Accepted Article View metadata,citationandsimilarpapersatcore.ac.uk This by is protectedarticle reserved. Allrights copyright. doi: 10.1111/bdi.12748 lead to differences between this version and the throughbeen the copyediting, pagination typesetting, which process, may and proofreading hasThis article been accepted publicationfor andundergone peerfull but review not has ,Clinic, University IDIBAPS, of Hospital CIBERSAM,2- Barcelona, , Brigham and1- – Medical HarvardHospital Boston, MA, USA School, Women’s PhD The :Editorial type Article DR. TAMSYNVAN RHEENEN (Orcid: 0000-0003-3339-6665) ID PROF. RICHARD PORTER (Orcid : 0000-0002-8695-3966) ID DR. KAMILLA WOZNICA MISKOWIAK (Orcid 0000-0003-2572-1384)ID : PROF. ROGER SMCINTYRE (Orcid 0000-0003-4733-2523) : ID DR. ANABEL MARTINEZ-ARAN (Orcid: 0000-0002-0623-6263) ID DR. KATHRYN EVELEWANDOWSKI (Orcid: ID 0000-0003-1477-6187) DR.LAFER (Orcid BENY 0000-0002-6132-9999) : ID DR.LARS KESSING (Orcid: ID 0000-0001-9377-9436) DR. ANDRE CARVALHO 0000-0001-5593-2778)(Orcid ID : DR.(Orcid: 0000-0002-1983-8861) CHRISTOPHER BOWIE ID DR. BURDICK KATHERINE 0000-0003-4417-4988) : (Orcid ID PhD, FRCP (Edin), FRCPsych, FRCP(C), FRSB FRCP(C), FRCPsych, (Edin), FRCP PhD, Porter, MD Porter, PhD Christopher Bowie, PhD Jaramillo, Jaramillo, MD, MSc, PhD McInnis, MD Gallagher, PhD Torres, PhD Katherine E.Burdick, PhD 23 11 I nternational Lakshmi N. Lakshmi Yatham, MBBS,DPM, FRCPC, MBA , Scott A. Langenecker, PhD 17 20 , 15

Scot Purdon PhD Purdon Scot , , Roger McIntyre, MD, FRCPC, Roger MD, McIntyre,

Tamsyn EVanRheenen, PhD 7 , Philip Harvey, PhD Con sortium sortium 3,4 14 , 1*

, David F. Marshall,, DavidF. PhD Andre F. Carvalho, MD, PhD , Caitlin E. Millett, PhD CaitlinE. , I nvestigating 18 , Kelly A Ryan, PhD A Ryan, Kelly , 12 ,Kathryn Lewandowski, E. PhD 8 , Lars Vedel Kessing, MD, DMSc N 16 eurocognition in 21,22 , Kamilla Miskowiak, PhDW. Version of Record. Please Version as this cite ofRecord. article , , Eduard Vieta, MD, PhD 24, 25 24, 1 , Caterina, del MarBonnín PhD 15 15 , Anabel Martinez-Aran, PhD

,

Tomiki Sumiyoshi, MD, PhD 20 3,4 , Allan Young, MB ChB, MPhil, ,

Lisa T Eyler, PhD B ipolar 13 D , Carlos López- 9,10 isorder ( , Beny MD, Lafer, 2 9,10 , Neil Woodward, 5,6 ,

, Peter Richard J. ICONIC-BD 2 2 , , Melvin 19 , Ivan J. Ivan , provided byNewcastleUniversityE-Prints ) brought toyouby CORE Accepted Article This by is protectedarticle reserved. Allrights copyright. King’sNeuroscience, CollegeLondon&South London, London, England, UK Departmentof24- Psychologicalof Psychiatry, Medicine, Psychology Institute and 23- Department of Psychiatry, Vanderbilt University, Nashville, TN, USA Swinburne University Technology, of Australia Victoria, Centreof22- SchoolHealth, forMental Health Faculty Sciences, Arts Health, of andDesign, Melbourne, Australia Victoria, Melbourne21- NeuropsychiatryDepartment Psychiatry, of Centre, TheUniversity of DepartmentPsychiatry,20- of British BritishColumbia; Canadaof Columbia, University Mental NationalNeurologyof Health, Center Psychiatry, and Tokyo,Japan DepartmentPreventive19- ofDisorders, InterventionofPsychiatric National for Institute 18- Department of Psychiatry, University of Alberta, Alberta, Canada Otago, University17- of NewChristchurch, Zealand of16Department Psychiatry, Toronto, Toronto, University Canada of Department15- Psychiatry,of Ann Michigan, of University Arbor, MI, USA Medellín, Colombia Antioquia; MoodDisordersHospital Program, SanVicente Universitario Fundación, of 14- Research Group in Psychiatry, Department of Psychiatry, Faculty Medicine, of University McLeanHospitalHarvard–13- Medical School,Boston, USA MA, The12- Lake City, SaltUtah, Utah, University USA of Department11- Psychiatry,of SãoPauloof Brazil UniversityPaulo, São MedicalSchool, Copenhagen, Denmark Rigshospitalet, Hospital, HealthRegionMental CADIC, of Capital Services, 10- Copenhagen Denmark, University 9- Department of Psychology, University Copenhagen, of Copenhagen, Denmark 8- University, UK Neuroscience,7- Newcastle of Institute VA San6- Diego HealthcareSystem, San USA Diego,CA, USASan California UniversityCA, 5- Diego,LaJolla, of Centre and4- for Addiction MentalHealth,Toronto, Canada ON, 3- Department of Psychology, Queen’s University, Kingston, ON, Canada U niversityMiller MiamiMedicine,of School of FL, Miami, USA Accepted Article This by is protectedarticle reserved. Allrights copyright. arevery differences subtle between-group that suggest andrecent meta-analyses studies, II) BD versus (BDI subtype bipolar inBD impairment cognitive with have been associated factors Several clinical BD? in heterogeneity functional and cognitive for account factors andclinical What diagnostic lives their of most for broadlydisabled are while others andsocial status occupational high-level achieving individuals withBD, some within seen functioning rangeof vast tothe attest BD can with patients who treat Clinicians Bipolar Disorder(BD)is the4 address: email5789; [email protected] Harvard MedicalSchool; 221Longwood AveSuite 4-42, Boston, MA 02115.Ph: 617-732- *Address Correspondence Katherineto: E Burdick, PhD at Brigham and Hospital,Women’s 25- Maudsley NHS Trust, Foundation Bethlem Royal Hospital,Beckenham, Kent, UK matched non-psychiatric controls) during periods of euthymia of during periods controls) non-psychiatric matched age- from different (not normal” “neuropsychologically as present BD patients of 30-50% approximately that data suggest SZ, in deficits cognitive of high rates veryto the contrast stark profiles in cognitive heterogeneity intoaccount totake inherently fail comparisons however, group-level lesssevere; consistently albeit (SZ), schizophrenia in seen those to similar qualitatively are and patients, BD euthymic in present are deficits resilience factors for cognitive impairment in BD. occupational functioning appearothers relatively cognitivedecline social resilient highlevelsof to and and maintain while deficits cognitive significant develop BD with patients some why of critical question symptom specific to BD surprisinglyremains As such,there areno limited. approved treatments thisdisabling for two ourunderstanding decades, underlying the of of the causes inBDcognitive deficits Alt andpreventions. treatments emerging for are targets and disability functional to contribute deficits these function; executive and learning, verbal attention, of inthedomains is common impairment trait-like Specifically, outcome. course and functional onclinical impact haveaprofound illnessand of symptoms and disabling persistent the most among are cognitive deficits illness, the with associated ages 10-24years. frequency of frequency of thegreater -dueto in atleast part may be- differences subgroup Previously-reported thought to contribute to cognitive and functional outcomes. Meta-analytic(cross-sectional)outcomes. functional and cognitive to contribute thought to heterogeneity, theillness varies thecourse of considerably BD andis among patients Bey hypotheses. fine-grained typesof these underpowered totest a neuroprogressive course; however, eachhowever,neuroprogressivea individual course; smallbeen andthereby study has indicative of impairment pronounced with cognitive associated are more history psychosis of data suggest thata longer duration ofillness, higher number ofprior mood episodes, and psychosis

Although the diagnosis is largely defined by the mood episodesdiagnosisis largely bythe Although the defined mood 1 in BD I vs BD II, but individual studies have thus far been far thus have studies individual but II, BD vs BD I in . . Large-scale. studiesare needed to better identify both risk and th hough considerable overthepast progresshasbeen made leading causeof disabilityworldwide young among people ; however, considerable discrepancy is notable across across is notable discrepancy however, considerable ; 2 . Research has shown that at the group level, cognitive cognitive group level, atthe that shown has Research . 3 . We cannot yet answer the the yet cannot answer . We within the disorder. In disorder. the ond diagnostic , including including 4 .

Accepted Article This by is protectedarticle reserved. Allrights copyright. optimizewill handle values to methods available information missingimplemented to be optimizetheQuality dataset.to harmonization utility the critical merged will of be control neurocognitiveweresites, data different As across used willdatabase batteries bebuilt. which will eachsite theirdata place for transfer to BWH andupon which masterthe intolabels)uniformeach provide measure, interestdefine from variablesplatform of (e.g. asingle of development wehavebegunthe data, theexisting nature evaluatingAfter of the >2000 healthy controls. 12/2018)initiative are>3000 of sample BD 1).Estimated (Table sizes individuals(as and participation who atotalfrom of 15sites have provided meta-data for inclusionin this executive committee whowill To overseethe effort. we date, alreadyhave enlisted Barcelona); andLakshmi Yatham (University ofBritish Columbia) forming a4-member Eduard(University Vieta Copenhagen); of (Universityof KamillaMiskowiak co-leaders byis joined She – USA,Burdick. ledby Katherine Massachusetts Medicalin Boston, School Brigham TheHospitalis the ICONIC-BD Harvardsite for and (BWH); coordinating Women’s to anycontribute with who investigator datato interested inparticipating. is whocognitive datainBDpatients and This us. haveexisting invitethem willjoin to beopen necessary. hope identify to investigatorsWe other viaPubMed searches and word of mouth BD; however, to optimize theimpact that this will consortium have, global is outreach We have assembled astrong ofteam investigators acrossfrom world the form to ICONIC- network. had datatocontribute enthusiastically agreed do so – to collaborativeindicating a strong members were contributedata to Each initially invited totheconsortium. whoinvestigator Targeting CognitionTask Force The thisproject ideafor fromstemmed the of some important these questionslarge-scale through mega-analyses. individualswith BD a to uniqueform consortium with unambiguouslyability the to address cognition inon data withexisting inBD experts of international team alarge, together brings International Consortium Investigati internationalinitiated highly the The focused first consortium onthis topic: significant we collaboration andopendata-sharing, have through toadvance thefield In aneffort sizes are however,and sample modest. others); among are understudied relativelythese conditions, andpsychiatric medical comorbid obesity, sleep, inBD(e.g. outcomes functional and cognitive to contribute to arelikely factors other illness-related Many effect? bidirectional is this a and impairment cognitive of andextent the nature affect severity symptom doescurrent inBD– how basicquestions the most of addressed one adequately studies have Interestingly,cognitive outcome. relevant to are effects ormedication illness, of very few such as whetherprior addressspecificunable durationquestions thepolarity to episodes, of

held All force inMexicomeeting 2018. City in March task ng Cognition in Bipolar Disorder ( International Bipolar for Society Disorder (ISBD) ICONIC-BD ). This effort ). Accepted Article variables for each individual eachvariables task. for test-level outcomes similar pre-determined z-scores across Finally,wellthe PCA tasks. calculating mean as as This by is protectedarticle reserved. Allrights copyright. isand this toepisodeload? performance,role do What illness cognitive relative f) influence history without psychosis ahistory? thanthose worse fare such of e)How doesduration of BD Ipatientsdiffer from patientsBD oncognitiveII d)measures? Do BD patients with a vs control)? b)How does current symptom mood severity influence cognition inBD? Do c) group,As how a compareBD with patients do healthy oncognitive outcomes controls (case a) to: notlimited but including questions first, simple by the begin asking Data analyseswill inclusion data allow metrics of to for different from scales.multiple constructs,Again, groups asdifferent useuniqueto these we tests assess willdevise how some capacity of to translates cognitive important the aspectsmost a of patient’s life. occupational and independent living will status beincorporated provideto abenchmark of Measures everyday includinginterpersonal,scale. sameon of the comorbidities) functioning, diagnosticcapture important # priorepisodes; features BDsubtype;(e.g. psychosis subtype; captured by diagnostic interviews SCID) will also vs different bestandardized MINI (i.e. to history Illness used inanalyses. be acommon to to willmetric assessment of beconverted Hamilton depression (HamD) Asrating scales]. such, severity symptoms at mood of time the however,site; not use scales allsites same the Montgomery [e.g. (MADRS) Asberg vs each standardized areavailable ratings several illness-relatedfrom scales.from Data mood summarized and intothe merged Thisdatabase. will include and information demographic otherData from are that measures related cognitiveto in outcome BDwill alsoneedtobe ‘ general ability cognitive Global outcomes Preliminarywill define analyses beconducted to primary outcome atthreelevels.measures control normative sample(e.g. z-scoreswith zero of and mean of standard one). deviation healthy scalesbaseduponthe to standard converted scores willbe necessary; andall test while integrity; data willdata beexamined normality for maintaining andtransformedas analyses will focus on analyseswill focus are impaired inBD such, orthe heterogeneity As cognitive exists. the secondlevel that of that such, it is ofpredictive many important functional outcomes. The relative disadvantageis captures alargepercentagethat it thevariance of cognitiveas and, onother domains/tests groups ofgroups tests rank people identically almost very with highly (approaching oneanother ( the derived general batteries, factors cognitive cognitiveon different test tested been have samples when large show that data that based on is This site. each used at included beleast 3cognitive to inanalyses,measures) regardless of batteries different the measure to calculate 3 tests) least at availablenumber (but tests of usingthe maximum as the an first factor unrotatedfrom PCA, which willbe separately conducted as each site g may not capture some of the more nuanced aspects of neurocognitiveof nuancedsome the of that aspects capture more functioning may not g has distinct advantages in consortium analyses, as it allows all cases (withatallcases allows analyses,in consortium as it advantages hasdistinct will calculatedusingprincipal analyses derive (PCA) be components ato will be selected based beselected will upon representative the (andmost available) domain-level outcomes, g ’ score. This will be done in a standard manner wherestandard ina manner bedone will This ’ score. r =1.0); that is, that is, =1.0); which will be defined based upon resultsbased upon from defined which willbe 5 . An additional this of advantage is measure g factors derived from different derived factors from g . The global g g is defined ) correlate correlate ) Accepted Article This by is protectedarticle reserved. Allrights copyright. KEB. to grant a via Institute Acknowledgements newgenerating using data commoninstruments and forward. moving methodologies in but onlyresearchagreement available data, across groups,not inanalyzing the foster may ICONIC-BD as such collaborative Moreover, initiatives plannedinICONIC-BD. isthat sharing anddata collaboration the kindof advancesthrough scientific support for Cognitive(ENIGMA); Genomics (COGENT), Consortium others] among providesstrong Genomics Consortium (PGC); Enhancing N consortia other of inpsychiatry success investigator/lab.similar The massive [Psychiatric on database cognition This inBD. will workpromote couldnot that be done by any single publicly-available the world’slargest, creationof initiative isthe this The goalof overarching alsolead toadditional this funding veryandfor important understudiedarea ofresearch. will worldwide network andinterconnected dataset this that hope cognition). targeting We interesteda network those for treatment with neuroimaging inestablishing data, trials or orthose DNA, have (e.g. additional that sites projects subcommittees collaborative those for Beyond base, thisdata of initialset-up ICONIC-BD the willalso platform as a serve for immediate effects on quality oflife for many patients with BD. and ultimatelythisto treatwhich prevent disablingsymptom, direct and would have largeofsubsetthe This with BD. how patients (andacritical)stepindetermining is first best these complex questions is key to understanding what causescognitiveimpairment in a establishing potentially meaningfulnew ‘subtypes’ inthelargeststudy Addressing todate. clustering,(e.g.used can latent profiles) to be heterogeneity,empirically cognitive parse addressoutcome can interactions among these key Classification methods illness features. factorial of nature cognition inBD. Analyses of and mediators of moderators cognitive conduct bettersophisticatedmore analyses can toanswerquestionsthat address the multi- answered in any single dataset. Moreover, with the power collaboration, of we will be ableto While questions may straightforward,these seem they beenunambiguously yet have not necessary to study a large population over time, in many andcultures locations. is it questions such answer Tostudy and inthebipolarpopulation? declinebe mitigated humanity, areindividuals with sooner?BD consequences How affected can the of such component aninevitable of with ageis Sincewith cognitivedecline the individual ages. BD the core the of collaboration, it isimperative to considerthe course of cognitive capacity as personal,vocational clinicaloutcome While social, related to and measures functioning form rich with dataset unmatchedpower statistical answer tobegin to them.many of The possiblequestions of list tobe addressed isextensive and ICONIC-BD will providea Howwe confounder can on of best addressthe effects cognitivemedication performance? anxietyg)outcome? (substancecomorbidities disorders) play in cognitive usedisorders, : Funding this for project was provided by theBrigham Research euroImaging Genetics through Meta-analysis Accepted Article This by is protectedarticle reserved. Allrights copyright. Mochida Pharmaceutical, Takeda Pharmaceutical, andNeuroCog Trials Co. Ltd. Dainippon Sumitomo Pharmaceutical, Otsuka Pharmaceutical, TS advisoryhonoraria speaker’srole consultations, for and/or hasreceived board, from the Society Mental of Health Research. Melbourne,Dicker Brain RebeccaLCooperFoundationand Barbara SciencesFoundation, BrockhoffFoundation,Jack University of Trust, Henry Freeman Club the Melbourne, TVR from has receivedgrantfunding Nationalthe Research Council, Health and Medical softwareuses scientific research for providedofcharge free by SBT-pro. Heand Servier. Lundbeck from meetings scientific travelto support for received RP has years. KM hasreceived consultancyLundbeck,from fees Janssen and Allergan inthepast three LLC. ai, last threeyears. He hasconsultedwithPharmaceuticals. Otsuka He is of a co-owner support Pharmaceuticals research withMM receives Janssen from inthe has consulted and work. to this SL has received consulting fees EPI-Q,from Cogstate LTD, and Gift of Hope, all unrelated grantaresearch Takeda from andfrom Stanleythe Foundation. Medical Research has Inc.He i-Function, of officer scientific chief is Battery. He the MATRICSandConsensus CognitioninSchizophrenia of Brief Assessment three years.the royalties Hereceives from Digital Health), Sanofi Pharma, Sunovion Pharma, Pharma, Takeda and Teva, within the last Therapies, Jazz LundbeckPharma, Pharma, Minerva Pharma, Otsuka America (Otsuka Pharma), Intra-Cellular ForumPharma,Biogen,Genentech (Roche Ingelheim, Boehringer PH or has travelreimbursements fees received consulting from Allergan, Alkermes, Akili, Boehringerfor Ingelheim, Lundbeckand Pfizer. CBsupport grant hasreceived Pfizer,Takeda,and Lundbeck from andacts asa consultant servedKEBadvisory on has Neuralstemand boardsfor Pharma. DainipponSumitomo Conflicts of Interest

priori priori Accepted Article

This by is protectedarticle reserved. Allrights copyright. CLBL,AC,work. KEL, andAM associated no have withthis conflicts or theDepartment Health. NIHR, of The views expressedarethoseof authors the and necessarily not theNHS, of the those South London at Centre andMaudsley College andKing’s Foundation Trust NHS London. Biomedical Research Health (NIHR) Research for Institute National AYsupported by is Janssen, Lilly, NARSAD, Otsuka, Pfizer, Servier, Stanely Foundation, Sunovion and Teva. Innovation,Research, CanadianFoundation Dainippon GSK, Sumitomo Pharma, for HealthAllergan,Myers of Alkermes, Astrazeneca,Canadian Bristol Institutes Squibb, LYbeen ofadvisorya receivedresearch has member speakeror boards, grants, been a for (NARSAD) andtheStanleyMedical Institute. Research European Framework Programme andHorizon Brain andthe 2020, Behaviour Foundation (CIBERSAM), theSeventh UniversitiesandInnovation Science, Spanish of Ministry Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain andBehaviour Foundation, the Glaxo-Smith-Kline, Gedeon Janssen, Lundbeck, Richter, Otsuka, Pfizer, SAGE,Roche, Squibb, Farmindustria,Pharma, Ferrer, Institute,Dainippon Sumitomo Forest Research entities: theadvisor orCME speaker as consultant, EVfollowing and served receivedgrants for has AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers has servedand as DainipponSumitomoconsultant andto Lundbeck Canada. Research (CIHR) Healthof Canadian from Institutes research received the IT funding has

Accepted Article This by is protectedarticle reserved. Allrights copyright. Brazil UniversityofDiego California San at Vanderbilt University Queens University Beny Lafer University of Michigan Canada McLean Hospital Torres Lakshmi, Yatham Ivan University Newcastle Japan Australia University of Sao Paulo UniversityofColumbia British Tamsyn VanRheenen Tomiki Sumiyoshi National Center for Neurology and Psychiatry LondonKing’s College Denmark USA Kamilla Miskowiak, Lars Kessing University of Melbourne University of Otago Katherine Burdick Copenhagen University Hospital Brigham and Women’s Hospital/Harvard Site T

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I NITIAL S ITES FORITES ICONIC-BD Eduard Vieta, Anabel Martinez-Aran Allan Young PorterRichard Investigator name(s) Lisa EylerLisa Neil Woodward, Stephan Heckers PulverAnn Christopher Bowie, Philip Harvey, Melvin McInnis LewandowskiKathryn Eve GallagherPeter

Spain UK Zealand New Location USA USA Canada USA USA UK

Accepted Article This by is protectedarticle reserved. Allrights copyright. BIBLIOGRAPHY . Johnson Bouchard,W, T. J., Jr., Krueger, R. F., McGue, M., & Gottesman, I. I. Just 5. Bora E. Neurocognitive in features clinical subgroups of bipolar disorder: A meta- 4. KE, M, Burdick Russo Frangoual.et S, Empiricaldiscrete evidence for 3. SoléCM, Bonnin B, Heterogeneity Jiménez etal. E, functionaloutcomes of in 2. KW, MiskowiakBurdick KE, Martinez-Aranet A, al. Methodologicalrecommendations 1. one g: Consistent Consistent g:one threeresults testbatteries.from Intelligence. 2004;32(1):95-107. analysis. J Affect Disord. 2018;229:125-134. 2014;44(14):3083-3096. subgroupsneurocognitive Psychol inbipolardisorder:Med. clinicalimplications. 2018;137(6):516-527. withpatients bipolardisorder:cluster-analytic aActaapproach. Psychiatr Scand. Disorders Targeting Cognition Task Force. Bipolar Disord. 2017;19(8):614-626. cognitionin bipolar forby disorder trials InternationalBipolar Society the for