Anxiety and Anxiolytic Drugs

569 Pages·2005·5.97 MB·English

by  C.T. Wotjak (auth.)

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
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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