CLINICAL SYNTHESIS

Staging Models in Bipolar Disorder

Juan F. Galvez, M.D., Ives C. Passos, M.D., Flavio P. Kapczinski, M.D., Ph.D., Jair C. Soares, M.D., Ph.D.

Since the initial description of bipolar disorder (BD), longitudinal observations suggested that episodes are more frequent as the
disorder progressed. Staging models in BD consider that there is a subset of patients who present a more severe course of illness
with a higher number of episodes and a propensity to treatment resistance. There is an emerging body of knowledge suggesting
that staging models may provide clinicians with a useful tool to predict the course of illness and organize treatment strategies to
individual patients. The aim of the present work is to review the evidence related to the use of staging models in bipolar disorder.
Focus 2015; 13:19–24; doi: 10.1176/appi.focus.130110

INTRODUCTION outcomes, such as reduced interepisode intervals, rapid cy-

Bipolar disorder (BD) affects about 2% of the world’s popula-
tion, with subthreshold forms affecting another 2% (1). Treat-
ment in BD conventionally focuses on acute stabilization of the
mood episode and on maintenance, in which the goals are re-
lapse prevention and reduction of subthreshold symptoms (2).
Even with syndromal treatment, about 37% of patients relapse
into depression or mania within 1 year and 60% within 2 years
(3). The rates of completed suicide in BD patients are 7.8% in
men and 4.9% in women (4).
Staging models have become an important contribution
to understanding disease progression, functional outcome, and
treatment response in medicine (5). Physicians and researchers
from different specialties rely on staging models to improve
available treatments and to generate novel interventions for
medical conditions such as heart failure (6), sepsis (7), chronic
obstructive pulmonary disease (8), and cancer (9). Staging
models in psychiatry assume that some mental illnesses may
progress from an at-risk stage to a treatment-refractory end
stage (10). Moreover, staging systems also emphasize that
while some patients may have a more benign course of ill-
ness, others may present with a higher propensity for epi-
sode recurrence and refractoriness (11, 12). Table 1 shows
staging models proposed for bipolar disorder.
Accordingly, recent studies suggest that staging may help
tailor treatment in a subset of BD patients (13). In view of
that, we aim to review the literature related to staging models
in BD and their potential clinical use.
ILLNESS PROGRESSION AND STAGING
BD patients may present different courses of illness progres-
sion (11). Trauma exposure, increased number of episodes, and
comorbidity are commonly associated with unfavorable clinical
cling, and cognitive and functional impairments, as well as
augmented rates of hospitalizations and suicide (14).
Cross-sectional and longitudinal studies assessed the im-
pact of trauma exposure on BD severity. A 24-month follow-
up study of 131 bipolar I disorder patients has shown that
trauma exposure predicted greater severity of interpersonal
chronic stressors (15). In addition, among 587 BD patients,
consistent associations between childhood trauma (emotional
abuse, sexual abuse, and emotional neglect) and more severe
clinical outcomes (suicide attempts, rapid cycling, and an in-
creased number of depressive episodes) have been reported
(16). A history of verbal abuse in 634 BD outpatients was re-
lated to an earlier age of onset of disease and other poor
prognosis characteristics, including rapid cycling, and a de-
teriorating illness course as reflected in ratings of increasing
frequency or severity of mania and depression (17).
Increased number of episodes may also have a predictive
effect on the risk of recurrence in BD, since vulnerability and
latency to relapse vary directly as a function of number of prior
hospital admissions (18). In the Systematic Treatment En-
hancement Program for Bipolar Disorder (STEP-BD), patients
with multiple previous episodes presented with worse function-
ing and lower quality of life. In addition, in the STEP-BD study,
patients with multiple episodes had more disability, as well as
more chronic and severe symptoms (19). Moreover, evidence
suggests that younger patients with fewer episodes present
a better response to treatment with conventional mood sta-
bilizers and psychoeducation (20). Of note, increasing episode
number is linked to a reduction in the likelihood of response to
lithium (21) and cognitive behavioral therapy (CBT) (22).
Regarding co-occurring disorders, a systematic review
with meta-regression has reported a significant correlation
of comorbid substance use disorders and suicide attempt (23).

Focus Vol. 13, No. 1, Winter 2015 focus.psychiatryonline.org 19

STAGING MODELS IN BIPOLAR DISORDER

TABLE 1. Proposed Clinical Models for the Staging System in BD

Berk et al., Kapczinski et al., Post et al., Duffy et al., Reinares et al., Cosci and Fava.
Stage 2007 (73) 2009 (74) 2010 (75) 2010 (76) 2013 (61) 2013 (77)
0 At risk, asymptomatic Latent phase: mood Well
period where and anxiety
a range of risk symptoms and
factors converge increased risk for
subthreshold BD

1a Mild or nonspecific Well-established Vulnerability Nonmood Low subsyndromal Mild or nonspecific

symptoms periods of psychiatric depressive symptoms/
euthymia and disorders (ADHD, symptoms, prodromal phase
1b Wide variety of absence of overt Well intervals anxiety and/or increased Cyclothymia
prodromal psychiatric sleep disorders) inhibitory control,
patterns morbidity or during childhood and estimated
impairment in verbal intelligence
between episodes associated with
good outcome

2 First episode of Rapid cycling and Minor mood Acute manifestations

either polarity, DSM–IV Axis I and disorders during of major depression
usually depressive III comorbidities childhood and/or or mania/hypomania
along with adolescence
transient
impairment in
functioning

3a First recurrence with Clinically relevant Prodrome Major depressive Residual depressive Residual symptoms
subthreshold pattern of episodes during symptoms with with cognitive and
symptoms cognitive and adolescence increased episode functional
3b Recurrences with functional density, low impairment
threshold illness deterioration inhibitory control, despite treatment
3c A subsequent pattern and estimated
of remission and verbal intelligence
recurrences associated with
poor outcome

4 Unremitting or Significant cognitive Illness onset First episode of Acute episodes

treatment and functional mania during late despite treatment
refractory course impairment and adolescence or
of BD unable to live early adulthood
autonomously with or without
associated
substance abuse

5 Episode
recurrence

6 Illness
progression

7 Treatment
refractoriness

8 End-stage BD
The different staging models proposed converge in stating that early-stage patients have less severe clinical features. These patients would require preventive
strategies and less complex treatment regimens. Late-stage patients would present a higher number of episodes and functional and cognitive impairment. Late-
stage patients would require more complex interventions and cognitive/functional rehabilitation.

Within this same meta-analysis, substance abuse disorder in
the preceding 8-week period predicted greater likelihood of
suicide attempt in a 5-year follow-up prospective study with
413 youths with BD (24). Current or past substance use dis-
orders have also been associated with greater risk of switch
into manic, mixed, or hypomanic states (25). Specifically, can-
nabis and alcohol use disorders were associated with higher
symptomatology and lower functioning in a longitudinal study
of 137 BD patients (26). Moreover, BD patients with attention
deficit hyperactivity disorder (ADHD) presented an earlier
onset and had a chronic course, irritable mood, and greater
clinical and functional impairment, and treatment resis-
tance (27). In a meta-regression analysis, comorbid ADHD
was significantly associated with suicide attempts (23).

20 focus.psychiatryonline.org Focus Vol. 13, No. 1, Winter 2015


Comorbid PTSD also was associated with poor outcomes,
including significantly worse social functioning (28), inter-
episode depression, and quality of life (29). In addition, there
is a body of literature suggesting that predictors of poor
prognosis (stressors, increased episode number, and comor-
bidity) may show sensitization to themselves and cross-
sensitization to the others, contributing to greater illness
burden and treatment resistance (14).
NEUROPROGRESSION
The term neuroprogression is used to describe the biological
underpinnings of illness progression in the context of BD (11)
and may shed some light on how such predictors interact
with the pathophysiology of BD (30). Such a process can
further disrupt the brain circuits that are responsible for
mood regulation and cognition, increasing the vulnerability
to illness (30). It is now becoming apparent that the bio-
chemical foundation of neuroprogression is multifactorial
and interactive, not only between pathways, but via stress
sensitization from the environment stressors and comorbid-
ities (11). As shown in recent meta-analyses and postmortem
studies, the core components of this biochemical process of
neuroprogression are abnormal levels of inflammatory cyto-
kines (31–33), markers of oxidative stress (34, 35), and neu-
rotrophins, including brain-derived neurotrophic factor
(BDNF) (36, 37). There seems to be a significant reduction in
BDNF expression and IL-6 levels along with significantly
higher levels of tumor necrosis factor–alpha (TNF–a) as
patients progress to more severe stages (38). In the same vein,
differential changes in oxidative stress activity levels have also
been reported as patients progress to later stages of BD (39). A
recent PET scan study showed microglial activation in the
right hippocampus of BD patients (40). Moreover, there is
evidence for the involvement of epigenetic changes, particu-
larly histone and DNA methylation (41, 42) and acetylation (43)
leading to long-acting effects on gene expression, which may
contribute to neuroprogression.
Noteworthy is the severity of comorbidity between PTSD
and BD, since reduced BDNF function from several contrib-
uting sources, including the met variant of the BDNF val66met
(rs6265) single-nucleotide polymorphism, trauma-induced
epigenetic regulation, and current stress, is associated with
core characteristics of both disorders (44). Trauma exposure
is also associated with significantly lower BDNF levels in BD
patients (45).
Structural neuroimaging studies have reported an associ-
ation between the number of episodes and the enlargement of
the lateral ventricles (46, 47) as well as decreases in cerebellar
vermal volume (48). While changes during the first episode of
mania seem to be related specifically to white matter pa-
thology (49, 50), progressive loss of gray matter volume in
prefrontal areas (51, 52) has been reported in late-stage BD
(53, 54). For instance, in contrast to findings in schizophrenia,
which have shown that hippocampal volume loss and ven-
tricular dilatation may occur prior to the first episode, the
Focus Vol. 13, No. 1, Winter 2015
GALVEZ ET AL.
literature suggests that in BD, gross brain structure is rela-
tively preserved during its early phases (53). BD patients have
shown hippocampal subfield volume reductions in cornu
ammonis (CA) subfields CA2/3, CA4/dentate gyrus, subiculum,
and right CA1 (55). Moreover, lithium treatment has been
shown to prevent such reduction (56, 57).
FUNCTIONAL OUTCOMES
Psychosocial functioning describes a person’s ability to func-
tion socially and occupationally and to live independently (58).
Patients with BD may suffer from functional impairment, even
when euthymic, and may experience serious dysfunction in
distinct life domains, such as work productivity, social activi-
ties, and autonomy (59). A 24-month follow-up study found
that almost 100% of first-episode manic patients with BD had
syndromal recovery within 2 years, but only one-third achieved
functional recovery (60). Therefore, functional and symptom-
atic recoveries are not always associated and may need dif-
ferent therapeutic approaches.
The ability to function in daily-life activities has also been
proposed as an important correlate of staging and illness
progression in BD (61, 62) and may provide clinicians with
a proxy of staging (63). By applying latent class analysis in
a sample of 106 remitted adults with BD, a recent study
identified two subtypes of patients presenting “good” and
“poor” functional outcome (61). Episode density, level of re-
sidual depressive symptoms, estimated verbal intelligence,
and inhibitory control emerged as the most significant pre-
dictors of such subtype membership (61). An interesting point
of this study is that functional outcome was not predicted by
illness duration, since the two groups were comparable in
age, age of onset, and illness duration (61). Prior studies have
also supported number of hospitalizations and comorbidity as
determinants of poor functional outcome (26, 64, 65).
BD patients may suffer from marked cognitive impair-
ment even when euthymic (66, 67), which could also limit
long-term psychosocial functioning (68, 69). Beyond esti-
mated verbal intelligence and inhibitory control, executive
and memory dysfunctions tend to show greater impairment
in daily-life activities (70, 71). In comparisons of neuro-
cognitive performance between patients with low and high
functioning scores, patients with poor functioning had sig-
nificantly more severe impairment in memory tasks, inhibitory
control, and working memory (72).
Functional staging in BD may provide a practical model
to evaluate the progressive course of illness, as well as guide
therapy to improve patient’s quality of life, the ultimate
goal of treatment. In this regard, a strong linear association
was found between functioning assessment short test scores
and the clinical stages described by Kapczinski (73), suggest-
ing a progressive functional decline from stage I through stage
IV of BD (63). Although significant differences in functional
status were found between patients in all stages, only patients
in severe stages (III and IV) were more impaired than healthy
subjects (63).
focus.psychiatryonline.org 21
STAGING MODELS IN BIPOLAR DISORDER
CONCLUDING REMARKS
It has been widely accepted that earlier interventions in BD
are likely to be associated with a better response to treatment
and lower rates of both functional and cognitive impairment
(63, 73). Conversely, interventions for late-stage BD patients
usually require more complex treatment regimens (73, 74).
While treatments such as lithium monotherapy, CBT, and
psychoeducation seem to be better suited to prevent further
recurrences in early-stage patients, complex pharmacological
strategies along with functional and cognitive remediation
may be considered optimal to alleviate functional changes and
prevent further deterioration in late-stage patients.
Clinical staging as a means to guide and tailor treatments
according to patient’s needs may provide an important tool
for clinicians working with BD patients. However, the po-
tential value of staging systems with regard to their specificity
and validity remains to be clarified by longitudinal studies. In
the meantime, targeting treatment for each BD patient from
a staging perspective may provide clinicians with a heu-
ristic model as to how to approach BD patients according to
their individual needs.
AUTHOR AND ARTICLE INFORMATION
Juan F. Galvez, M.D., Department of Psychiatry and Behavioral Sciences,
University of Texas Health Science Center, Houston, TX; Department of
Psychiatry Pontificia Universidad Javeriana School of Medicine, Bogotá,
Colombia
Ives C. Passos, M.D., Psychiatry, University of Texas Health Science
Center; Molecular Psychiatry, Laboratory UT Center of Excellence on
Mood Disorders, Houston, TX; Bipolar Disorders Program, Laboratory of
Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Universidade
de Federal do Rio Grande do Sul, Porto Alegre, Brazil
Flavio P. Kapczinski, M.D., Ph.D., Department of Psychiatry and Behavioral
Sciences, University of Texas Health Science Center; Harris County Psy-
chiatric Center; the Molecular Psychiatry Laboratory UT Center of Excel-
lence on Mood Disorders, Houston, TX; Bipolar Disorders Program,
Laboratory of Molecular Psychiatry, INCT for Translational Medicine, Hos-
pital de Clínicas de Porto Alegre, Universidade de Federal do Rio Grande do
Sul, Porto Alegre, Brazil
Jair C. Soares, M.D., Ph.D., Department of Psychiatry and Behavioral Sci-
ences, University of Texas Health Science Center, UT Center of Excellence
on Mood Disorders; Harris County Psychiatric Center, Houston, TX
Address correspondence to Jair.C.Soares@uth.tmc.edu or utmooddisorders@
uth.tmc.edu.
Dr. Kapczinski has received support from CNPQ, FAPERGS, FIPE-HCPA,
CAPES, NARSAD and SMRI. Dr. Soares has received research grants from
Bristol-Myers Squibb, Forest, and Merck and has received speaker’s fees
from Pfizer and Abbott. Juan F. Gálvez and Ives C. Passos report no
competing interests.
Supported in part by NIMH grant R01 085667, the Dunn Foundation, and
the Pat Rutherford, Jr. Endowed Chair in Psychiatry.
Research Lines: Bipolar Disorder, Biological Psychiatry, Pharmacotherapy
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Focus Vol. 13, No. 1, Winter 2015