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AVAILABLEEFFECTIVETREATMENTSFORPANICDISORDERANDAGORAPHOBIAANDSATISFACTIONWITHTREATMENTB.Bandelow,P.D.Dr.,Dipl.Psych.,ConsultantPsychiatrist,K.Sievert,Dr.M.Rthemeyer,G.Hajak,P.D.Dr.,ConsultantPsychiatrist,L.Adler,Dr.,ConsultantPsychiatrist,andE.Rther,Prof.Dr.,Gttingen,Germany.

Correspondence:

PDDr.B.Bandelow,Dept.ofPsychiatry,TheUniversityofGttingen,Germany

AbstractInordertocomparethecurrentstateoftreatmentofpanicdisorderandagoraphobia(PDA)withtherecommendationsderivedfromcontrolledstudies,100PDApatientsand103physicians,psychologistsandpsychotherapistswereinterviewedbymeansofstructuredinterviewsaboutthepsychologicalandpsychopharmacologicaltreatmentsusedinpanicdisorder.Bothinvestigationsrevealedthatpsychologicalandpharmacologicaltreatmentmodalitieswithprovenefficacyarebeingunderutilized(e.g.cognitivebehaviortherapy,exposuretherapy,tricyclicantidepressants,benzodiazepinesorselectiveserotoninreuptakeinhibitors).Ontheotherhand,methodswhoseefficacyhasnotbeenprovenarebeingwidelyapplied.Theretrospectiveinterviewswiththepatientsrevealedthattheyweremostsatisfiedwithtreatmentsthathavebeenproveneffectiveincontrolledstudies.Reasonsfortheinadequateuseofproventreatmentmodalitiescouldbeinsufficientknowledge,ideologicalissuesorthefactthat40percentofthehealthprofessionalsdidnotaccepttheterm"panicdisorder"asdefinedbyDSMIII.Treatmentofpanicdisordermightbeimprovedifmoreheedweretakenoftheresultsofclinicalstudies.

Keywords:PanicDisorderAgoraphobiaDrugtreatment,Psychologicaltreatment

IntroductionPatientswithpanicdisorderwithorwithoutagoraphobia(PDA)asdefinedbyDSMIIIRcanbeeffectivelytreatedwithpsychologicalandpsychopharmacologicaltreatmentmodalities.Foranoverview,all77PDAstudiesthatcouldbetracedbycomputeraidedliteraturesearchwereevaluated(updateofstudy[2]).InTable1andTable2,theresultsofcontrolledstudiesarelisted.AsummaryoftheseresultsispresentedinTable3.Asplacebotreatmentsareusuallyhighlyeffectiveinpanicdisorder[1],onlystudiesshouldbetakenintoaccountthatusedadrugplacebo,a"psychologicalplacebo"ora"waitinglist"conditionasacontrolgroup.Treatmentsthathaveproveneffectiveinsuchcomparisonsinclude:benzodiazepines(e.g.alprazolam[1]),tricyclicantidepressants(e.g.imipramine[7]orclomipramine[12]),irreversibleMAOinhibitors(e.g.phenelzine[22]),andserotoninreuptakeinhibitors(e.g.fluvoxamine[4]orparoxetine[19]).AconsensusconferenceoftheNationalInstituteofMentalHealthhasrecommendedthesedrugsfortreatmentofPDA[17].NeurolepticsarebeingwidelyappliedinanxietydisordersinEurope,thoughtheirefficacyhasnotbeenshowninPDAtrials.Treatmentstudieswithbetablockershaveshownconflictingresultsinsummary,convincingproofofefficacyismissing.Propranololwasnotbetterthanplaceboandlesseffectivethanalprazolam[16].Inanotherstudy,itwaslesseffectivethandiazepam[18].Herbalpreparationsorhomoeopathicformulationshavenotbeeninvestigated.

Psychologicalmethodswithprovenefficacyincludebehavioraltherapieslikeexposureorcognitivetherapy[36].Otherbehavioraltechniqueslikesystematicdesensitization[26]orprogressiverelaxation[11]werelesseffectivethanexposuretherapy[1315].PsychodynamicpsychotherapywasonlyinvestigatedonceinPDApatients:inthatstudy,acombinationofpsychodynamictherapyandexposurewassuperiortopurepsychodynamictherapy[10].Otherpsychologicaltherapies,e.g.clientcenteredtherapy[20],autogenictraining[21]orbiofeedback[9]haveneverbeeninvestigatedinPDApatients.

ComparisonsofpsychologicalandpsychopharmacologicaltherapieshavebeendiscussedindetailbyBandelowetal.[2].Thenumberofsuchcomparisonsislow,andtheirresultsareconflicting.Insummary,nomajoradvantageofeithermethodcanbefound.Becauseofthelownumbersoffollowupinvestigations,thewidelyheldopinionthatpsychologicaltherapiesaremoreeffectiveatfollowupwhencomparedtodrugtherapycannotbeproved.Thoughitissometimesemphasizedthatsimultaneousapplicationofpsychopharmacologicaldrugscouldinhibitpsychologicaltherapy,studieshaveshownthatacombinationofbothmodalitiesseemstobeadvantageous[25].

Tocomparetheresultsofclinicalresearchwiththestateoftreatmentinreality,twointerviewstudieswereconducted:first,amongPDApatients,andsecond,amonghealthprofessionalstreatingthesepatients.Patientswereaskedwhichtherapeuticmodalitieshadbeenappliedtothemandwhethertheyfeltthesetreatmentshadbeeneffective.Physicians,psychologistsandpsychotherapiststreatingpanicpatientsintheirdailypracticewereaskedabouttheirtreatmentpreferences.

Study1:PatientInterviewsMethods

OnehundredpatientswithcurrentorremittedDSMIIIRpanicdisorderandoragoraphobiawereaskedtoreportonanydrugandpsychologicaltreatmenttheyreceivedinthecourseoftheirillness.NinetypatientswereformerorpresentclientsoftheanxietydisordersunitoftheUniversityofGttingen,Germany.Thesepatientswerecontactedbymailoratavisitintheunit.Moreover,attemptsweremadetoconatactallPDApatientspresentlybeingtreatedintheurbaninpatientunitstreatinganxietypatients.Thus,10additionalpatientswhowerebeingtreatedinpsychiatricorpsychosomatichospitalsatpresentcouldbequestioned.Of207patientscontacted,24werenottraceable.Eightythreegavetheirconsenttotheinterview.Patientswerequestionedbymeansofastructuredinterviewconcerningthepharmacologicalandpsychologicaltreatmentmodalitiestheyhadreceivedduringthecourseoftheillness.Selfapplicabletreatmentssuchasautogenictrainingwerealsoevaluated.Singleacutetreatmentsofpanicattacks(e.g.emergencytreatmentswithbenzodiazepineinjections)werenotanalyzed.Onlytreatmentsthatwerewellrememberedbythepatientswereevaluated.Treatmentsthatweregiveneitherinasubclinicaldoseornotlongenoughtobeeffectivewereincluded.Fortricyclicantidepressants(TCAs),selectiveserotonininhibitors(SSRIs),andmonoamineoxidaseinhibitors(MAOIs)onlytreatmentswithaminimumdurationoffourweekscontinuousintakewereevaluated.Forbenzodiazepines,neurolepticsandherbalpreparations,aminimumintakedurationofoneweekwasrequired.Of241drugtreatmentsreportedbythepatients,28werenotevaluablebecauseofthiscriterion.Forallpsychologicaltreatmentsaminimumtreatmentdurationof8weekswasnecessaryforinclusion.Forinpatienttreatmentinapsychologicaltreatmentunit,aminimumdurationof4weekswasrequired.Fivepsychologicaltreatmentsoutof103hadtobeexcludedbecauseofinsufficientduration.

Patientswereaskedtoindicatetheirsatisfactionwithacertaintherapybyrespondingtothestatement,"thistherapyhasbeenveryhelpfulagainstmyfear"ona5pointLikertscale(from0="nottrue"to4="true").Asthescalewasassumedtobeofordinalranklevel,thecentraltendency("mean")oftheseanswerswastakenasa"satisfactionindex".CentraltendencieswerecomparedwithMannWhitneysUtest.StatisticalanalysiswereperformedwiththeStatisticalAnalysisSystem(SAS6.08,SASInstitute,Heidelberg).

Finally,54patientswhohadreceivedbothdrugs(notincludingherbalpreparations)andpsychologicaltreatmentsinthecourseoftheillnesshadtoindicatewhichkindoftreatmenthadhelpedmostinthecourseoftheillness.Onlyoneanswerwaspossibletothisquestion.

ResultsFrequencyofApplicationofTreatments

Fourpercentofthepatientshadnotreceivedanytreatmentsbeforetheinterview.Eightyeightpercentofthepatientshadreceiveddrugtreatmentsinthecourseoftheiranxietydisorder.Alltogether213drugtreatmentswereevaluated.AlistofsubstancegroupsappliedonthepatientsisshowninTable4.Benzodiazepineswerethemostfrequentlyuseddrugs,followedbytricyclicantidepressantsandherbalpreparations.Amongthebenzodiazepines,diazepam(21%)andlorazepam(13%)wereusedmostfrequently,amongtricyclicantidepressantsdoxepine(18%)andimipramine(10%).Themostusedneurolepticdrugwasfluspirilene(18%).

ThepercentageofpatientswhoreceivedacertainpsychologicaltreatmentisgiveninTable5.Fiftyeightpercentofthepatientshadreceivedoneoftheindicatedpsychologicaltreatments.Alargenumberofpatients(28%)couldnotindicatethespecificationorschool"ofpsychologicaltherapyappliedtothem.Noneofthesepatientsreportedtheapplicationofbehaviortechniqueslikeexposure.

Drugprescriptionbygeneralpractitionersandothernonpsychiatrists

Nonpsychiatrists(generalpractitioners,internistsandothers)showedadifferentprescriptionprofile,asreportedbythepatients.Benzodiazepines,neuroleptics,andherbalpreparationsweremoreoftenprescribedbynonpsychiatristsascomparedtopsychiatrists,whereaspsychiatriststendedtousemoretricyclicantidepressants(Table6).

Satisfactionwithtreatments

InFigure1thesatisfactionwiththedifferentdrugsappliedasratedbythepatientsisshown.Benzodiazepines,SSRIsandtricyclicantidepressantswerethemostfavoredpsychopharmacologicaldrugs.TheSSRIswereonlyusedin7%sothattheresultsmaynotberepresentative.Neurolepticswerenotratedveryhighly,andherbalpreparationsandbetablockerswereassessedaspracticallyineffective.InTable7thesignificantcomparisonsamongdrugtherapiesaregiven.

Amongpsychologicaltherapies,behaviortherapywaspreferred(Figure2).Satisfactionwiththismethodwassignificantlyhigherthanwithpsychodynamicallyorientedtherapy(p

psychoanalytictraining,comparedto17%ofthe22respondentswithbehaviorallyorientedtraining.

Discussion

Thetreatmentofpatientswithpanicdisorderandagoraphobia(PDA)couldfurtherbeimprovediftheresultsofclinicalstudieswereputintopractice.Thiswasshowninasurveyamong100patientswithPDAand103healthprofessionalstreatingPDApatients.Differencesbetweenthetwosurveyscanbeexplainedbythefactthatthepatientshadtoreportretrospectivelyabouttheirtreatments,whereasthehealthprofessionalshadtoreportaboutthestateoftheirknowledgetodate.Bothresultsmightbebiased:thepatientsanswersbythepossibilitythattheydidnotremembertheappliedtreatmentsverywell,andthehealthprofessionalsanswersbythefactthattheyhadthechancetoinformthemselvesintheliteraturebeforefillingoutthequestionnaire.Nevertheless,bothsurveyswereconsistentinshowingthattreatmentmodalitiesforwhichefficacyproofsexistwereunderutilized.Ontheotherhand,treatmentmodalitiesthathaveneverbeeninvestigatedinPDApatientsarebeingwidelyapplied.Forexample,nonpsychiatristsproposedherbalandhomoeopathicpreparationsasafirstlinetreatmentforpanicdisorder.Alowincidenceofadverseeventsisoftenofferedasanargumentfortheuseofthesepreparations.However,thechoiceofdrugtreatmentshouldnotbeguidedbysideeffects,butprimarilybyefficacy.Ifaprescriberputshishopeonlyintheplaceboeffect,aneffectivealternativetreatmentmightbewithheldfromthepatient.

InGermanyitiscommontotreatanxietydisorderswithneuroleptics,butproofofefficacyproofsislackingforpanicdisorderpatients.AconsensusconferenceoftheNationalInstituteofMentalHealthdidnotrecommendneurolepticsforpanicdisorder.Nevertheless,onethirdofthepatientsreportedhavingbeentreatedwithneurolepticsevenonethirdofthepsychiatristsindicatedthattheyuseneurolepticsfortreatmentofpanicdisorder.

Thoughnoconvincingefficacyproofsexistforbetablockers,theywerenamedby26%ofthepsychiatristsasapossibletreatmentoption.Ontheotherhand,only6%ofthepatientsindicatedthattheyhadbeentreatedwithbetablockers.

Selectiveserotoninreuptakeinhibitorswereunderrepresentedinbothsurveys.ThepossiblereasonmaybethatSSRIsarerelativelynewonthemarket.Tricyclicantidepressantswhichareproposedasfirstlinetreatmentintheliteraturehavenotevenbeentriedinhalfofthepatients.Onlyonequarterofnonpsychiatrists,butthreequartersofthepsychiatristsreportedprescribingthesedrugs.

Halfofthepatients(48%)reportedthattheyhadreceivedbenzodiazepinetreatment.Twiceasmanypsychiatrists(45%)asnonpsychiatrists(22%)reportedprescribingthesedrugs.However,accordingtothestatementsofthepatients,theyhadreceivedevenmorebenzodiazepineprescriptionsfromnonpsychiatrists.Inothercountriesbenzodiazepinesaremorefrequentlyprescribedtopanicpatients,ascomparablestudiesintheUnitedStates[8]andinCanada[24]haveshown.

Lookingatproposedpsychologicaltherapies,underutilizationofeffectivemethodsisevenmorestriking.Manypatientswereinstructedtotreattheirdisorderwithautogenictraining,thoughnoproofofefficacyisavailableforthistreatmentmodality.Onethirdofthepatientsindicatedtheyhadbeentreatedwithdepthpsychologyorpsychoanalytictherapy.Asstatedabove,thedatabaseforthistreatmentmethodispoorinspiteofitswidespreaduse.

Asubstantialnumberofpatientscouldnotindicatethepsychologicaltherapyschoolappliedtothem.Inthesecasespatientswereaskedifspecifictechniqueslikeexposuretofearfulsituationshadbeenperformedduringsessions.Inallcases,patientsdeniedtheuseofsuchtechniquessoitcanbeexcludedthatthesepatientshadbeentreatedwithbehaviortherapy.

InvestigationsintheUSAandCanadaalsoshowedalackofconcordancebetweenresultsofclinicalstudiesandthecurrentstateoftreatment[582324].InGermanyonereasonfortheuncriticaluseofineffectivetreatmentmodalitiesmaybeinsufficientknowledge,theotheronemaybethatthenewclassificationofanxietydisordersbyDSMIIIorICD10doesnotfindunequivocalacceptance:40%ofthehealthprofessionalsindicatedthattheywouldnotacceptthetermpanicdisorder"forthedescribedsymptompattern.AcceptanceofthemodernDSM/ICDclassificationoftheanxietydisordersbyhealthcareprofessionalstreatingthesepatientscouldhelptoimprovetheacceptanceofresearchresults.

Theresultsofthisretrospectiveinvestigationshouldbeinterpretedwithcautionbecauseanumberoffactorscouldnotbecontrolledinthestudy:properrecollectionofappliedtherapiesbythepatients,adequatedurationanddoseofthedrugs,complianceofdrugintake,availabilityofpsychologicaltreatments,adequatedurationofpsychologicaltreatments,classificationleveloftherapists,assessmentproblemsarisingfromcombinationtreatmentsandmanyotherfactors.Mostoftheinterviewedpatientswereclientsofourpsychopharmacologicalandbehaviorallyorientedanxietydisordersunit.Thismighthaveledtoadistortionofthepicture.Resultsmighthavebeendifferentiftheinterviewshadmostlybeenconductedinaninstitutionapplyingonlypsychologicaltherapy.However,acomparableinvestigationwasconductedinamainlybehavioraltreatmentinstitutionandshowedalmostthesameresults[24].Moreover,thestatementsofpatientsconcerningtheefficacyoftreatmentsrevealedthatpatientsappreciatedpreciselythosetreatmentmethodsthathavebeenshowntobeeffectiveincontrolledstudies.

Anotherreasonwhytheresultsshouldbeinterpretedwithcautionisthefactthatpatientsdonothavethesamepossibilitytojudgethe

risk/benefitratioofcertaintreatmentsashealthprofessionalsdo.Resultsmayhavebeenbiasedinfavoroftreatmentsshowingimmediatesuccess,suchasbenzodiazepinetreatment,ascomparedtotreatmentswithdelayedefficacy,likepsychologicaltherapies.Longtermeffectssuchaspossibleaddictiontobenzodiazepinesmaynothavebeentakenintoconsideration.

Muchefforthasbeenputintocontrolledstudiesontheefficacyofpanictreatments.Forthebenefitofthepatientsconcerned,theresultsoftheseinvestigationsshouldbeacceptedbyprofessionalstreatingpanicdisorderpatientsinordertoimprovetheoutcomeoftreatment.

Drug Positivestudies

Negativestudies*

Alprazolam15 1

Imipramine15 4

Fluvoxamine6 0

Clomipramine5 0

Paroxetine3 0

Adinazolam,clonazepam,lorazepam,diazepam,sertraline 2 0

Amitriptyline,brofaromine,carbamazepine,citalopram,desipramine,etizolam,inositol,lofepramine,phenelzine,valproicacid,zimelidine

1 0

Propranolol1 2

Bupropion,clonidine,ibuprofen,maprotiline,ritanserine,trazodone,verapamil

0 1

Buspirone2 3

Table1.Overviewoftheefficacyofdrugsinpanicdisorderandagoraphobia(doubleblindstudies)moreeffectivethanplacebooraseffectiveasreferencedrug*notmoreeffectivethanplaceboorlesseffectivethanreferencedrug

Psychologicaltreatment Positivestudies Negativestudies*

Cognitivetherapy6 2

Exposuretherapy3 2

Systematicdesensitization0 1

Table2.Efficacyofpsychologicaltreatmentsinpanicdisorderandagoraphobiamoreeffectivethancontrolcondition*nomoreeffectivethancontrolcondition

Drugs

Tricyclicantidepressants(e.g.imipramine,clomipramine)

Serotoninreuptakeinhibitors(e.g.fluvoxamine,citalopram,paroxetine)

Benzodiazepines(e.g.alprazolam)

IrreversibleMAOinhibitors(e.g.phenelzine)

Psychologicaltherapies

Cognitivetherapy

Exposuretherapy(foragoraphobicpatients)

Table3.Overview:treatmentmodalitiesforPDAthathavebeenshowntobeeffectiveincontrolledtrials

Drugs Percent

Benzodiazepines48%

Tricyclicantidepressants42%

Herbalpreparations32%

Neuroleptics29%

Serotoninreuptakeinhibitors7%

Betablockers6%

Tetracyclicantidepressants3%

IrreversibleMAOinhibitors2%

Table4.PercentageofPDApatientswhoreceiveddrugsinthecourseoftheirillness(n=100)

Psychologicaltreatment Percent

Autogenictraining43%

Psychodynamictherapy33%

Unknown28%

Cognitive/behaviortherapy20%

Biofeedback6%

Progressiverelaxation6%

Hypnosis4%

Table5.Psychologicaltherapies:frequencyofapplicationinpercent

nprescriptions

Psychiatrists Nonpsychiatrists

noprescription

unknown

Benzodiazepines77 40.2% 57.1% 2.6%

Tricyclicantidepressants 51 64.7% 31.4% 3.9%

Neuroleptics30 33.3% 63.3% 3.3%

Herbalpreparations 37 10.8% 54.9% 35.1% 0.0%

Total195 40.0% 50.7% 6.7% 2.6%

Table6.Prescriptionofdrugsbypsychiatristsandnonpsychiatrists(generalpractitioners,internists,andothers)

SSRI TCA Neuroleptics Herbalpreparations

BenzodiazepinesN.S. N.S. P

N.S.

Table7.Significanceofcomparisonsbetweendifferentmedications(MannWhitneysUtestBonferronicorrection)

All

physicians

(n=79)

Nonpsychiatricphysicians

(n=41)

Psychiatrists

(n=38)

Tricyclicantidepressants48% 24% 74%

Herbalpreparations40% 46% 29%

Benzodiazepines33% 22% 45%

Neuroleptics24% 20% 29%

Betablockers20% 15% 26%

Homoeopathicformulations18% 32% 3%

Serotoninreuptakeinhibitors13% 3% 24%

Irreversiblemonoamineoxidaseinhibitors 8% 0% 16%

Others1% 3% 3%

Table8.Percentageofdifferentgroupsofphysicianswhoproposedifferentdruggroups(morethanonechoicepossible)

Psychologicaltherapy All

psychologicaltherapists

(n=68)

Allphysicians

(n=49)

Psychiatrists

(n=33)

Psychologists

(n=22)

Psychoanalysis44% 57% 51% 9%

Clientcenteredtherapy(Rogerian) 28% 35% 33% 9%

Cognitive/behaviortherapy 28% 4% 6% 64%

Table9.Respondentspracticingpsychologicaltherapies:treatmentmodalityproposedinthefirstline

Figure1.Meansatisfactionwithdrugtherapy,indicatedona5pointscale(from0=notatallhelpfulto4=veryhelpful)

Figure2.Meansatisfactionwithpsychologicaltherapies,indicatedona5pointscale(from0=notatallhelpfulto4=veryhelpful)

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