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Acta Psychiatr Scand 2014: 130: 354363

All rights reserved


DOI: 10.1111/acps.12305

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ACTA PSYCHIATRICA SCANDINAVICA

Review

Staging systems in bipolar disorder: an


International Society for Bipolar Disorders
Task 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-SantAnna 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 in
bipolar disorder: an International Society for Bipolar Disorders Task
Force Report.
Objective: We discuss the rationale behind staging systems described
specically for bipolar disorders. Current applications, future directions
and research gaps in clinical staging models for bipolar disorders are
outlined.
Method: We reviewed the literature pertaining to bipolar disorders,
focusing on the rst episode onwards. We systematically searched data
on staging models for bipolar disorders and allied studies that could
inform the concept of staging.
Results: We report on several dimensions that are relevant to staging
concepts in bipolar disorder. We consider whether staging oers a
renement to current diagnoses by reviewing clinical studies of
treatment and functioning and the potential utility of neurocognitive,
neuroimaging and peripheral biomarkers.
Conclusion: Most studies to date indicate that globally dened latestage patients have a worse overall prognosis and poorer response to
standard treatment, consistent with patterns for end-stage medical
disorders. We believe it is possible at this juncture to speak broadly of
early- and late-stage bipolar disorder. Next steps require further
collaborative eorts to consider the details of preillness onset and
intermediary stages, and how many additional stages are optimal.

354

F. Kapczinski1,

P. V. S. Magalh~aes1,
V. Balanza-Martinez2, V. V. Dias3,
S. Frangou4, C. S. Gama1,
A. Gonzalez-Pinto5, I. Grande6,
K. Ha7, M. Kauer-SantAnna1,
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. Berk19,20
1
National Institute for Translational Medicine, Hospital
de Clnicas de Porto Alegre, Federal University of Rio
Grande do Sul, Porto Alegre, Brazil, 2Section of
Psychiatry, Department of Medicine, University of
Valencia-CIBERSAM and Hospital Universitari Doctor
Peset, Valencia, Spain, 3Bipolar Disorder Research
Program, Faculty of Medicine, Hospital Santa Maria,
University of Lisbon (FMUL), Lisbon, Portugal, 4Section
of Neurobiology of Psychosis, Department of Psychosis
Studies, Institute of Psychiatry, Kings College London,
London, UK, 5Hospital Universitario de Alava (Santiago),
University of the Basque Country, CIBERSAM, Vitoria,
6
Bipolar Disorder Unit, Institute of Neuroscience,
Hospital Clinic, University of Barcelona, IDIBAPS,
CIBERSAM, Barcelona, Catalonia, Spain, 7Department of
Psychiatry, Seoul National University, Seoul, Korea,
8
Department of Psychiatry, VU University Medical
Center, Amsterdam, the Netherlands, 9Department of
Psychiatry, Universite Paris-Est, Creteil, France,
10
Department of Psychiatry, Mood Disorders Program,
School of Medicine, University of Antioquia, Medellin,
Colombia, 11Bipolar Collaborative Network, Bethesda,
MD, USA, 12Department of Adult Psychiatry, Poznan
University of Medical Sciences, Poznan, Poland,
13
Academic Psychiatry, Institute of Neuroscience,
Newcastle University, Newcastle upon Tyne, 14Centre
for Affective Disorders, Institute of Psychiatry, London,
UK, 15Bipolar Disorder Program, Neurosciences Institute,
Favaloro University, Buenos Aires, Argentina,
16
Department of Psychiatry, University of New Mexico,
Albuquerque, NM, USA, 17Department of
Neurosciences, University of Palermo, Buenos Aires,
Argentina, 18Department of Psychiatry, University of
British Columbia, Vancouver, BC, Canada, 19IMPACT
Strategic Research Centre, School of Medicine and
Barwon Health, Deakin University, Geelong, Vic., and
20
Department of Psychiatry, Florey Institute of

Staging bipolar disorder


Neuroscience and Mental Health and Orygen Youth
Health Research Centre, University of Melbourne,
Parkville, Vic., Australia
Key words: bipolar disorder; clinical aspects; early
intervention
Flavio Kapczinski, Laboratory of Molecular Psychiatry,
Federal University of Rio Grande do Sul UFRGS,
Hospital de Clnicas de Porto Alegre HCPA, Rua
Ramiro Barcelos, 2350 CPE, Porto Alegre, RS CEP
90035-903, Brasil. E-mail: flavio.kapczinski@gmail.com

Accepted for publication May 30, 2014

Summations

Staging models have the potential of aiding in the selection of stage-specic interventions in bipolar
disorder.

Available data converge to suggest that broadly dening bipolar disorder as early and late stage is
heuristically useful.

The task force suggests specic strategies for advancing the utility of staging, including formal com-

parison between models, employing longitudinal designs and using stage as a stratications variable
in randomized trials.

Considerations

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


Studies specically investigating staging models and their comparative validity are rare.
Collaborative international eorts are needed to validate and conrm the utility of staging for people
with bipolar disorder.

Introduction

Prognostic staging has been gaining traction in


psychiatry in the past 10 years. This is mainly due
to its potential utility, especially in young adults
presenting to clinical services for the rst time (1).
A staging system is a heuristic tool intended to
indicate where an individual sits on a succession
from at risk but asymptomatic to end-stage
(poor prognosis) illness. In so doing, the clinician
is armed with information capable of aiding selection of stage-specic strategies for treatment.
Since the original proposals of staging for psychiatric disorders by Fava and Kellner in 1993 (2),
McGorry et al. proposed a model for psychosis,
with further proposals for models addressing specic disorders for a recent overview of staging in
other disorders such as anxiety, depression, eating
disorders and substance use disorders, see Cosci
and Fava (3). Within the youth mental health
movement, there is also a move toward trans-diagnostic models of staging (4). Proponents of
this lumping approach argue that the similari-

ties in presentation and lack of specicity of


subsyndromal symptoms make a single model of
early stages viable (5). However, for the purposes
of this manuscript, we wish to review whether there
is a place for employing clinical staging in bipolar
disorder alongside current diagnostic approaches.
There is now consistent evidence that, at least
for a signicant proportion of people with bipolar
disorder, clinical course and outcome are not as
benign as initially described (6). The evidence thus
far points to relevant dierences between early and
late stages of bipolar disorders in clinical course of
illness, neurobiology, systemic pathology and
treatment responsiveness (7). These all suggest that
staging is a viable addition to clinical care in
bipolar disorder.
Aims of the study

The purpose of this report was three-fold. First, we


provide a broad overview as an introduction to the
concept of clinical staging. Second, we discuss the
355

Kapczinski et al.
rationale behind the staging systems proposed specically for bipolar disorders. Lastly, we outline
conclusions regarding current applications, future
directions and research gaps.

8 on biomarkers and 7 on neuroimaging). Most


excluded reports were reviews or did not explicitly
recruit people with bipolar disorder.
Clinical staging in psychiatry and bipolar disorder

Material and methods

We systematically reviewed the extant literature


pertaining to staging and bipolar disorders. To
that end, we searched MEDLINE, PsychInfo and
Scopus with the terms bipolar disorder and staging, progression or prognosis published up to
September 2013. We planned to obtain all the
available information on staging regarding clinical
course of illness, functioning and cognition, dierential treatment response, serum biomarkers and
neuroimaging relevant for adults with bipolar disorder. Preclinical studies, as well as those involving
children and adolescents, were excluded. The reason for the latter is our interest in staging postillness onset for this report, and most cases of
bipolar disorder have their onset in early adulthood (8) (Table 1).
However, two caveats should be borne in mind:
First, the use of the term staging is relatively new
in psychiatry, and so literature searches were supplemented by references to work undertaken by
the authors of this document. In addition, some of
the literature on staging models targets preillness
onset phases of mental disorders and in many
instances examines trans-diagnostic rather than
disorder-specic characteristics. As studies of staging are relatively sparse, we examined the literature
on several linked issues that can inform the concept of staging, such as evidence regarding illness
progression, episode density, functioning and so
on. Using this strategy, 4381 references were
located, with 14 additional references found manually by task force members. After inspecting the
abstracts, 261 papers were read in full. Finally, 58
original articles and meta-analyses were included
in the present review (15 on clinical course and
outcomes, 28 on functioning and neurocognition,
Table 1. Literature search details
Inclusion
criteria

Exclusion
criteria

Search
terms

356

Manuscript includes participants with bipolar disorder


The study deals with a relevant aspect of staging, such
as course of illness or biomarkers, or specifically investigates
staging models
Areas of interest: clinical studies on course of illness,
functioning or cognition; studies on biomarkers or neuroimaging
Focus on other psychiatric disorders or mixed samples of patients
Studies conducted in children or adolescents
Early intervention studies of ultra-high-risk patients
Animal models of bipolar disorder
(Bipolar disorder or mania) AND (staging or prognosis
or progression)

Although the concept of clinical staging had been


previously noted in psychiatry (2), McGorry et al.
(1, 9, 10) comprehensively discussed its implications and benets. Clinical staging, as they proposed in these early publications, can be useful in
any disease that is likely to show progression over
time. This makes it valuable for many psychiatric
disorders, where the reliability of diagnostic categories is not matched by predictive validity (11).
This approach promotes two key notions for
clinical staging. The rst is that early-stage disease
has a better response to treatment than later
stages. The second is that early treatment may be
more eective and less hazardous than treatments
needed for late-stage disorders. This suggests that
treatments with a higher risk or lower benet are
often needed later (12). In the framework suggested by McGorry, any disorder that tends to
progress is amenable to staging (1, 9, 10). There is
a long-standing debate on whether bipolar disorder is a generally progressive illness (6), but the
possibility that a substantial proportion, perhaps
between 40% and 50% (13), of patients present a
progressive course makes clinical staging relevant.
In bipolar disorder, specic models of staging
have been put forward. Thus far, most empirical
studies have used either the model proposed by
Berk et al. (14, 15) and Kapczinski et al. (16).
Berks system more obviously reects the style of
McGorrys original formulation for psychosis,
and other authors followed, basically in the same
vein (1, 17, 18). It proposes a latency of stage 0
that identies individuals who are putatively at
higher than average risk of a disorder, but who
are currently asymptomatic. It then progresses to
subthreshold, then to threshold syndromes, then
to multiple bipolar episode relapses and nally to
an end stage of persistent and unremitting illness.
It fundamentally uses episode recurrence as a
proxy measure of disease progression. Postproposes a model similarly put together, harboring a
few more stages, going from vulnerability to end
stage (19, 20). Cosci and Favas (3) recent revision proposes a hybrid between using recurrences
and residual symptoms. These proposals are
displayed in Table 2.
The starting point in Kapczinskis model is also
an at-risk state, but it then moves to a stage
dened by the absence of impairment during
euthymia, then to marked impairment and nally

Staging bipolar disorder


Table 2. Current proposals for staging in bipolar disorder
Stage

Berk et al. (14, 15)

Kapczinski et al. (16)

Increased risk of mood disorder

1a

Mild or non-specific symptom

At risk, positive family history, mood or


anxiety symptoms
Well-defined periods of euthymia without
symptoms

1b
2

Prodromal features (ultra-high risk)


First threshold episode

3a

Recurrence of subthreshold mood


symptoms
First threshold relapse
Multiple relapses
Persistent unremitting illness

3b
3c
4

Post (19)

Cosci and Fava (3)

Vulnerability

Mild or non-specific symptoms/prodromal phase

Interepisodic symptoms related to


comorbidities
Marked impairment in cognition or
functioning

Well-interval

Unable to live autonomously due to


impairment

Illness onset

5
6
7
8

to the inability to live autonomously. It is thus a


model that emphasizes functioning, especially during euthymia, that is, in the interepisodic interval.
These bipolar-specic models converge on the
relevance of having an at-risk stage and a progression to illness persistence or deterioration. As
such, there should be non-trivial overlap between
the two models in classifying individual patients.
To our knowledge, their relative merits in terms
of clinical utility and predictive validity have not
been formally tested. Available data, as discussed
below, are based on either the Berk or the Kapczinski system. Recently, Reinares et al. (21)
employed latent class analysis to derive empirical
stages based on functional outcome. In that crosssectional analysis, they dened functioning during
remission as the primary outcome measure and
identied that in their model, two classes of
patients could be identied, best predicted by
episode density and residual depressive symptoms,
as well as by verbal intelligence and inhibitory
control.

Results
Evidence supporting the existence of clinical stages in established
bipolar disorders

We examine here evidence pertaining to individuals after the rst mania or hypomanic episode.
This includes studies comparing rst episode cases
with other groups or indirect evidence for staging
from post hoc analyses of recent large-scale randomized clinical trials.
Clinical studies. Ideally, a staging system would be
supported by prospective follow-up studies that
demonstrate that it is possible to prevent or delay

Prodrome

Cyclothymia
Acute manifestations of major depression or mania/
hypomania
Residual symptoms with cognitive and functional
impairment despite treatment

Acute episodes despite treatment

Episode recurrence
Illness progression
Treatment refractoriness
End stage

disease progression or by randomized controlled


treatment trials in cases at high risk of bipolar disorder. However, as only a few such studies exist so
far for psychosis (22) and denitive studies are not
available in bipolar disorder, we focus on studies
that have used proxy measures of staging (23).
With those caveats in mind, we review here studies
that address the assumptions behind staging as
mentioned earlier, that early treatment is more
benign, less complicated, more eective, and carries a better prognosis than later stages.
Recently, Magalhaes et al. (24) published an
analysis of the STEP-BD (25) database using number of episodes as a proxy of staging. In that large
dataset (n = 3345), patients naturalistically treated
in specialized facilities followed for up to 2 years
were stratied according to the number of previous
episodes (fewer than 5, between 5 and 9, 10 or
more). Controlling for a host of possible clinical
and demographic confounders, they were able to
demonstrate that those patients with bipolar disorders with multiple episodes had a worse prognosis
on symptom scores and functioning and quality of
life. They were generally more impaired at baseline
and tended not to improve as much in clinical and
functional measures. This analysis was able to
demonstrate that a proxy of staging number of
episodes is able to stratify prospectively clinical
and functional outcomes. This study has the
advantage of having a very large sample, felt to be
representative of those treated for bipolar disorder
in the United States and using outcomes that are
relevant to bipolar disorder.
Also of relevance, Rosa et al. (26) published the
analysis of a 1-year follow-up of in-patients with
bipolar disorder. Similar to the STEP-BD patients,
those with multiple episodes had many signicant
dierences at baseline and also displayed a worse
357

Kapczinski et al.
recovery rate at the end of the 1-year follow-up.
These data converge with those from the Stanley
Foundation Bipolar Collaborative (12, 27) and the
Emblem European Study (28).
Secondary data from two randomized psychotherapy trials also support the assumption that the
patients in earlier stages have a better response to
psychotherapy (21, 29). In the rst, Scott et al. (29)
reported that patients with fewer than 12 previous
episodes had a positive response to cognitive
behavioural therapy compared with those with
twelve or more episodes. In this trial, patients
(n = 253) were randomized to CBT or treatment as
usual, and only those with fewer than 12 episodes
had a lower rate of recurrence on CBT. In another
post hoc analysis, a randomized controlled trial of
family psychoeducation, Reinares et al. (30)
clinically stratied patients with established
bipolar disorder (n = 113) into early or late stages
according to number of prior illness episodes.
Again, they found a positive benet, in terms of
longer time to recurrence, for those in early-stage
bipolar disorder.
Berk et al. (31) used pooled data from olanzapine trials to evaluate stage-related dierences in
treatment response. Within this large dataset (12
studies, N = 4346), treatment response was higher
in cases with fewer episodes in the acute mania
studies, and there was a similar eect in relapse
prevention. However, there were no dierences in
responses in depression studies. Similarly, response
to certain agents, such as lithium and olanzapine,
appears greater in the early phase of the BD (32,
33). Higher serum lithium levels were also more
eective in preventing relapse in patients that had
three or more mood episodes in one study (34).
Finally, Magalhaes et al. (24) also examined
whether there were any dierential responses to
adjunctive antidepressants within the STEP-BD
study (35). However, in the subgroup allocated to
antidepressants, no interaction was found between
stage and outcomes.
A history of rapid cycling can also be used as a
proxy for a greater number of prior episodes.
Recently, Ghaemi et al. (36) demonstrated that
those with rapid cycling had a more adverse
response to antidepressant continuation in terms
of a greater number of depressive recurrences compared with those discontinuing antidepressants.
Psychosocial functioning and neurocognition. The
European Mania in Bipolar Longitudinal Evaluation of Medication study (n = 3115) reported that
a greater proportion of rst episode patients
achieve symptomatic and functional recovery
compared with those with multiple episodes (28).

358

Likewise, a recent 1-year functioning study


reported that patients at late stages were signicantly more impaired than those at early stage of
bipolar disorder in distinct domains of functioning
(26). Similar ndings have been reported for individuals in the early stages of illness presenting to
youth mental health services (18, 37). Signicant
clinical dierences, mainly in terms of severity of
depression, suicide attempts and the number of
years before receiving a correct diagnosis, have
been observed between patients with rst and multiple episodes (38). Taken together, these ndings
suggest that the episode frequency has an impact
on patients outcome, particularly on psychosocial
functioning.
Individuals with bipolar disorder often experience persistent neurocognitive decits and poor
psychosocial functioning even when they are euthymic (3943). Neurocognitive impairment has
been related to a worse clinical course and poor
psychosocial functioning (44, 45). For instance,
in a rst episode cohort, verbal learning at baseline was robustly associated with functional outcome at a 6-month follow-up even after
controlling for mood symptoms and substance
abuse comorbidity (46). More severe neurocognitive decits are not only associated with illness
severity (47, 48), but also associated with cumulative mood episodes (49, 50). For instance, euthymic patients who had at least three manic
episodes showed worse overall neurocognitive
performance compared with those with only one
previous episode of mania (51). In young adults
presenting with bipolar depression, Hermens
et al. (52) also identify signicant neurocognitive
decits in young adults presenting with in the
early stages of bipolar disorders. Memory, attention and executive dysfunction have been consistently reported in euthymic patients with bipolar
disorder (43, 53, 54), generally in proportion to
number of prior episodes (30), with verbal learning and memory impairment being signicant
predictors of long-term functioning (55).
The impact of neurocognitive impairment on
functioning led Torrent et al. (56) to develop a
functional remediation program specically for
bipolar disorders. This program is especially tailored for people with bipolar disorder who have
impairment during euthymia along the progression
of the disorder. Functional remediation showed
superiority to treatment as usual in improving psychosocial functioning at study endpoint. This
study suggests that functional remediation could
be more suited to patients in advanced stages,
whereas psychoeducation is likely to be more
eective in the early stages of illness.

Staging bipolar disorder


Peripheral markers. Peripheral biomarkers are pertinent to the theme of staging as they are conceptualized as mediators of allostasis (5759) and their
demonstration in dierent stages is one of the fundamental hypotheses of neuroprogression (60, 61).
Ultimately, they might be useful in selecting staged
interventions. For instance, concordant with the
allostatic load model, the presence of relevant
medical comorbidity is often associated with indications of late-stage bipolar disorder (62).
Recently, patients with such comorbidities were
shown to have a better response to N-acetyl-cysteine than those without medical conditions (63). If
conrmed, these ndings would suggest the use of
adjunctive antioxidants in those with comorbidities, which could be proxies of higher levels of
circulating free radicals.
Perhaps, the seminal study on the association
of biomarkers with staging was conducted by
Kauer-SantAnna et al. (64). In that case
control study, the authors were able to demonstrate that patients in a late stage (i.e., a
minimum of 10 years after the diagnosis of
bipolar disorder and with multiple previous episodes) showed many dierences in peripheral
inammation biomarkers when compared to
controls, which was not the case in early-stage
patients. Furthermore, in the case of tumor
necrosis factor a, where both groups of patients
had increased circulating levels, patients in late
stages had several-fold greater increases (see
Table 3). Further exploration of this sample
also revealed that glutathione S-transferase and
reductase were increased in late-stage patients,
although 3-nitrotyrosine was also found
increased in early-stage patients (65). These
alterations in oxidative biology imply a pro-oxidant pathology in bipolar disorder. Further
increases in protein and lipid damage have been
reported in patients with bipolar disorder seen
at tertiary facilities, which are generally latestage patients (66). However, a recent report of
a community-based sample also demonstrated
early-stage increases in protein damage (67).
Neurotrophins are also relevant to staging as
they are pertinent to the kindling hypothesis and
other models of illness progression (68, 69). In the
study mentioned above, Kauer-SantAnna et al.
(64) also demonstrated relevant decreases in brainderived neurotrophic factor (BDNF) in late-stage,
but not early-stage, patients. A later meta-analysis
demonstrated a correlation between the age and
length of illness and serum BDNF across seven
studies (70). A similar relationship was apparent
when a systemic toxicity index was examined in
late-stage patients compared with people with

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


Marker
BDNF (76, 82)
TNF a (76)
IL-6 (76)
IL-10 (76)
PCC (7779)
TBARS (78)
Systemic toxicity (83, 84)

Early stage

Late stage







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

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


Neuroimaging. Lin et al. (73) recently reviewed
neuroimaging evidence for staging in severe mental
disorders, including bipolar disorder. They highlight the possibility that structural and functional
networks could be dierently aected in each illness stage. White matter pathology could be
responsible for early-stage dysconnectivity. In rst
episode patients, for instance, recent meta-analysis
shows signicant white matter reductions, but not
gray matter (74). Another meta-analysis of voxelwise studies also demonstrated fewer alterations in
gray matter in rst episode patients (75). There
was no progression in gray matter loss in patients
with severe bipolar disorder during the rst 2 years
of follow-up, when compared with controls (76).
Stage changes were specically investigated in
only a few cross-sectional studies. In one MRI
study, the total number of episodes was correlated
with the size of the left hippocampus, and only
patients with fewer than 10 episodes had a larger
hippocampus compared with controls (77). Lagopoulus (78) compared a mixed cohort of people with
attenuated syndromes (stage 1) with patients with
discrete disorders (psychosis, bipolar disorder or
depression, stages two or three). Patients on stage
2 or 3 had a more widespread pattern of gray matter loss. In a region of interest study, Nery et al.
(79) showed similar orbitofrontal cortex gray matter volumes in individuals with bipolar disorder
and controls. However, the total number of episodes did not inuence signicantly the result.
A recent systematic review of longitudinal neuroimaging studies notes several caveats and a general dearth of prospective data (80), which mirrors
the neurocognitive literature (81). Among structural
neuroimaging studies, neuroprogressive changes
were more robustly noted in prefrontal, cingulate
and subgenual cortices and fusiform gyrus,
although total brain volume seems to be stable.

359

Kapczinski et al.
Discussion

Most of extant evidence relevant to staging models


is cross-sectional. This is surely the source of much
of the heterogeneity in the biomarker and neuroimaging data. Another source of weakness in the
current published literature is the small sample size
of the studies, which are mostly pilot studies in
nature. Even some of the most carefully designed
and strongest research such as the dierential
changes in peripheral biomarkers according to
stage demonstrated by Kauer-SantAnna et al.
(64) would benet from independent replication.
Transitions from at risk to subsyndromal and then
syndromal illness (where the individual meets diagnostic criteria) and between later stages should be
studied and validated with relevant clinical endpoints and possibly biomarker data. This will
likely require a multicenter eort, due to the inherent complexity of such endeavors.
The current staging models for bipolar disorder
should also be formally compared with each other
and also with other trans-diagnostic models (3). A
staging system should be able to predict disease
progression and stratify relevant outcomes in a
consistent way. However, this demonstrates an element of the current challenge for psychiatry.
Merely predicting future functioning or relapses
based on current functioning or previous relapses
contains an element of circularity that should be
avoided.
One attractive option is the use of putative
stages as a stratication variable in randomized
controlled treatment trials. This has only rarely
been performed, but would be clinically useful to
conrm previous secondary analyses with rigorous,
stage-tailored and hypothesis-driven trials. Alternatively, patients could be randomized to either
receive treatment as usual or stage-appropriate
interventions. Furthermore, there is a need to
develop and test the role of stage-specic treatments for at risk and rst episode cases: exemplars
being the studies led by Miklowitz (82) and by
MacNeil (83).
With the caveat that most data at present are
cross-sectional in nature, based on post hoc analysis or both, the bulk of the preliminary evidence
available suggests that staging has promising
clinical utility for postillness onset cases of bipolar
disorder. Clinically, the early- and late-stage distinction may appear obvious in the sense that such
patients have overtly dierent needs. Clinicians
have their own, probably idiosyncratic ways in
dealing with this issue (3). Nevertheless, conrming
these eects and estimating their magnitude matters. Also of consequence, such dierent cohorts of
360

patients are usually lumped in clinical trials, which


could obscure relevant treatment dierences. There
is growing consensus that early intervention is
valuable in individuals with severe mental disorders (84). Interventions for individuals in late
stages have been more problematic and less often
studied systematically (85).
Most studies to date conrm that globally
dened late-stage patients have a worse overall
prognosis and poorer response to standard treatment, consistent with patterns known in other
medical disorders. Although renement of staging
systems is certainly in need of further study, we
believe it is already proper at this juncture to speak
broadly of early and late stages. Early stages are
at the rst or the rst few episodes and are in
aggregate associated with better functioning after
recovery. Late stages are associated with multiple
episodes and tend to have impairment in multiple
areas of functioning. In other words, the models
proposed by Kapczinski and Berk concur on the
importance of early- or late-stage disease. The
next steps require consideration of the details of
intermediary stages and how many additional
stages are optimal. The ultimate goal should be
linking staging models with optimally tailored
therapy. This should be the subject of further local
and global collaborative eorts.
Declaration of interest
Prof. Kapczinski has received grants/research support from
AstraZeneca, Eli Lilly, Janssen-Cilag, Servier, CNPq, CAPES,
NARSAD and Stanley Medical Research Institute; has been a
member 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,
Sano-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, Pzer, Rao, Servier and Novartis within the last
3 years. Dr. I. Grande has received a research grant Ro Hortega 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 Balanz
a-Martnez has received grants and served as consultant,
advisor or CME speaker during the last 3 years for the following entities: Angelini, AstraZeneca, Bristol-Myers-Squibb,
Janssen, Juste, Lilly, Otsuka, the Spanish Ministry of Science
and Innovation (CIBERSAM), and Fundaci
on Alicia Koplowitz. Sergio A. Strejilevich has served as consultant or speaker
for Glaxo Smith Kline, AstraZeneca, Lilly, Abbott and has
received educational grants from Servier. Jan Scott has
received funding toward the costs of attending national and
international conferences, or fees for talks on psychosocial
aspects of bipolar disorders, or advisory board fees from Astra
Zeneca, BMS-Otsuka, Eli Lilly, GSK, Jansen-Cilag, Lundbeck, Sano-Aventis and Servier. Dr. Vieta has received grants
and served as consultant, advisor or CME speaker for the following entities: Adamed, Alexza, Almirall, AstraZeneca, Bial,

Staging bipolar disorder


Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest Research
Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen-Cilag,
Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pzer, Pierre-Fabre, Qualigen, Roche, SanoAventis, 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, United
Biosource Corporation, and Wyeth. Clarissa S Gama has
served as consultant or speaker for Actelion Pharmaceuticals,
Eli Lilly, Lundbeck and Roche. Michael Berk has received
grant/research support from the NIH, Cooperative Research
Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC,
Beyond Blue, Rotary Health, Geelong Medical Research
Foundation, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne
Pharma, Servier and Woolworths and has been a speaker for
AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pzer, Sano Synthelabo, Servier, Solvay and Wyeth, and served as a consultant to
AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck Merck and Servier. Dr. Yatham
is on speaker/advisory boards for or has received research
grants from: AstraZeneca, Bristol-Myers Squibb, CIHR,
CANMAT, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck,
the Michael Smith Foundation for Health Research, Pzer,
Servier, Sunovion and the Stanley Foundation. Janusz K. Rybakowski has acted over the past 2 years as a consultant or as
a speaker for the following companies: Bristol-Myers-Squibb,
Eli Lilly, Janssen-Cilag, Lundbeck, Sano-Aventis and Servier.
Marion Leboyer served as a speaker to Servier, AstraZeneca
and received research grants from Sano and Roche. Prof. Kauer-SantAnna has received research grants from NARSAD,
SMRI, Universal-CNPq, CNPq/INCT-TM, FIPE-HCPA, and
is on the speaker board for Eli-Lilly. Carlos Lopez-Jaramillo
has 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 SmithKline, Janssen Cilag, Lundbeck, Pzer, Sano Synthelabo, and
served as a consultant/speaker to Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag,
Lundbeck, Pzer and Servier. Dr. Gonzalez-Pinto has received
grants and served as consultant, advisor or CME speaker for
the following entities: AstraZeneca, Bristol-Myers Squibb,
Cephalon, Eli Lilly, Janssen-Cilag, Lundbeck, Merck, Otsuka,
Pzer, Sano-Aventis, Servier, the Spanish Ministry of Science
and Innovation (CIBERSAM), the Ministry of Science (Carlos
III Institute), the Basque Governement, the Stanley Medical
Research Institute, and Wyeth. Ralph Kupka received unrestricted research grants from AstraZeneca and served as a
speaker for AstraZeneca, Eli-Lilly, Lundbeck and BristolMyersSquibb.

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