Table Of ContentHandbook of Experimental Pharmacology
Volume 213
Editor-in-Chief
F.B. Hofmann, M€unchen
Editorial Board
J.A. Beavo, Seattle
J.E. Barrett, Philadelphia
D. Ganten, Berlin
P. Geppetti, Florence
M.C. Michel, Ingelheim
C.P. Page, London
W. Rosenthal, Berlin
For furthervolumes:
http://www.springer.com/series/164
.
Mark A. Geyer (cid:129) Gerhard Gross
Editors
Novel Antischizophrenia
Treatments
Editors
MarkA.Geyer GerhardGross
UniversityofCaliforniaSanDiego Abbott,NeuroscienceResearch,GPRD
DepartmentofPsychiatry Ludwigshafen,Germany
LaJolla Institutf€urPharmakologie
California Universit€atDuisburg-Essen
USA Universit€atsklinikumEssen
Essen
Germany
ISSN0171-2004 ISSN1865-0325(electronic)
ISBN978-3-642-25757-5 ISBN978-3-642-25758-2(eBook)
DOI10.1007/978-3-642-25758-2
SpringerHeidelbergNewYorkDordrechtLondon
LibraryofCongressControlNumber:2012947033
#Springer-VerlagBerlinHeidelberg2012
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Preface
Sixdecadesaftertheserendipitousdiscoveryofchlorpromazineasanantipsychotic
and four decades after the launch of clozapine, the first atypical or second-
generation antipsychotic, psychopharmacology has arrived at an important cross-
road. Revealing the different modes of action of available antipsychotics on bio-
chemical,electrophysiologic,neuroanatomic,andbehavioralgroundshasnotonly
helpedtodevelopnewmedicationswithimprovedtolerabilitybutalsocontributed
toourunderstanding ofmechanismsrelevantforpsychosis ingeneral andschizo-
phreniaandbipolardisorderinparticular.Itisremarkableinthiscontexttheextent
to which such research has moved towards using imaging techniques and more
empiricalclinicalassessments.Althoughresearchtargetedatspecificreceptorsand
pathwaysofantipsychoticdrugactionhasextendedourknowledgeconsiderably,it
remains true that all currently approved antipsychotic drugs share one common
mechanism,i.e.,dopamineD receptorantagonism.Thereisstilluncertaintyasto
2
whether first- and second-generation antipsychotics can really be separated and if
theassumedprogressexemplifiedbynewercompoundsissufficienttosurvivethe
challenges of evidence-based medicine. Although the use of antipsychotics has
becomesafer,adversemetabolicandcardiaceffectsremainasmajorissuesinthe
clinicandinthedevelopmentofnewagents.Itbecameclearthatallclinicallyused
antipsychoticmedicationsareeffectiveintreatingpositivesymptoms,butcertainly
notfornegativesymptomsandalsonotforthecorecognitivedeficitsthathavebeen
widely neglectedinresearchinthe time betweenKraepelin andthe Measurement
and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)
initiative.
The efforts to develop antipsychotics based on D receptor antagonism in
2
combination with effects on other receptors (with or without intention) have
remainedthefocusofthelasttwodecades.Itisclearthatpharmacologicalresearch
and pharmaceutical development must now focus on complementary or even
alternative mechanisms of action to address unmet medical needs, i.e., poorly
treated domains of schizophrenia, improved acceptance by patients, better adher-
encetomedication,safetyinpsychosesindementedpatients,andavoidingcardiac
and metabolic adverse effects. The first completely novel mechanisms evolving
v
vi Preface
from our insights into the pathophysiology of psychotic disorders, especially the
role of glutamatergic mechanisms in schizophrenia, are now under development,
andfurtherprinciplesareonthehorizon.Thissituation,inmanyrespectssimilarto
that when the initial second-generation antipsychotics became available, can be
rewardingforall.Preclinicalandclinicalresearchersnowhavetheopportunityto
confirm their hypotheses and the pharmaceutical industry may be able to develop
reallynovelclassesoftherapeutics.
WhenwewereapproachedbythepublishersoftheHandbookofExperimental
Pharmacology to prepare a new volume on antipsychotics, our intention was to
capture both the accumulated preclinical and clinical knowledge about current
antipsychoticsaswellasprospectsfornewandpotentiallymorespecificantischi-
zophreniaprinciples.Theseeffortsshouldbebasedonthepathophysiologyofthe
diseases and the affected neurotransmitter systems. Since preclinical research on
antipsychotic compounds is only reliable when intimately linked through transla-
tional aspects to clinical results, we decided to include clinical science as well. It
turned out that that this endeavor could not be covered by a single volume. We
thanktheeditorialboardandthepublishersforsupportingourdecisiontoprepare
two volumes: Current Antipsychotics and Novel Antischizophrenia Treatments.
These topics cannot really beseparatedfrom one another andshould beseen asa
composite entity despite the somewhat arbitrary separation of contributions into
two volumes. The continuing challenges of developing improved and safer anti-
psychoticmedicationsremainofconcernandarediscussedinthefirstvolume.The
newopportunitiesforthefieldtodevelopandlicenseadjunctivetreatmentsforthe
negativesymptomsandcognitivedeficitsthataretreatedinadequatelybyexisting
compounds have been incentivized recently and provide the focus for the second
volume. We hope these collective contributions will facilitate the development of
improved treatments for the full range of symptomatology seen in the group of
schizophreniasandothermajorpsychoticdisorders.
Ludwigshafen,Germany GerhardGross
LaJolla,CA MarkA.Geyer
Contents
ClinicalInstrumentstoEvaluateandGuideTreatment
inSchizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
StephenR.Marder
CognitiveImpairmentinSchizophrenia. . . . . . . . . . . . . . . . . . . . . . . . 11
RichardS.E.KeefeandPhilipD.Harvey
BehavioralAnimalModelstoAssessPro-cognitiveTreatments
forSchizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
JaredW.Young,NurithAmitai,andMarkA.Geyer
TowardsMedication-EnhancementofCognitiveInterventions
inSchizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Hsun-HuaChou,ElizabethTwamley,andNealR.Swerdlow
MutantMouseModelsinEvaluatingNovelApproaches
toAntipsychoticTreatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
ColmM.P.O’Tuathaigh,LieveDesbonnet,andJohnL.Waddington
5-HT AgonistsasTherapeuticsfortheTreatment
2C
ofSchizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
SharonRosenzweig-Lipson,ThomasA.Comery,KarenL.Marquis,
JonathanGross,andJohnDunlop
TheRoleofDopamineD ReceptorsinAntipsychoticActivity
3
andCognitiveFunctions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
GerhardGrossandKarlaDrescher
NicotinicMechanismsintheTreatmentofPsychoticDisorders:
AFocusonthea7NicotinicReceptor. . . . . . . . . . . . . . . . . . . . . . . . . 211
AnnOlincyandRobertFreedman
MuscarinicMechanismsinPsychoticDisorders. . . . . . . . . . . . . . . . . . 233
DavidL.McKinzieandFrankP.Bymaster
vii
viii Contents
GlutamatergicSynapticDysregulationinSchizophrenia:
TherapeuticImplications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
JosephT.Coyle,AloBasu,MichaelBenneyworth,DarrickBalu,
andGlennKonopaske
MetabotropicGlutamateReceptorsforNewTreatments
inSchizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
E.J.Herman,M.Bubser,P.J.Conn,andC.K.Jones
GlycineTransportInhibitorsintheTreatment
ofSchizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
DanielC.Javitt
NicotinicReceptorsandFunctionalRegulationofGABA
CellMicrocircuitryinBipolarDisorderandSchizophrenia. . . . . . . . . 401
FrancineM.Benes
DevelopmentofDisease-ModifyingTreatmentofSchizophrenia. . . . . 419
AntonBespalov,CorinnaKlein,BertholdBehl,GerhardGross,
andHansSchoemaker
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Contents of Volume 212
TheDopamineDysfunctioninSchizophreniaRevisited:New
InsightsintoTopographyandCourse. . . . .. . . . .. . . . .. . . . .. . . . .. 1
RebeccaKuepper,MetteSkinbjerg,andAnissaAbi-Dargham
RoleofDopamineD ReceptorsforAntipsychotic. . . . . . . . . . . . . . . . 27
2
NathalieGinovartandShitijKapur
DopamineReceptorSignalingandCurrentandFuture
AntipsychoticDrugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
KevinN.BoydandRichardB.Mailman
SerotonergicMechanismsasTargetsforExistingandNovel
Antipsychotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
HerbertY.Meltzer
ManagingtheProdromeofSchizophrenia. . . . . . . . . . . . . . . . . . . . . . 125
W.WolfgangFleischhackerandAlexanderM.Simma
MetabolicConsequencesofAntipsychoticTherapy:Preclinical
andClinicalPerspectivesonDiabetes,Diabetic
Ketoacidosis,andObesity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
DavidJ.Heal,JaneGosden,HelenC.Jackson,
SharonC.Cheetham,andSharonL.Smith
MedicalNeedsintheTreatmentofPsychoticDisorders. . . . . . . . . . . . 165
F.MarkusLeweke,ThorstenM.Odorfer,andJ.MalteBumb
AntipsychoticsintheTreatmentofBipolarDisorder. . . . . . . . . . . . . . 187
JaskaranSingh,GuangChen,andCarlaM.Canuso
ThePharmacogeneticsofAntipsychoticTreatment. . . . . . . . . . . . . . . 213
GavinP.Reynolds
ix
