Bipolar Disorders 2015: 17 (Suppl.

2): 41–55 © 2015 John Wiley & Sons A/S

Published by John Wiley & Sons Ltd.
BIPOLAR DISORDERS

Review Article

A review on the impact of cognitive

dysfunction on social, occupational, and
general functional outcomes in bipolar
disorder
Baune BT, Malhi GS. A review on the impact of cognitive dysfunction Bernhard T Baunea and Gin S
on social, occupational, and general functional outcomes in bipolar Malhib,c
disorder. a
Discipline of Psychiatry, University of Adelaide,
Bipolar Disord 2015: 17 (Suppl. 2): 41–55. © 2015 John Wiley & Sons A/ Adelaide, SA, bCADE Clinic, Department of
S. Psychiatry, Royal North Shore Hospital,
Published by John Wiley & Sons Ltd. c
Discipline of Psychiatry, Kolling Institute,
Sydney Medical School, University of Sydney,
Objectives: Bipolar disorder (BD) is associated with significant Sydney, NSW, Australia
impairment in cognitive performance across multiple domains of
function that often persist after clinical recovery. It remains unclear,
however, as to whether this process is related to the clinical status of BD
being depressed, manic/hypomanic, or euthymic. In this review, we
examine the literature on the cross-sectional and longitudinal
relationships between cognitive function and general function depending
on the clinical phase of BD.

Methods: A systematic review of original research that studied both

cognitive function and general function in adults (18–60 years),
restricted to BD, was conducted in a total of 18 studies meeting
inclusion/exclusion criteria.

Results: Results show cross-sectional and prospective relationships

between cognitive function and general function in patients with BD in doi: 10.1111/bdi.12341
both symptomatic and euthymic patients with BD. While studies using
general measures of function (e.g., Global Assessment of Function scale) Key words: bipolar disorder – cognitive
show more inconsistent associations with cognitive function, those function – depression – general function –
employing assessments of domain specific function, suggest a consistent mood state – neurobiology
relationship between social and occupational function and cognitive
performance. Executive function is commonly affected by cognitive Received 5 May 2015, revised and accepted for
deficits in these patients, but in addition a variety of domains show publication 25 September 2015
associations with functional outcomes (e.g., social function,
occupational function). Notably, the emerging evidence suggests that Corresponding author:
cognitive function may be a better predictor of future general function Bernhard T. Baune, Ph.D., M.D., M.P.H.,
than affective symptom severity. F.R.A.N.Z.C.P.
Discipline of Psychiatry
Conclusions: Despite some inconsistencies, in sum the literature on the School of Medicine
relationship between cognitive function and general function in BD University of Adelaide
implicates both cross-sectional and longitudinal associations, both in Adelaide, SA 5005
symptomatic and euthymic patients with BD. And in terms of capturing Australia
these changes functional scales in particular domain-specific measures Fax: +61-8-8222-2774
seem superior to general measures. E-mail: bernhard.baune@adelaide.edu.au

The World Health Organization (WHO) Global disorders, including bipolar disorder (BD),
Burden of Disease study currently ranks mood among the leading cause of disease burden in

41
Baune and Malhi
the world (1). BD is associated with significant
impairment in multiple functional domains. The
WHO’s International Classification of Function-
ing, Disability and Health defines general func-
tion to encompass body functions (physiological
actions of the body), activities (execution of
tasks) and involvement in life situations in many
domains including self-care, interpersonal,
domestic, education, occupation, community,
social and civic life (2). General function impair-
ments in patients with BD may affect a range of
areas for both the individual and their broader
social structure. For the individual, illness can
negatively affect physical functioning, ability to
perform in work, school or domestic roles and
social interactions, as well as their emotional
health, mental health, general health and vitality
(3, 4).
Specifically, the literature demonstrates that
symptomatic BD is associated with functional defi-
cits in a wide variety of areas including impair-
ments in work and employment (5–8), social (8, 9),
and psychological, physical, and environmental
domains (7). A large proportion of patients with
BD show moderate to severe work impairment and
overall patients report much higher unemployment
rates than healthy controls (10). Frequent prob-
lems with employment such as disturbed work con-
tinuity due to days taken off work from illness,
problems handling interpersonal problems with
colleagues and stigma associated with disclosure of
mental illness in the workplace are reported by
13–34% of employed patients (7, 10). Patients also
experience a compromise in social functioning
including problems with interpersonal relation-
ships, enjoyment of recreational activity and over-
all contentment compared to controls (11). Family
functioning may also be affected since patients
with BD are more likely to be separated, widowed
or divorced (11). Disability of patients with BD
may also affect family members as 93% of care-
givers to patients with BD report at least moderate
distress related to the patient’s problem behavior,
social dysfunction, or the illness’ adverse effects on
the caregiver’s work, social and leisure time (12).
These functional deficits frequently persist long
after symptomatic recovery and contribute signifi-
cantly to morbidity in BD (11, 13). In addition,
families and care-givers of individuals with BD
report difficulties in employment themselves
because of their responsibilities to care for the indi-
vidual and financial difficulties that arise because
of a reduced ability to work (14).
The majority of clinical research in the area of
general function in BD has focused on investigat-
ing the contribution of clinical characteristics such
42
as depressive and manic symptom severity, number
of affective episodes, number of psychiatric hospi-
talizations and duration of illness on general func-
tion. Another important contributor to poor
functional outcomes in BD is the area of cognitive
function. Patients with BD experience decreased
cognitive function in a variety of domains includ-
ing executive function, memory, verbal learning,
attention and processing speed (15–18). It has been
demonstrated that cognitive function may still be
decreased after symptom remission (19) and may
be associated with patients’ level of functioning in
the short and long-term. Specifically, performance
in executive function, verbal learning and memory,
attention and processing speed has been associated
with everyday functioning of patients with BD
both in cross-section and longitudinally (19–21).
In addition, a recent review by Wingo et al. (22)
and a meta-analysis by Depp et al. (23) conducted
in symptomatic and euthymic patients with BD
provided insight into the correlations between cog-
nitive function and general function. However, the
meta-analysis examined patients with schizophre-
nia and BD across a spectrum and included late-
life depression and some studies that showed no
associations between cognitive function and gen-
eral function were included in the meta-analysis
(24–26). Therefore, a review on the topic of cogni-
tive function and general function restricted to
bipolar disorder and the adult age group while
considering the clinical phases of BD is needed.
This forms the aim of our review.
Methods
A systematic review of the published literature was
conducted according to PRISMA guidelines (27)
to identify studies on the relationship between cog-
nitive function and general function in BD using
common data bases (GoogleScholar, PubMed, and
PsychINFO) published until 2015. Key search
terms included clinical (mood disorder, depression,
BD, bipolar depression), cognitive (cognition, cogni-
tive deficit, neurocognition, neuropsychology, mem-
ory, attention and executive function), and
functional terms (function, work, social, occupation,
employment, QoL). Most search combinations
comprised of one clinical term and one functional
term and one cognitive term. Searches with combi-
nations of only clinical and functional terms and
only cognitive and functional terms were also per-
formed. Inclusion criteria of studies were publica-
tion in peer-reviewed journals in English language,
assessment of relationship between cognitive
domains (attention, executive function, verbal
learning and memory, verbal fluency, processing
 Cognitive and functional dysfunction in bipolar disorder
speed, working memory, visual learning and mem-
ory, psychomotor speed, visuo-spatial ability) and
function [as measured by the following scales:
Social Adjustment Scale (SAS), Brief Disability
Questionnaire, Global Assessment of Function
(GAF), Short Form Health Survey–12 (SF-12),
Short Form Health Survey–36 (SF-36), Social
and Occupational Functioning Scale (SOFAS),
WHO Disability Assessment Schedule (WHO-
DAS), Multi-dimensional Scale of Independent
Functioning (MSIF), Functional Assessment
Short Test (FAST), Levenstein–Klein–Pollack
scale (LKP) scale, Strauss–Carpenter scale,
Activities of Daily Living (ADL), and Instru-
mental Activities of Daily Living (IADL)]
restricted to patients with BD. Studies were pre-
sented in the tables according to clinical status
(depressed, manic, euthymic). Studies were
excluded when neurological comorbidities which
impair cognitive function (e.g., dementia,
Parkinson’s disease, organic brain disease, or
lesions) were present, when pediatric or adoles-
cent depression (mean age of patient group
<18 years) or elderly depression (mean age of
patient group >60 years) was focused and when
patient groups other than BD (e.g., major
depressive disorder, schizophrenia, Alzheimer’s
disease) were included. According to these crite-
ria, 127 potentially relevant articles were identi-
fied according to inclusion criteria. Abstracts of
these 127 articles were retrieved for further
evaluation. Applying exclusion criteria, 106 arti-
cles were disregarded. Finally, 21 studies met
127 articles were identified via database searches with
PubMed, GoogleScholar, and PsychINFO; and cross-
referencing from relevant articles
127 abstracts were retrieved for
further evaluation
21 studies were included in the final analysis
Fig. 1. Flowchart of articles identified and selected for this review.
inclusion and exclusion criteria and were
included in the review (Fig. 1).
Results
In total, 21 studies provided results on the cross-
sectional or prospective analyses of the relation-
ship between cognitive function and general
function in either euthymic or symptomatic
patients with bipolar I disorder (BD-I) or bipolar
II disorder (BD-II). In symptomatic patients with
BD, eight studies were found (five cross-sectional
studies and three prospective studies), whereas in
euthymic patients with BD, 13 studies were con-
ducted (eight cross-sectional and five prospective
studies). Some studies had included both symp-
tomatic and euthymic patients, hence some of these
studies appear twice in the tables in the text
sections.
Measures of general functional impairment
Function is inherently difficult to measure and the
studies sampled used a variety of different func-
tional measures. Measures of function can be
broadly divided into four different measurement
categories: self-report measures (WHO-DAS), clin-
ician-rated measures (GAF, SOFAS, SAS, FAST,
and MSIF), real-world functional measures (occu-
pation status, SSA disability status), and perfor-
mance-based measures (Strauss–Carpenter scale,
LKP scale) (23). Some scales give a global assess-
ment of the patient’s state including the patient’s
106 articles were excluded
due to exclusion criteria
43
Baune and Malhi
mental health, physical health and functional state.
Such scales include the GAF and SOFAS, which
give a global measure of psychological, social, and
occupational function (28). Other scales of general
function do not measure mental and physical
health but give more in-depth assessment of gen-
eral function by measuring the different domains
of function. These scales include the WHO-DAS
which measures personal, occupational, familiar,
and social function (29); the MSIF which measures
function in occupational, education, and residen-
tial (family and home-tasks) domains (30); the
FAST which assesses function in autonomy, occu-
pational, cognitive, financial, interpersonal, and
leisure domains (31); and the SAS which assesses
function in work, social, leisure, and familial
domains (32). Some studies also used measures of
function, which were specific to one functional
domain, in addition to their measures of general
function. These include occupation status or the
Strauss–Carpenter scale which purely measured
occupational function (33) and the LKP scale
which purely measured social function (33). In the
results section, we refer to general function when
assessed by global scales such as GAF and
SOFAS. We refer to domains of functioning when
scales measuring multiple domains of function,
e.g., WHO-DAS, MSIF, FAST, and SAS were
employed.
Relationship between cognitive performance and
general function in BD: symptomatic patients (Table 1)
Cross-sectional studies. Associations between cog-
nitive performance and impairments in general
function may be mood-state dependent. In a num-
ber of cross-sectional studies, poorer general func-
tion, assessed with the GAF scale in depressed
patients with BD, has been associated with worse
performance in several domains of cognitive func-
tion including executive function (24, 34, 35), ver-
bal learning (24, 33, 35), verbal memory (34, 35),
attention (34), and reaction time (24). In contrast,
no associations were observed between cognitive
performance and general function assessed with
the GAF scale in depressed patients with BD (25).
Studies that assessed patients in additional mood
states (mania, hypomania) found that executive
function (34, 35), verbal learning, verbal memory
(35) and attention (34) were related to poorer gen-
eral function (GAF) across all mood states.
In a single cross-sectional study on cognitive
performance and general functioning, mood states
(depressed, manic, euthymic) were assessed at mul-
tiple time points over 30 months in 25 patients
44
with BD (24). In individual cross-sectional analy-
ses, depressed and manic patients were impaired in
executive function, memory and attention, and in
addition depressed patients showed further impair-
ment in psychomotor function and reaction time.
Different cognitive domains correlated with gen-
eral function depending on the mood states. In the
depressed state, patients who performed better in
executive function and reaction time, had better
general function as measured by GAF as opposed
to patients in the manic state, who had better gen-
eral function on the GAF when showing better
performance on both executive function and verbal
learning (24).
When social and occupational functioning were
assessed, it was found that processing speed corre-
lated positively with social function and verbal
learning with occupational function across differ-
ent mood states in patients with BD, which indi-
cates an association between cognitive and social/
occupational function independent of mood states
(33). Moreover, a higher likelihood of disability
was observed in association with poorer perfor-
mance in verbal memory, executive function and
attention across all mood states (34).
Prospective studies. A key question in this area of
research is whether cognitive performance predicts
functioning over time. In a six-month longitudinal
study of first-episode manic patients it was found,
that better baseline performance in verbal learning
and memory has been associated with higher six-
month general function as measured by MSIF
(21). Furthermore, higher baseline processing
speed performance predicted better six-month
social function as measured by SAS (36) and
higher baseline ideational fluency predicted better
12-month general function on the MSIF scale (30).
In contrast, lack of evidence was shown for associ-
ations between verbal memory, verbal learning
performance, and general function over time in
symptomatic patients with BD (30), and more
broadly for any baseline cognitive performance
and general function (GAF sale) in a separate
study in 53 first-episode manic patients with BD
(21). Investigating occupational status in relation
to cognitive function, no association was observed
for the relationship between any cognitive mea-
sures and occupational status during a six-month
observational period (36).
Interestingly, some evidence suggests that cogni-
tive function may be a better predictor of future
general function than affective symptom severity
as shown in several studies (20, 36). Specifically, a
12-month longitudinal study of 78 symptomatic
patients with BD showed that higher scores on
 Table 1. Relationship between neurocognitive performance and general function in symptomatic bipolar disorder (depressed and manic states)
Study Aim
Symptomatic BD: cross-sectional studies
Martinez-Aran To ascertain whether
et al. 2002 (25) neurocognitive domains were
related to general function in
both depressed and euthymic
patients
Martinez-Aran To determine relationships
et al. 2004 (35) among neurocognitive
performance and general
function in patients with BD
across all mood states
Malhi et al. To characterize the
2007 (24) neurocognitive profile of BD and
examine its contribution to
general functional impairment
across all three states of the
illness
Burdick et al. To identify which neurocognitive
2010 (33) domains in BD were significantly
associated with social or
occupational function at 15-year
follow-up
Levy et al. To assess associations between
2011 (34) neurocognitive performance
and general function in patients
with BD
45
Study design and subjects
Cross-sectional
Depressed (n = 30)
17 F/13 M; mean age: 43.4 years
Euthymic (n = 30)
15 F/15 M; mean age: 40.1 years
Cross-sectional
Depressed (n = 30)
15 F/15 M; mean age: 43.4 years
Hypomanic/manic (n = 34)
17 F/17 M; mean age: 42.4 years
Euthymic (n = 44)
26 F/18 M; mean age: 39.6 years
Healthy controls (n = 30)
22 F/8 M; mean age: 38.9 years
30-month longitudinal study; patients were
assessed at multiple times across manic,
depressed, and euthymic states
throughout the 30-month period. Cross-
sectional analysis performed at each time-
point.
BD patients assessed in manic, depressed,
and euthymic states (n = 25)
17 F/8 M; mean age: 38.6 years
15-year longitudinal study; patients were
assessed at baseline and follow-up
Baseline: manic BD patients (n = 33)
Follow-up: Depressive episode in past
month (n = 5)
Manic episode in past month (n = 7)
Euthymic patients (n = 21)
15 F/18 M; mean age: 40.2 years
Cross-sectional
BD (n = 63)
Manic (n = 41)
Depressed (n = 11)
In mixed state 24–48 hours post-hospital
discharge (n = 11)
28 F/35 M; age range: 18–59 years (mean
age not given)
Scales
Clinical: SCID-DSM-IV, HDRS-17,
YMRS
Neurocognitive: WAIS, TMT-A & B,
COWAT, SCWT, WCST, CVLT
Functional: GAF
Clinical: PANSS
Neurocognitive: WAIS, WCST, SCWT,
COWAT, TMT-A & B, CVLT, WMS-R
Functional: GAF (not assessed in
controls)
Clinical: HDRS-21, MADRS, YMRS
Neurocognitive: Digit Span
Backwards, TMT-A & B, COWAT,
RAVLT, Stroop Word Reading Task
Functional: GAF
Clinical: SADS
Neurocognitive: CVLT, WAIS, TMT-A &
B, COWAT, WCST
Functional: LKP scale, Strauss–
Carpenter scale
Clinical: BDI, BHS, YMRS
Neurocognitive: WAIS-III, RCFT, WMS-
III, CVLT, TMT-A & B, SCWT, Symbol
Letter Cancellation Test, WCST,
COWAT, Animal Naming Task
Functional: GAF, SSA disability status
Findings
↓ Verbal fluency performance
associated with ↓ general function on
GAF in euthymic BD patients
Neurocognitive performance not
associated with general function on
GAF in depressed BD patients
↓ Executive function, verbal learning,
and verbal memory performance
associated with ↓ general function on
GAF in all BD groups
Depressed patients with ↓ executive
function and reaction time performance
and hypomanic patients with ↓
executive function and verbal learning
performance had ↓ general function on
GAF
Neurocognitive performance not
associated with general function on
GAF in euthymic BD patients
↑ Processing speed performance at
follow-up associated with ↑ social
function on LKP scale at follow-up in all
BD groups
↑ Verbal learning performance at follow-
up associated with ↑ occupational
function on Strauss–Carpenter scale at
follow-up in all BD patients
↓ Performance in some measures of
executive function and attention
associated with ↓ general function on
GAF in all BD groups
↓ Verbal memory, executive function,
and attention performance associated
with ↑ likelihood of disabled SSA status
in all BD groups
Cognitive and functional dysfunction in bipolar disorder
46
Table 1. (Continued)

Study Aim Study design and subjects Scales Findings

Symptomatic BD: longitudinal studies

Jaeger et al. To examine whether 12-month longitudinal study; patients were Clinical: HDRS, CARS-M
Baune and Malhi

↑ Baseline performance in ideational

2007 (20) neurocognitive performance,
measured following
hospitalization for an acute
affective episode, is predictive
of 12-month general function
Dickerson et al. To identify neurocognitive
2010 (36) predictors of 6-month general
function and occupational status
in patients with BD
Torres et al. To evaluate the relationship
2011 (21) between baseline
neurocognitive performance
and 6-month general function in
recently diagnosed clinically
stable patients with BD
assessed at baseline and 12-month
follow-up
Baseline: manic (n = 36), depressed
(n = 19), mixed BD-I (n = 11), BD-II or
BD-NOS (n = 12)
Follow-up: depressed (n = 8), manic
(n = 5), sub-threshold depressive or
manic (n = 46), euthymic BD (n = 19)
51 F/27 M; mean age: 35.8 years
6-month longitudinal study; patients were
assessed at baseline and 6-month
follow-up
Baseline: depressed (n = 13), manic
(n = 14), mixed BD-I (n = 11), BD-II or
BD-NOS (n = 14)
Follow-up: depressed or manic (n = 24),
partially remitted (n = 7), euthymic BD
(n = 21)
10 F/42 M; mean age: 30.5 years
6-month longitudinal study; patients were
assessed at baseline and 6-month
follow-up
Baseline: first-episode manic BD (n = 53)
Follow-up: euthymic (n = 38), non-remitted
(n = 15)
28 F/25 M; mean age: 22.7 years
Neurocognitive: SCWT, TMT-A & B,
WAIS-R, COWAT, WMS-R
Functional: MSIF
Clinical: SCID DSM-IV, HDRS, YMRS,
BPRS
Neurocognitive: Hopkins Verbal
Learning Task, WMS-III, WCST, SCWT,
Brief Visuo-spatial Learning Test, Letter
and Category Fluency, TMT-A & B,
WAIS-III, Digit Symbol, CCPT, WRAT
Functional: SAS, occupational status
Clinical: symptom ratings conducted by
trained psychiatrists
Neurocognitive: NART, K-BIT, JLO,
TMT-A & B, SCWT, CANTAB, CVLT-II,
COWAT, WMS-III
Functional: MSIF, GAF
fluency associated with ↑ 12-month
general function on MSIF in all BD
groups
Neither baseline verbal memory or
verbal learning performance or
baseline symptom severity associated
with 12-month general function on
MSIF in all BD groups
↑ Processing speed performance at
baseline associated with ↑ 6-month
general function on SAS at follow-up in
all BD groups
Performance on no baseline
neurocognitive tests associated with
occupational status at follow-up in all
BD groups
↑ Performance in verbal learning and
memory at baseline associated with ↑
6-month general function on MSIF in all
BD groups
No baseline neurocognitive
performance associated with 6-month
general function on GAF in all BD
groups

BD = bipolar disorder; BD-I = bipolar I disorder; BD-II = bipolar II disorder; BD-NOS = bipolar disorder not otherwise specified; F = female; M = male ↑ = increase; ↓ = decrease.
Clinical measures: SCID = Structured Clinical Interview; HDRS = Hamilton Depression Rating Scale; YMRS = Young Mania Rating Scale; PANSS = Positive and Negative Symptoms Scale;
MADRS = Montgomery– Asberg Depressive Rating Scale; SADS = Schedule for Affective Disorders and Schizophrenia; BDI = Beck Depression Inventory; BHS = Beck Hopelessness
Scale; BPRS = Brief Psychiatric Rating Scale; CARS-M = Clinician Administered Rating Scale for Mania.
Neurocognitive measures: WAIS = Wechsler Adult Intelligence Scale; WCST = Wisconsin Card Sorting Test; WMS-R = Wechsler Memory Scale; CVLT = Californian Verbal Learning Test;
SCWT = Stroop Colour Word Test; COWAT = Controlled Oral Word Association Test; TMT = Trail Making Test; RCFT = Rey Complex Figure Test; RAVLT = Rey Auditory Verbal Learning
Test; TOVA = Test of Variable Attention; WRAT = Wide Range Achievement Test; CCPT = Conners Continuous Performance Test.
Functional measures: GAF = Global Assessment of Function; LKP = Levenstein–Klein–Pollack 8-point scale measuring social function; SSA disability status = eligibility for psychiatric
disability benefits as assessed by social security administration in Massachusetts; MSIF = Multidimensional Scale of Independent Functioning; SAS = Social Adjustment Scale; NART =
National Adult Reading Test; K-BIT = Kaufman’s Brief Intelligence Test; JLO = Benton Judgement of Line Orientation; CANTAB = Cambridge Neuropsychological Test Automated Battery.
 Cognitive and functional dysfunction in bipolar disorder
attention and ideational fluency at baseline were
predictive of better general function on the MSIF
scale after 12-months, while baseline severity of
depressive symptoms [Hamilton Depression Rat-
ing Scale (HDRS)] and manic symptoms [Clinician
Administered Rating Scale for Mania (CARS-M)]
were not (20). Similarly, a six-month longitudinal
study among 52 symptomatic patients with BD
showed that improved general function measured
by SAS was only predicted by better baseline pro-
cessing speed performance as opposed to baseline
manic [Young Mania Rating Scale (YMRS)] or
depressive (HDRS) symptom severity (36). This
has led to the suggestion that performance in some
cognitive domains can perhaps be used as a prog-
nostic marker for future functional course of the
illness as assessed by general and domain specific
functional measures (20). On a similar note, a
prospective longitudinal study of 53 initially manic
patients with BD showed that better general func-
tion after six months as measured by MSIF was
predicted by better baseline verbal learning and
memory performance, but not by baseline affective
symptom severity (21). These results suggest that
cognitive function at baseline may be a better pre-
dictor of future functional outcome than symptom
severity at baseline.
Relationship between cognitive performance and
general function in BD: euthymic patients (Table 2)
Cross-sectional analyses. Cognitive deficits often
persist in the euthymic BD state and these deficits
have been associated with general function in a
number of small-scale cross-sectional studies (25,
35, 37, 38, 49, 50). Specifically, better performance
in executive function (35, 37–39), verbal learning
and memory (35, 37, 38), and verbal fluency (25)
was associated with better general function in
euthymic patients. Moreover, in a study of patients
with BD-I and BD-II, processing speed was found
to be associated with psychosocial function and
visual memory with occupational function (26). In
addition, a cross-sectional case–control study
found that poor functional status regarding recre-
ation and independent living were significantly
associated with lower performance on planning
and verbal and non-verbal fluency while recreation
(Self-reported Social Functioning Scale) was corre-
lated with executive function (49). When assessing
cognitive performance related to work place func-
tioning, a cross-sectional study reported that manic
episodes together with number of perseverative
errors in the Wechsler Adult Intelligence Scale
(indicating poorer executive functioning) con-
tributed to poor work adjustment (50). To the con-
trary, no significant cross-sectional correlations
were seen between cognitive function and general
function on GAF in the euthymic state (24). The
longitudinal study design in the study by Malhi
et al. with multiple cross-sectional time points and
analyses may have contributed to this opposing
finding. However, additional support for this nega-
tive finding comes from another study using the
GAF as a functional outcome measure. A lack of
correlation between GAF and cognitive function
in the euthymic state has been reported in a cross-
sectional study of 44 euthymic patients (26).
Importantly, in the same study, different domains
of function as measured by WHO-DAS correlated
with cognitive function, suggesting that a domain
specific assessment of function may be more sensi-
tive and thus more capable of identifying associa-
tions with cognitive measures as compared to
general function measures. Specifically, Mur et al.
(26) reported that better processing speed perfor-
mance correlated with less personal, occupational
and familiar disability on WHO-DAS, while better
executive function performance correlated with
less familiar disability on WHO-DAS. This sug-
gests the existence of some correlation between
cognitive function and specific domains of general
function in euthymic patients that are not captured
by GAF.
Prospective studies. Several studies have demon-
strated that general function is impaired in BD in
the long-term. Therefore, it is clinically relevant to
ask the question whether cognitive function is pre-
dictive of general function in euthymic bipolar dis-
order patients prospectively by virtue of exerting
residual clinical effects that can also serve as poten-
tial predictive markers. To date, a limited number
of longitudinal studies have been conducted inves-
tigating this question. When GAF is used as the
functional outcome measure, mixed results have
been observed in two different studies. While a
two-year follow-up study found no associations
between cognitive function at baseline and GAF at
follow-up (16), a one-year longitudinal study
reported that cognitive measures of attention, ver-
bal memory and executive performance at baseline
are associated with GAF measured general func-
tion at follow-up (40).
However, when general function is assessed
more specifically such as occupational function or
using the FAST measure, consistent associations
between cognitive and general function are found
in euthymic bipolar disorder. Specifically, higher
baseline performance in processing speed is associ-
ated with active occupation two years later, while
47
48
Table 2. Relationship between neurocognitive performance and functional outcome in euthymic bipolar disorder
Study Aim
Euthymic BD: cross-sectional studies
Martinez-Aran To ascertain whether neurocognitive
et al. 2002 (25) domains were related to general
function in both depressed and
euthymic patients
Martinez-Aran To determine relationships among
et al. 2004 (35) neurocognitive performance and
general function in patients with BD
across all mood states
Malhi et al. 2007 To characterize the neurocognitive
(24) profile of BD and examine its
contribution to general functional
impairment across all three states of
the illness
Mur et al. 2009 To measure the impact of the clinical
(26) course, the residual mood symptoms,
and the cognitive variables on the
psychosocial and occupational
functioning in patients with BD in
remission
Altshuler et al. To assess the relationship between
2008 (37) neurocognitive status and role function
in euthymic BD
Study type and subjects
Cross-sectional
Depressed (n = 30)
17 F/13 M; mean age: 43.4 years
Euthymic (n = 30)
15 F/15 M; mean age: 40.1 years
Cross-sectional
Depressed (n = 30)
15 F/15 M; mean age: 43.4 years
Hypomanic/manic (n = 34)
17 F/17 M; mean age: 42.4 years
Euthymic (n = 44)
26 F/18 M; mean age: 39.6 years
Healthy controls (n = 30)
22 F/8 M; mean age: 38.9 years
30-month longitudinal study; patients
were assessed at multiple times
across manic, depressed, and
euthymic states throughout the 30-
month period. Cross-sectional a
nalysis performed at each time-
point.
BD patients assessed in manic,
depressed, and euthymic states
(n = 25)
17 F/8 M; mean age: 38.6 years
Euthymic lithium outpatients with
BD-I or BD-II (n = 44)
Occupational status: active:
(n = 24), inactive (n = 20)
22 F/22 M; mean age: 42.9 years
Euthymic BD-I according to DSM-IV;
no Axis I comorbidity
Mean age: 49.7 years
Scales
Clinical: SCID-DSM-IV, HDRS-17, YMRS
Neurocognitive: WAIS, TMT-A & B,
COWAT, SCWT, WCST, CVLT
Functional: GAF
Clinical: PANSS
Neurocognitive: WAIS, WCST, SCWT,
COWAT, TMT-A & B, CVLT, WMS-R
Functional: GAF (not assessed in
controls)
Clinical: HDRS-21, MADRS, YMRS
Neurocognitive: Digit Span Backwards,
TMT-A & B, COWAT, RAVLT, Stroop
Word Reading Task
Functional: GAF
Clinical: YMRS, HDRS, MADRS
Neurocognitive: Executive function
(TMT-B, FAS, Digit Backward), Attention
(Stroop interference, CPT-II), Processing
speed (TMT-A, CPT reaction time),
Verbal Memory (CVLT measures), Visual
Memory (ROCF Immediate- and
Delayed-recall)
Functional: GAF, World Health
Organization Disability Assessment
Schedule, occupational status (active
versus inactive)
Clinical: YMRS < 6 and
HDRS < 7 = euthymic
Neurocognitive: CVLT, WCST
Functional: GAF
Baune and Malhi
Findings
↓ Verbal fluency performance
associated with ↓ general function on
GAF in euthymic BD patients
↓ Executive function, verbal learning,
and verbal memory performance
associated with ↓ general function on
GAF in all BD groups
Neurocognitive performance not
associated with general function on
GAF in euthymic BD patients
↑ Processing speed performance
associated with ↑ psychosocial
function
Visual memory associated with
occupational function
Association between cognitive
impairment in both verbal declarative
memory and executive function and
poor role function
 Table 2. (Continued)
Study Aim
Sole et al. 2012 To ascertain whether euthymic patients
(39) with BD-II present with neurocognitive
disturbances and to evaluate their
impact on functional outcome
Miguelez-Pan To investigate the influence of executive
et al. 2014 (49) function on functional outcomes
Bonnin et al. To study the clinical and neurocognitive
2014 (50) variables that best explain poor work
adjustment in euthymic patients with
BD-I
Euthymic BD: longitudinal studies
Mur et al. 2008 To investigate whether neurocognitive
(16) performance is related to general
function in a sample of euthymic
patients with BD over a 2-year period
Martino et al. To determine whether neurocognitive
2009 (40) impairments are predictive of 12-month
general function in euthymic patients
with BD
49
Study type and subjects
BD-II (n = 43); 23 F/20 M; mean
age: 46.6 years
Matched healthy controls (n = 42);
27 F/15 M; mean age: 44.3 years
Cross-sectional
Depressed BD (n = 31); 13 F/18 M;
mean age: 41.3 years
Healthy controls (n = 25); 10 F/15 M;
mean age: 40.4 years
Euthymic BD-I (n = 85)
44 F/41 M; mean age 40.1 years
2-year longitudinal study; patients
were assessed at baseline and
2-year follow-up
Euthymic BD (n = 33)
16 F/17 M; mean age: 40.7 years
Healthy matched controls (n = 33)
16 F/17 M; mean age: 41.7 years
12-month longitudinal study; patients
were assessed at baseline and 12-
month follow-up
Euthymic BD (n = 35)
23 F/12 M; mean age: 43 years
Healthy controls (n = 30)
Scales
Clinical: YMRS < 7 and
HDRS < 7 = euthymic
Neurocognitive: CVLT, WCST, FAS, Ani-
mal Naming, Digits Backwards from WAIS,
TMT-A & B, Digits Forward (attention)
Functional: SOFAS
Clinical: HDRS-17, YMRS, Token test,
Symptom Global index
Neurocognitive: WAIS-III (Digits
Forward/Backwards, Vocabulary
subtest, Token test, WCST, TMT-A & B,
FAS, Stroop, FAB, Five-point test, ToL)
Functional: GAF, SFS, employment
status (yes/no)
Clinical: HDRS, YMRS
Neurocognitive: WAIS-III, WCST, SCWT,
FAS, TMT-B, CVLT
Functional: Work adjustment was
assessed by means of work focused
interviews following criteria of EMBLEM
study (good adjustment = having
competitive employment full/part-time on
regular basis)
Clinical: HDRS, YMRS
Neurocognitive: WAIS III, WCST, SCWT,
COWAT, TMT-A & B, CCPT-II, CVLT,
RCFT
Functional: GAF, occupational status
Clinical: SCID-DSM-IV, HDRS, YMRS
Neurocognitive: Forward Digit Span,
TMT-A & B, WCST, WAIS, Memory
Battery of Signoret
Functional: GAF, FAST (not assessed in
controls)
Findings
Lower performance on measures of
attention, learning and verbal memory,
and executive function compared with
healthy controls
TMT-B predicted psychosocial
functioning measured with the SOFAS
↓ Poor functional status regarding
recreation and independent living were
significantly associated with ↓ lower
performance on planning and verbal
and non-verbal fluency (p < 0.05)
Recreation (SFS) was correlated with
executive function
Manic episodes together with number of
perseverative errors in the WCST
contributed to poor work adjustment
Cognitive and functional dysfunction in bipolar disorder
Neither baseline or 2-year
neurocognitive performance
associated with 2-year general function
on GAF in euthymic BD patients
↑ Baseline processing speed
performance associated with ↑
likelihood of active occupation status at
2-year in euthymic BD patients
↑ Reaction time and executive function
performance at 2-year associated with
↑ likelihood of active occupation status
at 2-year in euthymic BD patients
↑ Attention, verbal memory, and
executive function performance at
baseline associated with ↑ 12-month
general function on GAF in euthymic
BD patients
↑ Attention and executive function
performance at baseline associated
with ↑ 12-month general function on
FAST in euthymic BD patients
50

Baune and Malhi

Table 2. (Continued)

Study Aim Study type and subjects Scales Findings

Bonnin et al. To identify neurocognitive predictors of 4-year longitudinal study; patients Clinical: SCID DSM-IV, HDRS ↑ Verbal learning and memory
2010 (41) 4-year general function in euthymic were assessed at baseline and Neurocognitive: WAIS-III, CVLT, WCST, performance at baseline associated
patients with BD 4-year follow-up SCWT, COWAT, TMT-A & B, Digit with ↑ 4-year general function on overall
Euthymic BD (n = 32) Backwards FAST in euthymic BD patients
15 F/17 M; mean age: 43.5 years Functional: GAF: assessed at baseline ↑ Executive function performance at
and follow-up baseline associated with ↑ 4-year
FAST: assessed at follow-up occupational function on FAST in
euthymic BD patients
Mora et al. 2013 To determine the longitudinal course of 6-year longitudinal study; patients Clinical: HDRS-17, YMRS ↓ In executive function, processing
(42) neurocognitive impairment and its were assessed at baseline and Neurocognitive: WAIS-III, CVLT, WCST, speed, and delayed-memory
impact on general function in euthymic 6 years later SCWT, COWAT, TMT-A & B, CCPT-II, performance from baseline to follow-up
patients with BD Euthymic BD (n = 26) RCFT associated with ↓ 6-year general
12 F/14 M; mean age: 41.71 years Functional: GAF assessed at baseline function on FAST in euthymic BD
Healthy controls (n = 26) and follow-up patients
14 F/12 M; mean age: 41.38 years FAST assessed at follow-up ↓ In executive function and processing
speed performance from baseline to
follow-up associated with ↓ 6-year
occupational function on FAST in
euthymic BD patients
Bearden et al. To evaluate the relationship between 79 symptomatically recovered Clinical: SCID, HDRS-28, YMRS ≤ 7 Over 6 months, cognitive measures at
2011 (53) cognition and occupational function in patients (n = 45; 56%) achieved Neurocognitive: WAIS-III, CVLT, WCST, the time of symptomatic recovery,
symptomatically recovered patients recovery within 6 months after an LNS, DSCPT, TMT-A & B particularly in the domains of working
with BD-I acute manic episode Functional: LFQ memory/attention and speed of
Age range 18–65 years processing, are strongly associated
with concurrent occupational recovery,
even after accounting for the effects of
age and depression severity

BD = bipolar disorder; BD-I = bipolar I disorder; BD-II = bipolar II disorder; BD-NOS = bipolar disorder not otherwise specified; F = female; M = male; ↑ = increase; ↓ = decrease.
Clinical measures: HDRS = Hamilton Depression Rating Scale; SCID = Structured Clinical Interview; YMRS = Young Mania Rating Scale; PANSS = Positive and Negative Symptoms Scale;
MADRS = Montgomery– Asberg Depressive Rating Scale.
Neurocognitive measures: SCWT = Stroop Colour Word Test; TMT = Trial Making Test; WAIS = Wechsler Adult Intelligence Scale; COWAT = Controlled Oral Word Association Test; WMS-
R = Wechsler Memory Scale; CCPT = Conners Continuous Performance Test; CVLT = Californian Verbal Learning Test; WCST = Wisconsin Card Sorting Test; RCFT = Rey Complex Fig-
ure Test; FAB = frontal assessment battery; FAS = verbal fluency; ToL = Tower of London; LNS = letter-numbering sequence test; DSCPT = degraded stimulus continuous performance
test; RAVLT = Rey Auditory Verbal Learning Test; CPT = Continuous Performance Test; ROCF = Rey–Osterrieth Complex Figure Test.
Functional Measures: SFS = Self-reported Social Functioning Scale; GAF = Global Assessment of Function; FAST = Functional Assessment Short Test; SOFAS = Social and Occupational
Functioning Scale; LFQ = Life Functioning Questionnaire.
 Cognitive and functional dysfunction in bipolar disorder
both executive function and reaction time is associ-
ated with active occupation at two-year follow-up
(16). Similarly, attention and executive function
performance at baseline has been associated with
better 12-months general function as measured by
FAST (40) and better verbal learning and memory
performance at baseline is related to higher func-
tion four years later assessed using the FAST scale
(41). In an impressive six-year longitudinal study,
changes in cognitive and general function between
baseline and follow-up and their relationships have
been explored in more depth. A worsening of cog-
nitive function (executive function, processing
speed and delayed memory) between baseline and
six-year follow-up predicted poorer general func-
tion at follow-up on the FAST scale (42). Simi-
larly, a decrease in executive function and
processing speed performance from baseline to six-
year follow-up, a decline of occupational function
(measured by FAST) was observed (42). In another
study on the relationship between cognitive and
occupational function in euthymic patients it was
reported that over six months, cognitive measures
at the time of symptomatic recovery, particularly
in the domains of working memory/attention and
speed of processing, were strongly associated with
concurrent occupational recovery, even after
accounting for the effects of age and depression
severity (53). These findings suggest that a decline
in cognitive function over time can be paralleled by
a functional decline in occupation despite euthymic
state in bipolar disorder. This observation in
euthymic patients could be due to a causal rela-
tionship between cognitive and general function in
that worse cognitive function leads to poorer gen-
eral and occupational function or it could be a pro-
cess of both cognitive and functional decline that is
caused by brain alterations specifically affecting
these domains rather than mood domains. Further
research linking these clinical findings to neurobio-
logical and imaging investigations is warranted. In
addition, it remains to be specifically investigated
if a targeted early treatment of cognitive deficits in
BD would prevent some of the functional decline
over time.
Discussion
This review on the relationship between cognitive
function and general function in patients with BD
demonstrates that multiple cross-sectional and
prospective relationships exist depending on both
mood states and types of functional measures
employed. In symptomatic BD, patients across
mood states showed consistently a cross-sectional
association between a range of cognitive domains
and general function, even when assessed with a
broader measure such as the GAF as well as social
and occupational function. However, studies
employing GAF as a measure have been used more
frequently than domain specific function measures
such as occupational and social function. Impor-
tantly, these associations have also been found in
some prospective analyses, however, not consis-
tently in symptomatic patients with BD. However,
several findings suggest that cognitive function
may be a better predictor of long-term general
function than clinical severity measures. Moreover,
in euthymic patients, the review found various
studies supporting cross-sectional associations
between a variety of cognitive domains and general
function, social and occupational function,
although a lack of such association was reported
repeatedly when GAF was used as a single measure
of general function, indicating a possible lack of
sensitivity to detect finer deficits in function as
opposed to specific domains of function such as
social and occupational function that showed con-
sistently association with cognitive function even
in euthymic patients. This finding is also true for
longitudinal studies showing a consistent associa-
tion between a broad range of cognitive domains
and domain specific function measures over two-,
four-, and six-year follow-up periods as opposed to
mixed results when using GAF as a general func-
tional outcome measure. Overall, this review found
that cognitive function is associated with general
and domain-specific function across mood states in
BD cross-sectionally and prospectively. However,
the literature is still inconclusive as to which speci-
fic cognitive domains show the most consistent
association with general and domain-specific func-
tion.
Our results are in line with previous reviews on
this topic. A recent important meta-analysis by
Depp et al. (23) indicated the magnitude of contri-
bution of cognitive function to deficits in general
function in BD, showing a mean strength of corre-
lation between overall cognitive ability and general
function of 0.27. Depp et al. (23) also reported sig-
nificant and fairly consistent correlations between
various cognitive domains and general function,
which is inconsistent with our findings. Some
important methodological differences between
their meta-analysis and our systematic review need
to be considered. Depp et al. included numerous
articles, which examined schizophrenia and
patients with BD across a spectrum while our
review is limited to studies including patient popu-
lations of BD only. Furthermore, while both stud-
ies excluded pediatric depression, Depp et al.
included studies of late life depression while our
51
Baune and Malhi
sampling was restricted to studies with populations
between ages 18–60 years (23). Lastly, several
studies included in our review which showed no
associations between cognitive function and gen-
eral function (24–26) were not included in Depp
et al.’s meta-analysis due to a different set of inclu-
sion criteria between studies.
An important point of our review is the exami-
nation of the longitudinal relationship between
baseline cognitive function and general function in
BD. In symptomatic patients with either depres-
sion or mania at assessment, poorer performance
in various baseline cognitive domains was associ-
ated with worse general and domain specific func-
tion at six-month and 12-month follow-up.
Similarly, even long prospective studies up to six
years showed in euthymic patients a consistent
relationship between cognitive domains and func-
tion—if domain specific functional assessment was
employed. These findings suggest that cognitive
assessment can potentially be used as a prognostic
clinical tool of function in BD. More generally,
more research is required to understand better the
temporal relationship between cognitive and gen-
eral function and it is unclear whether decreased
cognitive impairment leads to decreased general
function or whether an intervention improving
cognitive function would lead to long-term
improvement of general function in patients with
BD. In addition, the two clinically important areas
of cognitive and general function exert multiple
effects on each other. Current findings suggests
that the relationship between the two areas may be
bi-directional, as cognitive remediation treatment
has been shown to improve cognitive function and
improve occupational and general functioning in
18 patients with BD (43). This suggestion is sup-
ported by findings in patients with BD showing
that decreased general activity associated with
functional impairment can lead to decreased cogni-
tive stimulation, resulting in decreased cognitive
function (44). Furthermore, most of these studies
were small scale with very heterogeneous clinical
samples, which raised power issues in some cases.
Larger scale longitudinal studies of patients with
BD with well-defined clinical samples would be
needed to determine whether cognitive function is
actually useful as a prognostic tool for future gen-
eral functional outcome of the disorder. Further-
more, a large variation in clinical phenotypes has
been observed in many samples. While some stud-
ies had strictly samples of patients with BD-I or
BD-II, most others included a mixture of patients
with BD-I, BD-II, and BD not otherwise specified
leading to potential confounding since it has been
suggested that patients with BD-I experience more
52
cognitive and functional deficits than patients with
BD-II (15). Moreover, studies with symptomatic
patients with BD tended to analyse these as one
clinically homogenous group regardless of
depressed, hypomanic and manic mood states.
This appears methodologically flawed given study
results showing that cognitive impairment varies in
BD across acutely depressed BD, acutely manic
BD, and euthymic states (24, 35, 45).
Differences in functional scales used between
studies may also contribute significantly to the
heterogeneity of correlations between cognitive
domains across studies. It is interesting to note that
studies that found no association between cogni-
tive function and general function (24, 26) often
used scales, which give a global impression of the
general health and functional status of the patient.
In contrast, results of studies using functional
scales that assess multiple functional domains, e.g.,
WHO-DAS (26) showed more consistently associa-
tions between cognitive function and various
domains of function, while functional scales that
incorporate assessment of mental health, e.g.,
GAF, did not. The GAF has been criticized for
combining measures of symptoms and general
function in the same scale, which means that func-
tional measurements may be skewed by the sever-
ity of symptoms (46). This observation is especially
relevant in euthymic patients as GAF may give an
abnormally high measure of function due to
decreased depressive or manic symptom severity
leading to a possible masking effect of ongoing
functional deficits that are not properly captured
on the GAF. The use of functional measurements,
e.g., WHO-DAS, FAST, and MSIF, or assessing
occupational status, which provide more compre-
hensive and domain-specific functional assessments
without assessing the health status, may be better
suited to obtain a realistic association between cog-
nition and general and domain specific function.
This observed broad-range use of functional mea-
sures also applies to the use of a variety of cogni-
tive performance measures even within the same
cognitive domain, but also the heterogeneity of
cognitive deficits in bipolar disorder may also be
an important contributor to the role of cognition
in general daily function above that of symptom
status (e.g., current versus non-symptomatic,
euthymic, depressed, manic). Further research into
the longitudinal impact of various cognitive deficits
on functioning is warranted.
Furthermore, the effect of type of functional
measures whether it is clinician-rated, self-report,
performance based and real-world functional
based measures needs further consideration.
Although no specific data for functional assess-
 Cognitive and functional dysfunction in bipolar disorder
ments are available, a potential bias can be
assumed since clinician-based measures often have
large inter-rater variability (47) self-report measure
can be influenced by self-rating response bias (48)
while performance and real-world functional mea-
sures may provide only a limited range of function
(16). A recent meta-analysis, that showed that real-
world functional measures and performance-based
measures had stronger associations with cognitive
ability than clinician-rated and self-report mea-
sures (23), supports the use of such real-world and
performance-based measures. Similarly, in our
review we found that real-world functional mea-
sures of occupation status showed correlations
with cognitive function whereas clinician-rated
measures, e.g., GAF did not (16). However, better
research comparing the sensitivity of the different
types of functional measures in relation to a possi-
ble association with cognitive function is required
in patients with BD. Additionally, the relationship
between cognition and general function may be
influenced by a variety of clinical factors (15),
although our review suggests that cognitive mea-
sures may be a better predictor of future function
as compared to clinical severity measures (20, 36).
The heterogeneity of results may at least in part be
explained by treatment effects, such as lithium
treatment, and developmental trajectories in BD.
As recently shown, high-risk offspring of at least
one parent with BD had a higher risk of develop-
ing psychotic disorder if the parent was non-
responsive to lithium treatment (51). This indicates
that the developmental trajectory may exert a
strong effect on long-term outcomes and disease
development. Moreover, it has been shown that
chronic lithium administration increases total gray
matter volume in the human brain of patients with
manic-depressive illness, suggesting a neurotrophic
effect. As a possible conclusion, it has been sug-
gested that optimal long-term treatment using
agents with neurotrophic/neuroprotective effects
may enhance the long-term outcome of severe and
recurrent mood disorder (52).
Conclusions
Despite some inconsistencies, the overall literature
on the relationship between cognitive function and
general function in BD suggests both cross-
sectional and longitudinal associations in symp-
tomatic and euthymic patients with BD. The review
has not identified major differences between symp-
tomatic and euthymic patients in the relationship
between cognitive function and general function,
which could be interpreted that this relationship is
a trait marker of bipolar disorder rather than a
state marker. The successful prediction of func-
tional outcomes by cognitive measures seems to
depend on the use of general versus domain specific
measures of general function (e.g., occupational
status, social function). No specific cognitive
domains have been consistently associated with
general and domain-specific function in BD. The
suggestion that cognitive function in general may
be useful as a prognostic clinical marker of future
functional outcome is an exciting prospect, but one
that requires further exploration in large studies
with well-differentiated clinical samples using com-
prehensive functional scales assessing multiple
domains of function in patients with BD.
Acknowledgements
Funding for this project was provided by a NHMRC Program
Grant (GSM).
Disclosures
BTB has received research funding from AstraZeneca; and
consultant and speaker honoraria from Lundbeck, Pfizer, and
AstraZeneca. GSM has received research funding from Astra-
Zeneca, Eli Lilly & Co., Organon, Pfizer, Servier, and Wyeth;
is a speaker for AstraZeneca, Eli Lilly & Co., Janssen-Cilag,
Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and is a con-
sultant for AstraZeneca, Eli Lilly & Co., Janssen-Cilag, Lund-
beck, and Servier.
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