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2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ACTA PSYCHIATRICA SCANDINAVICA
Review
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
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
Introduction
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.
Exclusion
criteria
Search
terms
356
1a
1b
2
3a
3b
3c
4
Post (19)
Vulnerability
Well-interval
Illness onset
5
6
7
8
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
Episode recurrence
Illness progression
Treatment refractoriness
End stage
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
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.
359
Kapczinski et al.
Discussion
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