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201. Moving beyond symptom reduction
Friday Abstracts
BIOLPSYCHIATRY 1998;43:1S-133S
FRZDA~ MAY 29 PLENARY SESSION Frontiers of Antipsychotic Treatment Friday,May 29, 8:30 AM–11:00 AM, Location: Harbour Ballroom Chairperson: David L. Braff 199. COMPARING NEW ANTI-PSYCHOTIC MEDICATIONS: WHAT DO THE DATA SAY? N.R. Schooler HiflsideHospitrd,LongIslandJewishMedicalCenter,Glen Oaks,NY 11004 Since 1990 a number of new anti-psychoticagents have become available.Four anti-psychoticmedicationshave been marketedin the United States; clozapine,olanzapine,quetiapineand risperidone.The labeledindicationfor clozapineis for “treatmentrefractoryschizophrenia”;the othersare indicatedfor “treatmentof psychosis.”The &ta that supportthese labeled indicationsare drawn from triafs comparingthe medicationsto placeboor to olderanti-psychoticagentsin schizophrenic subjects.Thosestudiesare of greatvafue,but do not addressthe obvious criticalquestionof comparisonsamongthese newermedicationsin the treatmentof schizophrenia. This presentationwill draw upontwo sourcesto addressthis question. Thefret, andmorepowerful,is the verylimitednumberof clinicaltriafs that have includeddirectcomparisonsof these medications.The second is data from clinicrdtrials that comparedone of the medicationsto an older anti-psychoticmedicationbut did not includea directcomparison to another newer medication. Rather than evaluating whether one medicationis “better”overrdl,comparisonswill be made in terms of a number of more specific parameters: positive psychotic symptoms; disorganization;negative symptoms;parkinsordsm;akathisia; tardive dyskinesia;weightgain; drowsiness;preventionof relapse. Thisreviewhas obviouslimitations.First,as notedabove,tiere are very few directcomparisons.Second,studyresultsare notreadilycomparable because of differingdesign characteristicssuch as patient population, dosage,studydurationand assessmentmeasures.Nonetheless,exarnirration of the availabledata may identify some differencesand areas in whichstudiesare neededto providemore definitiveanswers.
59s
dorsolateral prefrontal cortex (DLPFC) may represent an important nerrrobiological substratefor this cognitivedysfunction.In particular,the demonstratedrole of dopamirre(DA)in the mediationof thesecognitive processessuggeststhat the elementsof DLPFCcircuitryinfluencedby DA afferentsmight be especiallyvulnerablein schizophrenia.Consequently,the fmt part of this presentationwill focuson recentinvestigations of the DA innervationof the primate DLPFC.For example,in additionto targetingpyramidalneurons,DA terminalsappearto synaptically innervate only certain populationsof GABA-containinglocal circuitneurons.In addition,boththissubclassof GABAcellsandthe DA afferents to the DLPFC undergo substantialrefinementsduring late adolescence,the typical age of onset of schizophrenia.These findings suggestthat thesecomponentsof DLPFCcircuitrymaybe prcferentiafly affectedin schizophrenia.Resultsof studiesin postmortemhumanbrain specimensdesignedto test this hypothesiswill be presented,and the implicationsof these findingsfor the developmentand testing of new therapeuticagentswill be discussed.
201. MOVING BEYOND SYMPTOM REDUCTION M.F. Green UCLADepartmentof Psychiatryand BiobehavioralSciencesand the West Los AngelesVA MedicafCenter Problems in neurocognition(e.g., sustained and selective attention, verbal and spatial memory, executive functioning)have long been considered central to schizophrenia.Many of these neuroeognitive deficitsappearto he quiteindependentof the symptomsof the illness,the medicationsthat the patientsreceive,and the effects of institutionalization.Since1990,a largenumberof studieshaveassessedthe associations between neurocognitivedeficits and the daily functioningof scbizopbrenicpatients.Despitewide variationin the selectionof nerrmeognitive measuresacrossstudies,someconsistenciesarc evident.Neurocognitive capacities such as verbal memory and vigilance appear to be neeessaryfor adequatefunctionedoutcome.Deficitsin these areas may restrict the patient from attainingtheir optimaladaptation.In contrast, psychoticsymptomsare rather weak predictorsand cnrrclatesof functionaloutcome.Hence,neurocognitivedeficitspresentreasonabletargets for behavioraland/orpharmacologicalinterventions.New antipsychotic medicationsappearto offer an advantagefor neurocognitivecapacities compared with conventionalantipsychoticagents. In a double-bfind randomizedstudyfromour laboratory,risperidonehas shownsignificant beneficial effects comparedwith haloperidolfor measures of verbal workingmemory,secondarymemory,reactiontime, and perceptionof emotion.However,risperidonetreatmentdidnotyieldbenefitsfor motor learning,nor improvementsin verballearningstrategy.Severalmodels have been constmctedin an attemptto integratethese tindings into a unified framework. Jn these models, neuroeognitiveconstructs are essential for explainingthe pathwaysbetweenpsychopharrna cological treatmentand tinrctionaloutcome.
200. DOPAMINE SYSTEMS AND VULNERABLE CORTICAL CIRCUITS IN SCHIZOPHRENIA D.A. Lewis Departmentsof Psychiatryand Neuroscience,Universityof Pittsburgh, Pittsburgh,PA 15213 A critical frontier in the managementof schizophreniaand related disordersinvolvesthe developmentof therapeuticagents that not only ameliorate the positive symptomsof these disorders, but that also improvethe associateddisturbancesin cognitivefirnction.Convergent linesof evidencesuggestthat abnormalitiesin the neuralcircuitryof the
202. BEYOND DOPAMINE RECEPTOR BASED PHARMACOTHERAPIES OF PSYCHOSIS H.C. Fibiger Eli Lilly and Company,Indianapolis,Indiana46285 All currentlyprescribedantipsychoticagents,bothtypicaIand atypical, are antagonistsat D2-fikereceptors,this beingoneof the cornerstonesof
BIOLPSYCHIATRY 1998;43:1S-133S
FRZDA~ MAY 29 PLENARY SESSION Frontiers of Antipsychotic Treatment Friday,May 29, 8:30 AM–11:00 AM, Location: Harbour Ballroom Chairperson: David L. Braff 199. COMPARING NEW ANTI-PSYCHOTIC MEDICATIONS: WHAT DO THE DATA SAY? N.R. Schooler HiflsideHospitrd,LongIslandJewishMedicalCenter,Glen Oaks,NY 11004 Since 1990 a number of new anti-psychoticagents have become available.Four anti-psychoticmedicationshave been marketedin the United States; clozapine,olanzapine,quetiapineand risperidone.The labeledindicationfor clozapineis for “treatmentrefractoryschizophrenia”;the othersare indicatedfor “treatmentof psychosis.”The &ta that supportthese labeled indicationsare drawn from triafs comparingthe medicationsto placeboor to olderanti-psychoticagentsin schizophrenic subjects.Thosestudiesare of greatvafue,but do not addressthe obvious criticalquestionof comparisonsamongthese newermedicationsin the treatmentof schizophrenia. This presentationwill draw upontwo sourcesto addressthis question. Thefret, andmorepowerful,is the verylimitednumberof clinicaltriafs that have includeddirectcomparisonsof these medications.The second is data from clinicrdtrials that comparedone of the medicationsto an older anti-psychoticmedicationbut did not includea directcomparison to another newer medication. Rather than evaluating whether one medicationis “better”overrdl,comparisonswill be made in terms of a number of more specific parameters: positive psychotic symptoms; disorganization;negative symptoms;parkinsordsm;akathisia; tardive dyskinesia;weightgain; drowsiness;preventionof relapse. Thisreviewhas obviouslimitations.First,as notedabove,tiere are very few directcomparisons.Second,studyresultsare notreadilycomparable because of differingdesign characteristicssuch as patient population, dosage,studydurationand assessmentmeasures.Nonetheless,exarnirration of the availabledata may identify some differencesand areas in whichstudiesare neededto providemore definitiveanswers.
59s
dorsolateral prefrontal cortex (DLPFC) may represent an important nerrrobiological substratefor this cognitivedysfunction.In particular,the demonstratedrole of dopamirre(DA)in the mediationof thesecognitive processessuggeststhat the elementsof DLPFCcircuitryinfluencedby DA afferentsmight be especiallyvulnerablein schizophrenia.Consequently,the fmt part of this presentationwill focuson recentinvestigations of the DA innervationof the primate DLPFC.For example,in additionto targetingpyramidalneurons,DA terminalsappearto synaptically innervate only certain populationsof GABA-containinglocal circuitneurons.In addition,boththissubclassof GABAcellsandthe DA afferents to the DLPFC undergo substantialrefinementsduring late adolescence,the typical age of onset of schizophrenia.These findings suggestthat thesecomponentsof DLPFCcircuitrymaybe prcferentiafly affectedin schizophrenia.Resultsof studiesin postmortemhumanbrain specimensdesignedto test this hypothesiswill be presented,and the implicationsof these findingsfor the developmentand testing of new therapeuticagentswill be discussed.
201. MOVING BEYOND SYMPTOM REDUCTION M.F. Green UCLADepartmentof Psychiatryand BiobehavioralSciencesand the West Los AngelesVA MedicafCenter Problems in neurocognition(e.g., sustained and selective attention, verbal and spatial memory, executive functioning)have long been considered central to schizophrenia.Many of these neuroeognitive deficitsappearto he quiteindependentof the symptomsof the illness,the medicationsthat the patientsreceive,and the effects of institutionalization.Since1990,a largenumberof studieshaveassessedthe associations between neurocognitivedeficits and the daily functioningof scbizopbrenicpatients.Despitewide variationin the selectionof nerrmeognitive measuresacrossstudies,someconsistenciesarc evident.Neurocognitive capacities such as verbal memory and vigilance appear to be neeessaryfor adequatefunctionedoutcome.Deficitsin these areas may restrict the patient from attainingtheir optimaladaptation.In contrast, psychoticsymptomsare rather weak predictorsand cnrrclatesof functionaloutcome.Hence,neurocognitivedeficitspresentreasonabletargets for behavioraland/orpharmacologicalinterventions.New antipsychotic medicationsappearto offer an advantagefor neurocognitivecapacities compared with conventionalantipsychoticagents. In a double-bfind randomizedstudyfromour laboratory,risperidonehas shownsignificant beneficial effects comparedwith haloperidolfor measures of verbal workingmemory,secondarymemory,reactiontime, and perceptionof emotion.However,risperidonetreatmentdidnotyieldbenefitsfor motor learning,nor improvementsin verballearningstrategy.Severalmodels have been constmctedin an attemptto integratethese tindings into a unified framework. Jn these models, neuroeognitiveconstructs are essential for explainingthe pathwaysbetweenpsychopharrna cological treatmentand tinrctionaloutcome.
200. DOPAMINE SYSTEMS AND VULNERABLE CORTICAL CIRCUITS IN SCHIZOPHRENIA D.A. Lewis Departmentsof Psychiatryand Neuroscience,Universityof Pittsburgh, Pittsburgh,PA 15213 A critical frontier in the managementof schizophreniaand related disordersinvolvesthe developmentof therapeuticagents that not only ameliorate the positive symptomsof these disorders, but that also improvethe associateddisturbancesin cognitivefirnction.Convergent linesof evidencesuggestthat abnormalitiesin the neuralcircuitryof the
202. BEYOND DOPAMINE RECEPTOR BASED PHARMACOTHERAPIES OF PSYCHOSIS H.C. Fibiger Eli Lilly and Company,Indianapolis,Indiana46285 All currentlyprescribedantipsychoticagents,bothtypicaIand atypical, are antagonistsat D2-fikereceptors,this beingoneof the cornerstonesof