Behavioral Neurobiology of Schizophrenia and Its Treatment PDF
Preview Behavioral Neurobiology of Schizophrenia and Its Treatment
Current Topics in Behavioral Neurosciences Series Editors: Mark Geyer, La Jolla, CA, USA Bart Ellenbroek, Hamburg, Germany Charles Marsden, Nottingham, UK Aboutthisseries Current Topics in Behavioral Neurosciences provides critical and comprehensive discussions of the most significant areas of behavioral neuroscience research, written by leading international authorities. Each volume offers an informative andcontemporaryaccountofitssubject,makingitanunrivalledreferencesource. Titlesinthisseriesareavailableinbothprintandelectronicformats. With the development of new methodologies for brain imaging, genetic and genomicanalyses,molecularengineeringofmutantanimals,novelroutesfordrug delivery,andsophisticatedcross-speciesbehavioralassessments,itisnowpossible tostudybehaviorrelevanttopsychiatricandneurologicaldiseasesanddisorderson the physiological level.The Behavioral Neurosciences series focuses on ‘‘transla- tional medicine’’ and cutting-edge technologies. Preclinical and clinical trials for thedevelopment ofnewdiagnosticsandtherapeuticsaswellasprevention efforts arecoveredwheneverpossible. . Neal R. Swerdlow Editor Behavioral Neurobiology of Schizophrenia and Its Treatment Editor Prof.NealR.Swerdlow UniversityofCaliforniaSanDiego Dept.ofPsychiatry–MC0804 9500GilmanDrive LaJolla,California92093 USA [email protected] ISSN1866-3370 e-ISSN1866-3389 ISBN978-3-642-13716-7 e-ISBN978-3-642-13717-4 DOI10.1007/978-3-642-13717-4 SpringerHeidelbergDordrechtLondonNewYork LibraryofCongressControlNumber:2010933954 #Springer-VerlagBerlinHeidelberg2010 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting, reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationofthispublication orpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLawofSeptember9, 1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfromSpringer.Violationsare liabletoprosecutionundertheGermanCopyrightLaw. Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnotimply, evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotectivelaws andregulationsandthereforefreeforgeneraluse. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and applicationcontained in thisbook.In everyindividualcasethe usermust checksuchinformationby consultingtherelevantliterature. Coverillustration:Artisticrepresentationofoscillatorysynchronyandtimingofneuronsinnetworksby GyorgyBuzsaki Coverdesign:WMXDesignGmbH,Heidelberg,Germany Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Preface TheDevelopingFieldofSchizophreniaResearch Therearedevelopmentalmilestonesinthelifeofadisorder–themomentsthatit isdefined(orredefined)atadiagnosticlevel,themomentsthatitisunderstood(or betterunderstood)atascientificlevel,andthemomentsthatitiseffectivelytreated (or more effectively treated) at a clinical level. Deciding when to pause and take stock of these milestones is a matter of choice, particularly in the absence of a transformativeeventliketheidentificationofadefinitivegene(e.g.,BRCAorthe Huntington’s gene), causative agent (e.g., HIV), enzyme (e.g., Lesch–Nyhan syn- drome), or intervention (e.g., the polio vaccine). We do not have such clear transformativemilestonestomarkourunderstandingortreatmentofschizophrenia; smaller milestones are either part of the distant past (e.g., Bleuler’s diagnostic reformulation,ortheadventofmodernantipsychoticsandresulting“deinstitution- alization”ofschizophrenia)orperhapsourevolvingpresent(e.g.,thegrowinglist ofcandidategenes). But just as our field aspires to reject biological determinism in the etiology of schizophrenia, we should hold that the path toward understanding this disorder is not predetermined. For this reason, pausing to assess the field’s milestones, even (especially) in the absence of transformative events, affords us the opportunity to betternurtureit:towillfullymake(ornotmake)midcoursecorrectionsandthereby alter (or sustain) its developmental trajectory. To do so is not an admission of failure,buttonotdosowouldbeaseriousomission,andinmyopinion,anactof scientificarrogance. Where onthisdevelopmentalpath dowefindourselves?Asthechaptersin this volumesuggest,wearestillina“learningstage.”Diagnostically,theboundariesof theschizophreniasarelessclearlymarkedthanweoncebelieved,expandinginsome directionstowardthebipolardisorders,inotherstowardthe“ClusterA”personality spectrum, and in still others toward “pure” genetic disorders such as Velo-Cardio- Facial Syndrome. In its pathogenesis, we are recognizing a multiplying number of candidate“risk”genes,aswellasepigenetic“risk”factors.Initspathophysiology,we haveagrowingarrayofincreasinglysophisticatedexperimentaltoolstocharacterize its aberrant neural substrates at nano-, micro-, and macro-systems levels, neural v vi Preface information at millisecond–microvolt resolution, and gene networks and neural signalingpathwaysthatseemtointeractwithintwo-,three-,andfour-dimensions. Whereisthis“learningstage”takingourfield?Asboundariesexpandandlistsof genes,neuralelements,andsignalmoleculesgrow,andasthetemporalandspatial resolutionofourmeasuresincreasetorevealmoreandmoreaboutlessandless,it canappearthatthis“learningstage”ofschizophreniologyisteeteringtowardastate offixation,morethanofgrowth.Thisconclusionwouldbebolsteredbythefactthat developmentsinantipsychoticefficacy,sohighlytoutedbyourcommercialcoun- terparts,havenotwithstoodthelightofdata,bringingusfullcircle,moreorless,to wherewestarted50yearsago,thoughmanypoundsheavier.So,arewe“fixated”in thislearningstage?Acloserinspectionofourdevelopmentalpath,describedinthe chaptersinthistext,maysuggestotherwise. AsBromleyandBrekkedescribe,ourfieldnowhastoolstoassessandtargetnot merelypsychosisbutalsoreal-life functionandfunctionaloutcome intheschizo- phrenias. This seemingly simple recognition of the importance of “real-life func- tion”inthestudyofanydisorder,butparticularlyschizophrenia,chartsapathaway from“learningforlearning’ssake,”andtowardanextdevelopmentalstage.These real-lifemetricswillbecomenewbenchmarksforassessingtheefficacyofcurrent “next generation” interventions, delivered toward different clinical (Barch; Kaur and Cadenhead) or receptor targets (Kim and Stahl), or via different technologies (Rabin and Siegel), even as we better understand and address the failings of the “formergeneration”interventions(Meyer). These chapters on schizophrenia neuroimaging (Brown and Thompson; Urban andAbi-Dargham;Levittetal.),neurophysiology(RisslingandLight;Levyetal.; Braff), neurocognition (Kalkstein et al.), and preclinical models (Young et al; Powell) report that our field has developed a highly advanced ability to submit the neurobiology of the schizophrenias to rigorous experimental analysis. While some of these developments might appear fixated within nitty-gritty experimental issues–findingthemostinformativeligand,evokedwaveform,stimuluscondition, scanning state, or neurocognitive domain – they are actually the grist for healthy scientific development: for testing hypotheses under controlled conditions to gen- erateinterpretabledataandconclusions.Andsuchinquiryacrossmultiplelevelsof analysis, and across species, creates the opportunity for converging lines of evi- dence–scientifictriangulation–soessentialforestablishingnewknowledgeabout disordersofbrain,mind,andbehavior. At this developmental stage, convergent information has focused our attention onabnormalitiesinspecificbrainregionsandcircuits,includingsystemswithinand interconnecting the prefrontal cortex (Volk and Lewis), specific thalamic nuclei (CronenwettandCsernansky),andmesialtemporallobe(HeckersandConradi),as causativeeventsinthepathophysiologyoftheschizophrenias.Theseabnormalities havebeenidentifiedandcharacterizedusingstrategiesofvolumetric,neurochemi- cal,andfunctionalneuroimagingdescribedinearlierchaptersinthisvolume,and extendtodetailedneuropathologicalstudies,andstudiesofaltereddevelopmental andmolecularprocesses.Infact,wheretheschizophreniaswereoncecharacterized pejoratively as “functional” based on the paucity of clear neuropathological Preface vii findings,itisnowcharacterizedpejorativelyas“heterogeneous,”basedonthelong listandmultiplecombinationsofsuchfindingsacrossstudies.Nobodysaiddevel- opmentwaseasy. Perhaps the most studied (at least in terms of sheer “N”) and rapidly evolving facet of our developing field is schizophrenia genetics. Some candidates have emerged as prime “risk gene” suspects (e.g., COMT, NRG1, and DISC1, among others),yetperhapsthebiggerdevelopmentaladvancementisthegrowingaware- nessthattraditionalstrategiesforidentifyingdisordergenes–evenwithheroically (andsomemightsayexcessively)poweredsamples–maynotbemostinformative for schizophrenia. Rather, the key to genetic risk in schizophrenia may lie in aberrant patterns of copy number variants (Mantripagada et al.), rare mutations, orDNAmethylation(Akbarian)thatcharacterizethisdisorder.Thewiderangeof different possible genetic disturbances in this disorder might gain coherence via their action within a smaller number of critical molecular signaling pathways (Kvajoetal.)thatmightultimatelyberesponsiblefordownstreamdisturbancesin thedevelopmentandfunctionofneuronsandthelimbic-corticalcircuitsthatthey populate. With this pause to assess the developmental trajectory of our field comes the opportunity – and I would say, the obligation – to consider and discuss what lies ahead in our understanding of the neurobiology and treatment of the schizophre- nias. Does our “growth chart” suggest that we will ultimately be able to use a molecular toolbox to “fix” this disorder? Or, projecting out some years, will our trajectorymakeusamenabletoothertherapeuticapproaches?Whichparadigms– scientificortherapeutic–onceviewedwithpromisehavewenowoutgrown?And with what will they be replaced? As I note in my chapter, should “midcourse changes” be necessary, this is a sign of growth and not of failure. There can be no question that, with countless dedicated lifetimes of work, our field has learned great amounts about an exquisitely complex biology of schizophrenia; but, I suggest,anequallyimportantquestioniswhether,givenallthatweknow,wecan hopetopredictablyandeffectivelymanipulatethisbiologywithinourlifetimes,in awaythatwillfundamentallychangethecourseofthisdisorder.Iftheconsensusis “no,”oreven“whoknows?”thenourfieldmightconsiderotherapproaches(andI raise the speculative example of pharmacologically augmented cognitive thera- pies), for which the biological and clinical complexity of the intervention is developmentallysuitedtoourabilitytodeliverit. Thekeymilestonesinschizophreniaresearchandtreatmentwillbereachedonly if we maintain a healthy developmental course, and this means that we cannot tolerate fixation. Knowing what we know, and having developed such a rich scientific and clinical knowledge base, to pause and consider whether we are approaching this disorder correctly, is perhaps the best way that we can help our fieldandthefamiliesthatweserve. Summer2010 NealR.Swerdlow . Contents PartI Function,OutcomeandTreatmentinSchizophrenia AssessingFunctionandFunctionalOutcomeinSchizophrenia .............. 3 ElizabethBromleyandJohnS.Brekke AntipsychoticsandMetabolicsinthePost-CATIEEra ..................... 23 JonathanM.Meyer PharmacologicalStrategiesforEnhancingCognition inSchizophrenia ................................................................ 43 DeannaM.Barch TreatmentImplicationsoftheSchizophreniaProdrome .................... 97 TejalKaurandKristinS.Cadenhead AntipsychoticDrugDevelopment ............................................ 123 DennisH.KimandStephenM.Stahl AntipsychoticDosingandDrugDelivery ................................... 141 CaraR.RabinandStevenJ.Siegel PartII Experimentalmeasuresofbrainfunctionanddysfunction inschizophenia FunctionalBrainImaginginSchizophrenia:SelectedResults andMethods ................................................................... 181 GregoryG.BrownandWesleyK.Thompson NeurochemicalImaginginSchizophrenia .................................. 215 NinaUrbanandAnissaAbi-Dargham ix
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