrenisduetoan
allergicreactionofthebladder.itbecomessmaller,presumablyduetoincreasedtensionand
thickeningofthebladderwall.Whentheoffendingfoodisremovedthebladderrelaxesandinafew
weekstheyarenormal.Reintroducingtheoffendingfood,oftenmilk,quicklyreestablishesthe
bedwettingproblem.Perhapsthesearethechildrenwhorespondedbesttoimipramine.Ihavealso
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usedtricyclicantidepressantsforobesityandtocontrolvoraciousappetitesforcertainfoods,aswell
asforanumberofsomaticallergicreactions.
Manyobesepatientshaveavoraciousappetiteforfoodstowhichtheyareallergic.Theywilleata
loafofbreadinanhour,willdrink16glassesofmilkinaday,willeatapoundofchocolateinafew
minutes.Theseareallergicreactionsgonewildandhavebecomesevereaddictions.Ihavefoundthat
formanyofthesethetricyclicshelpreducetheintensityofthedesireforthesefoods,andhavehelped
manyobesepatientsbringtheirweightdownslowly.
Antidepressantsmaybeveryhelpfulintreatingchildrenwithlearningandbehaviouraldisorders
probablyhalfofthesechildrensufferfromcerebralallergies.Speer(1970)describedtheallergic
tensionstateas"aclinicalallergicstatewhichismarkedbydiffuseneuropsychicoveractivity.It
includesbothamotorcomponent(hyperkinesis)andasensorycomponent(hyperesthesia).Usually
botharepresentintheoversensitiveallergicchild."
CONCLUSION
Tricyclicantidepressantsareantidepressantslargelybecauseoftheirantihistaminicproperties.This
conclusionisbaseduponthefollowingobservations:
1.Thecloseassociationbetweendepressionandallergies.Itisraretofindonewithouttheother
whenoneisrelieved,soistheother.
2.Mianserinisapowerfulantidepressantwhichdiffersfromthetricyclicsinhavingnoeffectonthe
metabolisminthebrainofcatecholaminesorserotonin.Itisagoodantihistamine,apropertycommon
tothetricyclicsaswell.
3.Tricyclicantidepressantsareusefulintreatingallergicreactionsnomatterwhatformtheyhave
taken.Thisrangesfromallergicaddictionsuchasobesitytoenuresis.
Isuggestneuropsychopharmacologistsoncemoreexamineseriouslytheantihistaminicpropertiesof
theantidepressants.

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