Accepted Article

MRS. GABRIELA LÉDA-RÊGO (Orcid ID : 0000-0002-9556-2019)

DR. SEVERINO BEZERRA-FILHO (Orcid ID : 0000-0003-4772-0331)

Article type : Review

Functioning in euthymic patients with bipolar disorder: a systematic review

and meta-analysis using the Functioning Assessment Short Test
Functioning in bipolar disorder

Gabriela Léda-Rêgoa,b,, Severino Bezerra-Filhoa,b, Ângela Miranda-Scippaa,b,c

a Mood and Anxiety Disorders Program (CETHA), Federal University of Bahia (UFBA), Salvador, BA, Brazil.
b Postgraduate Program in Medicine and Health, UFBA, Salvador, BA, Brazil.
c Department of Neurosciences and Mental Health, Medical School, UFBA, Salvador, BA, Brazil.

 Corresponding author:
Gabriela Léda Rêgo de Amorim, Department of Research in Psychiatry, Professor Edgard Santos
University Hospital, 3rd floor, Street Augusto Vianna, s/n, Canela, CEP 40110-909, Salvador, BA,
Brazil. Telephone Number: 55 71 3283-8076
Email: gabrielamlrego@gmail.com

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/BDI.12904
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Accepted Article
Acknowledgments: The authors would like to thank the following individuals: Cristina Brasil and
Amanda Lemos (Stat: Coaching in Scientific Production) for their assistance with the statistical
analyses; all the authors for their special help in answering our communications and sending
complementary data; and Martha Martínez-Silveira for her help with the methodology for
systematic review. This research did not receive any specific grant from funding agencies in the
public, commercial, or not-for-profit sectors.
Abstract

Objectives: Systematically review the prevalence of functional impairment (FI) in euthymic

patients with bipolar disorder, as assessed only with the Functioning Assessment Short Test
(FAST), explore the prevalence of this impairment among all the domains, identify the most
compromised of them and the clinical variables associated with low functioning in this population.

Methods: Systematic review and meta-analyses were performed, searching for relevant papers
published from 2007 to 2019 in Medline, Embase, Cochrane, PsycINFO databases and via hand-
searching, without language restrictions. 1128 studies were initially identified, 13 of which were
ultimately chosen based on the eligibility criteria. A two-step meta-analysis was performed using
the mean difference with a 95% confidence interval for continuous variables and proportion
estimation with a fixed-effects model for categorical variables.

Results: In the first step, all FAST domains showed worse FI in patients than in healthy controls,
with significant differences between groups. In the second step, the prevalence of FI domains were
as follows: global, 58.6%; occupational, 65.6%; cognitive, 49.2%; autonomy, 42.6%; interpersonal
relationships, 42.1%; leisure, 29.2%; and financial issues, 28.8%. Residual depressive symptoms
were the most frequently cited variable associated with FI.

Conclusions: This study reinforces the relevant functional impact of BD in this population,
suggesting that the occupational domain may be the most impaired. Greater efforts should be
directed toward targeting functioning in patient care, as it constitutes the most meaningful

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 endpoint of response to treatment, especially with occupational and cognitive rehabilitation, thus
Accepted Article
allowing patients to overcome the course of illness and carry fulfilling lives.

Keywords: functioning; functional impairment; bipolar disorder; euthymia; systematic review;

meta-analyses.

Introduction

Bipolar disorder (BD) is a chronic and severe psychiatric disease characterized by

pathological mood instability (1), with an estimated prevalence reaching 2.4% when the classic
forms of the disorder are considered (2). This diagnosis is marked by a considerable degree of
morbi-mortality, and it is frequently associated with significant impacts in several domains of
patients’ lives (3–5). In addition, BD is considered a potentially lethal illness: the risk of suicide
attempts averages 31.1% in this population (6), with suicide rates estimated to be 20- to 30-fold
greater than in the general population (7).
As a result, BD is reportedly one of the top-20 causes of the global burden of disease and
years lived with disability (8), with documented moderate to severe functional impairment (FI) and
low levels of quality of life (QoL) (9-11). Functioning is described as the capacity to execute tasks
associated with daily living and to engage in reciprocal gratifying relationships (12). It is a wide and
complex concept, traditionally described as involving the ability to study, work, live with
autonomy, have leisure time, and engage in social relationships (13). In fact, even during the
euthymic phase, 60% of the patients with BD showed poor functional outcomes compared to
13.1% of the healthy control (HC) group (14).
With respect to the history of BD, for a long time, the outcome of this condition was
considered favorable when only the symptomatic perspective was contemplated (13). However,
cumulative clinical evidence and modern studies have transposed this analysis, as researchers
began to note the difficulty of patients achieving previous functional status, despite euthymia and
adequate treatment (15–17). After 2 years of treatment follow-up, although 64% of patients with BD
achieved remission (symptomatic recovery), only 34% of them achieved functional recovery (18).

Thus, the most recent studies have shown that the most meaningful outcome is not merely

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 improvement or remission but rather functional recovery, which is the most expressive outcome of
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a patient’s response to treatment (19,20).
Moreover, the connection between symptomatic and functional outcomes is still unknown and
should not be considered unidirectional, as the outcomes in one area can predict poorer outcomes
in the other (21). In this sense, the variability in functional outcomes may arise from a broad
collection of factors, such as sociodemographic variables, onset at an early age, the presence of
subthreshold and residual depressive symptoms, the number of episodes and hospitalizations,
comorbid conditions, cognitive impairment, and stigma (3,22–24). Despite the rising number of
recent studies, data are still inconclusive regarding the contribution of specific factors in the
prediction of functional outcomes (3,25,26)
The present article addresses similar topics explored in earlier reviews (3,9,21,27,28);

nevertheless, we approach this topic in a different manner, as well as explore complementary

issues. No previous studies have investigated the prevalence of FI in BD patients using a meta-
analysis design with exclusively euthymic criteria for sample selection, or have assessed global
and specific functional domains with only one instrument to allow the homogenization of data (the
inclusion of different instruments with different scoring methodologies, scopes and cut-off points
would stunt comparison among studies).
For this reason, this study aims to systematically review recent research on FI evaluated in
euthymic BD patients through the Functioning Assessment Short Test (FAST), specifically
exploring the prevalence of this impairment among all the domains, the most compromised of
them, and the cited clinical variables associated with low functioning in this population.

Materials and Methods

Search strategy and study identification

A systematic review and data extraction were performed following the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with a protocol
registered in the PROSPERO database (reference number CRD42018107143). Relevant articles
were searched in the Medline/PubMed, Embase, The Cochrane Library (Central), and PsycINFO

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 databases. Furthermore, hand-searching was performed to find additional relevant studies; both the
Accepted Article
references lists of the selected articles and papers included in the reviews published on this topic
were explored. The search was narrowed to studies published between June 2007 (the date on
which the FAST was validated) and April 2019, without language restrictions. The studies were
filtered by date and human species.
The basic search strategy included a combination of the following sets of terms, grouping
synonyms and Boolean operators, and using Medical Subject Headings (MeSH) when available:
(“functioning” OR “functional impairment” OR “functional outcome” OR “functional recovery”
OR “psychosocial functioning” OR “disability”) AND (“bipolar disorder” OR “affective disorder”
OR “bipolar patient” OR “mood disorder”) AND (“FAST” OR “Functioning Assessment Test”).
The analysis of the articles followed previously determined eligibility criteria: a) adults
(≥18 years old); b) both genders; c) BD type I, type II and/or not otherwise specified, all
diagnosed through structured clinical interviews (SCID-I/MINI); d) separate data from patients
clearly defined as being in the euthymic phase; and e) the assessment of functional measures only
with the FAST (which is considered one of the most recommended instruments for the assessment
of functioning in patients with BD (29–31), as it probes both global and specific functional domains
and was developed to focus on the main areas of difficulties experienced by this specific
population). Studies with overlapping samples were excluded; in such cases, we selected the paper
that was more compatible with our criteria. A second study of the same research group was only
included if the authors reported having data from different patients’ samples. When the paper met
all inclusion criteria but lacked access to the raw data of FAST scores (medians and/or
percentage), it was only included in the qualitative synthesis (and was excluded from the meta-
analysis steps).

Functioning measure
The FAST is an interviewer-administered instrument with easy and quick application. This
scale was developed by the Barcelona Bipolar Disorders Program and emerged in response to the
lack of specific instruments that could perform a clinical evaluation of the main difficulties
experienced by patients with mental disorders, especially those with BD. It can be used in both
clinical practice and research, providing a global and six specific domain scores. It has been
validated in several languages and comprises 24 items that evaluate impairment in 6 specific areas
of functioning: autonomy, occupational functioning, cognitive functioning, financial issues,

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 interpersonal relationships, and leisure time. Additionally, regarding its validity and reliability, it
Accepted Article
has shown high internal consistency (Cronbach's alpha of 0.909), resulting in strong psychometric
properties and sensitivity to different mood states (32,33).
Autonomy is related to the patient’s ability to perform tasks alone and take care of
himself/herself. Occupational functioning refers to the capacity to sustain paid employment and
efficient tasks as well as work and earn according to one’s level of education and position.
Cognitive functioning involves abilities such as concentrating, performing mental calculations,
solving problems and learning new information. The financial domain refers to the ability to
manage one’s own finances and engage in balanced spending. The interpersonal relationships
domain is related to the involvement and maintenance of relationships (friends, family, and
sexual), social activities and the capacity to defend one’s own interests. Leisure time refers to the
ability to perform physical activities and the enjoyment of personal hobbies (32,33)
Items are rated on a four-point Likert-type scale, where 0 corresponds to no difficulty, 1
mild difficulty, 2 moderate difficulty and 3 severe difficulty. The FAST-global score ranges from
0 to 72, where higher results indicate poorer functional status. The cut-off points are as follows:
autonomy >1, occupational functioning >1, cognitive functioning >2, financial issues > 1,
interpersonal relationships >3, leisure time >3, and global > 11. A threshold equal to or above
those scores indicates the presence of FI in the given domain, and the global score (representing
the overall functioning score) is obtained by summing the scores for the six separate dimensional
domains (14,32,33).

Study selection, data extraction, synthesis and analysis

Two authors (GLR and SBF), following the established criteria, independently conducted
the search and revision of the titles and abstracts of the retrieved studies, excluding duplicate
publications, selecting items for full-text reading, and following the exclusion criteria for
ineligible papers. Divergences and disagreements in those processes were clarified by a third
author (AMS). In addition, the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for
Analytical Cross-Sectional Studies was used to assess the methodological quality of the papers
included.
Once the final eligible studies were chosen, their information was extracted and tabulated
by GLR, and cross-checked by SBF. The extracted data included the study’s year of publication
and country, the size and characteristics of the sample, the criteria for the definition of the

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 euthymic state, and participants’ ages. With regard to functional measures, the following data were
Accepted Article
extracted: the mean and standard deviation from FAST scores (global and six specific domains
from patients and controls); n (%) of the BD sample considered to have FI, as determined by the
FAST cut-off points (standardized cut-off points through all the included studies); and the
variables described by the studies as associated with functional outcomes. In cases where the
information provided by the studies was insufficient to perform the proposed analysis of
prevalence, the reviewers contacted the authors to obtain the extra data. Additionally, some of the
studies had BD samples divided into groups: with/without history of psychotic symptoms (31) and
with/without attention-deficit/hyperactivity disorder (ADHD) (32). In those cases, the authors were
contacted, and the data used in the current analysis were the unified data sent by the authors
regarding the whole group of euthymic patients with BD (not divided by groups).
A meta-analysis was performed using the Cochrane Collaboration's Review Manager
Software (version 5.3) for continuous variables and the Comprehensive Meta-Analysis V2 for
categorical variables. For continuous variables, as all studies had outcomes were measured with
the same evaluation instrument (FAST), the mean difference (MD) was used, with a 95%
confidence interval (95% CI) considered in all calculations. The homogeneity of the studies was
verified through the heterogeneity test, from which the studies were considered homogeneous
when p assumed a value greater than 0.05. For the meta-analysis of categoric variables, the
proportion estimation was used to verify the prevalence of FI. Considering that the outcomes were
measured by the same instrument in all included papers, the fixed-effects model was chosen for
this step. In addition, as the studies differed in their objectives for measuring the clinical variables
associated with functional outcomes, we provided a narrative synthesis of those data from all
included papers.
All these records were used to create a series of frequency tables and consequent forest
plots to clearly establish the following: a) the main characteristics of the included studies; b) the
prevalence of FI in the euthymic BD patients from the included literature; c) the FAST domain
that indicated the area of greatest impairment in this population; and d) the most cited clinical
variables associated with low functioning.

Results
The aforementioned search strategies resulted in the identification of 1128 articles:
Medline/PubMed (460), Embase (365), The Cochrane Library-Central (120), PsycINFO (155),

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 and supplementary search (28). Of those articles, only 13 fulfilled all of our eligibility criteria and
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were included in our final sample (Figure 1). The number of records excluded for any given
reason did not meet the total number of excluded records, as each paper could be placed in more
than one category.

[Insert Figure 1]

The results of the methodological quality assessment of the 13 papers are presented in
Table 1.

[Insert Table 1]

Key characteristics of the 13 included articles are summarized in Table 2; 1 article lacked
access to all raw data from the FAST and was therefore only included in the qualitative synthesis
(36). Study designs were all cross-sectional (including one validation study). 3 studies (34,37,38)

included samples composed only of BD-I patients; the other 10 studies reported data on mixed BD
samples (composed of type I, type II and/or not otherwise specified). The sample size mostly
varied between 12 and 150 individuals, with only 1 study having a large sample of 241 individuals
(39), thus differing from the others.

[Insert Table 2]

Functioning scores: Meta-analytical results for prevalence of FI

Of the 13 papers included in this review, 12 had or provided enough information to qualify
for inclusion in the meta-analysis stage. In the first step (mean difference), 3 studies were
excluded (35,39,40), as they lacked data from the control group. In the second step (proportion
estimation), 1 study (41) was excluded, as it lacked the proportion of the sample falling below the
cut-off point defined for impairment.
With regard to FAST scores, all domains showed impairment in the BD group compared to
the HC group. In the first meta-analysis, 9 studies were included, considering a total sample of 662
patients and 587 HCs. All effect sizes were in the same direction, suggesting worse performance
in the patient group than in the HC. The following forest plots show significant differences

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 between groups in all functional domains, with an emphasis on global and occupational scores
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(Figure 2).

[Insert Figure 2]

To calculate the prevalence of FI, we had to obtain access to the proportion of the sample
falling below the cut-off point defined for impairment by the instrument chosen in this study. Only
1 study (40) had these data already available in the paper, and the other authors provided these data
by email.
Categorical meta-analysis included 11 studies, with a total sample of 1083 patients. As
presented by the following forest plots, we can see a prevalence of global FI of 58.6%. With
regard to the specific domains, this meta-analysis presents an impairment prevalence in the
domains as following: 65.6% in the occupational, 49.2% in the cognitive, 42.6% in the autonomy,
42.1% in the interpersonal relationships, 29.2% in the leisure, and 28.8% in the financial issues, all
of which were statistically significant.

[Insert Figure 3]

Variables associated with FI

As shown in Table 3, the majority of the articles provided information regarding the
association between various sociodemographic and/or clinical variables and poorer functioning,
with variations in the statistical testing and adjustment of potential confounders.
Of the 13 studies, 3 (42–44) lacked analyses regarding variables associated with FI. From the
other 10 studies, despite the variability in the methodology, residual depressive symptoms were
the most-cited variable associated with functional outcomes (appearing in 8 studies), followed by
cognition (cited 4 times). Other cited variables were emotion processing, impulsivity, number of
hospitalizations, history of psychotic symptoms, mood instability, stress, coping and self-esteem
(see Table 3).

[Insert Table 3]

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Accepted Article
Discussion

The primary finding of this meta-analysis was the high prevalence of FI in patients with
BD (58.6%) who were evaluated in the euthymic phase, with occupational functioning as the most
impaired domain (65.6%) and residual depressive symptoms as the most cited correlate underlying
functional outcomes. In fact, cumulative evidence has shown a high degree of functional loss in
patients with BD, and our prevalence was in line with estimates found in prior studies described in
the literature, showing approximately 60% of patients presenting a functional decrease (27,45,46).
Some minor heterogeneity could be seen in the mean differences and in the FI prevalence
of the studies. Although our study defined euthymia criteria, it is important to highlight that there
was not a predetermined definition for it; hence, the included studies had different cut-off points
and temporal criteria. The slight variation in the definition of euthymia used in each study could
have led to possible interference of residual mood symptoms, which could have underlain the
abovementioned variance.
Although there could be a slight dissimilarity among the prevalence results of all of the
studies, the study by Strejilevich (40) had a distinguished smaller prevalence for almost all of the
FAST domains than did the other studies included in this meta-analysis. The author himself
pointed out some specificities among his sample characteristics that could explain the
heterogeneity regarding its functional outcome. In his study, the included patients had a higher
educational level and were less symptomatic than in other studies. Moreover, his study was
composed of a mixture of first consult and a tertiary level of patients, including patients from
middle to upper social classes.

Functioning domains
In response to our second aim, the worst-performing functional domain was the
occupational, with a prevalence of 65.6% impairment. Previous research has indeed accused low
proportion of patients in paid employment, regardless of educational attainment (47,48). Likewise,
claims data from the National Health Insurance Research Database used in a cohort of 502 patients
detected poorer employments outcomes in patients than in HCs, with a greater risk of occupational
deterioration in the years after disease incidence (49). In addition, studies suggest that the social

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 disadvantages (including education level, employment status, income level and occupational
Accepted Article
prestige) frequently seen in this population increase their risk of FI (50).
Still regarding occupational impairment, population studies showed a higher rate of
absenteeism and presenteeism, which can trigger low occupational performance and a low
expectation of functional progression in this disease population (51). Several studies have attempted
to elucidate the possible variables associated with this field. A severe course of BD illness,
duration of illness, comorbid disorders, depression symptoms, patients’ subjective perceptions of
their ability to work, emotion processing, executive tasks, persistent sleep disturbance, and
cognitive flexibility are some of the predictors found in the BD literature related to receiving
disability pension and presenting overall work disability and/or unemployment (52–55).
Within the occupational expression, studies have reported illness history as one of its
predictors, pointing out that a better clinical course indicates better occupational functioning (56).

Another variable that can partially explain the work disability found in this population is
neurocognition, as it is known for subserving complex, abstract and everyday processing (57).

Consequently, individuals would benefit from targeted vocational rehabilitation programs with
tailored cognitive remediation, helping them avert similar future dismissals and improve their
outcomes (54). Another intervention described in the literature is functional remediation (58), a 21-
week rehabilitation program that resulted from a multicenter, randomized and rater-blind clinical
trial and addressed neurocognitive issues with the focus of enhancing daily routines. The results
have shown significantly greater improvement in patient functioning, especially in the
interpersonal and occupational domains, helping individuals to get a job or improve their
occupational performance after intervention. This is also corroborated by the International Society
for Bipolar Disorders (ISBD), which has recently recommended addressing these deficits with
remediation strategies as a treatment target in this population (59).
The second-most impaired domain of our FAST analysis was the cognitive, with a 49.2%
prevalence of impairment. This finding is in line with previous literature that have described the
relevant cognitive impairment in adults in all phases of BD (60–62), noting that nearly half of
patients present neuropsychological deficits 11. Considering those impaired patients, the deficits
are described as being present since the onset of the disease (63,64), with a tendency toward
progressive functional loss found in some groups of patients throughout BD course (65). In fact,
cluster analysis studies have reported within-group heterogeneity in the cognitive performance of
individuals with BD, suggesting the existence of subgroups based on performance. While some

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 authors divide them into similar to the HC range and selective cognitive impairment (representing
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almost one-third of the sample) (66,67), others divide the impaired group into selective cognitive
impairment (modest deficits on only a subset of domains) and global severe impairment (deficit
across most of the cognitive domains) (68–71).
Furthermore, cognition is said to play a marked role in the course and prognosis of BD
illness (53), but its expression varies when objective and subjective assessments are compared.
Studies report a weak correlation between these two types of cognitive assessment (71,73,74).

Although subjectively reported cognitive complaints and objectively assessed neuropsychological

tests are intertwined by certain discrepancies, it is important to highlight that FAST is a semi-
objective instrument; therefore, these data reinforce the cognitive impairment found in other
studies and underscore the importance of this topic in patients’ lives and functioning (60).
Although autonomy (42.6%) and interpersonal relationships (42.1%) showed low
impairment (given that the prevalence for both <50%), its clinical impact should be noted. Indeed,
the literature indicates a bidirectional relation in interpersonal relationships: on the one hand, the
dysfunctional symptoms and reduction in positive emotions found in these patients may interfere
in their ability to sustain socialization; on the other hand, the insufficient social support they
perceive appears to be a vulnerability for the recurrence and severity of symptoms (75–77).

Additionally, a recent study by our group also found that these patients report deficient levels of
social support and that a positive correlation is evident between social support and QoL (78).
Lastly, the financial domain was the least affected across the sample studied (28.8%),
which corroborates findings in the literature (79). With respect to this, the succinct examination of
this domain on FAST scale cannot be disregarded, as it is composed of only two items, in contrast
to the other domains, which are assessed by a set of four to six items. Additionally, the main
dysfunctional behaviors towards spending are mostly found during mood episodes, especially
hypomanic/manic, also correlated with depression and stress (80), all of which could not be
assessed in this review because of the inclusion criteria of euthymia.

Variables associated with FI

The most cited factor underlying functional outcomes was residual depressive symptoms,
followed by cognition, which is in line with findings from previous research that highlighted the
exact same variables as having a direct impact on the functioning of a BD sample during inter-

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 episodic periods
Accepted Article (81). In fact, even in the euthymic state, the occurrence of residual
symptomatology represents one of the most outstanding clinical predictors of FI (21,82–85).
Regarding euthymia, Rocha and Correia (86) recently pointed out that, despite some
recommendations, there is no precise description of the state of euthymia, leading to a large
variation of its definition across study designs. Studies have been using wide-range criteria, and
this lack of specificity imposes major difficulties for both clinical and research practice. In
addition, in line with the results of this systematic review and the data found in other studies in the
literature, we see that satisfactory clinical control is rarely achieved within this disease: patients
frequently maintain residual and subsyndromic psychopathology, even in states of “euthymia”,
which calls the validity of this concept into question. Moreover, the gap in the precise criteria for
euthymia thwarts the assessment of remitted states in medical practice. This has relevant
therapeutic implications (87), as well as brings up a debate regarding functioning targets.
Hence, all these points not only reinforce the harsh and chronic profile of BD disease but
also emphasize the relevance of therapeutic interventions towards minimizing and preventing the
impact of these symptoms on the course of illness, thus facilitating the accomplishment of full
recovery between episodes (55,82,88,89).

Limitations and strengths

The present results must be interpreted in light of some limitations. The first one is the
review procedure, given the heterogeneity found in BD samples through meta-analysis procedures
and the differences between the specific aims of the studies. The second limitation was the cross-
sectional design of all papers included, which might have also narrowed the generalizability of our
results. Third, the instrument chosen (FAST) only captures information from the past 15 days,
which is short term in nature considering the conclusions related to FI, thus limiting the
interpretation of our data. Fourth, in some cases, the necessary data were not available in the
published study, and unfortunately, some authors could not send the information requested by
email, which could have led to a reduction in the number of studies included.
Nonetheless, this was the first review to systematically collect FI prevalence data of only
euthymic patients with BD, diagnosed with a necessarily structured interview and with functional
outcomes measured by only one instrument (FAST), which complements the previous reviews
conducted on this topic. Although there were no maximum age criteria for paper inclusion, it is

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 worth noting that the mean age of all studies was approximately 40 years old, which minimizes the
Accepted Article
risk of additional contributions of age-related functional decline.

Conclusions

Our meta-analyses reinforce the overwhelmingly functional loss observed in patients with
BD evaluated in the euthymic phase and suggest that occupational may be the most impaired
domain. In addition, the main cited variable intertwined with this outcome was residual depressive
symptoms. Therefore, greater efforts should be made to gather representative patient samples and
further examine this specific field to better understand the behavior of functional outcomes and the
role of associated variables to improve patient rehabilitation. We continue to see a gap between
symptomatic and functional recovery, which underscores the significance of targeting functional
recovery through patient care. There is little point in patients achieving remission if they cannot
perform their jobs or daily life activities; hence, functioning has become the most meaningful
endpoint of response to treatment, as it is the pathway that allows patients to overcome the course
of illness and lead fulfilling lives.

Declarations of interest: None

Supporting Data: The data that support the findings of this study are available from the
corresponding author upon reasonable request.

Authors Contributions: GLR conceived, designed and conducted the study, and managed the
search, extraction and analysis of data, as well as the writing and revision of the manuscript. SBF
assisted as a second researcher in the conduction of the study and helped with the extraction and
analysis of the data. AMS managed the conduction and coordination of the study, oversaw the data
analyses and contributed to the revision of the manuscript.
All authors contributed to and approved the final manuscript.

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Accepted Article
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Table 1: JBI critical appraisal checklist for analytical cross-sectional studies
Appraisal*
Criteria Not
Yes No Unclear
Applicable
1. Were the criteria for inclusion in the sample
clearly defined? 13 - - -

2. Were the study subjects and the setting

described in detail? 13 - - -
3. Was the exposure measured in a valid and
reliable way? 13 - - -

4. Were objective, standard criteria used for

measurement of the condition? 13 - - -
5. Were confounding factors identified? 7 2 4 -
6. Were strategies to deal with confounding
factors stated? 8 3 2 -

7. Were the outcomes measured in a valid and

reliable way? 13 - - -
8. Was appropriate statistical analysis used? 7 - 6 -
JBI: Joanna Briggs Institute
*Numbers within cells correspond to the total number of studies that fulfilled each criterion.
Table 2: Overview of the general characteristics from the thirteen included articles
Author/Country Mean age Mean (SD)
Sample n Euthymia definition
(Year) BD FAST G BD
HDRS <7
Aparicio et al (28) 60 BD-I YMRS <6
44.9 (11.6) 18.7 (14.0)
Spain (2017) 60 HC At least the previous 3
months.
Aydemir and
70 BD-I/II HDRS < 7
Uykur (62) 40.7 (11.9) 21.4 (17.6)
134 HC YMRS < 4
Turkey (2012)
Barrera et al (35) 12 BD-I/II HDRS < 7
48.2 (11.2) 32.9 (10.9)
Argentina (2013) 12 HC YMRS < 8
HDRS < 7
Chan et al (64) 90 BD-I/II 43.32 11.27
YMRS < 5
China (2018) 90 HC (11.26) (10.08)
For more than 2 months.
Jiménez et al (33) 138 BD-I/II HDRS  8 25.78
46.9 (12.89)
Spain (2012) No HC YMRS  6 (15.01)
Jiménez-López et HDRS < 7
41.83
al (29) 100 BD-I YMRS < 6 17.81
(11.60)
Spain (2018) 51 HC At least 3 consecutive (15.01)
monthly evaluations.
Rosa et al (38)
68 BD-I/II HDRS < 7 48.06 11.76
Spain (2010)
61 HC YMRS < 7 (13.76) (12.73)
241 BD-
Roux et al (31) MADRS < 10
I/II/N 41 (11.3) 16.8 (13.2)
France (2017) YMRS < 10
No HC
Solé et al (63) HDRS 8
143 BD-I/II 41.22 18.87
Spain (2018) YMRS ≤6
60 HC (10.80) (12.29)
At least 3 months
Strejilevich et al
(34) HDRS ≤ 8
55 BD-I/II 46.15
YMRS ≤ 6 9.25 (6.828)
Argentina (2013) No HC (17.45)
At least 8 weeks
Torres et al (32)
86 BD-I/II HDRS ≤ 8
Spain (2017) 41.3 (11.15) 18.65 (11.8)
76 HC YMRS < 7
Vasconcelos-
HDRS ≤ 7
Moreno (30) 32 BD-I 47.25 23.91
YMRS ≤ 7
Brazil (2016) 43 HC (10.16) (11.35)
At least 45 days
Wesley et al (27) 150 BD HDRS ≤ 7 20.71
33
India (2018) No HC YMRS ≤ 7 (16.79)
BD-I: bipolar disorder type I/BD-II: bipolar disorder type II/BD-N: bipolar disorder not otherwise
specified/HC: healthy control/HDRS: Hamilton Depression Rating Scale/YMRS: Young Mania Rating
Scale/MADRS: Montgomery-Asberg Depression Rating Scale/FAST G BD: FAST’s Global Score of BD
sample

Table 3: Variables cited by the included articles as associated with FI

Author/Year Procedure Variables associated with FI

Aparicio et al. Pearson correlation Residual depressive symptomatology [(r=0.302;

(2017) and regression p=0.019)], explaining 9.1% of the variance;
analysis. emotion processing (r= -0.311; p= 0.016),
explaining an additional increase of 8.6% of the
variance [statistical significance of F(1.57) =
5.97; p= 0.018]; neurocognition (r= -0.30; p=
0.018), explaining an increase of only 1.4% of
the variance, without reaching statistical
significance [F(1.57)= 0.92; p= 0.341)].

Aydemir and Analyze the Lacked analyses regarding variables associated

Uykur reliability and with FI.
(2012) validity of FAST’s
Turkish version.

Barrera et al. Correlation Absence of significant correlations between

(2013) functioning and theory of mind. Lacked
description of correlation analyses between
functioning and other variables.

Chan et al. Sequential and Analyses were performed for variables

(2018) hierarchical explaining variance in mood states. Lacked
regression analyses regarding variables associated with FI.

Jiménez et al. Spearman or Impulsivity (β=0.319; p=0.004), depressive

(2012) Pearson correlation symptoms (β=1.580; p<0.001) and number of
and multiple linear hospitalizations (β=0.837; p=0.019) were
regression associated with overall FI, even after
adjustments were made for gender, age and
current mood state. This model accounted for
 31.1% of the functioning variance (F=6.854,
df=9, p<0.001, adjusted R2=0.311).

Jiménez-López Chi-square test, Neurocognition, HDRS score, number of

et al. (2018) ANOVA and hospitalizations and history of psychotic
MANOVAs symptoms, explaining 36.9% of the variance in
FAST (neurocognition explained the greatest
proportion of the variance (21.1%), followed by
residual depressive symptoms, and the smallest
proportion of the variance was explained by
psychotic symptoms (2.7%)).

Rosa et al. Chi-square test and Analyses were made aiming to assess
(2010) ANOVA functioning across different mood states.
Lacked examination regarding variables
associated with FI.

Roux et al. PCA and linear Significant positive association with MADRS, a
(2017) regression analyses significant negative association with verbal
memory, and a significant negative association
with ‘verbal fluency and inhibition’. This model
explained 30% of the variance in functioning.

Solé et al. T-tests, χ2 tests and Functionally impaired patients were marked by
(2018) hierarchical cluster a higher rate of unemployment, more residual
analysis symptomatology and lower scores on cognitive
performance (specifically processing speed and
executive functioning). A gradual increase in
residual depressive symptomatology was
observed from the good to the low-functioning
group.

Strejilevich et al. Spearman bivariate Weeks with subsyndromal depressive symptoms

(2013) correlations and ( = 0.133, t = 2.556, P = 0.014), weeks with
multiple linear mild manic symptoms (= 1.441, t= 3.10, P=
regression 0.003) and mood instability ( = 0.105, t =
3.593, P = 0.001): this model accounted for
approximately 46% of the variance in the FAST
total score (adjusted R2 = 0.460; F (3, 47) =
15.18, P <0.001).

Torres et al. Chi-square, Fisher’s Although there was no further analysis in the
(2017) exact test, Pearson main variables associated with FI, the authors
correlation, only noted that the HDRS score (F= 5.061, df=
ANOVA, 1, p = 0.026) played a significant role in the
ANCOVA functional outcome, an even greater role in BD
+ ADHD and, more specifically, in cognitive
functional domain.

Vasconcelos- Pearson correlation, The HDRS score was the only variable to
Moreno et al. linear regression remain a significant predictor of the FAST total
 (2016) model and score ( = 1.81, standard error = 0.57, p =
MANCOVA 0.004).

Wesley et al. T-test, chi-square, Poor global functioning was positively

(2018) Pearson correlation correlated with depression and mania scores.
and stepwise linear Stress, coping, and self-esteem accounted for a
regression total of 51.4% of the variance (stress accounted
for the higher percentage (33%), and self-
esteem accounted for the smaller percentage
(2.8%)).

FI: Functional Impairment/FAST: Functioning Assessment Short Test/ANOVA: Analysis of

Variance/ANCOVA: Analysis of Covariance/MANOVA: Multivariate Analysis of
Variance/MANCOVA: Multivariate Analysis of Covariance/HDRS: Hamilton Depression Rating
Scale/BD: Bipolar Disorder/ADHD: Attention Deficit Hyperactivity Disorder/MADRS: Montgomery-
Asberg Depression Rating Scale/PCA: Principal Component Analysis.

Figure Legends

Figure 1: Preferred Reporting Data for Systematic Reviews and Meta-Analysis

(PRISMA) flow diagram: overview of search strategy.

Figure 2: Metanalytic results comparing functioning scores among 662 patients with BD
and 587 HCs.

Figure 3: FI prevalence in global and specific FAST domains from 1083 euthymic
bipolar patients.
 bdi_12904_f1.docx

Accepted Article
Identification

Records identified through Additional records identified

database searching through other sources
(n = 1100) (n = 28) Records excluded
(n = 512)
a) Patients <18 years old (n=47);
b) Review/protocol/letter
Records after duplicates removed (n=105);
(n = 888) c) Other disorders or mixed
diagnostic groups (n=464);
d) Not BD patients, assessing
families, youth at risk of BD
Screening

Records screened (n=8);

(n = 888)

Full-text articles excluded

Full-text articles assessed (n = 363)
for eligibility a) Full-text not available or other
(n = 376) style of text without access to
raw data (for example, poster)
Eligibility

(n= 45);
b) Diagnosis of BD without
structured interview (n= 46);
Studies included in c) Symptomatic patients or not
qualitative synthesis presenting separated data
(n = 13) from euthymic patients
(n=96);
d) Used other instruments
instead of FAST (n= 75)
Included

e) Lacked objective measure of

functioning or analysis of few
Studies included in aspects of functioning instead
quantitative synthesis of global functioning (n= 56);
(meta-analysis)
(n = 12)

Figure 1. Preferred Reporting Data for Systematic Reviews and Meta-Analysis

(PRISMA) flow diagram: overview of search strategy.

This article is protected by copyright. All rights reserved

Figure 2: Metanalytic results comparing functioning scores among 662 patients with BD and 587 HCs.

Global Score

Autonomy Financial

Occupational Interpersonal Relationships

Cognitive Leisure Time

 Figure 3: FI prevalence in global and specific FAST domains from 1.083 euthymic
bipolar patients.

Study name Statistics for each study Event rate and 95% CI
Event Lower Upper
rate limit limit Z-Value p-Value
Sole, 2018 0,643 0,562 0,718 3,379 0,001
Jiménez-López, 2018 0,510 0,413 0,606 0,200 0,841
Rosa, 2010 0,588 0,468 0,698 1,448 0,148
Torres, 2017 0,663 0,557 0,755 2,963 0,003
Jiménez, 2012 0,819 0,746 0,875 6,825 0,000
Strejilevich, 2013 0,345 0,232 0,479 -2,254 0,024
Aparicio, 2017 0,583 0,456 0,701 1,285 0,199
Vasconcelos, 2016 0,844 0,675 0,933 3,464 0,001
Chan,2018 0,378 0,284 0,482 -2,295 0,022
Aydemir, 2012 0,614 0,496 0,720 1,895 0,058
Roux, 2017 0,556 0,493 0,618 1,736 0,083
0,586 0,556 0,617 5,441 0,000
-1,00 -0,50 0,00 0,50 1,00

Favours A Favours B
Global
Meta Analysis
Study name Statistics for each study Event rate and 95% CI Study name Statistics for each study Event rate and 95% CI
Event Lower Upper Event Lower Upper
rate limit limit Z-Value p-Value rate limit limit Z-Value p-Value
Sole, 2018 0,713 0,634 0,781 4,929 0,000 Sole, 2018 0,552 0,470 0,632 1,252 0,211
Jiménez-López, 2018 0,640 0,542 0,728 2,762 0,006 Jiménez-López, 2018 0,300 0,218 0,397 -3,883 0,000
Rosa, 2010 0,853 0,748 0,919 5,134 0,000 Rosa, 2010 0,706 0,588 0,802 3,289 0,001
Torres, 2017 0,709 0,605 0,795 3,756 0,000 Torres, 2017 0,535 0,429 0,637 0,646 0,518
Jiménez, 2012 0,768 0,690 0,831 5,938 0,000 Jiménez, 2012 0,819 0,746 0,875 6,825 0,000
Strejilevich, 2013 0,509 0,379 0,638 0,135 0,893 Strejilevich, 2013 0,273 0,172 0,404 -3,240 0,001
Aparicio, 2017 0,750 0,626 0,843 3,685 0,000 Aparicio, 2017 0,250 0,157 0,374 -3,685 0,000
Vasconcelos, 2016 0,750 0,574 0,870 2,691 0,007 Vasconcelos, 2016 0,844 0,675 0,933 3,464 0,001
Chan,2018 0,256 0,176 0,355 -4,424 0,000 Chan,2018 0,122 0,069 0,207 -6,126 0,000
Aydemir, 2012 0,686 0,568 0,783 3,030 0,002 Aydemir, 2012 0,600 0,482 0,708 1,662 0,097
Roux, 2017 0,631 0,568 0,689 4,010 0,000 Roux, 2017 0,436 0,374 0,499 -1,991 0,046
0,656 0,625 0,685 9,595 0,000 0,492 0,459 0,524 -0,508 0,611
-1,00 -0,50 0,00 0,50 1,00 -1,00 -0,50 0,00 0,50 1,00

Occupational Favours A Favours B Cognitive Favours A Favours B

Meta Analysis Meta Analysis

Study name Statistics for each study Event rate and 95% CI Study name Statistics for each study Event rate and 95% CI
Event Lower Upper Event Lower Upper
rate limit limit Z-Value p-Value rate limit limit Z-Value p-Value
Sole, 2018 0,392 0,315 0,474 -2,572 0,010 Sole, 2018 0,399 0,322 0,481 -2,408 0,016
Jiménez-López, 2018 0,350 0,263 0,448 -2,953 0,003 Jiménez-López, 2018 0,390 0,300 0,489 -2,182 0,029
Rosa, 2010 0,838 0,731 0,908 4,996 0,000 Rosa, 2010 0,632 0,512 0,738 2,156 0,031
Torres, 2017 0,419 0,319 0,525 -1,503 0,133 Torres, 2017 0,314 0,225 0,419 -3,364 0,001
Jiménez, 2012 0,638 0,554 0,713 3,192 0,001 Jiménez, 2012 0,572 0,489 0,652 1,696 0,090
Strejilevich, 2013 0,145 0,074 0,265 -4,630 0,000 Strejilevich, 2013 0,145 0,074 0,265 -4,630 0,000
Aparicio, 2017 0,317 0,212 0,444 -2,771 0,006 Aparicio, 2017 0,400 0,285 0,528 -1,539 0,124
Vasconcelos, 2016 0,688 0,510 0,823 2,067 0,039 Vasconcelos, 2016 0,594 0,419 0,747 1,054 0,292
Chan,2018 0,422 0,325 0,526 -1,470 0,142 Chan,2018 0,500 0,398 0,602 0,000 1,000
Aydemir, 2012 0,543 0,426 0,655 0,716 0,474 Aydemir, 2012 0,629 0,510 0,733 2,127 0,033
Roux, 2017 0,278 0,225 0,338 -6,638 0,000 Roux, 2017 0,066 0,041 0,106 -10,217 0,000
0,426 0,395 0,458 -4,551 0,000 0,421 0,388 0,454 -4,614 0,000
-1,00 -0,50 0,00 0,50 1,00 -1,00 -0,50 0,00 0,50 1,00

Autonomy Favours A Favours B

Interpersonal Relationship Favours A Favours B

Meta Analysis Meta Analysis

Study name Statistics for each study Event rate and 95% CI Study name Statistics for each study Event rate and 95% CI
Event Lower Upper Event Lower Upper
rate limit limit Z-Value p-Value rate limit limit Z-Value p-Value
Sole, 2018 0,098 0,059 0,159 -7,892 0,000 Sole, 2018 0,196 0,139 0,269 -6,704 0,000
Jiménez-López, 2018 0,590 0,491 0,682 1,790 0,073 Jiménez-López, 2018 0,210 0,141 0,301 -5,397 0,000
Rosa, 2010 0,500 0,383 0,617 0,000 1,000 Rosa, 2010 0,971 0,890 0,993 4,872 0,000
Torres, 2017 0,081 0,039 0,161 -6,146 0,000 Torres, 2017 0,256 0,175 0,358 -4,321 0,000
Jiménez, 2012 0,319 0,247 0,401 -4,156 0,000 Jiménez, 2012 0,435 0,355 0,519 -1,528 0,127
Strejilevich, 2013 0,036 0,009 0,134 -4,550 0,000 Strejilevich, 2013 0,036 0,009 0,134 -4,550 0,000
Aparicio, 2017 0,583 0,456 0,701 1,285 0,199 Aparicio, 2017 0,217 0,130 0,338 -4,101 0,000
Vasconcelos, 2016 0,188 0,087 0,359 -3,238 0,001 Vasconcelos, 2016 0,531 0,361 0,694 0,353 0,724
Chan,2018 0,156 0,094 0,246 -5,817 0,000 Chan,2018 0,344 0,254 0,448 -2,901 0,004
Aydemir, 2012 0,357 0,254 0,475 -2,356 0,018 Aydemir, 2012 0,400 0,292 0,518 -1,662 0,097
Roux, 2017 0,129 0,092 0,177 -9,943 0,000 Roux, 2017 0,170 0,128 0,223 -9,244 0,000
0,292 0,262 0,325 -11,412 0,000 0,288 0,259 0,318 -12,256 0,000
-1,00 -0,50 0,00 0,50 1,00 -1,00 -0,50 0,00 0,50 1,00

Leisure Time Favours A Favours B Financial Issues Favours A Favours B

Meta Analysis Meta Analysis