Anxiety and Anxiolytic Drugs PDF
Preview Anxiety and Anxiolytic Drugs
Reprintfrom HandbookofExperimentalPharmacology,Vol. 169 Anxiety and Anxiolytic Drugs Editor:Florian Holsboer and Andreas Ströhle ©Springer-VerlagBerlinHeidelberg2005 PrintedinTheNetherlands.NotforSale. ReprintonlyallowedwithpermissionfromSpringerVerlag. 123 Handbook of Experimental Pharmacology Volume 169 Editor-in-Chief K.Starke,Freiburgi.Br. EditorialBoard G.V.R.Born,London M.Eichelbaum,Stuttgart D.Ganten,Berlin F.Hofmann,München W.Rosenthal,Berlin G.Rubanyi,Richmond,CA Anxiety and Anxiolytic Drugs Contributors A.Bilkei-Gorzo,E.B.Binder,D.S.Charney,F.Crestani, R.J.Daher,W.Danysz,C.H.Duman,R.S.Duman,F.Holsboer, M.E.Keck,R.Landgraf,K.P.Lesch,R.Lieb,K.-M.Lin, M.T.Lin,A.C.E.Linthorst,N.C.P.Low,H.Möhler,M.B.Müller, K.R.Merikangas,J.R.Nash,A.Neumeister,D.J.Nutt,F.Ohl, C.G.Parsons,U.Rudolph,A.Ströhle,C.W.Turck,K.Vogt, C.T.Wotjak,R.Yehuda,W.Zieglgänsberger,A.Zimmer Editors Florian Holsboer and Andreas Ströhle 123 ProfessorDr.Dr.FlorianHolsboer Max-Planck-InstitutfürPsychiatrie Kraepelinstr.10 80804München,Germany e-mail:[email protected] Priv.-Doz.Dr.AndreasStröhle KlinikfürPsychiatrieundPsychotherapie CharitéCampusMitte Charité–UniversitätsmedizinBerlin Schuhmannstr.20/21 10117Berlin,Germany e-mail:[email protected] With139Figuresand30Tables ISSN0171-2004 ISBN-103-540-22568-4SpringerBerlinHeidelbergNewYork ISBN-13978-3-540-22568-3SpringerBerlinHeidelbergNewYork LibraryofCongressControlNumber:2004115902 Thisworkissubjecttocopyright.Allrightsreserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broad- casting,reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationof thispublicationorpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLaw ofSeptember9,1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfrom Springer.ViolationsareliableforprosecutionundertheGermanCopyrightLaw. SpringerisapartofSpringerScience+BusinessMedia springeronline.com ©Springer-VerlagBerlinHeidelberg2005 PrintedinGermany Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnot imply, even in theabsence of a specific statement, thatsuchnames are exempt from the relevant protectivelawsandregulationsandthereforefreeforgeneraluse. Productliability:Thepublisherscannotguaranteetheaccuracyofanyinformationaboutdosageand applicationcontainedinthisbook.Ineveryindividualcasetheusermustchecksuchinformationby consultingtherelevantliterature. Editor:Dr.P.Roos DeskEditor:S.Dathe Coverdesign:design&productionGmbH,Heidelberg,Germany Typesettingandproduction:LE-TEXJelonek,Schmidt&VöcklerGbR,Leipzig,Germany Printedonacid-freepaper 27/3151-YL-543210 Preface Researchonanxietyandanxietydisordersisundergoingaparadigmatictrans- formationasdisparateareasofpsychiatricnosology,epidemiology,pharma- cologyandcognitiveneuroscienceconvergetowardsanintegratedunderstand- ingofthepathophysiologyofthesedisorders. Inthelastcentury,thebasictreatmentindicatedforpatientswithanxiety disorderswastoemploypsychotherapytofacilitatechangesinbehaviourand developwaysofcopingwithstressfullifeevents.Awidespectrumofsomatic treatments from catharsis and emetics to opium and strengthening tonics, from atropine and digitalis to potassium bromide and chloral hydrate, from benzodiazepinestoantidepressantscametobeusedaswell.Systematicstudies of antidepressants revealed that these drugs have antipanic properties inde- pendentoftheirantidepressiveeffects.Thisfindingstirredanewclassification of anxiety disorders, which is reflected in the current classification systems, suchastheinternationalclassificationofdiseases(ICD)publishedbytheWorld HealthOrganization(WHO).Anxietyhasevolvedasadefensivemechanism disposing the individual to recognize changes. As a warning signal, anxiety haslife-savingqualities,andaspecieswithoutappropriateanxietywouldnot survive. While normal anxiety is beneficial to co-ordinate response patterns inathreateningsituation,pathologicalanxietyhasmanyfacetsthatcanbur- den an individual substantially and warrants therapeutic intervention. The newclassificationofanxietydisordersencouragedbasicandclinicalresearch on the pathophysiology and treatment of pathological anxiety. Using newly developedmethodsandtechniques,wearenowbeginningtounderstandthe molecular mechanisms of anxiety, anxiety disorders and their treatment. In parallel, new drug targets have been generated and the first clinical studies withnewcompoundshavebeenstarted. Inthefirstchapter,C.T.Wotjakdescribestheresultsofstudiesonthecellular basisoflearningandmemorytogetherwithadescriptionofthemethodsthat ledtothesediscoveries.Aversivelymotivatedlearningandmemoryenableus torecognizeandtoappropriatelyrespondtopotentiallydangeroussituations. Theseabilities,whichensuredthesurvivalofhumansandanimalsthroughout evolution,beartheriskofpathologicalalterationthatmightbedirectlylinked todistincthumananxietydisorders,suchasphobiasorpost-traumaticstress disorder. VI Preface Adetailedoverviewofanimalmodelsforanxiety-relatedbehaviourispre- sentedbyF.Ohl.Thesemodelsareindispensabletoolstounraveltheneuro- biologicalmechanismsunderlyingnormalanxietyaswellasitspathological variations.Themainconceptsingeneratinganimalsmodelsforanxiety,i.e.se- lectivebreeding,experience-relatedmodels,geneticallyengineeredmice,and phenotype-drivenapproaches,aredescribedandthepotentialopportunities andcaveatsofcurrentmodelsaswellastheemergingpossibilitiesofferedby genetechnologyarediscussed. Although current views emphasize the joint influence of genes and envi- ronmental sources during early brain development, the physiological com- plexities of multiplegene and environment interactions as well as cross-talk betweenminor gene variants inthedevelopmentalneurobiologyof fearand anxietyremainpoorlyunderstood.Focusingonthehypothalamic–pituitary– adrenocorticalsystem,substancePandtheserotonergicsystem,threechapters describetheimpactofmutagenesisandknockouttechniquesonourcurrent understandingofanxiety-relatedbehaviour.K.P.Leschreviewsfindingsshow- ingthatvariationsingenescodingforproteinsthatcontrolserotonin(5-HT) systemdevelopmentandplasticityestablish5-HTneuronidentityandmodu- late5-HTreceptor-mediatedsignaltransduction,andcellularpathwayshave beenimplicatedinthegeneticsofanxietyandrelateddisorders.Inparticular, pertinentapproachesregardingphenotypicchangesinmicebearinginactiva- tionmutationsof5-HTreceptors,5-HTtransporter,monoamineoxidaseAand othergenesrelatedto5-HTsignallingarediscussed.M.E.KeckandM.B.Müller describe how neuroendocrine and behavioural phenotypes of anxiety disor- ders are at least in part mediated via modulation of corticotropin-releasing- hormone (CRH) and vasopressin (AVP) neurocircuitry and that normaliza- tionofanalteredneurotransmissionaftertreatmentmayleadtorestorationof disease-relatedalterations.A.Bilkei-GorzoandA.Zimmershowthatanxiety anddepression-relatedphenotypesareprofoundlyaffectedbythetachykinin system. ThegeneticepidemiologyofanxietydisordersisreviewedbyK.R.Merikan- gas and N.C.P. Low. They conclude that better comprehension of the phe- nomenologyofthespecificanxietydisordersandtheiroverlapshouldguide the development of the next phase of diagnostic categories. In light of the rapidlyaccumulatinginformationongeneticvariationsassociatedwithanx- ietydisorders,wecanexpectthatbasedonthesegeneticdatanewdrugswill emerge not only for better treatment of the clinical conditions but also for preventingtheironset. The interactions betweenCRH and 5-HT and the implicationsfor theae- tiology and treatment of anxiety disorders are reviewed by A.C.E. Linthorst. A. Neumeister, R.J. Daher and D.S. Charney focus on the central role of no- radrenergic neurotransmission for fear, anxiety and consequently the devel- opment and treatment of anxiety disorders. H. Möhler, K. Vogt, F. Crestani γ and U. Rudolph review the pathophysiology and pharmacology of the - Preface VII aminobutyricacid(GABA) receptors.ThediversityoftheGABA receptors A A as described in the past decade is the basis for novel subtype selective ben- zodiazepinesiteligandswithhypnotic,anxiolytic,anticonvulsiveormemory- enhancingactivity. Thephysiologyandpathologyofexcitatoryaminoacidneurotransmission isdescribedbyC.G.Parsons,W.DanyszandW.Zieglgänsberger.Atpresent, thereseemstobeaconsensusthatcompetitiveAMPAandN-methyl-d-aspar- tate (NMDA) receptor antagonists have a low chance of finding therapeutic applications. Antagonists showing moderate affinity and satisfactory selec- tivity for certain NMDA receptor subtypes seem to have a more favourable profile. C.H. and R.S. Duman focus on signal transduction and neural plasticity in the neurobiology and therapy of anxiety. The challenge of identifying in- tracellularsignallingpathwaysandrelatedmolecularandstructuralchanges thatarecriticaltotheaetiologyandtreatmentofanxietydisorderswillfurther confirm the importance of mechanisms of neuronal plasticity in functional outcomeandimprovetreatmentstrategies. Anxiety modulation by neuropeptides is described by R. Landgraf. Par- ticularly due to their high number and diversity, the dynamics of their cen- tral release and the multiple and variable modes of interneuronal commu- nication they are involved in, neuropeptides play a major role in the reg- ulation of anxiety-related behaviour. Despite the immense progress in the field of neuropeptides and anxiety, we are far from mimicking these pro- cesses simply by administering synthetic agonists or selectively attenuating thepathology byadministrationof receptorantagonists.The onlyexception seemsthedevelopmentofantagonistsblockingtheeffectsofCRH.Oneofthe CRH receptor antagonists has been probed in a clinical study with promis- ing results. From the clinical perspective, R. Yehuda describes the neuroen- docrine aspects of post-traumatic stress disorder (PTSD). The observations in PTSD are part of a growing body of neuroendocrine data providing ev- idence of insufficient glucocorticoid signalling in stress-related psychiatric disorders. Theclinicalpresentationofanxietydisordersaccordingtothefourthedition of the Diagnostic and Statistical Manual of Mental Disorders is summarized by R. Lieb. In addition, selected aspects (prevalence, correlates, risk factors andcomorbidity)ofepidemiologicalknowledgeonanxietydisordersarepre- sented. Pharmacogenetics is a field of research increasing our knowledge on the use of psychotropic drugs in different ethnic patient populations. K.-M. and M.T.Lin’schapterontransculturalissuessummarizescurrentknowledgeon themetabolismofanxiolyticagentswithemphasisonpharmacogeneticsand ethnicvariationsindrugresponses. Challenge studies in anxiety disorders are highlighted by M.E. Keck and A. Ströhle. The heterogeneity of agents capable of producing panic attacks VIII Preface insusceptiblepatientsandtheinconsistencyofautonomicresponsesduring apanicattackhasledtotheassumptionthatpanicoriginatesinanabnormally sensitivefearnetwork,whichincludestheprefrontalcortex,insula,thalamus, amygdalaandamygdalarprojectionstothebrainstemandhypothalamus.The differences in sensitivity to certain panicogens, therefore, might be fruitful in serving as biological markers of subtypes of panic disorders and should be a major focus of research, as the identification of reliable endopheno- types is currently one of the major rate-limiting steps in psychiatric genetic studies. Thecurrentstateonthepharmacotherapyofanxietydisordersissumma- rizedbyJ.R.NashandD.J.Nutt.Therecentshiftinclinicalpracticetowardsthe useofantidepressants,particularlySSRIs,forthefirst-linetreatmentofanxi- etydisordersissupportedbyresearchevidencefromrandomizedcontrolled trials. It is only in recent years that drugs acting via GABA neurotransmis- sionhavebeensupplantedasfirst-linetreatments,andnewdrugsinthisclass with improved tolerability compared to the benzodiazepines are likely to be marketedinthenearfuture. Newdevelopmentsinthepharmacologicaltreatmentofanxietydisorders aresummarizedbyA.Ströhle.Furthercharacterizationofpathophysiological processesincludingevolvingtechniquesofgenomicsandproteomicswillgen- eratenewdrugtargets.Drugdevelopmentdesignwillgeneratenewpharma- cologicalsubstanceswithspecificactionatspecificneurotransmitterandneu- ropeptidereceptorsortheirreuptakeandmetabolism.Newanxiolyticdrugs maytargetreceptorsystemswhichonlyrecentlyhavebeenlinkedtoanxiety- relatedbehaviour.Combiningpsychopharmacologicalandpsychotherapeuti- calinterventionsisafurtherfieldwherebenefitsforthetreatmentofanxiety disorderscouldbeachieved.Althoughtheroadofdrugdevelopmentisardu- ous,improvementsinthepharmacologicaltreatmentofanxietydisordersare expectedforthenearfuture. PharmacogeneticstrategiesinanxietydisordersaredescribedbyE.B.Binder and F. Holsboer. This field holds great promise for the treatment of anxiety disorders, and in the future psychiatrists may be able to base the decision regardingthetypeanddoseofadescribeddrugonmoreobjectiveparameters thanonlythediagnosticattributionsusedsofar.Thiswilllimitadversedrug reactionsandcouldreducetimetoresponse,resultinginamoreindividualized pharmacotherapy. Introducingproteomics,C.W.Turckshowsthatthecomprehensiveanalysis of the protein complement of the genome of an organism is becoming an increasinglyimportantdisciplinefortheidentificationofdiseasetargets.The effectsofdrugtreatmentandmetabolismcannowbestudiedontheprotein levelinacomprehensivemanner. Wethank allthecontributingauthorsfor theirexcellentmanuscripts. We thankK.Starke,whohasinitiatedthisvolumeandtheSpringer-Verlagteam, especially S. Dathe, for the smooth co-operation. With this volume of the Preface IX HandbookofExperimentalPharmacology,wearehappytopresentanoverview onthecurrentstateofbasicandclinicalresearchon“AnxietyandAnxiolytic Drugs”. MunichandBerlin,March2005 F.Holsboer,A.Ströhle
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