kapczinski2014

Review

Staging systems in bipolar disorder: anInternational Society for Bipolar DisordersTask Force Report

Kapczinski F, Magalh~aes PVS, Balanz�a-Martinez V, Dias VV,Frangou S, Gama CS, Gonzalez-Pinto A, Grande I, Ha K,Kauer-Sant’Anna M, Kunz M, Kupka R, Leboyer M,Lopez-Jaramillo C, Post RM, Rybakowski JK, Scott J, Strejilevitch S,Tohen M, Vazquez G, Yatham L, Vieta E, Berk M. Staging systems inbipolar disorder: an International Society for Bipolar Disorders TaskForce Report.

Objective: We discuss the rationale behind staging systems describedspecifically for bipolar disorders. Current applications, future directionsand research gaps in clinical staging models for bipolar disorders areoutlined.Method: We reviewed the literature pertaining to bipolar disorders,focusing on the first episode onwards. We systematically searched dataon staging models for bipolar disorders and allied studies that couldinform the concept of staging.Results: We report on several dimensions that are relevant to stagingconcepts in bipolar disorder. We consider whether staging offers arefinement to current diagnoses by reviewing clinical studies oftreatment and functioning and the potential utility of neurocognitive,neuroimaging and peripheral biomarkers.Conclusion: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response tostandard treatment, consistent with patterns for end-stage medicaldisorders. We believe it is possible at this juncture to speak broadly of‘early’- and ‘late’-stage bipolar disorder. Next steps require furthercollaborative efforts to consider the details of preillness onset andintermediary stages, and how many additional stages are optimal.

F. Kapczinski1,P. V. S. Magalh~aes1,V. Balanz�a-Martinez2, V. V. Dias3,S. Frangou4, C. S. Gama1,A. Gonzalez-Pinto5, I. Grande6,K. Ha7, M. Kauer-Sant’Anna1,M. Kunz1, R. Kupka8, M. Leboyer9,C. Lopez-Jaramillo10, R. M. Post11,J. K. Rybakowski12, J. Scott13,14,S. Strejilevitch15, M. Tohen16,G. Vazquez17, L. Yatham18,E. Vieta6, M. Berk19,201National Institute for Translational Medicine, Hospitalde Clínicas de Porto Alegre, Federal University of RioGrande do Sul, Porto Alegre, Brazil, 2Section ofPsychiatry, Department of Medicine, University ofValencia-CIBERSAM and Hospital Universitari DoctorPeset, Valencia, Spain, 3Bipolar Disorder ResearchProgram, Faculty of Medicine, Hospital Santa Maria,University of Lisbon (FMUL), Lisbon, Portugal, 4Sectionof Neurobiology of Psychosis, Department of PsychosisStudies, Institute of Psychiatry, King’s College London,London, UK, 5Hospital Universitario de Alava (Santiago),University of the Basque Country, CIBERSAM, Vitoria,6Bipolar Disorder Unit, Institute of Neuroscience,Hospital Clinic, University of Barcelona, IDIBAPS,CIBERSAM, Barcelona, Catalonia, Spain, 7Department ofPsychiatry, Seoul National University, Seoul, Korea,8Department of Psychiatry, VU University MedicalCenter, Amsterdam, the Netherlands, 9Department ofPsychiatry, Universit�e Paris-Est, Cr�eteil, France,10Department of Psychiatry, Mood Disorders Program,School of Medicine, University of Antioquia, Medellin,Colombia, 11Bipolar Collaborative Network, Bethesda,MD, USA, 12Department of Adult Psychiatry, PoznanUniversity of Medical Sciences, Poznan, Poland,13Academic Psychiatry, Institute of Neuroscience,Newcastle University, Newcastle upon Tyne, 14Centrefor Affective Disorders, Institute of Psychiatry, London,UK, 15Bipolar Disorder Program, Neurosciences Institute,Favaloro University, Buenos Aires, Argentina,16Department of Psychiatry, University of New Mexico,Albuquerque, NM, USA, 17Department ofNeurosciences, University of Palermo, Buenos Aires,Argentina, 18Department of Psychiatry, University ofBritish Columbia, Vancouver, BC, Canada, 19IMPACTStrategic Research Centre, School of Medicine andBarwon Health, Deakin University, Geelong, Vic., and20Department of Psychiatry, Florey Institute of

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Acta Psychiatr Scand 2014: 130: 354–363 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons LtdAll rights reservedDOI: 10.1111/acps.12305

ACTA PSYCHIATRICA SCANDINAVICA

Neuroscience and Mental Health and Orygen YouthHealth Research Centre, University of Melbourne,Parkville, Vic., Australia

Key words: bipolar disorder; clinical aspects; earlyintervention

Fl�avio Kapczinski, Laboratory of Molecular Psychiatry,Federal University of Rio Grande do Sul – UFRGS,Hospital de Clínicas de Porto Alegre – HCPA, RuaRamiro Barcelos, 2350 – CPE, Porto Alegre, RS CEP90035-903, Brasil. E-mail: [email protected]

Accepted for publication May 30, 2014

Summations

• Staging models have the potential of aiding in the selection of stage-specific interventions in bipolardisorder.

• Available data converge to suggest that broadly defining bipolar disorder as early and late stage isheuristically useful.

• The task force suggests specific strategies for advancing the utility of staging, including formal com-parison between models, employing longitudinal designs and using stage as a stratifications variablein randomized trials.

Considerations

• The preponderance of data is either cross-sectional or secondary in nature.

• Studies specifically investigating staging models and their comparative validity are rare.

• Collaborative international efforts are needed to validate and confirm the utility of staging for peoplewith bipolar disorder.

Introduction

Prognostic staging has been gaining traction inpsychiatry in the past 10 years. This is mainly dueto its potential utility, especially in young adultspresenting to clinical services for the first time (1).A staging system is a heuristic tool intended toindicate where an individual sits on a successionfrom ‘at risk’ but asymptomatic to ‘end-stage’(poor prognosis) illness. In so doing, the clinicianis armed with information capable of aiding selec-tion of stage-specific strategies for treatment.

Since the original proposals of staging for psy-chiatric disorders by Fava and Kellner in 1993 (2),McGorry et al. proposed a model for psychosis,with further proposals for models addressing spe-cific disorders – for a recent overview of staging inother disorders such as anxiety, depression, eatingdisorders and substance use disorders, see Cosciand Fava (3). Within the youth mental healthmovement, there is also a move toward trans-diag-nostic models of staging (4). Proponents ofthis ‘lumping’ approach argue that the similari-

ties in presentation and lack of specificity ofsubsyndromal symptoms make a single model ofearly stages viable (5). However, for the purposesof this manuscript, we wish to review whether thereis a place for employing clinical staging in bipolardisorder alongside current diagnostic approaches.

There is now consistent evidence that, at leastfor a significant proportion of people with bipolardisorder, clinical course and outcome are not asbenign as initially described (6). The evidence thusfar points to relevant differences between early andlate stages of bipolar disorders in clinical course ofillness, neurobiology, systemic pathology andtreatment responsiveness (7). These all suggest thatstaging is a viable addition to clinical care inbipolar disorder.

Aims of the study

The purpose of this report was three-fold. First, weprovide a broad overview as an introduction to theconcept of clinical staging. Second, we discuss the

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rationale behind the staging systems proposed spe-cifically for bipolar disorders. Lastly, we outlineconclusions regarding current applications, futuredirections and research gaps.

Material and methods

We systematically reviewed the extant literaturepertaining to staging and bipolar disorders. Tothat end, we searched MEDLINE, PsychInfo andScopus with the terms ‘bipolar disorder’ and ‘stag-ing’, ‘progression’ or ‘prognosis’ published up toSeptember 2013. We planned to obtain all theavailable information on staging regarding clinicalcourse of illness, functioning and cognition, differ-ential treatment response, serum biomarkers andneuroimaging relevant for adults with bipolar dis-order. Preclinical studies, as well as those involvingchildren and adolescents, were excluded. The rea-son for the latter is our interest in staging postill-ness onset for this report, and most cases ofbipolar disorder have their onset in early adult-hood (8) (Table 1).

However, two caveats should be borne in mind:First, the use of the term ‘staging’ is relatively newin psychiatry, and so literature searches were sup-plemented by references to work undertaken bythe authors of this document. In addition, some ofthe literature on staging models targets preillnessonset phases of mental disorders and in manyinstances examines trans-diagnostic rather thandisorder-specific characteristics. As studies of stag-ing are relatively sparse, we examined the literatureon several linked issues that can inform the con-cept of staging, such as evidence regarding illnessprogression, episode density, functioning and soon. Using this strategy, 4381 references werelocated, with 14 additional references found manu-ally by task force members. After inspecting theabstracts, 261 papers were read in full. Finally, 58original articles and meta-analyses were includedin the present review (15 on clinical course andoutcomes, 28 on functioning and neurocognition,

8 on biomarkers and 7 on neuroimaging). Mostexcluded reports were reviews or did not explicitlyrecruit people with bipolar disorder.

Clinical staging in psychiatry and bipolar disorder

Although the concept of clinical staging had beenpreviously noted in psychiatry (2), McGorry et al.(1, 9, 10) comprehensively discussed its implica-tions and benefits. Clinical staging, as they pro-posed in these early publications, can be useful inany disease that is likely to show progression overtime. This makes it valuable for many psychiatricdisorders, where the reliability of diagnostic cate-gories is not matched by predictive validity (11).

This approach promotes two key notions forclinical staging. The first is that early-stage diseasehas a better response to treatment than laterstages. The second is that early treatment may bemore effective and less hazardous than treatmentsneeded for late-stage disorders. This suggests thattreatments with a higher risk or lower benefit areoften needed later (12). In the framework sug-gested by McGorry, any disorder that tends toprogress is amenable to staging (1, 9, 10). There isa long-standing debate on whether bipolar disor-der is a generally progressive illness (6), but thepossibility that a substantial proportion, perhapsbetween 40% and 50% (13), of patients present aprogressive course makes clinical staging relevant.

In bipolar disorder, specific models of staginghave been put forward. Thus far, most empiricalstudies have used either the model proposed byBerk et al. (14, 15) and Kapczinski et al. (16).Berk’s system more obviously reflects the style ofMcGorry’s original formulation for psychosis,and other authors followed, basically in the samevein (1, 17, 18). It proposes a latency of ‘stage 0’that identifies individuals who are putatively athigher than average risk of a disorder, but whoare currently asymptomatic. It then progresses tosubthreshold, then to threshold syndromes, thento multiple bipolar episode relapses and finally toan end stage of persistent and unremitting illness.It fundamentally uses episode recurrence as aproxy measure of disease progression. Postpro-poses a model similarly put together, harboring afew more stages, going from vulnerability to endstage (19, 20). Cosci and Fava’s (3) recent revi-sion proposes a hybrid between using recurrencesand residual symptoms. These proposals aredisplayed in Table 2.

The starting point in Kapczinski’s model is alsoan at-risk state, but it then moves to a stagedefined by the absence of impairment duringeuthymia, then to marked impairment and finally

Table 1. Literature search details

Inclusioncriteria

Manuscript includes participants with bipolar disorderThe study deals with a relevant aspect of staging, suchas course of illness or biomarkers, or specifically investigatesstaging modelsAreas of interest: clinical studies on course of illness,functioning or cognition; studies on biomarkers or neuroimaging

Exclusioncriteria

Focus on other psychiatric disorders or mixed samples of patientsStudies conducted in children or adolescentsEarly intervention studies of ultra-high-risk patientsAnimal models of bipolar disorder

Searchterms

(‘Bipolar disorder’ or ‘mania’) AND (‘staging’ or ‘prognosis’or ‘progression’)

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to the inability to live autonomously. It is thus amodel that emphasizes functioning, especially dur-ing euthymia, that is, in the interepisodic interval.These bipolar-specific models converge on therelevance of having an ‘at-risk’ stage and a pro-gression to illness persistence or deterioration. Assuch, there should be non-trivial overlap betweenthe two models in classifying individual patients.

To our knowledge, their relative merits in termsof clinical utility and predictive validity have notbeen formally tested. Available data, as discussedbelow, are based on either the Berk or the Kapc-zinski system. Recently, Reinares et al. (21)employed latent class analysis to derive empiricalstages based on functional outcome. In that cross-sectional analysis, they defined functioning duringremission as the primary outcome measure andidentified that in their model, two classes ofpatients could be identified, best predicted byepisode density and residual depressive symptoms,as well as by verbal intelligence and inhibitorycontrol.

Results

Evidence supporting the existence of clinical stages in establishedbipolar disorders

We examine here evidence pertaining to individu-als after the first mania or hypomanic episode.This includes studies comparing first episode caseswith other groups or indirect evidence for stagingfrom post hoc analyses of recent large-scale ran-domized clinical trials.

Clinical studies. Ideally, a staging system would besupported by prospective follow-up studies thatdemonstrate that it is possible to prevent or delay

disease progression or by randomized controlledtreatment trials in cases at high risk of bipolar dis-order. However, as only a few such studies exist sofar for psychosis (22) and definitive studies are notavailable in bipolar disorder, we focus on studiesthat have used ‘proxy’ measures of staging (23).With those caveats in mind, we review here studiesthat address the assumptions behind staging asmentioned earlier, that early treatment is morebenign, less complicated, more effective, and car-ries a better prognosis than later stages.

Recently, Magalhaes et al. (24) published ananalysis of the STEP-BD (25) database using num-ber of episodes as a proxy of staging. In that largedataset (n = 3345), patients naturalistically treatedin specialized facilities followed for up to 2 yearswere stratified according to the number of previousepisodes (fewer than 5, between 5 and 9, 10 ormore). Controlling for a host of possible clinicaland demographic confounders, they were able todemonstrate that those patients with bipolar disor-ders with multiple episodes had a worse prognosison symptom scores and functioning and quality oflife. They were generally more impaired at baselineand tended not to improve as much in clinical andfunctional measures. This analysis was able todemonstrate that a proxy of staging – number ofepisodes – is able to stratify prospectively clinicaland functional outcomes. This study has theadvantage of having a very large sample, felt to berepresentative of those treated for bipolar disorderin the United States and using outcomes that arerelevant to bipolar disorder.

Also of relevance, Rosa et al. (26) published theanalysis of a 1-year follow-up of in-patients withbipolar disorder. Similar to the STEP-BD patients,those with multiple episodes had many significantdifferences at baseline and also displayed a worse

Table 2. Current proposals for staging in bipolar disorder

Stage Berk et al. (14, 15) Kapczinski et al. (16) Post (19) Cosci and Fava (3)

0 Increased risk of mood disorder At risk, positive family history, mood oranxiety symptoms

1a Mild or non-specific symptom Well-defined periods of euthymia withoutsymptoms

Vulnerability Mild or non-specific symptoms/prodromal phase

1b Prodromal features (ultra-high risk) Cyclothymia2 First threshold episode Interepisodic symptoms related to

comorbiditiesWell-interval Acute manifestations of major depression or mania/

hypomania3a Recurrence of subthreshold mood

symptomsMarked impairment in cognition orfunctioning

Prodrome Residual symptoms with cognitive and functionalimpairment despite treatment

3b First threshold relapse3c Multiple relapses4 Persistent unremitting illness Unable to live autonomously due to

impairmentIllness onset Acute episodes despite treatment

5 Episode recurrence6 Illness progression7 Treatment refractoriness8 End stage

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recovery rate at the end of the 1-year follow-up.These data converge with those from the StanleyFoundation Bipolar Collaborative (12, 27) and theEmblem European Study (28).

Secondary data from two randomized psycho-therapy trials also support the assumption that thepatients in earlier stages have a better response topsychotherapy (21, 29). In the first, Scott et al. (29)reported that patients with fewer than 12 previousepisodes had a positive response to cognitivebehavioural therapy compared with those withtwelve or more episodes. In this trial, patients(n = 253) were randomized to CBT or treatment asusual, and only those with fewer than 12 episodeshad a lower rate of recurrence on CBT. In anotherpost hoc analysis, a randomized controlled trial offamily psychoeducation, Reinares et al. (30)clinically stratified patients with establishedbipolar disorder (n = 113) into early or late stagesaccording to number of prior illness episodes.Again, they found a positive benefit, in terms oflonger time to recurrence, for those in early-stagebipolar disorder.

Berk et al. (31) used pooled data from olanza-pine trials to evaluate stage-related differences intreatment response. Within this large dataset (12studies, N = 4346), treatment response was higherin cases with fewer episodes in the acute maniastudies, and there was a similar effect in relapseprevention. However, there were no differences inresponses in depression studies. Similarly, responseto certain agents, such as lithium and olanzapine,appears greater in the early phase of the BD (32,33). Higher serum lithium levels were also moreeffective in preventing relapse in patients that hadthree or more mood episodes in one study (34).Finally, Magalhaes et al. (24) also examinedwhether there were any differential responses toadjunctive antidepressants within the STEP-BDstudy (35). However, in the subgroup allocated toantidepressants, no interaction was found betweenstage and outcomes.

A history of rapid cycling can also be used as aproxy for a greater number of prior episodes.Recently, Ghaemi et al. (36) demonstrated thatthose with rapid cycling had a more adverseresponse to antidepressant continuation in termsof a greater number of depressive recurrences com-pared with those discontinuing antidepressants.

Psychosocial functioning and neurocognition. TheEuropean Mania in Bipolar Longitudinal Evalua-tion of Medication study (n = 3115) reported thata greater proportion of first episode patientsachieve symptomatic and functional recoverycompared with those with multiple episodes (28).

Likewise, a recent 1-year functioning studyreported that patients at late stages were signifi-cantly more impaired than those at early stage ofbipolar disorder in distinct domains of functioning(26). Similar findings have been reported for indi-viduals in the early stages of illness presenting toyouth mental health services (18, 37). Significantclinical differences, mainly in terms of severity ofdepression, suicide attempts and the number ofyears before receiving a correct diagnosis, havebeen observed between patients with first and mul-tiple episodes (38). Taken together, these findingssuggest that the episode frequency has an impacton patient’s outcome, particularly on psychosocialfunctioning.

Individuals with bipolar disorder often experi-ence persistent neurocognitive deficits and poorpsychosocial functioning even when they are eu-thymic (39–43). Neurocognitive impairment hasbeen related to a worse clinical course and poorpsychosocial functioning (44, 45). For instance,in a first episode cohort, verbal learning at base-line was robustly associated with functional out-come at a 6-month follow-up even aftercontrolling for mood symptoms and substanceabuse comorbidity (46). More severe neurocogni-tive deficits are not only associated with illnessseverity (47, 48), but also associated with cumu-lative mood episodes (49, 50). For instance, eu-thymic patients who had at least three manicepisodes showed worse overall neurocognitiveperformance compared with those with only oneprevious episode of mania (51). In young adultspresenting with bipolar depression, Hermenset al. (52) also identify significant neurocognitivedeficits in young adults presenting with in theearly stages of bipolar disorders. Memory, atten-tion and executive dysfunction have been consis-tently reported in euthymic patients with bipolardisorder (43, 53, 54), generally in proportion tonumber of prior episodes (30), with verbal learn-ing and memory impairment being significantpredictors of long-term functioning (55).

The impact of neurocognitive impairment onfunctioning led Torrent et al. (56) to develop afunctional remediation program specifically forbipolar disorders. This program is especially tai-lored for people with bipolar disorder who haveimpairment during euthymia along the progressionof the disorder. Functional remediation showedsuperiority to treatment as usual in improving psy-chosocial functioning at study endpoint. Thisstudy suggests that functional remediation couldbe more suited to patients in advanced stages,whereas psychoeducation is likely to be moreeffective in the early stages of illness.

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Peripheral markers. Peripheral biomarkers are per-tinent to the theme of staging as they are conceptu-alized as mediators of allostasis (57–59) and theirdemonstration in different stages is one of the fun-damental hypotheses of neuroprogression (60, 61).Ultimately, they might be useful in selecting stagedinterventions. For instance, concordant with theallostatic load model, the presence of relevantmedical comorbidity is often associated with indi-cations of late-stage bipolar disorder (62).Recently, patients with such comorbidities wereshown to have a better response to N-acetyl-cyste-ine than those without medical conditions (63). Ifconfirmed, these findings would suggest the use ofadjunctive antioxidants in those with comorbidi-ties, which could be proxies of higher levels ofcirculating free radicals.

Perhaps, the seminal study on the associationof biomarkers with staging was conducted byKauer-Sant’Anna et al. (64). In that case–control study, the authors were able to dem-onstrate that patients in a late stage (i.e., aminimum of 10 years after the diagnosis ofbipolar disorder and with multiple previous epi-sodes) showed many differences in peripheralinflammation biomarkers when compared tocontrols, which was not the case in early-stagepatients. Furthermore, in the case of tumornecrosis factor a, where both groups of patientshad increased circulating levels, patients in latestages had several-fold greater increases (seeTable 3). Further exploration of this samplealso revealed that glutathione S-transferase andreductase were increased in late-stage patients,although 3-nitrotyrosine was also foundincreased in early-stage patients (65). Thesealterations in oxidative biology imply a pro-oxi-dant pathology in bipolar disorder. Furtherincreases in protein and lipid damage have beenreported in patients with bipolar disorder seenat tertiary facilities, which are generally late-stage patients (66). However, a recent report ofa community-based sample also demonstratedearly-stage increases in protein damage (67).

Neurotrophins are also relevant to staging asthey are pertinent to the kindling hypothesis andother models of illness progression (68, 69). In thestudy mentioned above, Kauer-Sant’Anna et al.(64) also demonstrated relevant decreases in brain-derived neurotrophic factor (BDNF) in late-stage,but not early-stage, patients. A later meta-analysisdemonstrated a correlation between the age andlength of illness and serum BDNF across sevenstudies (70). A similar relationship was apparentwhen a ‘systemic toxicity index’ was examined inlate-stage patients compared with people with

early-stage bipolar disorder from the general popu-lation (71, 72).

Neuroimaging. Lin et al. (73) recently reviewedneuroimaging evidence for staging in severe mentaldisorders, including bipolar disorder. They high-light the possibility that structural and functionalnetworks could be differently affected in each ill-ness stage. White matter pathology could beresponsible for early-stage dysconnectivity. In firstepisode patients, for instance, recent meta-analysisshows significant white matter reductions, but notgray matter (74). Another meta-analysis of voxel-wise studies also demonstrated fewer alterations ingray matter in first episode patients (75). Therewas no progression in gray matter loss in patientswith severe bipolar disorder during the first 2 yearsof follow-up, when compared with controls (76).

Stage changes were specifically investigated inonly a few cross-sectional studies. In one MRIstudy, the total number of episodes was correlatedwith the size of the left hippocampus, and onlypatients with fewer than 10 episodes had a largerhippocampus compared with controls (77). Lagop-oulus (78) compared a mixed cohort of people with‘attenuated syndromes’ (stage 1) with patients with‘discrete disorders’ (psychosis, bipolar disorder ordepression, stages two or three). Patients on stage2 or 3 had a more widespread pattern of gray mat-ter loss. In a region of interest study, Nery et al.(79) showed similar orbitofrontal cortex gray mat-ter volumes in individuals with bipolar disorderand controls. However, the total number of epi-sodes did not influence significantly the result.

A recent systematic review of longitudinal neu-roimaging studies notes several caveats and a gen-eral dearth of prospective data (80), which mirrorsthe neurocognitive literature (81). Among structuralneuroimaging studies, neuroprogressive changeswere more robustly noted in prefrontal, cingulateand subgenual cortices and fusiform gyrus,although total brain volume seems to be stable.

Table 3. Selected circulating biomarkers in early- and late-stage bipolar disorder

Marker Early stage Late stage

BDNF (76, 82) � ↓↓TNF a (76) ↑ ↑↑IL-6 (76) ↑ ↑IL-10 (76) ↑ �PCC (77–79) ↑� �TBARS (78) � ↑↑Systemic toxicity (83, 84) ↑ ↑↑

BDNF, brain-derived neurotrophic factor; TNF-a, tumor necrosis factor a; IL, interleu-kin; PCC, protein carbonyl content; TBARS, thiobarbituric acid reactive substances.� No change, ↑ modest increase, ↑↑ substantial increase, ↑� mixed results, ↓↓substantial decrease.

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Discussion

Most of extant evidence relevant to staging modelsis cross-sectional. This is surely the source of muchof the heterogeneity in the biomarker and neuroi-maging data. Another source of weakness in thecurrent published literature is the small sample sizeof the studies, which are mostly pilot studies innature. Even some of the most carefully designedand strongest research such as the differentialchanges in peripheral biomarkers according tostage demonstrated by Kauer-Sant’Anna et al.(64) would benefit from independent replication.Transitions from at risk to subsyndromal and thensyndromal illness (where the individual meets diag-nostic criteria) and between later stages should bestudied and validated with relevant clinical end-points – and possibly biomarker data. This willlikely require a multicenter effort, due to the inher-ent complexity of such endeavors.

The current staging models for bipolar disordershould also be formally compared with each otherand also with other trans-diagnostic models (3). Astaging system should be able to predict diseaseprogression and stratify relevant outcomes in aconsistent way. However, this demonstrates an ele-ment of the current challenge for psychiatry.Merely predicting future functioning or relapsesbased on current functioning or previous relapsescontains an element of circularity that should beavoided.

One attractive option is the use of putativestages as a stratification variable in randomizedcontrolled treatment trials. This has only rarelybeen performed, but would be clinically useful toconfirm previous secondary analyses with rigorous,stage-tailored and hypothesis-driven trials. Alter-natively, patients could be randomized to eitherreceive treatment as usual or ‘stage-appropriate’interventions. Furthermore, there is a need todevelop and test the role of stage-specific treat-ments for at risk and first episode cases: exemplarsbeing the studies led by Miklowitz (82) and byMacNeil (83).

With the caveat that most data at present arecross-sectional in nature, based on post hoc analy-sis or both, the bulk of the preliminary evidenceavailable suggests that staging has promisingclinical utility for postillness onset cases of bipolardisorder. Clinically, the early- and late-stage dis-tinction may appear obvious in the sense that suchpatients have overtly different needs. Clinicianshave their own, probably idiosyncratic ways indealing with this issue (3). Nevertheless, confirmingthese effects and estimating their magnitude mat-ters. Also of consequence, such different cohorts of

patients are usually lumped in clinical trials, whichcould obscure relevant treatment differences. Thereis growing consensus that early intervention isvaluable in individuals with severe mental disor-ders (84). Interventions for individuals in latestages have been more problematic and less oftenstudied systematically (85).

Most studies to date confirm that globallydefined late-stage patients have a worse overallprognosis and poorer response to standard treat-ment, consistent with patterns known in othermedical disorders. Although refinement of stagingsystems is certainly in need of further study, webelieve it is already proper at this juncture to speakbroadly of ‘early’ and ‘late’ stages. Early stages areat the first or the first few episodes and are inaggregate associated with better functioning afterrecovery. Late stages are associated with multipleepisodes and tend to have impairment in multipleareas of functioning. In other words, the modelsproposed by Kapczinski and Berk concur on theimportance of ‘early’- or ‘late’-stage disease. Thenext steps require consideration of the details ofintermediary stages and how many additionalstages are optimal. The ultimate goal should belinking staging models with optimally tailoredtherapy. This should be the subject of further localand global collaborative efforts.

Declaration of interest

Prof. Kapczinski has received grants/research support fromAstraZeneca, Eli Lilly, Janssen-Cilag, Servier, CNPq, CAPES,NARSAD and Stanley Medical Research Institute; has been amember of the board of speakers for AstraZeneca, Eli Lilly,Janssen and Servier; and has served as a consultant for Servier.Vasco Videira Dias is consultant for Angelini Pharmaceutical,Portugal, and has received educational grants from Lundbeck,Sanofi-Aventis, AstraZeneca and Bristol-Myers Squibb. Dr.V�azquez has served as consultant or speaker for Abbott,AstraZeneca, Gador, Glaxo-SmithKline, Ivax/Teva, Eli Lilly,Lundbeck, Pfizer, Raffo, Servier and Novartis within the last3 years. Dr. I. Grande has received a research grant R�ıo Hort-ega Contract (CM12/00062), Instituto de Salud Carlos III,Spanish Ministry of Economy and Competiveness, Barcelona,Spain, and has served as a speaker for AstraZeneca. Dr Ba-lanz�a-Mart�ınez has received grants and served as consultant,advisor or CME speaker during the last 3 years for the follow-ing entities: Angelini, AstraZeneca, Bristol-Myers-Squibb,Janssen, Juste, Lilly, Otsuka, the Spanish Ministry of Scienceand Innovation (CIBERSAM), and ´Fundaci�on Alicia Koplo-witz´. Sergio A. Strejilevich has served as consultant or speakerfor Glaxo Smith Kline, AstraZeneca, Lilly, Abbott and hasreceived educational grants from Servier. Jan Scott hasreceived funding toward the costs of attending national andinternational conferences, or fees for talks on psychosocialaspects of bipolar disorders, or advisory board fees from AstraZeneca, BMS-Otsuka, Eli Lilly, GSK, Jansen-Cilag, Lund-beck, Sanofi-Aventis and Servier. Dr. Vieta has received grantsand served as consultant, advisor or CME speaker for the fol-lowing entities: Adamed, Alexza, Almirall, AstraZeneca, Bial,

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Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest ResearchInstitute, Gedeon Richter, Glaxo-Smith-Kline, Janssen-Cilag,Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Orga-non, Otsuka, Pfizer, Pierre-Fabre, Qualigen, Roche, Sanofi-Aventis, Servier, Shering-Plough, Shire, Solvay, Sunovion,Takeda, Teva, the Spanish Ministry of Science and Innovation(CIBERSAM), the Seventh European Framework Programme(ENBREC), the Stanley Medical Research Institute, UnitedBiosource Corporation, and Wyeth. Clarissa S Gama hasserved as consultant or speaker for Actelion Pharmaceuticals,Eli Lilly, Lundbeck and Roche. Michael Berk has receivedgrant/research support from the NIH, Cooperative ResearchCentre, Simons Autism Foundation, Cancer Council of Victo-ria, Stanley Medical Research Foundation, MBF, NHMRC,Beyond Blue, Rotary Health, Geelong Medical ResearchFoundation, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithK-line, Meat and Livestock Board, Organon, Novartis, MaynePharma, Servier and Woolworths and has been a speaker forAstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithK-line, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthe-labo, Servier, Solvay and Wyeth, and served as a consultant toAstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithK-line, Janssen Cilag, Lundbeck Merck and Servier. Dr. Yathamis on speaker/advisory boards for or has received researchgrants from: AstraZeneca, Bristol-Myers Squibb, CIHR,CANMAT, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck,the Michael Smith Foundation for Health Research, Pfizer,Servier, Sunovion and the Stanley Foundation. Janusz K. Ry-bakowski has acted over the past 2 years as a consultant or asa speaker for the following companies: Bristol-Myers-Squibb,Eli Lilly, Janssen-Cilag, Lundbeck, Sanofi-Aventis and Servier.Marion Leboyer served as a speaker to Servier, AstraZenecaand received research grants from Sanofi and Roche. Prof. Ka-uer-Sant’Anna has received research grants from NARSAD,SMRI, Universal-CNPq, CNPq/INCT-TM, FIPE-HCPA, andis on the speaker board for Eli-Lilly. Carlos Lopez-Jaramillohas received Grant/Research Support from the Colciencias,Universidad de Antioquia, NIMH, and Abbott, AstraZeneca,Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Novartis,AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithK-line, Janssen Cilag, Lundbeck, Pfizer, Sanofi Synthelabo, andserved as a consultant/speaker to Abbott, AstraZeneca, Bris-tol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag,Lundbeck, Pfizer and Servier. Dr. Gonzalez-Pinto has receivedgrants and served as consultant, advisor or CME speaker forthe following entities: AstraZeneca, Bristol-Myers Squibb,Cephalon, Eli Lilly, Janssen-Cilag, Lundbeck, Merck, Otsuka,Pfizer, Sanofi-Aventis, Servier, the Spanish Ministry of Scienceand Innovation (CIBERSAM), the Ministry of Science (CarlosIII Institute), the Basque Governement, the Stanley MedicalResearch Institute, and Wyeth. Ralph Kupka received unre-stricted research grants from AstraZeneca and served as aspeaker for AstraZeneca, Eli-Lilly, Lundbeck and Bristol-MyersSquibb.

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