抑郁症的影响及其治疗心率可变性和瞳孔光反射参数

JournalofAffectiveDisorders82(2004)245

–252

http://wendang.chazidian.com/locate/jad

Researchreport

Theinfluenceofmajordepressionanditstreatmentonheartrate

variabilityandpupillarylightreflexparameters

Karl-Ju¨r*,WolfGreiner,ThomasJochum,MarcFriedrich,¨rgenBa

GerdWagner,HeinrichSauer

DepartmentofPsychiatry,Friedrich-Schiller-UniversityofJena,Philosophenweg3,07743Jena,Germany

Received8July2003;receivedinrevisedform22December2003;accepted22December2003

Abstract

Background:Thelinkbetweendepressionandautonomicdysfunctionhasattractedmoreattentionsinceepidemiologicalstudieshaverevealedthatdepressedpatientshaveanaugmentedriskofcardiovascularmorbidityandmortality.Formerstudiesofautonomicdysfunctioninmajordepressionhaveshowninconclusiveresults.Aims:Tofurtherelucidatetheeffectofdepressionandmedicationonautonomicfunction,18patientsand18matchedcontrolsubjectswerecomprehensivelyassessedoncemedicatedandoncenon-medicatedaswellasafterfullclinicalrecovery.Methods:Cardiacautonomicfunctionwasevaluatedbymeasuringheartratevariability(HRV)parameters,andcentralautonomictonewasinvestigatedbyobtainingparametersofthepupillarylightreflex(PLR).Results:Acutelydepressedpatientswhohadnottakenantidepressantmedicationfor8weekspriortotheinvestigationdifferedsignificantlyneitherinheartrateparametersnorinparametersofthePLRfromtheircontrols.However,after2daysofantidepressanttreatment(SSRIandNaSSRI),parametersofheartrateanalysisandPLR(exceptrelativeamplitude)changedsignificantlyandremainedsignificantlydifferentafterclinicalrecovery.Limitations:Thestudyneedstoberepeatedusinglargerpatientgroups.Long-termstudiesareabsolutelyessential.Conclusion:Thestateofdepressiondidnotinfluenceautonomicparameterssignificantly.Infact,treatmentinfluencedautonomicfunctionfarmorethanthediseaseitself.Otherbranchesoftheautonomicnervoussystem(ANS),aswellasnewtechniquesshouldbeappliedtoelucidatewhethersmallchangesinautonomicfunctionexist.Thismightclarifywhetherdiseaseortreatmentmightinfluencecardiacmortalityindepression.

D2004ElsevierB.V.Allrightsreserved.

Keywords:Depression;Autonomicfunction;Heartratevariability;Pupil;Pupillometry;Selectiveserotoninreuptakeinhibitors(SSRI)

1.Introduction

Manysymptomsofdepression(e.g.,drymouthorconstipation)aresuggestiveofautonomicdysfunction

*Correspondingauthor.Tel.:+49-3641-935282;fax:+49-3641-935280.

E-mailaddress:Karl-Juergen.Baer@med.uni-jena.de(K.-J.Ba¨r).0165-0327/$-seefrontmatterD2004ElsevierB.V.Allrightsreserved.doi:10.1016/j.jad.2003.12.016

(DavidsonandTurnbull,1986;Bicakova-Rocheretal.,1996).Thelinkbetweendepressionandautonomicdysfunctionhasattractedmoreattentionsinceepide-miologicalstudieshaverevealedthatdepressedpatientshaveanaugmentedriskofcardiovascularmorbidityandmortality(Rabinsetal.,1985).Similar-ly,patientssufferingfromdepressionaftermyocardialinfarctionareknowntohaveareducedshort-andlong-termsurvivalrate(Andaetal.,1993;Frasure-Smithet

246K.-J.Ba¨retal./JournalofAffectiveDisorders82(2004)245–252

al.,1995,1999,2002;Pitzalisetal.,2001).While

definitemechanismsforthiscardiacvulnerabilityareunknown,itisassumedthatanalteredautonomicneurocardiacregulationisatleastoneimportantpath-ophysiologicalfactor(Agelinketal.,2001).

Heartratevariability(HRV)isaparticularlysen-sitivemethodusedtostudyautonomicdysfunction(LowandPfeifer,1997).Itshowstheextentofaverageheartratefluctuationsandreflectstheinter-playandbalancebetweensympatheticandparasym-patheticinputdisplayedonthecardiacpacemaker.AhighdegreeofHRVisobservedinpatientswithnormallyfunctioninghearts,whereassignificantlydecreasedlevelsofHRVcanbeobservedinpatientswithlowparasympathetictone.ConventionalHRVanalysishasbeenincorporatedintoclinicalstandardsinboththetimeandfrequencydomains(Malik,1996;GuidelinesoftheEuropeanSocietyofCardiology).Investigationsconcerningtheautonomicnervoussystem(ANS)indepression,mainlythosestudiesdealingwithheartratevariability,haverevealedconflictingresults.Somereportadecreaseinpara-sympatheticfunction(DalackandRoose,1990;Rechlinetal.,1994b;Guinjoanetal.,1995)whereasothersreportnochangeincomparisontotheircon-trols(Yeraganietal.,1991;Moseretal.,1998).Asimilarlyconfusingsituationexistswithregardtothesympathetictone.Therearereportsofanincreased(Guinjoanetal.,1995),adecreased(Tulenetal.,1996b)oranunaltered(Moseretal.,1998)sympa-theticfunctionunderrestingconditionsindepressedpatients.

Theinconsistenciesintheabovestudiesaremostlikelyduetotheapplicationofdifferentdiagnosticcriteria,thepresenceorabsenceofmedication,andpossiblyafailureinmatchingthecontrolgroup.Inthisstudy,wehavethereforeassessedperipheralautonomicfunctionbytheevaluationofHRVassuggestedbytheTaskForceReport(Novaketal.,1997).Amorecentralautonomictonewasstudiedbyobtainingthepupillarylightreflex(PLR),aputativemarkerofbothcentralsympatheticandparasympa-theticbalance.Todistinguishbetweentheinfluencesofmedicationandthedisease,severelydepressedpatientswerethoroughlyinvestigatedtwice,onceinthemedicatedstateandonceinthenon-medicatedstate.Finally,patientswereinvestigatedintheclini-callyrecoveredstate.

2.Materialsandmethods2.1.Subjects

Standardizedheartrateassessment(HRA)wasperformedon18right-handedpatientssufferingfrommajordepressionand18matchedcontrols(Table1).Werecruitedpatientsdiagnosedbyastaffpsychiatrist(allfulfillingDSM-IVcriteriaformajordepressivedisorder,noneforbipolardisorderIorII)whowereadmittedtoourinpatientwards.

Patientswhohadnottakenantidepressantsforatleast8weekspriortotheinvestigationswereallocatedtothefirsttimecategory(A)andinvesti-gatedagainforasecondtime(B)afterreceivingantidepressants(2–4days).Afterfullclinicalrecov-ery(C,6–9monthsfollowingtimecategoryB),thesepatientswereinvestigatedforthethirdtime.Controlsubjectsmatchedinageandsexwerealsostudiedthreetimesinparalleltopatients(sametimeintervals).

AllparticipantsgavewrittenconsenttoaprotocolapprovedbytheEthicsCommitteeoftheMedical

Table1

Demographicdataofpatientsandcontrolsubjects

Depressedpatients

ControlsubjectsParticipants

n=18;female:12

n=18;female:12DemographicdataAge(years)43.2F14.3(20–66)41.8F11.9(22–66)Schoolprimary:n=6

primary:n=8secondary:n=12

secondary:n=10Smokersn=3n=4

ClinicalratingscalesBDIa(A);23.11F4.5;28.9F6.1

4.1F1.7HAMDb

(A)BDI(B);24.6F7.7.0;29.1F6.73.4F1.4HAMD(B)BDI(C);5.1F4.5;2.8F3.7;3.9F1.7

HAMD(C)Medication(B)SSRI:n=7,NaSSRI:n=11Medication(C)

SSRI:n=6;NaSSRI:n=10;offmedication:n=2

a

Beck’sdepressioninventory.

b

Hamiltondepressionratingscale;SSRI:selectiveserotoninreuptakeinhibitors;NaSSRI:norepinephrineandselectiveseroto-ninereuptakeinhibitors.

K.-J.Ba¨retal./JournalofAffectiveDisorders82(2004)245–252247

FacultyoftheFriedrich-Schiller-University,Jena.

Controlpersonswererecruitedfromhospitalstaff.Patientsandcontrolpersonshadtobefreeofanyrelevantmedicalorpsychiatricdisease(includingdiabetes)andreceivednointerferingmedication.Patientsandcontrolswereaskedtorefrainfromsmoking(3controlsubjectsweresmoker),heavyeatingorexercising2hbeforetheinvestigation.Theseverityofdepressionwasassessedbasedonasemi-structuredclinicalinterview,theHamiltonde-pressionratingscale(HAMD;Hamilton,1960)andBeck’sdepressioninventory(BDI).Controlswerealsointerviewed(includingBDIrating)toassuretheabsenceofapsychiatricdisorder.2.2.Cardiovasculartestbattery

Standardizedheartrateassessment(HRA)wasperformedinasupinepositionwithanECGanalysisbytheNeurodiagRsoftwareprogram(H.Lambeck,Munich,Germany)intheeveningbetween4:00and8:00PM.AqualitativedescriptiveassessmentoftheECGwasmadeandtheQTtimewasdeterminedmanuallyincludingcalculationoffrequency-correctedQTtimes(QTc).

2.2.1.Five-minuterestingstudyofHRV

TheobtainmentandevaluationofHRVmeasure-mentswasbaseduponpreviouslypublishedexperi-mentalprocedures(WeinbergandPfeifer,1984;Ziegleretal.,1992).Therestingheartrate(HRr)wasdefinedastheaverageheartrateduringthe5-minexamination.TimedomainvariablesincludedthevariationcoefficientCVrandtherootmeansquareofsuccessiveinter-beatintervals(RMSSDr),whichwerecalculatedfrom150artifact-freeheartbeats.

DatausedforcalculatingthespectralanalysisweretheartifactfreeR–Rintervalsregisteredoverthetimeperiodof5minatatemporalresolutionof1ms.Thisseriesofintervalswasconvertedintoadiscretesignalof1024levelsbyusingamathematicalalgorithm(Bergeretal.,1986).TheresultingpowerspectrumwascalculatedbyuseofaFast-Fouriertransforma-tion.Thefollowingfrequencybandswereautomati-callyseparated:VLFband(verylowfrequency:0.003–0.04Hz),LFband(lowfrequency:0.04–0.15Hz)andHFband(highfrequency:0.15–0.4Hz).TheLFbandisassociatedwithbothsympathetic

andparasympatheticactivity,whiletheHFbandreflectsrespiratorysinusarrhythmiaresultingfromcentrallymediatedcardiacvagalcontrol(Novaketal.,1997).

2.2.2.Deepbreathingtest

Participantswereinstructedtotakesixdeepbreathsperminute(6sinspiration,4sexpiration).Fromatotalof100artifact-freeR–Rintervals,theheartrate(HRd),thevariationcoefficient(CVd)andtherootmeansquareofsuccessivedifferences(RMSSDd)weredetermined.2.3.Pupillometry

SubjectswereplacedcomfortablyinanadjustablechairinfrontofaCompactIntegratedPupillograph(CIPVersion8.0,AMTech,Weinsheim,Germany)inadarkroomfor10min.Subjectsthenplacedtheirheadinthechinandforeheadrests.Theywereaskedtofixtheirgazeatablackspotlocated10jtotherightatadistanceof2m.Thesystemelectronicallydetectedthepupilmarginsunderinfraredilluminationandcontin-uouslytrackedthepupildiameterusingstandardizedlighting(200ms;4Â103cd/http://wendang.chazidian.comingthelefteyeasasource,theparametersofpupillarylightreflex,namelythepupildiameter(mm),latencytothebegin-ningofconstriction(ms),theamplitudeofconstriction(mm)andtherelativeamplitudeofconstriction(%)werecalculated.2.4.Dataanalysis

WeperformedaMANOVAforrepeatedmeasure-mentsforcardiovascular,respiratory,pupillometryandclinicaldatausingthewithin-subjectsfactorTIME(alltimecategories)andthebetween-subjectsfactorGROUP(patientsvs.controls).Follow-upunivariateANOVAswereperformedtoevaluatethespecificeffectofsingleDVs.Posthocpair-wiset-testswerecarriedouttocomparetimecategoryAvs.B(effectofmedication)andBvs.C(effectofrecovery).

Sincegroupswerematchedforageandsex,nocovariateswereusedforfurthercalculations.

Anadditionalrepeated-measureMANOVAwasperformedtolookfordifferentialeffectsofselectiveserotoninereuptakeinhibitors(SSRI)andnorepineph-rineandselectiveserotoninere-uptakeinhibitors

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248K.-J.Ba¨retal./JournalofAffectiveDisorders82(2004)245–252

Fig.1.Meansandstandarddeviationsofheartrate(a),variationcoefficient(b),RMMSD(c),andLF–HFquotient(d)atrestandheartrate(e),

andRMMSD(f)duringdeeprespirationofdepressivepatientsandcontrolsontimecategoriesA(acute,notmedicated),B(acute,medicated)andC(recovered).Fortheillustrationpurposesoffigures,valuesofpatientsandcontrolswerecomparedateachtimepointusingt-tests(*p<0.05;**p<0.01;***p<0.001).

K.-J.Ba¨retal./JournalofAffectiveDisorders82(2004)245–252249

(NaSSRI).Whenappropriate,degreesoffreedomwere

correctedusingtheGreenhouse–Geisserprocedure.

3.Results

Multivariaterepeated-measureANOVAforalltimecategoriesrevealedasignificanteffectforGROUPs(Wilks’lambda=0.315;F(14,21)=3,25;p=0.007).Follow-upunivariateANOVAsshowedTIMEÂGROUPinteractionforRMSSDratrest[F(2,68)=4.14;p=0.02],forRMSSDd[F(2,68)=3.79;p=0.027]duringdeeprespiration.

Atrendwasobservedforthevariationcoefficient(CVr)[F(2,68)=2.76;p=0.07]atrestaswellastheheartfrequency[F(2,68)=2.817;p=0.06]andthevariationcoefficient(CVd)[F(2,68)=2.94;p=0.06]duringdeeprespiration(seeFig.1b,c).Thisindicatesachangeofparametersoverthreetimecategoriesatleastinonegroup(Figs.1and2).NodifferenceswerefoundforVLF,LFandQTctimeatanytimepoint.Anon-significanttrendwasobservedforHF(LF/HFRatio,Fig.1d).3.1.Effectofmedication

Posthocpair-wiset-testswereperformedtocomparetimecategoriesAandBinordertoanalyzetheeffectofmedicationonautonomicparameters.Significantdifferencesfordepressedpatientswerefoundatrestforthevariationcoefficient(CVr)[t(17)=2.8;p=0.02]andtheRMSSDr[t(17)=2.8;p=0.01].Duringdeeprespirationthevariationcoef-ficient(CVd)[t(17)=1.9;P=0.06]displayedatrend.Thisimpliesthatparameterschangedsignificantlyovertimeresultinginaloweredparasympatheticactivity.

Arepeated-measuremultivariateANOVAwiththebetween-subjectsfactorMEDICATION(SSRIvs.NaSSRI)didnotdemonstrateanoveralldifferenceforspecificmedication.

Nosignificantchangeswereobservedfortheuntreatedcontrolgroup.3.2.Effectofdiseaserecovery

Tostudytheeffectofclinicalrecoveryonauto-nomicparameters,posthocpair-wiset-testswereused

http://wendang.chazidian.comparisonofdiameterofthepupil,reactionlatencyandrelativeamplitudeofpatientsandcontrolsonalltimecategories.Fortheillustrationpurposeoffiguresvaluesofpatientsandcontrolswerecomparedateachtimepointusingt-tests(*p<0.05;**p<0.01;***p<0.001).Therewasnosignificantdifferencefordiameterofthepupilwhereasrelativeamplitudewassignificantlydifferentonalltimecategories.

tocomparetimecategoriesB(onmedication)andC(recovered,onmedication).Noneoftheperformedanalysesrevealedanysignificantdifferenceforpatientsand

controls.