University of Groningen
New approaches in psychiatric drug development
van der Doef, Thalia F.; Domingo, Silvia Zaragoza; Jacobs, Gabriel E.; Drevets, Wayne C.;
Marston, Hugh M.; Nathan, Pradeep J.; Tome, Maria B.; Tamminga, Carol A.; van Gerven,
Joop M. A.; Kas, Martien J. H.
Published in:
European Neuropsychopharmacology
DOI:
10.1016/j.euroneuro.2018.06.006
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
van der Doef, T. F., Domingo, S. Z., Jacobs, G. E., Drevets, W. C., Marston, H. M., Nathan, P. J., Tome, M.
B., Tamminga, C. A., van Gerven, J. M. A., & Kas, M. J. H. (2018). New approaches in psychiatric drug
development. European Neuropsychopharmacology, 28(9), 983-993.
https://doi.org/10.1016/j.euroneuro.2018.06.006
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
www.elsevier.com/locate/euroneuro
REVIEW
New
approaches
in
psychiatric
drug
development
Thalia
F.
van
der
Doef
a,
Silvia
Zaragoza
Domingo
b,
Gabriel
E.
Jacobs
a,c,
Wayne
C.
Drevets
d,
Hugh
M.
Marston
e,
Pradeep
J.
Nathan
f,g,
Maria
B.
Tome
h,
Carol
A.
Tamminga
i,
Joop
M.A.
van
Gerven
a,c,1,
Martien
J.H.
Kas
j,1,∗aCentreforHumanDrugResearch,Leiden,TheNetherlands
bResearchandDevelopmentDepartment,H.LundbeckA/S,Valby,Denmark cLeidenUniversityMedicalCentre,Leiden,TheNetherlands
dJanssenResearch&Development,LLC,Johnson&Johnson,UnitedStates eLillyResearchLaboratories,EliLillyandCo,Windlesham,UK
fHeptaresTherapeuticsLtd,Cambridge,UK
gDepartmentofPsychiatry,UniversityofCambridge,Cambridge,UK
hEuropeanMedicinesAgency(EMA),30ChurchillPlace,CanaryWharf,London,UK
iDepartmentofPsychiatry,UniversityofTexas,SouthwesternMedicalSchool,Dallas,TX,UnitedStates jFacultyofScienceandEngineering,GroningenInstituteforEvolutionaryLifeSciences,Universityof
Groningen,Nijenborgh7,9747AGGroningen,TheNetherlands
Received 17March2018;receivedinrevisedform18June2018;accepted25June2018
KEYWORDS Drugdiscovery; Neuroimaging; Translationalresearch; Psychiatry; Precisionmedicine Abstract
Numerousnovelneuroscience-baseddrug targetshavebeenidentifiedinrecentyears. How-ever,itremainsunclear how thesetargets relate totheexpression ofsymptomsincentral nervoussystem(CNS)disordersingeneralandpsychiatricdisordersinparticular.Todiscussthis issue,aNewFrontiersMeetingsofEuropeanCollegeofNeuropsychopharmacology(ECNP)was organizedtoaddressthechallengesintranslationalneuroscienceresearchthatareimpeding theeffectivedevelopmentofnewtreatments.
Themainaimofthismeetingwastodiscuss scientificinsights,concepts andmethodologies inordertoimprovedrugdevelopmentforpsychiatricdisorders.Themeetingwasdesignedto bringtogetherstakeholdersfromacademia,pharmaceuticalindustry,andregulatoryagencies.
∗Correspondingauthor.
E-mailaddresses:m.j.h.kas@rug.nl ,tvddoef@chdr.nl (M.J.H.Kas).
1Bothauthorssharedlastauthorship.
https://doi.org/10.1016/j.euroneuro.2018.06.006
Hereweprovideasynopsisoftheproceedingsfromthemeetingentitled‘Newapproachesto psychiatricdrug development’.Newviews onpsychiatricdrugdevelopmentwere presented toaddressthechallengesandpitfallsasidentifiedbythedifferentstakeholders.Thegeneral conclusionofthemeetingwasthatdrugdiscoverycouldbestimulatedbydesigningnew classifi-cationandsensitiveassessmenttoolsforpsychiatricdisorders,whichbearcloserrelationships toneuropharmacologicalandneuroscientificdevelopments.Thisisinline withthevisionof precision psychiatryinwhichpatients areclustered,notmerely onsymptoms,butprimarily onbiologicalphenotypesthatrepresentpathophysiologicalrelevantand‘drugable’processes. Toachievethesegoals,aclosercollaborationbetweenallstakeholdersinearlystagesof de-velopmentisessentialtodefinetheresearchcriteriatogetherandtoreachconsensusonnew quantitativebiologicalmethodologiesandetiology-directedtreatments.
© 2018ElsevierB.V.andECNP.Allrightsreserved.
1.
Introduction
The neuroscience field is currently advancing insight
into the functional processes that underlie central
ner-vous system (CNS) derangement in psychiatric illness.
Such progress is the result of the development of more
advanced technologies in the field, that include but
are not limited to neuroimaging, and various
‘omics’-technologies like (epi)genomics, transcriptomics,
pro-teomicsandmetabolomics.Advancesinothermedical
dis-ciplines, such as clinical genetics and immunology, also
contributetoabetterunderstanding ofbraindisorders.In
addition, innovative ways to quantify human and animal
behaviour, such asby means of clinical phenotyping,
pro-videnewtranslationalresearchoptions.Byapplying
sophis-ticated biologicalmechanism basedmethodologies,an
in-creasingnumber of potential ’drugable’CNS targets have
been identified which may potentially benefit both
clini-cal management of psychiatric conditions and psychiatric
drugdevelopmentinthefuture.However,amajorconcern
is that psychiatry has been unable to effectively exploit
theadvancesthatneurosciencehasyieldeduptonow.For
manynovelneuroscience-basedtargets,itstillremains
un-clearhowtheyrelatetosymptomsortoclinicalexpression
of thedisorders thatmake up psychiatric diagnostic
enti-ties.Therefore,stakeholdershaveyettoreachagreement
onhowtomoveforward(Hyman,2016).
The number of US Food and Drugadministration (FDA)
approvednewdrugsinthelastdecadesshowsthat
psychi-atricdrugdevelopmentislaggingbehindcomparedtoother
medicaldisciplines(Bjornsson,2016).Toillustrate,in2015
the total numberof new registered drugs since 1975 was
33 in psychiatryversus 54in neurology (Bjornsson,2016).
One aspect of the backlog of drug approvals in
psychia-try is a limited number of new mechanisms of action. In
many areas, such asneurology and oncology, drugs
regu-larlyappearonthemarketthathavenovelorsignificantly
modifiedmechanismsofaction.Inpsychiatry,however,only
veryfewmechanismsofactionhavebeenintroducedsince
thedevelopmentof monoaminereuptake inhibitorsinthe
eighties and nineties(Bjornsson, 2016). This can be
illus-tratedby thetimecourseof an ‘innovationindex’,which
canbedefinedasthenumbersofmechanismof action
di-videdbythenumberofregistereddrugs.Highlyinnovative
disciplines likeimmunology and oncology have innovation
indicesof40%–60%.Itisinterestingtocomparethecourseof
drugdevelopmentinpsychiatryandneurology,whichboth
dealwiththesame humanorgan,thebrain.Fifteenyears
ago,neurologyandpsychiatrybothhadinnovation indices
ofabout30%,meaningthatineachdisciplinesthree
regis-tereddrugssharedasinglemechanismofaction.In
neurol-ogy,theindexhassinceincreasedslightlytoastablelevel
of35%, whichreflects developments inmultiple sclerosis,
epilepsy,Parkinson’sdisease,strokeandotherindications.
Psychiatry, however, has seen a steady decline of the
in-dextoabout20%(4–5drugspermechanism).Psychiatryand
cardiologyaretheonlymedicalfieldswheretheinnovation
indexhasdecreasedsincethebeginningofthismillennium
(Bjornsson,2016).Incardiology,significant advanceswere
madeinpreventiveandinnovativesurgicalandradiological
interventions.Inpsychiatry,however,improvementsin
cog-nitivebehaviouralstrategies andchangesinthequalityof
psychiatriccarehaveofferednocompensationfortheslow
developmentofnewpsychiatricmedications.
The complexity of psychiatric drug development is
re-lated to several factors. First, thereare pharmacological
restrictionsdue totheinviolabilityof thehumanbrain. It
isdifficulttoachieveblood-brainbarrier(BBB)penetration
and to assess target engagement, and complex methods
arerequired todetermine this(in)directly,suchasinvivo
positronemissiontomography(PET)imaging,functionalCNS
tests,post-mortemstudiesandCSFsampling.Neurologyis
helpedinthisrespectby itsfocusonstructural
abnormal-ities.Second,thereisadisconnectionbetweenthe
defini-tionofthebiologicalprocessesthatunderlieanimalmodels
and human research,which has limited the identification
ofcross-speciesclinicallyrelevantmechanisms.Asa
conse-quence,insights fromanimalstudies cannotbetranslated
directlyintohumandrugtargets.Innovativediseasemodels
inneurology have profitedmore fromscientific advances,
particularlyin geneticsand immunology.Third, thereis a
clinical heterogeneity in psychiatric disorders since their
classificationisbasedonthepredominantlyphenomenology
basedDiagnosticandStatisticalManualofMentalDisorders
(DSM)andtheneurobiologicalmechanismsformost
disrup-tionsof CNS functions (behavioural, emotional, cognitive)
haveonlypartlybeenunraveled.
Thetreatmentofapsychiatricpatientmayrequirea
mul-tifacetedandinteractiveapproach.Thisisnotaneasy
situ-ationfordrugdevelopment,andmanylargepharmaceutical
industrieshaveshiedawayfromthisarea.Nonetheless,
psychiatric diseases,itremainsimportanttodevelop
inno-vativetherapies,whichareonlyeffectiveforapartofthe
problem,orforasubgroupofpatients,orwhichmerely
sup-port other pharmacological or psychosocial interventions.
Withinthismorenarrowedscope,newapproachesare
nec-essaryandpossible.Ultimately,thismayleadto
incremen-tal improvements, whichovertimemayprovidemore
sci-entific insights andlargerclinical benefits.Examples from
neurology (stroke, multiple sclerosis, tumors) show that
consecutive smalldevelopmentswhich in isolationare
of-tenhighlydisputedfortheirapparentlackofclinical
rele-vancefortraditionallydefinedpatients,ultimatelyprovide
realimprovementsforpatientswithnewlydefined
diagnos-ticcharacteristics.This incrementalinnovationalsoseems
toberelatedtocontinuingsupportforclinicalresearch
net-worksandinfrastructure,whichrapidlydeteriorateifsmall
successesareconsideredinsignificant.
Inclinicaldisciplineswithseveral-foldhigherinnovation
indicesthanpsychiatry(likeimmunologyandoncology),
in-novation is mainly drive by similar factors as in
neurol-ogy. Occasionally, theadvances areenhancedby a
break-throughthatistakenupbyseveralcompanies(withdrugs
that arebasedonthenewmechanism or aderived
modi-fication). However,most areasareabletosustaina slow
butsteadysupplyofalternativeorslightlyimproved
medi-cations,onthebasisofcontinuousdrugimprovementsand
clinical research with more modest results and
expecta-tions.
To stimulate neuroscience-based adaptive approaches
to psychiatric drug research and development, the
Na-tional Institute of Mental Health (NIMH) launched the
Research Domain Criteria (RDoC) framework, which also
supports new approaches to classification of mental
dis-orders (www.nimh.nih.gov/research-priorities/rdoc/index.
shtml)(Inseletal.,2010).The RDoCinitiative asks
inves-tigators to step back from diagnoses based on
heteroge-neous clustersof symptoms and, instead,tofocus on
ba-sicdimensionsoffunctioningacrossthewellnessspectrum
thatmightrelatetovariousaspectsofsymptoms.TheRDoC
framework is centered around dimensional psychological
constructsandmethodsusedtoinvestigateandunderstand
constructs(termed‘unitsofanalysis’)includingmolecular,
genetic, neurocircuitry and behavioural assessments. The
RDoCframeworkcanfacilitatenewapproachesfordrug
de-velopment byusingthedimensionalapproachtotest new
drugs.
The ECNP new frontiers meeting entitled ‘New
ap-proachestopsychiatricdrugdevelopment’washeldinNice
at 12 and 13March 2017 andcontinued itsdiscussions on
the 30thECNP Congress in Paris later that year. The aim
ofthemeetingswastodiscussscientificinsights,concepts
and methodologiesin ordertoimprovedrug development
for psychiatricdisorders.Translationalgapsbetweennovel
targets, CNS functionsand clinicalphenomenahave tobe
bridged if psychiatry wants to improve the condition of
patientswithpsychiatric disordersbyutilizing
mechanism-basedCNStargets.Hence,itiscrucialthatneuroscientists,
clinicians, industry and regulators understand each other
and collaborate. The meeting was dedicated to discuss
strategiestoaddressthisissueandtopromoteinteractions
and discussions between different involved stakeholders
fromacademia,industry,clinicians,methodologists,
regula-torsandpatients.Duringthemeeting,different
stakehold-ersfromacademia,industryand regulatoryagenciesgave
presentationswhichwerefollowedbyplenarydiscussions.
Here,weprovideanintegratedreviewofthepresentations
anddiscussions of themeeting,which iswritten fromthe
author’sperspectives.Thishasledtotherecommendations
for new approaches in psychiatric drugdevelopment that
arewrittenbelow.
2.
From
disease
category
to
pharmacology
At the start of the meeting, a conceptual framework of
drugdiscoveryinpsychiatrywasproposed(seeFig.1).This
schemeisbasedonthenotionthattheCNSconsistsof
neu-ronalnetworks,whichusemolecularmechanismstoexpress
thebrain’svariousfunctions.Dysregulationsofthese
func-tionscauseneuropsychiatricsymptoms,whichformthe
ba-sis of psychiatric disorders (see top of Fig. 1).
Neuropsy-chiatric drugs act on the molecular level (see bottom of
Fig.1),andtherebyinducecascadicchangesonbrain
net-worksthatultimatelyaffecttheirfunctionality.Thetargets
of CNS active drugs (neurobiological receptors, enzymes
etc.)areonlyindirectlyrelatedtochangesofnetworksand
their associated functions. The relationship between CNS
functionsandDSM-constructs,whichareoftenalsoremote,
furtheraddtothecomplexityofpsychiatricdrug
develop-ment.
Traditionalpsychiatricdrugdevelopmentisusuallyaimed
at DSM-constructs,and thereforeignores thecomplex
un-derlying cascade of events. Innovative drug development
forpsychiatricsymptomswillrequirecloserattentiontothe
interactionsbetweendrugactionandfunctional
disorgani-zation,andtotheadaptivenatureofbrainnetworks.This
mayinclude a reconsiderationof psychiatric symptoms or
phenotypes, which are modulated by genetics (i.e.
geno-type),asdysregulationsoffunctionalnetworks.Itwillalso
requirethedevelopmentandapplicationofmethods,which
measuresstrategichubsatdifferentlevels,i.e.molecular,
circuit,functional,ofthecascadicprocesses.
Fig.1 isaschematicillustrationwhichindicatesthat
in-dividualsymptomsaremorecloselyrelatedtonetworksand
underlyingmolecularbiologythantomultidimensional
dis-easeconstructs.Psychiatricdisordersarecurrentlymainly
diagnosed based on qualitative assessment of symptoms,
ratherthanquantitativeanalysisofaberrantneurobiology.
In practicethis means thatthesymptoms arewell
under-stood,butthepathophysiologyandtherapeutictargetsstill
remain unclear. As thepatient willadapt to physiological
orpsychosocialchangesandthediseasemayprogress
dur-ing life,the distance between the underlying
pathophysi-ologyand thesymptomatology increases.This directly
in-fluencesdrugdevelopment,sinceitisunclearwhetherthe
pathophysiologycanpredictthetreatmentresponse.Inthe
future, patients may be selected for different treatment
optionsbasedontheirsymptomsandunderlyingbiological
profile.
For psychiatry, the most important outputs of brain
functioning arebehaviour, emotion andcognition.
Psychi-atricdisordersinherentlyimply adifferencebetween
nor-mal (adapted) and abnormal (maladapted). Therefore,as
RE SI LI EN CE /RE COV ER Y PA THOGE N ES IS/V UL NE RAB ILI TY DISEASE CATEGORY SYMPTOM FUNCTION NETWORK MOLECULAR BIOLOGY/ PHARMACOLOGY Mood disorders Negave bias Panic
aack Withdrawal Paranoia
Autonomic response Emoon regulaon Memory processing Salience aribuon
Hypothalamus Amygdala Hippocampus Ventral striatum
Noradrenaline Serotonin Inflammatory
pathways Dopamine Social Anxiety Disorder Generalized Anxiety Disorder Schizophrenia
Fig.1 Multidimensionalcharacteristicsofpsychiatricdisorders.
has been dominated by the DSM and the International
ClassificationofDisorders (ICD),whichstillplayan
impor-tantroleindefiningtheboundarybetweenwellandunwell
(Millanetal.,2015).Anothercriticismhasbeenmadethat
psychiatricdisordersformacontinuousspectrumwith
nor-mality,inthewaythat‘healthy’subjectsmaydisplay
tran-sient,mildandisolatedsymptomsofpsychiatricconditions
suchasanxiety,depressedmoodandevenpsychosis.
Network analysiscan beusedasa predictionfor
treat-ment outcome. Neuroimaging methods, such as
pharma-cological magnetic resonance imaging (phMRI),
electroen-cephalography(EEG)andPETimaging,canbeusedastools
for this prediction.The effects of psychopharmacological
agentsonbehaviouraldomainsoflarge-scalenetworkscan
bemeasured withphMRI,providinginformationabout the
pharmacodynamicsandunderlyingneurotransmitter
mech-anisms (Honey and Bullmore, 2004; Khalili-Mahani et al.,
2017).Several factorsneedtobetakenintoaccountwith
the standardizationand refinementof network analysisin
ordertoreducetheirsusceptibilitytopossibleconfounders.
Theselectionoftheregionsofinterest(ROIs),forexample,
caninfluencetheaccuracyoftheinferrednetwork
organi-zation,sincetheanatomicalseparationof thecortexmay
inaccurately define the functional ROIs resulting in a
dif-ferentdefinitionofthenetworknodes(Smithetal.,2011).
Hierarchyoffunctionalsub-regions basedonspatially
seg-regatedfunctionalnetworkscanbeusedforfurther
refine-ment(connectopicmapping).Recently,Instantaneous
Con-nectivity Parcellation (ICP) has been shown as a specific
quantification method to generate (sub)cortical
parcella-tions (top-down functional parcellation) (van Oort et al.,
2017).Otherrefinementmethodsarefoundinthe
implica-tionofmultipleimagingtechniquestogether,suchas
corre-lationmapsthatintegratebothfMRIandPETdata.Studies
oftheeffectsofpsychiatricdrugswillhelptoprovidemore
insightsintokeynetworkphenomena(Khalili-Mahanietal.,
2017).
A potential helpful concept in dealing with the
multi-levelcomplexityduringCNSdrugdevelopmentis so-called
question-baseddrugdevelopment(Cohenetal.,2015).This
basicallytranslatesallconsecutive stepsthatconnect the
drugtoitseffects(therapeuticoradverse),intoquestions
whichneedtobeaddressedduringthedrugdevelopmental
process.Eachstepconstitutesanuncertainty,whichcanbe
reducedbyappropriatemeasurements,inastudythat
em-ploysthepropermethodologyanddesign.Table1 provides
anindicationofsometypicalquestionsforpsychiatricdrug
development,whichfollowstheschemeofFig.1,including
somesuggestedmethodsto(indirectly)addresseach
ques-tion.
3.
Precision
psychiatry
Theheterogeneityofpsychiatricdisorderscomplicatestheir
definition, which is partly explained by genetic
variabil-ity.Evidencefordifferentsubtypesofpsychiatricdisorders
hasbeenfound, whichgivesan explanationfortreatment
resistance in several indications, such as depression and
schizophrenia.
Precisionmedicineisbasedontheclusteringof
individu-alswithpsychiatricsymptomsbasedonrelevantbiological
phenotypes(biotypes)insteadofclinicalphenomenological
classifications.Anexample ofthisapproachis providedin
Fig.2 (Clementz et al., 2016). Since the behavioural
do-mainscovertheentireneuropsychiatricspectrum,the
con-ceptis tostratify patientsbeforehand ondefined
Table1 Question-basedapproachtostepsthatlinkthepharmacologicalactivityofacentralnervoussystem(CNS)-activedrug tofunctionalCNS-effectsandrelatedpsychiatricallydysregulatedfunctions.Methodsareexamplesofapproachestomeasurethe activityattherelevantstep.EEG,electroencephalography;ERP,event-relatedpotential;MRI,magneticresonanceimaging;PET, positronemissiontomography.
Consecutivestep Question Method
Targetengagement Targetsitepenetration Doesthedrugreachitssiteof action?
Cerebrospinalfluid concentration,PETimaging
Targetbinding Doesthedrugbindtoits
moleculartarget?
PETimaging Cascadicdrugaction Pharmacologicalactivity Doesthedrughaveitsintended
pharmacologicaleffect?
Neuronalexcitability (EEG/ERP,MEG),target substrate,metabolomics
Networkactivity Howdoesthepharmacological
effectinfluenceafunctional neurocircuit?
RestingstatefunctionalMRI, EEGnetworkanalysis,PET imaging,cognitiveand emotionalprocessingtests probingspecificcircuits Neurophysiologicalactivity
(CNSfunction)
WhichCNSfunctionsare affectedbythedrug(positively ornegatively)?
CNScognitiveoremotionaltest battery
Symptomaticeffect
(psychiatricsymptomatology)
Whataretheeffectsofthe drugonthepsychiatric dysregulationoftheaffected CNSfunction?
Psychiatriccoresymptom scores/functiontests
Therapeuticwindow Clinicaleffect:beneficial Howdoesthedrugaffect patientswhoprominently expressthecorefeaturesof thedisease?
Clinical/patient/caregiver ratingscales(subgroups)
Clinicaleffect:adverse Whataretheadverse(CNS) effectsofthedrug(inthe vulnerablesubpopulation)?
Sideeffectmeasurements
lead toclinical phenotypes,which have been anonymized
beforehand.Thismethodnotonlycandistinguishdifferent
psychiatricdisorders,butisalsoapplicabletodifferentiate
controlparticipantsfrompatients.Here,inFig.2,patients
with a psychoticdisorder underwent a deep phenotyping
analysisusingcognitive,neuroimaging,oculomotoraswell
asgenetic,clinicalandclinicalcoursemarkers,with
multi-plemarkers collectedpermeasurementcategory.Noneof
thesebiomarkersfeelintoanyconventionaldiagnoseswith
enough powertobediagnostic.Sothephenotypic
charac-teristics of the individuals were usedindependent of the
clinicaldiagnosistodevelopbiologicallybaseddisease
clus-ters. One might assumethat ‘psychosis’ isanalogous toa
diagnosis of‘congestiveheartfailure’andthatBiotypes1,
2,and3areanalogousto‘cardiac’vs‘renal’vs‘pulmonary’
causesofcongestiveheartfailure.Thismakesitincumbent
toidentifythedistinctiveandcausalbiologyofthebiotype,
providingbiologicaltargets.
Thus, precision medicineis atargeted approachto
dis-eases where molecular diagnosis leads tobetter defined,
individualizedtreatmentswithimprovedoutcomes(Collins
andVarmus,2015;Inseletal.,2015).Diagnostictestsbased
on genetics or other molecular mechanisms can be used
to better predict patients’ response to targeted therapy
(Hamburg and Collins, 2010). However, there are several
challenges in geneticsor genome-wideassociation studies
(GWAS)studies,suchaspleiotropywhichresultsin shared
commongeneticbasesfordifferenthumantraits.To
over-comethis,phenotypeswithrelativelyhighgenetic
correla-tionscan becombinedtoenhance genomicprediction
ac-curacyinprecisionmedicine(Lietal.,2014; Maieretal.,
2018).
Theconceptofprecisionmedicinehasbeenwelldefined
in other research disciplines,such asoncology and
infec-tious diseases. In these areas, ‘precision therapy’ is
con-ceptually linkedto molecular biological properties of the
disease(orcausativeagent)thatarerelevantforthedrug’s
mechanism of action. For drug development in precision
psychiatryitwillalsobeessentialthatpsychiatricbiotypes
arebasedon‘drugable’characteristics,andtosomeextent
thepatientwillhavetobematchedtothemostappropriate
drug.Sofar,however,clusteringofpsychiatricdisordershas
notoftenbeenbasedonCNS-functionswithclose
relation-shipstoneuropharmacologicalprocesses.Atpresent,
clus-tering is primarily basedon neurobehavioural phenotypes
thatarepartoftheclinical spectrumofpsychiatric
disor-ders.PrecisionpsychiatryisinlinewiththeRDoCframework
oftheNIMH(Inseletal.,2015).
Several attempts are currently made to deconstruct
traditional symptom-based categories. Recently, the
Psy-chiatric Ratings using Intermediate Stratified Markers
(PRISM)projectreceivedfundingthroughtheEU-Innovative
Medicine Initiative (IMI)todevelop aquantitative
neu-Fig.2 Clusteringpatientsbasedonneurobehaviouralphenotypeinsteadofdiagnosticdisorder(Clementzetal.,2016)Reprinted withpermissionfromTheAmericanJournalofPsychiatry,(Copyright©2016).AmericanPsychiatricAssociation.AllRightsReserved.
ropsychiatricdiseases.Theideahasbeenputforwardthat
clustering patientsonthebasisof thebiologyratherthan
theirclinicaldiagnosiswillstimulatethediscoveryand
de-velopment of better treatments for patients (Kas et al.,
2017).
ThePRISMprojectaimstoidentifyandvalidateclinically
relevantbiologicalsubstratesofneuropsychiatricsymptom
constellations through the use of quantitative
technolo-gies.Forthatpurpose,aclinicaldeepphenotypingstudyon
commontraits,i.e. socialwithdrawal,sensoryprocessing,
attention and working memory, shared between a
multi-factorial psychiatric disorder (schizophrenia) and a
neu-rodegenerative disorder (Alzheimer’s disease, AD) will be
performed tocluster patientgroups basedonquantitative
biological parameters, such as EEG and fMRI measures,
ratherthan on conventional diagnosis. Aligned preclinical
andclinicalresearchmethodswillbeimplementedto
pro-vide the best predictive models for future drug
discov-erystudiesandforvalidatinghumanmolecularlandscaping
analyses to develop better understanding of the complex
pathophysiological relationshipsunderlying thesecommon
traits.Itisaimedtoprovidenovelclassificationand
assess-menttoolsformoreeffectiveidentificationoftheright
pa-tientfor agiventreatmentofaspecificsymptom
constel-lationthattranslatesintoabetterfunctionandqualityof
life(Fig.3)(Kasetal.,2017).Toprovidenewclassification
tools for neuropsychiatric disordersbased onquantitative
biologicalparameters,schizophreniaandADpatients with
highorlowsocialwithdrawalwillbeselectedforaclinical
deepphenotypingstudyatthelevelofbiologicalsubstrates
(genetic andepigenetics), EEGassessments(e.g., sensory
processing),neuroimaging(structural andfunctional MRI),
andbehaviouralassessments,e.g.,smartphoneapplication
(app)remotepassivebehavioural monitoring.Apreclinical
platform withparadigmshomologous tothose assessedin
patientswillbeimplementedforreversetranslationof
hu-manfindings.Together,thesestudieswillprovidenew
clas-sification,assessmenttoolsandapproachstrategiesfor
so-cialandcognitiveperformanceacrossneuropsychiatric
dis-orders,clinically relevant substrates for treatment
devel-opment,andpredictive,preclinicalanimalsystemsfor
sub-sequent neurobiological and pharmacological testing (Kas
etal.,2017).
4.
Pathophysiology
biomarkers
for
psychiatric
disorders
Atpresent,nodiagnostictestorbiologicalbatteryis
avail-able for psychiatric disorders, which are
phenomenologi-callydefined.Animportantgoalofphenotypingpatientsis
todevelopimprovedbiomarkers.Ideally,biomarkersshould
beavailableformultiplemechanisms(1)theycanfunction
aspredictorsoftransitiontopsychiatricdisordersinan
at-riskpopulation,and(2)theypredictandmonitortreatment
Fig.3 SchematicrepresentationoftheresearchelementsaddressedwithinthePRISMproject(Kasetal.,2017).
The term‘biomarker’hasbeenwidelyusedandcan
ap-ply to a wide range of measurements including markers
in biological material, e.g. serum, plasma, cerebrospinal
fluid,DNA,andmRNA,neuroimagingmeasurements
includ-ing (ph/f)MRI andPET, cognitive test-batteries,and
phys-iological measurements, suchas heart rate, saccadic eye
movements and many more. Since one measurement has
insufficient predictive value, combined methods are
ex-amined toenhance the validity. Forexample, the results
of markers in serumcan be combinedtogetherwith
neu-roimagingandphysiologicalmeasurements.
Thus, there are many potential biomarkers, and even
more possibleassociationswithdiseaseor patient
charac-teristics.Fromadrugdevelopmentalperspective,
biomark-ers are most informative if they represent well-defined
steps along the pathophysiology cascade (Danhof et al.,
2005).
Drivenby the boostofimmunologicalresearch inmany
areas of medicine, there is growing interest in
biomark-ersof theimmunesysteminseveralpsychiatric disorders.
Clearly, this will have an effecton the design of clinical
trials, in which patients can bestratified on
immunologi-calparameters.Duringthemeeting, itwasdiscussedthat
majordepressivedisorderisassociatedwithanincreasein
peripheral markers likeinterleukin-6(IL-6) andC-reactive
protein(CRP)(Khandakeretal.,2017).Giventhatthese
im-munemarkersarealsoincreasedintreatmentresistant
de-pression suggeststhatpatients maybestratifiedbasedon
their serumprofile.Aniche fornewinterventions for
psy-chiatric disorders couldbe monoclonal antibodies (mAbs)
that are prescribed for other immune disorders. For
ex-ample,IL-6antibodieslikesiltuximab,whichisprescribed
for rheumatoidarthritis(RA),andIL-12/23antibodieslike
ustekinumab, which is used for psoriasis, may have
anti-depressant effect.Targetingtheimmunesystem may
pro-videapromisingsecondlineoption fortreatmentof
resis-tantpatients.
Most of the biomarkers that are currently investigated
inpsychiatry,focusonneurophysiologicaland
neurobehav-ioral characteristics of DSM-based disease concepts.
Clus-teringbasedontruly‘deep’psychopathological
phenotyp-ingwillalsorequiremeasurementsofthebiomarkercourse
andneuropharmacologicalprocessesthatunderlie
derange-mentsof behavioural,emotional, andcognitive functions.
Otherfactorsthathavebeenstudiedarepredictorsof
an-tidepressant treatment response like negative emotional
biasindepression.Negativeemotionalbiashasbeen
asso-ciatedwithdepression andchanges in emotional biascan
predict laterclinicalchangesinsymptoms.Recent studies
suggeststhatantidepressantdrugadministrationmodulates
emotional processing in depressed patients very early in
treatment(Harmeretal.,2017,2009).
5.
Translational
medicine
approaches
Preclinical and clinical researchshould complement each
other.Preclinicalresearchprovidesinsightaboutpotential
mechanisms underlying neuronal dysfunction and clinical
research provideshuman relevance.To move the field of
psychiatry forward, an integrated experimental medicine
clinical data.The lack of distinct endophenotypes of
psy-chiatricdisordershascomplicatedthedevelopmentof
spe-cificanimalmodels.Thequestionishowtodevelop
cross-species,clinicallyrelevantquantitativephenotypes?During
the meeting,it wasrecommendedtouse reverse
transla-tion fromclinical topreclinical research.The concept of
the reversetranslational approachis thathomologous
hu-man and animal endpoints, which are highly quantitative
and neutrally based, are being defined to facilitate the
translationfromhumanstomiceandviceversa.The
ques-tion remains howtoaddress this homology? Forexample,
Perry and colleagues explored ‘open field’ studies in
ro-dentsandhumanpatientsattheleveloffacevalidity(Perry
etal.,2009).Inthisstudy,exploratorybehaviourofpatients
withbipolardisorderandschizophreniawasquantified
us-ingahumanopenfieldparadigm.Exploratorybehaviourhas
beenwelldefinedinanimalstudies,buthasbeenless
stud-ied in patients withpsychiatric disorders. In the study of
Perryetal.(2009),adifferencewasfoundinexploratory
be-haviourbetweenhealthycontrolsandbipolarpatients,
al-thoughthiswasnotdemonstratedinschizophrenia.A
sim-ilar phenotype as that of thebipolar groupwas shown in
a mouse model with a geneticor pharmacological
inhibi-tionofthedopaminetransportercomparedtocontrols.
Ac-cording to these results the current amphetamine model
ofmania,whichisconsideredthestandardmodel,maybe
refined. In addition,physiological measurements couldbe
considered, such as event-related potentials (ERPs), that
canbeassessedbothinrodentspeciesandhuman,andmay
bemorecloserrelatedtopathophysiologyofthedisorders
at the level of neurocircuitry (Kaset al.,2017).Fordrug
studies, reverse translational endpoints can be selected,
whichcharacterizerelevantaspectsofpsychiatricdisorders
andaredrugsensitiveinanimalmodels.Ingeneral,
trans-lational endpoints will be measures of distinct functions
andbehaviours,ratherthanofdiseaseconstructs.Further
research is needed to identify homologous phenotypes in
humanandanimals.Ideally,thesehomologousphenotypes
shouldbecome quantitatively assessed andareassociated
withprocessesunderlyingdiseaseorigin.
6.
Digital
technology
Asmentionedpreviously,themultidimensionaldefinitionof
psychiatricdisordersconstitutesaproblemfordevelopment
of psychiatric medications. On the one hand, this is
re-lated to theheterogeneity of phenomenology-based,
psy-chiatric diagnosticcategories and theirpoorly understood
pathophysiology, whichis probablyjust asheterogeneous.
Ontheotherhand,drugsactattargetsthatinterferewith
specificCNSfunctions,whichinmostpsychiatricconditions
onlyplayapartialormodulatoryrole.Precisionpsychiatry
couldfacilitate theswitchfroma symptom-based
diagno-sis toa biological-baseddiagnosis, ashas been suggested
withthe RDoC dimensions (Inseletal., 2010). Toidentify
subgroupsthathavebiological validitynovel technologyis
required.Thequestionremainshowdigitaltechnologymay
help thefieldforward.A currentissue is thedefinitionof
the read outs of the clinical research studies. It is
ques-tionedwhetherthesearerobust andclinical relevantand
whether the methods actually measure what is needed.
For example, several clinical outcome assessment (COA)
tools like questionnaires are available to set a diagnosis
forpsychiatricdisordersandtoevaluatesymptomseverity.
However,mostquestionnairesaresubjectiveand/ordonot
provide quantitative outcomes. Second, since psychiatric
disordersarecomplexbraindisordersisitdifficulttograsp
thesebraindeficitsintheexistingCOAslikequestionnaires.
Assuch,thequestionnairesmaynotcoverthewhole
spec-trumofcognitive,behaviouraloremotionalfunctionsasthis
isfartoocomplexforaquestionnaire.Thismaybetheniche
fornoveltechnology.
Newtechnologiesarerequiredtoprovidequantitative
bi-ologicalparameterstodefinepatientsubgroups.Advanced
techniquesinthefield,suchasneuroimaging,andtheomics
technologiesmayprovidesuitablemeasuresofrelevant
bio-logicalprocesses.Digitaltechnologiesandinnovative
meth-odscanalsobeusedtomeasurefunctionallyandclinically
relevantparametersinpatients’dailylives.This could
in-clude medical devices, more sophisticated computerized
batteriesofneurocognitivetests,andmobilehealth
appli-cations (apps). There is growing interest for research
us-ingsmartphonedataor mobilehealthyapps. Thisleadsto
allkind of newpossibilities, fromactively askingpatients
howtheyfeelatdifferenttimepointsaday,whichiscalled
ecologicalmomentary assessment(Shiffman etal., 2008),
to monitoring a subject’s spontaneous behaviour. Passive
monitoringcanresultincollectingmultiple dataincluding
locationusing GPS signaling, time,social behaviour
mea-suredbytelephonecallsandduration,anduseandcontent
oftext-messengerapplicationsandsocialmediaplatforms
(Marzanoetal.,2015;vanOsetal.,2017).Whenthesedata
sourcesarecombined, asocialrhythmofasubjectcanbe
identified.If anomalies in these rhythms occur, this gives
relevantinformationwhichmayhelptopredictoridentify
functional deficits like social withdrawal. This couldhelp
predictpsychiatricillnessexacerbation,or the
responsive-nesstodrugsthataretargetedatfunctionalderangements
ratherthannosologicalentities.
Atpresent,real-life(‘smartphone’)researchin
psychia-tryisstillinitsinfancy,andformostpsychiatricallyrelevant
behaviours,emotionsand functions,validated ambulatory
measurementsarestillunavailable.Therearemany
techni-calandmethodologicalaswellasethicalissues.Assuch,it
isrecommendedtohavevalidationstudiesintheupcoming
yearstogainexperiencewiththeprocurementandanalysis
ofthese bigdata sets. At present, therearealready
sev-eralsuccessful exampleslike thedevelopment of devices
tomonitortreatment compliance,anddevicestomeasure
PatientReportedOutcomes(PROs),whichishighly
encour-agedbyregulatoryagencies.Forexample,Wacean,an
on-lineplatformcreatedbytheDravetSyndromeFoundation,
isapatient-driventoolfordatacaptureofPROassessment.
Inordertosucceed,thenoveltechnologyincludingapps
measuringbehaviourshouldbepre-validatedbyregulatory
bodies beforethey can be accepted asendpoint in
clini-caltrials.TheEuropeanMedicinesAgency(EMA)hasan
ex-peditedrugdevelopmentprogramtofacilitatethisrequest
andisusedtoacceleratetheprocessforinitiativesatthis
level.Itisgettingevereasiertobuildsmartphone
applica-tionsand web-basedtoolsfor psychiatryor drug
develop-ment.Thisisalreadyleadingtoanabundanceofmethods,
similar tools. There is an increasingneed for more
struc-tured approaches. A centralized European network would
behelpful toresolve questionsby offeringcommunication
betweengroupswithpastexperiences.Thereisalsoaneed
forharmonizationanddevelopmentofstandards,
compara-bletoICH-GCP.
7.
Regulatory
and
advisory
agencies
At the ECNP meeting, academia, industry and regulatory
agencieswerebroughttogetherduringfocuseddiscussions.
Therewasagreementthatcollaborationofacademiaand
in-dustrywithregulatoryandadvisoryagenciestogethercould
be strengthened.In general,academia,biotechand
phar-maceuticalindustriesarethedriversofinnovationon
clin-icalendpointsandhaveaclosecollaborationinwhichthey
can easily connect and discuss these outcome
measure-ments.Moreover,thesegroupsarethesourceofthelarge
groups ofvolunteersneededtoadvancethefield,but this
will require common projects and collaborations.
Regula-tory and advisory agencies (RAs) advise on clinical
end-points to includein study protocolsand provide approval
for specific clinical endpoint measurements. Theyarethe
main driversfor thefinal COA and COAinstrument
selec-tion.In principle,regulatoryagenciesareopen to
sugges-tions fromacademiaandindustry,buttheoutcomeofthe
study needs tobepredefined.Problems occurwhen
inno-vativeoutcomemeasurementsaredevelopedbyacademia
and industry without timely communication withthe
reg-ulatoryagencies.Withoutappropriatevalidationandprior
agreement,itmaybedifficulttoachieveregulatory
accep-tanceofsuchnovelmethodologiesindrugdevelopment.It
mightbeworthwhiletoperformvalidationstudies
examin-ing COAs that can beused in further developmentplans.
As such,pre-competitive strategiescan beadvisedto
dif-ferentpharmaceutical companieswiththeaimtodevelop
applicable instruments for specific indications (IMIfunded
projects).
Another issue is that the definition of innovative
end-points in relation todiagnostic or therapeutic objectives,
which is provided to RAs, is often not specific enough.
Therefore,thedisease-specificguidanceissuedbyRAsare
opentodiscussion,andconsequentlyCOAinstrument
selec-tionrequiresamoreinterdisciplinaryapproach. Thereisa
tendencytoreplicatepreviousstudydesignsfornewdrugs,
which leads to repetition of the same problems that
oc-curredinthepastandrefutesinnovation.Theuseofscales
which inthemselvesarewell accomplished,maybe
unac-ceptablefor RAsif theyareusedfor otherindications for
which they werenot validated.For example,batteries in
dementia clinical trials like the cognitivesubscale of the
Alzheimer’s Disease Assessment Scale (ADAS-Cog) (Rosen
etal.,1984)hasbeen designedtomeasurecognitive
out-come inAD,butitssensitivityvarieswithdiseaseseverity
withpoorsensitivityinearlyAD(i.e.largeceilingeffectson
most itemsofthescale inpatientswithMini-MentalState
Examination(MMSE)’sabove20(Karinetal.,2014).Despite
thisknowledge,clinicaltrialscontinuetousethismeasure
in all stages of the illness limiting theability todetect a
truedrugeffect(Frölichetal.,2011;Goldetal.,2010).
Learnings from success and failure in innovative drug
developmentin neurosciences, shows thatmore emphasis
should be placed on development of more sensitive
end-point/outcomemeasures andvalidation ofthese outcome
measuresinexperimentalmedicinestudiesaheadofphase
2 and3 studies with drugcandidates, aiming for markers
andoutcomemeasuresthataresensitive(i.e.diseaseand
pharmacological activity) and able to capture
pathophys-iologically relevant phenotypes. In an early stage of drug
development,thedevelopmentofnewtests andoutcome
measuresandvalidationofthesemeasuresneedstobe
per-formedincooperationwithregulatoryagencies.Thisis
par-ticularly relevant for new methods that will be used not
onlyfor internaldecision making,butalsoforregistration
or marketing. Regular communications with the FDA and
the EMA,andcollaborations or pre-competitiveinitiatives
between academic, industry and funding bodies, arealso
importanttoexchangeviewsandshareexpertise.
Thus,collaborationbetweenacademyandindustrywith
regulatoryagenciesinanearlystageiswarrantedtodefine
the research criteriatogether for clinical endpoints. This
is essential if the new drugs require gradual adaptations
ofstudydesignsandmethodologies,andofclinical
indica-tionsandeffects.Suchfundamentaldevelopmentsmayalso
have important consequences for patients and clinicians,
andsometimesevenforthehealthcaresystemandsociety.
Similarchangesalsooccurredwhencurrentlyavailable
psy-chiatricmedicationsbecamewidelyused.Therefore,these
important stakeholders shouldalso be involved in
design-ingstudies,selectivemethodsandredefiningrelevant
out-comes.
8.
Patient
participation
Drugsareintendedtotreatindividualswhoseekhelp,and
their needs are the central drivers of drugdevelopment.
This must be realized if new approaches are adopted to
select drug targets, design diagnostic tools and redefine
diseaseentities.Newdiagnosticortherapeuticapproaches
mayaffectmanyaspectsofpatients’lives.Atthemost
ba-siclevel,thiswillinfluencetheirtrustinthetreatmentand
influencesdrugcompliance.Psychiatricdisordersareoften
chronic after a firstepisode and present sometimes for a
lifetime,whichmeansthatalong-termmaintenance
phar-macologicaltreatment mayberequired.Inordertofulfill
thedrugcompliance,thepharmacologicaltreatmentshould
beattractive andeasy toadminister. However,thesmell,
taste,or effectofthedrugshouldbenottootemptingto
preventsubstancemisuseoraddiction.Newtoolsto
moni-toraspectsofbehaviouralsoposenewethicalandsocietal
questions.Diagnosticclassificationshaveamajorimpacton
thepositionofpatientsinsociety,andnewwaystodefine
‘disease’willalsoturnnewpeopleinto‘patients’.
In all areas of medicine the principles of Early
Detec-tion andEarly Treatment area given. Nowthat evidence
isemergingthatEarlyTreatmentwillresultinbetter
over-allrecovery fromamentalillness, psychiatrywillhaveto
respondwithanemphasisonbothearlydetectionandearly
treatment alongwithafull rangeoftreatmentswhich
in-cludecognitive,psychologicalandneurostimulationaswell
Table2 Researchideasfornewapproachesinpsychiatricdrugdevelopment.
1 Deconstructthemultidimensionalcharacteristicsofpsychiatricdisordersintodistinctneurobiologicalfunctional abnormalities.
2 Clusterpatientsprimarilyonbiologicalphenotypesthatrepresentpathophysiologicallyrelevantand‘drugable’ processes.
3 Developandvalidatebiomarkersthatunderliethepathophysiologyofpsychiatricdisordersand/orwhichrepresent pharmacologicalprocesses.
4 Baseexperimentalapproachesinhumansonreversetranslationfromclinicaltopreclinicalresearch,focusingon evolutionarilypreservedneurobiologicalandneuropharmacologicalsystems.
5 Digitaltechnologiescanbeusefultoquantifypathophysiologicallyrelevantbiologicalparameters,whichcanprovide mechanism-basedcharacterizationsofpatientsubgroupsandclinicaleffects.
6 Collaborationbetweenacademyandindustrywithregulatoryagenciesinanearlystageisrecommendedtodefinethe researchcriteriatogetherforclinicaloutcomeendpoints.
7 Involvepatientsinthedesignofnewdiagnostictoolsandtherapeuticapproaches,clinicaltrialsanddefinitionof clinicaloutcomemeasurements.
It is recommendedtherefore that patients and patient
societiesarecloselyinvolvedinthedesignofclinicaltrials
and definition of clinical outcome measurements,
prefer-ably in an early stage. Although much has been changed
in consideration of the patients’ perspectives during the
lastdecades,itisnotthecurrentstandardineachclinical
trialtoincludepatientsandpatientsocieties.Insome
Eu-ropeanresearchinstitutestheinvolvementofpatientshas
beenstandard practicealready.Forexample,theNational
Institute for Health Research (NIHR) Maudsley Biomedical
Research Centre(BRC) hasa Service UserAdvisory Group
whichconsistsofpeoplewithexperienceofmentalillness
andaninterestinmentalhealthresearch.Researchersfrom
theNIHRMaudsleyBRCdiscusstheirstudydesignwiththis
advisorycommittee toreceive feedback inan early stage
(beforefinalizationoftheprotocol).
Individualswithadisorder,caregivers,andhealth
profes-sionalsdonotalwayshavethesameviewsontheimpactof
thediseasesymptomsoradversedrugeffects.The
appreci-ationofdrug-inducedsedationforinstancecandiffer
con-siderably betweenpatient,caregiver,employerand
physi-cian.New diagnosticor therapeutic approachesmay have
complexunexpectedconsequencesfor thepatientandhis
orhersocialenvironment.Thislargelyunexploredterritory
may beparticularly suitable for newdigital technologies,
whichcanonlybedesignedincloseinteractionwiththe
pa-tientsandtheirsocialstructures.
9.
Discussion
Basedonthepresentationsanddiscussionsinthemeeting,
several suggestions for new approaches to drug
develop-mentinpsychiatryaresummarizedinTable2.
How can we put these new approaches into practice?
When psychiatric disorders areclassified according tothe
principleofprecisionpsychiatry,patientscanbeclustered
on mechanistic biological phenotypes. Measures of
phar-macologicalresponsivenesscouldstrengthenthelinkswith
‘drugable’targets.Theknowledgeaboutthebiological
phe-notypesislargelydrivenbytheavailabilityofappropriate
methods,whicharecontinuouslyrenewedbytechnological
innovations.Theoutcomemeasurementsofavailable
tech-niques, such as neuroimaging, ‘omics’ and ‘smartphone’
applications,maybe integratedin ordertoassess the
bi-ological phenotypes and to provide simple, and accurate
biomarkers.Inaddition,reversetranslationfromclinicalto
preclinicalresearchmayhelptounravelthebiological
back-groundofimportantaspectsofpsychiatricdisorders.When
modelsthatcan translatebetweenpreclinicalandclinical
resultsarealsodrugsensitive,theeffectsof
pharmaceuti-calsof different speciescan bemore easily translatedas
well.
If drug development will follow this pattern, patients
maybestratifiedfordifferenttreatmentoptionsbasedon
their symptoms and underlying biological (drug-sensitive)
profiles.Anewapproachtodrugdevelopmentmayrequire
closerattentiontotheinteractionsbetweendrugactionand
functionaldisorganization.Thismayincludea
reconsidera-tionofpsychiatricsymptomsasdysregulationsoffunctional
networks.
Novel approaches to psychiatric drug development
af-fect many aspectsof psychiatry. This can onlybe
accom-plishedifallstakeholderscollaborateatearlystagesofdrug
development,whennewmethodologicalapproachesoften
stilllargely need tobe validated. Notonly academia and
industryshouldwork closely togetherwithregulatory and
advisoryagencies,but societies of patientsand
represen-tativesshould alsobeinvolved. In ordertoachieve these
ambitiousgoals, communicationbetweenthestakeholders
is key.This can beaccomplishedby regular meetingslike
theECNPmeetingsandconferences.Furthermore,
commu-nicationcanbestrengthenedviatechnologyplatformswith
theaimtoshare expertise.Asanexample,theInnovative
MedicinesInitiative (IMI) provides a pre-competitive
plat-formtoinitiatesuchcollaborations.
Acknowledgements
Theauthorswouldliketoacknowledgethepresentersand
participantsoftheNewFrontiersMeeting2017.
Conflict
of
interest
The views expressed in this publication are the personal
asbeingmadeonbehalfoforreflectingthepositionofEMA
or one ofitscommittees or workingpartiesor any of the
nationalagencies.
Contributors
ParticipantsoftheNewFrontiersMeeting2017.Chairs:
Mar-tien Kas and Joop van Gerven. Co-chairs: Thalia van der
DoefandGabrielJacobs.Presenters:ChristianF.Beckmann,
EdwardT.Bullmore,WayneC.Drevets,CatherineJ.Harmer,
HughMarston,PradeepJ.Nathan,CarolA.Tamminga,Maria
B.Tome
Role
of
the
funding
source
The New Frontiers Meeting was financially supported by
the ECNP that had no influence on the content of this
manuscript.
References
Bjornsson,T.D.,2016.ProgressionofModernTherapeutics(2015 Re-port).
Clementz, B.A. , Sweeney, J.A. , Hamm, J.P. , Ivleva, E.I. , Ethridge, L.E. , Pearlson, G.D. , Keshavan, M.S. , Tamminga, C.A. , 2016. Identification of distinct psychosis biotypes using brain-based biomarkers. Am. J. Psychiatry 173, 373–384 . Cohen, A.F. , Burggraaf, J. , Van Gerven, J.M.A. , Moerland, M. ,
Groeneveld, G.J. , 2015. The use of biomarkers in human phar- macology (Phase I) studies. Annu. Rev. Pharmacol. Toxicol 55, 55–74 .
Collins, F.S. , Varmus, H. , 2015. A new initiative on precision medicine. N. Engl. J. Med 372, 793–795 .
Danhof, M. , Alvan, G. , Dahl, S.G. , Kuhlmann, J. , Paintaud, G. , 2005. Mechanism-based pharmacokinetic–pharmacodynamic modeling—a new classification of biomarkers. Pharm. Res. 22, 1432–1437 .
Frölich, L. , Ashwood, T. , Nilsson, J. , Eckerwall, G. , 2011. Effects of AZD3480 on cognition in patients with mild-to-moderate alzheimer’s disease: a phase IIb dose-finding study. J. Alzheimer Dis. 24, 363–374 .
Gold, M. , Alderton, C. , Zvartau-Hind, M. , Egginton, S. , Saun- ders, A.M. , Irizarry, M. , Craft, S. , Landreth, G. , Linnamagi, U. , Sawchak, S. , 2010. Rosiglitazone monotherapy in mild-to-mod- erate Alzheimer’s disease: results from a randomized, dou- ble-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 30, 131–146 .
Hamburg, M.A. , Collins, F.S. , 2010. The path to personalized medicine – perspective. N. Engl. J. Med. 363 (11), 1092 . Harmer, C.J. , Duman, R.S. , Cowen, P.J. , 2017. How do antidepres-
sants work? New perspectives for refining future treatment ap- proaches. Lancet Psychiatry 27 (2), 141–142 .
Harmer, C.J. , Goodwin, G.M. , Cowen, P.J. , 2009. Why do antide- pressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br. J. Psychiatry 195 (2), 102–108 .
Honey, G. , Bullmore, E. , 2004. Human pharmacological MRI. Trends Pharmacol. Sci 25 (7), 366–374 .
Hyman, S.E. , 2016. Back to basics: luring industry back into neuro- science. Nat. Neurosci 19 (11), 1383–1384 .
Insel, T. , Cuthbert, B. , Garvey, M. , Heinssen, R. , Pine, D.S. , Quinn, K. , Sanislow, C. , Wang, P. , 2010. Research Domain Crite- ria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167 (7), 748–751 .
Insel, T.R. , Cuthbert, B.N. , Whiteford, H.A. , Collins, F.S. , Var- mus, H. , Insel, T. , Lee, S.H. , Goodkind, M. , Dichter, G.S. , Cole, M.W. , Karalunas, S.L. , Tamminga, C.A. , Hall, B.S. , McCoy, T.H. , Schumann, G. , Rosa, M.A. , Lisanby, S.H. , Crocker, L.D. , 2015. Medicine. Brain disorders? Precisely. Sci. 348, 499–500 .
Karin, A. , Hannesdottir, K. , Jaeger, J. , Annas, P. , Segerdahl, M. , Karlsson, P. , Sjögren, N. , von Rosen, T. , Miller, F. , 2014. Psy- chometric evaluation of ADAS-Cog and NTB for measuring drug response. Acta Neurol. Scand. 129, 114–122 .
Kas, M.J., Penninx, B., Sommer, B., Serretti, A., Arango, C., Marston,H.,2017.Aquantitativeapproachtoneuropsychiatry: Thewhyandthehow.Neurosci.Biobehav.Revdoi:10.1016/j. neubiorev.2017.12.008 ,inpress.
Khalili-Mahani, N. , Rombouts, S.A.R.B. , van Osch, M.J.P. , Duff, E.P. , Carbonell, F. , Nickerson, L.D. , Becerra, L. , Dahan, A. , Evans, A.C. , Soucy, J.P. , Wise, R. , Zijdenbos, A.P. , van Ger- ven, J.M. , 2017. Biomarkers, designs, and interpretations of resting-state fMRI in translational pharmacological research: A review of state-of-the-art, challenges, and opportunities for studying brain chemistry. Hum. Brain Mapp. 38, 2276–2325 . Khandaker, G.M. , Zammit, S. , Burgess, S. , Lewis, G. , Jones, P.B. ,
2017. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a popula- tion-based birth cohort. Brain. Behav. Immun 69, 264–272 . Li, C. , Yang, C. , Gelernter, J. , Zhao, H. , 2014. Improving genetic
risk prediction by leveraging pleiotropy. Hum. Genet 133 (5), 639–650 .
Maier, R.M. , Zhu, Z. , Lee, S.H. , Trzaskowski, M. , Ruderfer, D.M. , Stahl, E.A. , Ripke, S. , Wray, N.R. , Yang, J. , Visscher, P.M. , Robin- son, M.R. , 2018. Improving genetic prediction by leveraging ge- netic correlations among human diseases and traits. Nat. Com- mun 9 (1), 989 .
Marzano, L. , Bardill, A. , Fields, B. , Herd, K. , Veale, D. , Grey, N. , Moran, P. , 2015. The application of mHealth to mental health: opportunities and challenges. Lancet Psychiatry 2 (10), 942–948 . Millan, M.J. , Goodwin, G.M. , Meyer-Lindenberg, A. , Ove Ogren, S. , 2015. Learning from the past and looking to the future: Emerg- ing perspectives for improving the treatment of psychiatric dis- orders. Eur. Neuropsychopharmacol 25 (5), 599–656 .
Perry, W. , Minassian, A. , Paulus, M.P. , Young, J.W. , Kincaid, M.J. , Ferguson, E.J. , Henry, B.L. , Zhuang, X. , Masten, V.L. , Sharp, R.F. , Geyer, M.A. , 2009. A reverse-translational study of dysfunctional exploration in psychiatric disorders: from mice to men. Arch. Gen. Psychiatry 66, 1072–1080 .
Rosen, W.G. , Mohs, R.C. , Davis, K.L. , 1984. A new rating scale for Alzheimer’s disease. Am. J. Psychiatry 141 (11), 1356–1364 . Shiffman, S. , Stone, A.A. , Hufford, M.R. , 2008. Ecological momen-
tary assessment. Annu. Rev. Clin. Psychol 4, 1–32 .
Smith, S.M. , Miller, K.L. , Salimi-Khorshidi, G. , Webster, M. , Beck- mann, C.F. , Nichols, T.E. , Ramsey, J.D. , Woolrich, M.W. , 2011. Network modelling methods for FMRI. Neuroimage 54, 875–891 . van Oort, E.S.B. , Mennes, M. , Navarro Schröder, T. , Kumar, V.J. , Zaragoza Jimenez, N.I. , Grodd, W. , Doeller, C.F. , Beck- mann, C.F. , 2017. Functional parcellation using time courses of instantaneous connectivity. Neuroimage 170, 31–40 .
van Os, J. , Verhagen, S. , Marsman, A. , Peeters, F. , Bak, M. , Marcelis, M. , Drukker, M. , Reininghaus, U. , Jacobs, N. , Lataster, T. , Simons, C. , Lousberg, R. , Gülöksüz, S. , Leue, C. , Groot, P.C. , Viechtbauer, W. , Delespaul, P. , 2017. The expe- rience sampling method as an mHealth tool to support self– monitoring, self-insight, and personalized health care in clinical practice. Depress. Anxiety 34, 481–493 .
