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Bipolar Disorders. 2022;24:115–136.
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115wileyonlinelibrary.com/journal/bdi
DOI : 10.1111/bdi.13175
REVIEW
Cognition in older adults with bipolar disorder: An ISBD
task force systematic review and meta- analysis based on a
comprehensive neuropsychological assessment
Laura Montejo1 | Carla Torrent1 | Esther Jiménez1 | Anabel Martínez- Arán1 |
Hilary P. Blumberg2 | Katherine E. Burdick3 | Peijun Chen4 | Annemieke Dols5 |
Lisa T. Eyler6,7 | Brent P. Forester8,9 | Jennifer R. Gatchel8,9 | Ariel Gildengers10 |
Lars V. Kessing11 | Kamilla W. Miskowiak11,12 | Andrew T. Olagunju13 |
Regan E. Patrick8,9 | Sigfried Schouws5 | Joaquim Radua14,15,16,17 |
Caterina del M. Bonnín1 | Eduard Vieta1 | International Society for Bipolar Disorders
(ISBD) Older Adults with Bipolar Disorder (OABD) Task Force
1Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic of Barcelona, IDIBAPS, CIBERSAM, University of Barcelona, Barcelona,
Catalonia, Spain
2Mood Disorders Research Program, Yale School of Medicine, New Haven, Connecticut, USA
3Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
4Section of Geriatric Psychiatry, Department of Psychiatry & VISN10 Geriatric Research, Education and Clinical Center, VA Northeast Ohio Healthcare System
Cleveland VA Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
5GGZ inGeest, Department of Psychiatry, Amsterdam UMC, location VU Medical Center, Amsterdam Neuroscience, Amsterdam Public Health Research
Institute, Amsterdam, the Netherlands
6Depar tment of Psychiatr y, Universit y of California, San Diego, California, USA
7Deser t- Pacific Mental Illness Research, Education and Clinical Center, VA San Diego Healthcare System, San Diego, C alifornia, USA
8Division of Geriatric Psychiatry, McLean Hospital, Belmont, MA, USA
9Harvard Medical School, Boston, MA, USA
10Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
11Copenhagen Affective Disorder research Center (CADIC), Psychiatric Center Copenhagen, Copenhagen, Denmark
12Department of Psychology, University of Copenhagen, Copenhagen, Denmark
13Department of Psychiatry and Behavioral Neurosciences, McMaster University/St Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada
14Imaging of Mood- and Anxiety- Related Disorders (IMARD) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
15CIBERSAM, Madrid, Spain
16Early Psychosis: Interventions and Clinical- detection (EPIC) L ab, Institute of Psychiatry, Psycholog y and Neuroscience, King's College London, London, UK
17Depar tment of Clinical Neuroscience, Stockholm Health Care Services, Stockholm County Council, Karolinska Institutet, Stockholm, Sweden
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Correspondence
Joaquim Radua, Imaging of Mood and
Anxiety- Related Disorders (IMARD)
Group, Institut d'Investigacions
Biomèdiques August Pi i Sunyer (IDIBAPS),
Barcelona, Spain.
Email: radua@clinic.cat
Abstract
Objectives: We aim to characterize the cognitive performance in euthymic older
adults with bipolar disorder (OABD) through a comprehensive neuropsychological as-
sessment to obtain a detailed neuropsychological profile.
Methods: We conducted a systematic search in MEDLINE/Pubmed, Cochrane, and
PsycInfo databases. Original studies assessing cognitive function in OABD (age
116
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MO NTEJO E T al.
1 | INTRODUCTION
Older age bipolar disorder (OABD), defined as adults aged 50 and
over, represent 25% of the bipolar disorder (BD) population1 and this
figure is expected to increase to over 50% in the next two decades2
due to increased life expectancy and to changing population demo-
graphics (i.e., increasing proportion of older adults). OABD presents
different clinical, cognitive, and psychosocial features with respect
to young and middle- aged (50 years of age or below) patients.3,4
For that reason, several authors have claimed to consider this sub-
group of patients as a special subtype of the population requiring
specific research efforts. Therefore, international efforts and task
forces focused on this topic are urgently needed to achieve this
objective.5,6 Cognitive impairment is well- documented in younger
and middle- aged euthymic adults with BD, with the greatest impair-
ment reported in the domains of processing speed, attention, verbal
memory, and executive functions.7– 9 Nevertheless, despite cogni-
tive dysfunction being widely considered to be a core feature of BD,
there is a lack of specific knowledge about cognitive performance
in OABD. Cognitive dysfunction is prevalent in more than half of
individuals with OABD, as compared with healthy controls (HC).10
A meta- analysis11 conducted in OABD revealed poor performance
in episodic memory, attention, information processing speed, verbal
fluency, and some domains of the executive functions as compared
with HC. In addition, psychosocial functioning is also affected in
OABD,12 and the negative impact of cognitive impairment on daily-
life activities is also noteworthy.13– 1 5 These functional implications
of cognitive difficulties highlight the importance of updating our
knowledge on the pattern and severity of cognitive impairments in
OABD.
The study of cognition in OABD as a function of normal aging
allows us to understand the evolution of cognitive performance
throughout the life span since older ages are included. Currently, it
is not entirely clear whether cognitive function declines faster with
age in BD relative to the cognitive decline seen in healthy aging.16
Although there are not strong conclusions about the progression of
cognitive performance in late- life stages, a cross- sectional analysis
comparing early and late stages17 of the dise ase did not find evide nce
of cognitive deterioration in late- life BD compared with a recent-
onset group. On the other hand, more than 10 long- term population-
based studies provide evidence for increased rates of dementia— the
end stage of cognitive progression— over decades in patients with
BD compared with healthy peers1 8– 22 and other psychiatric popu-
lations.23 The large cognitive heterogeneity usually observed in BD
could be contributing to these mixed findings. In addition, patients
with dementia or prodromal mild cognitive impairment (MCI) are
generally excluded from cross- sectional neuropsychological studies.
For a deeper understanding of cognitive performance throughout
the lifespan in BD and its progression, it is necessary to include sam-
ples from an older population as well as longitudinal studies.
≥50 years ) conta ining, at a minimum, the d omains of attention/process ing speed,
memory, and executive functions were included. A random- effects meta- analysis was
conducted to summarize differences between patients and matched controls in each
cognitive domain. We also conducted meta- regressions to estimate the impact of
clinical and socio- demographic variables on these differences.
Results: Eight articles, providing data for 328 euthymic OABD patients and
302 healthy controls, were included in the meta- analysis. OABD showed worse
performance in comparison with healthy controls, with large significant effect sizes
(Hedge's gfrom−0.77 to−0.89; p < 0.001) in verbal learning and verbal and visual
delayed memory. They also displayed statistically significant deficits, with moderate
effect size, in processing speed, working memory, immediate memory, cognitive flex-
ibility, verbal fluency, psychomotor function, executive functions, attention, inhibi-
tion, and recognition (Hedge's gfrom−0.52to−0.76;p < 0.001), but not in language
and visuoconstruction domains. None of the examined variables were associated with
these deficits.
Conclusions: Cognitive dysfunction is present in OABD, with important deficits in al-
most all cognitive domains, especially in the memory domain. Our results highlight the
importance of including a routine complete neuropsychological assessment in OABD
and also considering therapeutic strategies in OABD.
KEYWORDS
bipolar disorder, cognition, elderly, meta- analysis, neuropsychology, older adults, systematic
review
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MONTE JO ET al.
Despite the clinical importance of cognitive performance in
OABD, clinical studies with detailed data on neurocognition are lack-
ing in OABD2 and remain inconclusive for different reasons. The stud-
ies conducted to date are based on small samples; longitudinal studies
have a short timeframe and, finally, the factors that could have an im-
pact on cognition are highly variable. Moreover, some results come
from inadequate neuropsychological assessments, which sometimes
are limited to assessment using screening tools. The assessment of
neuropsychological performance in OABD using a comprehensive
testing battery will provides a better understanding regarding cogni-
tive impairment progression and a unique opportunity to develop spe-
cific interventions for this population. This cognitive profile can also be
clinically helpful in differentiating between different underlying etiol-
ogies including neurodegenerative disorders. Despite there is a previ-
ous meta- analysis of cognitive performance in OABD,11 we consider
that there is a need for updating data. Different from that, our meta-
analysis considers as the main inclusion criteria studies that include an
extensive neuropsychological evaluation leading to a detailed cogni-
tive profile. Following the guidance of good clinical neuropsychologi-
cal practice,24– 26 detailed knowledge of the cognitive profile is needed
in order to make inferences about cognitive function. In this sense, we
decided to use a restrictive and demanding methodology to guaran-
tee a comprehensive interpretation of cognitive profile. Performance
in any single cognitive domain should not be interpreted in isolation,
since cognitive functions work in an interrelated way.
We expect that the group of OABD will exhibit cognitive deficits in
comparison to HC group across all the cognitive domains explored. The
aims of the present study were to perform a systematic review and a meta-
analysis to characterize the cognitive performance in euthymic OABD
sample compared with healthy controls by including only those studies
that have utilized a comprehensive neuropsychological assessment in
order to obtain a complete neuropsychological profile of this population.
2 | METHODS
This systematic review and meta- analysis were conducted according
to the PRISMA statement (Preferred Reporting Items of Systematic
Reviews and Meta- Analyses).27 The protocol was registered in
PROSPERO (no of register: CRD42020159293). Two researchers
(LM and CMB) carried out independently the selection of articles
(title, abstract and full text), the data extraction, and the method-
ological quality assessment. Other researchers (CT, EJ) were con-
sulted whenever a consensus could not be reached.
2.1 | Search strategy
We searched for articles published in Medline/PubMed, Cochrane,
and PsycInfo electronic databases up until July 2019. The strategy
search was as follows: bipolar disorder AND (elder* OR old OR "late
life" OR "older age") AND (cognit* OR neurocognit*). We used the
same strategy in all electronic databases.
2.2 | Eligibility criteria and study selection
Records were selected according to the following inclusion criteria:
(1)bipolardisordertypeIand/orIIaged≥50;(2)neuropsychological
assessment must include at least three cognitive domains: executive
function, memor y, attention, and/or processing speed; (3) samples
comprising euthymic patients at the time of neuropsychological as-
sessment; (4) results compared with a healthy control group, that
is, individuals with no psychiatric and neurological disorder; (5) lon-
gitudinal or cross- sectional articles; (6) articles written in English
or Spanish. The exclusion criteria were: (1) use of screening tools
or screening batteries as the only neuropsychological assessment;
(2) neuropsychological batteries providing only a total global score
of cognitive performance without detailing different cognitive do-
mains; (3) studies based on heterogeneous samples including sam-
ples with other diagnostic groups than BD and without providing
data separately by groups; (4) case reports, letters to the editor, re-
views, opinions or commentaries, and short communications.
Articles selected were required to present separate scores for each
domain. With regards specifically to the inclusion criteria for atten-
tion and/or processing speed cognitive domains, we established that
neuropsychological assessment ought to include at least one of these
two functions, given that both domains can overlap and sometimes
the same assessment tool could be classified as one or the other, de-
pending on the authors’ criteria (e.g., Trail Making Test- part A (TMT- A).
2.3 | Data extraction
For each study, we transferred to a data base the sample sizes,
means, and standard deviations of the demographic, clinical and
neuropsychological variables detailed below for the correspond-
ing two- sample tests. Where studies included different diagnostic
groups, we only collected data from the BD group and the corre-
sponding HC group. Regarding neuropsychological variables, raw
or standardized scores, depending on which were reported in the
manuscripts, were transferred to their corresponding cognitive do-
main. When domain attribution discrepancy was detected (i.e the
same test was classified by different authors in different cognitive
domains), we took into consideration the criteria used by the major-
ity of authors. This was the case for the TMT- A, verbal fluency, for-
ward and backward digit span from Wechsler Adult Intelligence Scale
(WAIS)28 and digit span from Repeatable Battery for the Assessment of
Neuropsychological Status (RBANS).29
2.4 | Neuropsychological variables
We first collected data from the main cognitive domains proposed in
our inclusion criteria: attention, processing speed, memory, and execu-
tive functions. To obtain more information about the cognitive profile
in OABD, additional cognitive domains were included if they were as-
sessed in any study; thus, working memory, psychomotor function,
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MO NTEJO E T al.
visuoconstruction, and language were also included. Moreover, al-
though the overall score of the domain was maintained, two cognitive
domains (memory and executive functions) were also divided into sub-
domains to obtain more detailed information: memory was split into
learning, immediate recall, delayed recall, and recognition; executive
functions were separated in inhibition, verbal fluency, and cognitive
flexibility. The test included in memory and executive functions subdo-
mains are displayed in Data S1. All cognitive test were transferred to the
appropriate domain; that is, we decided to include all tests, regardless
of whether they were used by the other studies or not, since the objec-
tive was to achieve a comprehensive cognitive profile across cognitive
domains. However, it should be noted that, for delayed recall, visual and
verbal memory domains were merged due to the scarcity of data from
the former, where only two studies assessed visual memory.30,31
Finally, the cognitive domains analyzed comprised the following tests:
1. Attention: Continuous Performance Test (CPT) and their com-
ponents (hits, latency, false alarms),32 forward digit span of
Wechsler Adult Intelligence Scale,28 digit span of Repeatable
Battery for the Assessment of Neuropsychological Status
(RBANS),29 and forward Corsi block from WMS- III33
2. Processing speed: simple reaction time (SRT),34 letter compari-
son,35 Trail Making Test- Part A (TMT- A),36 digit symbol from
WAIS- III,37 grooved pegboard.38
3. Psychomotor function: simple (dominant and non- dominant)
and complex tapping, the Amsterdam Short- Term Memory Test
(ASTM 1– 10 ) , 39 finger tapping.
4. Visuoconstruction: clock drawing,40,41 modified version of ROCF—
copy,42,43 simple drawing,44 block design of WAIS- III,37 figure cop-
ying of Amsterdam Dementia Screening test (ADS6),45 TMTB/A.
5. Working memory: Letter Number Sequence (LNS) of WAIS-
III,37 backward Corsi block from WMS- III,33 digit backward of
WAIS- R,46 reading span47
6. Memory: Cued Recall 48 items (CR48)48 (delayed recall), 10 item
word of Consortium to Establish and Registry for Alzheimer's Disease
(CERAD)49 (third recall), 10 word of Auditory Verbal Learning Test
(AVLT)50(learning, retention, recognition), California Verbal Learning
Test (CVLT)51 (delayed recall), logic memory of Wechsler Memory
Scale (WMS- III)33 (delayed recall), Rey- Osterrieth Complex Figure
(ROCF) (delayed recall), memory battery of Signoret52 (immediate
recall, delayed recall, free delayed recall, serial learning, recognition,
immediate logical memory, delayed logical memory).
7. Executive functions: Stroop Color Word Test (SCWT),53 – 55
number letter,56 consonant updating task,57 phonemic fluency
through COWAT,58,59 semantic fluency,59– 61 Tr ail Ma king Test
Part B (TMT- B),36 Wisconsin Card Sorting Test (WCST)62,63 (cat-
egories, total errors, perseverative errors, errors), Color Trail
Making Test (CTMT),64 mazes (1– 4) of Wechsler Intelligence Scale
for Children (WISC),65 rule shift card of Behavioral Assessment of
Dysexecutive Syndrome (BADS),66 Executive interview (EXIT).67
8. Language: Boston Naming Test (BNT),68 Speed and Capacity of
Language Processing Test (SCOLP)69 (speed of comprehension,
spot- the- word).
9. Overall Cognitive Status: MMSE and IQ: MiniMental State
Examination (MMSE)70 and Intelligence Quotient (IQ) with WAIS37,46
vocabulary subtest and with Dutch Reading Test for Adults.61
2.5 | Methodological quality assessment
The Newcastle- Ottawa Scale (NOS)71 for observational stud-
ies (case- control form) was selected to assess the methodological
quality of the included studies. Six out of nine articles presented
good methodological quality (with a total score of 7 or more on the
NOS). Furthermore, the inter- rater reliability was high (95.06%), and
Cohen's kappa coefficient, calculated to determine the agreement
between raters for each item, was also very high (k = 0.879).
2.6 | Statistical analysis
The meta- analyses procedure was performed using The Metafor72
and MetaNSUE73 packages for R version 2.4.73 Means and stand-
ard deviations of cognitive scores were included, as well as com-
posite scores of cognitive domains, that is, a global score of the
cognitive domain combining all test scores, if they were provided
by the sources. We first performed a meta- analysis of the main
cognitive domains (attention, processing speed, psychomotor
function, visuoconstruction, memory, working memory, executive
functions, and language), and secondly, a meta- analysis of the sub-
domains of executive functions and memory. Only subdomains
assessed by a minimum of three studies were considered. We
calculated the effect size (Hedges’ g) of the comparison of each
cognitive domain between patients and controls using a random-
effects model, which assumes potential heterogeneity between
studies. Significance was established in p < 0.05 for all measures.
Moreover, to analyze the effects of possible moderators on the
effect sizes, such as years of education, intelligence quotient (IQ),
duration illness, psychosis history, and the number of hospitaliza-
tions, meta- regression was carried out. Heterogeneity was exam-
ined using the I2 statistic. Potential publication bias was assessed
using the Egger's test as well as a visual inspection of the funnel
plots. We used the Bonferroni method to correct for multiple test-
ing: for the 15 primary meta- analyses of cognitive domains and
subdomains, we applied threshold p- value of 0.003 and for the
54 meta- regressions a p- value <0.001 was required.
3 | RESULTS
3.1 | Search and systematic review
The search strategy yielded a total of 724 articles. After duplicates were
removed, the title/abstract of 599 articles was screened, of which 516
were excluded, and 83 full- text articles were reviewed. Of these, 74
were excluded for different reasons (see flow- chart in Figure 1). Of note,
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MONTE JO ET al.
after reviewing the study samples, despite meeting the inclusion crite-
ria, eight studies were excluded because they shared study samples, of
those four were longitudinal14,74– 76 and three77– 79 were cross- sectional
sharing the same sample; in these cases, the study with the largest sam-
ple size was selected. The study of Besga et al.80 assessed all cognitive
domains but did not provide the scores of the neuropsychological test
(only the significant effect (p- value)). For that reason, it could not be in-
cluded in the meta- analysis, but was included in the systematic review.
Finally, a total of nine reports were included in the systematic re-
view,30,31,80– 86 of which a total of eight articles were included in the meta-
analysis.30,31,81– 86 However, for the meta- analytical procedure, one of the
studies85 was each divided into two separate samples because it presented
data from two independent elderly groups: one focused in late- onset and
the other in early- onset of the disease. As a result, the meta- analysis fi-
nally included a total of nine different samples. Detailed information of the
tests and domains according to each author is displayed in Table 1 where
neuropsychological assessment is presented just as classified by authors.
3.2 | Description and primary results of the
included studies in the systematic review
A total of nine cross- sectional studies met the inclusion criteria
for the systematic review. In all studies, the BD group had poorer
FIGURE 1 PRISMAflowchartofstudy
selection for systematic review and meta-
analysis
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MO NTEJO E T al.
TAB LE 1 Characteristicsofthestudiesincludedinthesystematicreviewandmeta-analysis
First author and
year Sample size BD/HC Age Mean (SD). BD/HC Study design Aim of the study Neuropsychological assessment battery
Mood scales.
Mean (SD) BD/HC Main results
Qualit y
assessment
(NOS scale)
1 Besga et al.,
2015a
32/26
Other groups: AD:
n = 37
68.88 (8.61)/72.81 (8.70) Cross- sectional To assess the significance of clinical
variables, neuropsychological
performance and blood plasma
biomarkers in the diagnosis of
AD and LOBD.
Memory: WMS- III: auditory memory,
visual memory, visual working
memory, immediate memory, delayed
memory
Executive Functions: WCST, SCWT
(interference), TMT- B, FAS.
Attention: TMT- A, SCW T (color- word)
and digit forward (WAIS- III)
N/V LOBD scores lower than HC in all cognitive
measures assesses (executive function,
attention and memory)
Only significant differences in memory were found
between LOBD and AD
3/9
2 Canuto et al.,
2010
22/62
Other group: EOD:
n = 36
68.5 (5.47)/71.06 (7.22) Cross- sectional To explore cognitive and personality
changes in OABD and EOD comparing
with controls
Memory:CR−48;10itemwordlist
(CERAD).
Executive Functions:
SCWTb; number- letterb; consonant
updating taskb; phonemic and
semantic verbal fluency (animals and
letter P).
Processing speed: SRTb; letter comparison
Working memory: LNS (WAIS- III);
Corsi Block (WMS- III) (forward and
backward)
N/V The group of OABD patients differs to controls
in processing speed, working memory and
episodic memory. EOD had all cognitive
measures preserved. The cognitive dysfunction
was not associated with personality traits.
7/9
3 Delaloye et al.,
2009
22/22 68.45(5.47)/68.91(6.77) Cross- sectional To determine the pattern and the
magnitude of cognitive deficits
in OABD
Memory:
CR−4 8.
Executive Functions:
SCWTb; CTMT; Phonemic and semantic
verbal fluency (animals and letter P);
consonant updating.
Processing speed: SRTb; letter comparison
Working memory: LNS; reading span
testb; Corsi Block (WMS- III) (forward
and backward)
GDS: 1.59 (1.56)/1.55 (1.57)
YMRS: 1.09 (1.41)/0.18(0.50)
Lower per formance in processing speed, working
memory, verbal fluency and episodic memory
in BD patients compared with controls
7/9
4Gildengers et al.,
2007
20/4 0 73 .6 (8. 4)/69.9
(7.2 )
Cross- sectional To analyze the relationship between
activities daily living and cognition
in OABD.
Memory: logical memory (WMS- III);
ROCF- memor y; CVLT (delayed free
recall).
Executive Functions: EXIT; TMT- B;
SCWT; WCST (errors).
Processing speed: Digit symbol (WAIS
III);grooved pegboard, TMT- A
Visuospatial: block design (WAIS- III);
clock; ROCFc- copy, simple drawings.
Language: spot- the- word (SCOLP),
phonemic and semantic fluency (F- A- S
from COWAT and animals); BNT
HDRS: 4.8 (3.3)/2.4 (2)
YMRS: 1 (1.3)
BD group significantly more impaired in processing
speed and executive function, followed by
visuospatial and visual memory. Processing
speed and executive function are the cognitive
domains more related with poor functioning in
IADL. Vascular and heart measures (CIRS- G)
were not associated with any cognitive domain
6/9
5 Martino et al.,
2008
20/20 66.6(8.2)/70.5(9.1) Cross- sectional To compare the cognitive and motor
functioning between elderly BD and
HC and determine the correlation with
psychosocial functioning
Memory: Memory Battery of Signoret.
Executive Functions: WCST.
Attention: CPT
Psychomotor speed: Simple and Complex
Tapping.
Global: MMSE and IQ with WAIS- III
vocabulary subtest
HDRS: 2.5 (3)/2.5 (2.2).
YMRS: 1.7(2.1)/0.7(0.9)
Patients with BD had lower performance in verbal
memory, executive function and psychomotor
speed.
Extrapyramidal symptoms are associated with
more severe cognitive impairment
7/9
6 Martino et al.,
2018
66/30 63.65 (8.03)/65.13
(10.14)
Cross- sectional To estimate the prevalence of cognitive
deficit s in a sample of OABD and its
relation to functional outcome.
Memory: Memory Battery of Signoret
Executive Functions: WCST, TMT- B,
digit backward from WAIS- R and
phonological fluency (COWAT)
Attention: Forward Digit Span of WAIS- R,
TM T- A
Language: BNT
Estimated IQ: WAIS- R vocabulary subtest
HDRS: 1.64 (2.52)/2.17 (2.05)
YMRS: 1.06 (1.68)/0.57 (0.82)
33.3% patients without clinically significant
cognitive deficits, 36,4% with selective
cognitive deficits and 30,3% with global
deficit s. Domains as memor y, attention and
executive functions were significantly more
affected than controls. Better psychosocial
functioning outcome in group with cognitive
deficits
5/9
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MONTE JO ET al.
TAB LE 1 Characteristicsofthestudiesincludedinthesystematicreviewandmeta-analysis
First author and
year Sample size BD/HC Age Mean (SD). BD/HC Study design Aim of the study Neuropsychological assessment battery
Mood scales.
Mean (SD) BD/HC Main results
Qualit y
assessment
(NOS scale)
1 Besga et al.,
2015a
32/26
Other groups: AD:
n = 37
68.88 (8.61)/72.81 (8.70) Cross- sectional To assess the significance of clinical
variables, neuropsychological
performance and blood plasma
biomarkers in the diagnosis of
AD and LOBD.
Memory: WMS- III: auditory memory,
visual memory, visual working
memory, immediate memory, delayed
memory
Executive Functions: WCST, SCWT
(interference), TMT- B, FAS.
Attention: TMT- A, SCW T (color- word)
and digit forward (WAIS- III)
N/V LOBD scores lower than HC in all cognitive
measures assesses (executive function,
attention and memory)
Only significant differences in memory were found
between LOBD and AD
3/9
2 Canuto et al.,
2010
22/62
Other group: EOD:
n = 36
68.5 (5.47)/71.06 (7.22) Cross- sectional To explore cognitive and personality
changes in OABD and EOD comparing
with controls
Memory:CR−48;10itemwordlist
(CERAD).
Executive Functions:
SCWTb; number- letterb; consonant
updating taskb; phonemic and
semantic verbal fluency (animals and
letter P).
Processing speed: SRTb; letter comparison
Working memory: LNS (WAIS- III);
Corsi Block (WMS- III) (forward and
backward)
N/V The group of OABD patients differs to controls
in processing speed, working memory and
episodic memory. EOD had all cognitive
measures preserved. The cognitive dysfunction
was not associated with personality traits.
7/9
3 Delaloye et al.,
2009
22/22 68.45(5.47)/68.91(6.77) Cross- sectional To determine the pattern and the
magnitude of cognitive deficits
in OABD
Memory:
CR−4 8.
Executive Functions:
SCWTb; CTMT; Phonemic and semantic
verbal fluency (animals and letter P);
consonant updating.
Processing speed: SRTb; letter comparison
Working memory: LNS; reading span
testb; Corsi Block (WMS- III) (forward
and backward)
GDS: 1.59 (1.56)/1.55 (1.57)
YMRS: 1.09 (1.41)/0.18(0.50)
Lower per formance in processing speed, working
memory, verbal fluency and episodic memory
in BD patients compared with controls
7/9
4Gildengers et al.,
2007
20/4 0 73 .6 (8. 4)/69.9
(7.2 )
Cross- sectional To analyze the relationship between
activities daily living and cognition
in OABD.
Memory: logical memory (WMS- III);
ROCF- memor y; CVLT (delayed free
recall).
Executive Functions: EXIT; TMT- B;
SCWT; WCST (errors).
Processing speed: Digit symbol (WAIS
III);grooved pegboard, TMT- A
Visuospatial: block design (WAIS- III);
clock; ROCFc- copy, simple drawings.
Language: spot- the- word (SCOLP),
phonemic and semantic fluency (F- A- S
from COWAT and animals); BNT
HDRS: 4.8 (3.3)/2.4 (2)
YMRS: 1 (1.3)
BD group significantly more impaired in processing
speed and executive function, followed by
visuospatial and visual memory. Processing
speed and executive function are the cognitive
domains more related with poor functioning in
IADL. Vascular and heart measures (CIRS- G)
were not associated with any cognitive domain
6/9
5 Martino et al.,
2008
20/20 66.6(8.2)/70.5(9.1) Cross- sectional To compare the cognitive and motor
functioning between elderly BD and
HC and determine the correlation with
psychosocial functioning
Memory: Memory Battery of Signoret.
Executive Functions: WCST.
Attention: CPT
Psychomotor speed: Simple and Complex
Tapping.
Global: MMSE and IQ with WAIS- III
vocabulary subtest
HDRS: 2.5 (3)/2.5 (2.2).
YMRS: 1.7(2.1)/0.7(0.9)
Patients with BD had lower performance in verbal
memory, executive function and psychomotor
speed.
Extrapyramidal symptoms are associated with
more severe cognitive impairment
7/9
6 Martino et al.,
2018
66/30 63.65 (8.03)/65.13
(10.14)
Cross- sectional To estimate the prevalence of cognitive
deficit s in a sample of OABD and its
relation to functional outcome.
Memory: Memory Battery of Signoret
Executive Functions: WCST, TMT- B,
digit backward from WAIS- R and
phonological fluency (COWAT)
Attention: Forward Digit Span of WAIS- R,
TM T- A
Language: BNT
Estimated IQ: WAIS- R vocabulary subtest
HDRS: 1.64 (2.52)/2.17 (2.05)
YMRS: 1.06 (1.68)/0.57 (0.82)
33.3% patients without clinically significant
cognitive deficits, 36,4% with selective
cognitive deficits and 30,3% with global
deficit s. Domains as memor y, attention and
executive functions were significantly more
affected than controls. Better psychosocial
functioning outcome in group with cognitive
deficits
5/9
122
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MO NTEJO E T al.
performance in multiple cognitive areas compared with HC. As a
qualitative summary, regarding the main cognitive domains in the
scope of our inclusion criteria, seven studies reported poorer per-
formance in some measures of executive function as compared
with the control group,30,31,80,83,84,87,88 but one study82 only found
deficits in the verbal fluency component. Also, OABD had lower
performance than HC in verbal memory in all the included stud-
ies, with the exception of the study of Gildengers et al.,31 which
First author and
year Sample size BD/HC Age Mean (SD). BD/HC Study design Aim of the study Neuropsychological assessment battery
Mood scales.
Mean (SD) BD/HC Main results
Qualit y
assessment
(NOS scale)
7 Schouws et al.,
2009
119/78
EOBD: n =59
LOBD: n =60
EOBD: 68.41 (6.2) LOBD:
72.32 (7.5)
HC: 71.86 (8.0)
Cross- sectional To compare clinical and cognitive
characteristics between early onset BD,
late onset BD and comparison group
Memory: The 10 Words Test (AVLT)
Attention and Executive Functioning:
Digit
Span (WAIS- III); SCWTc; TMT- B; COWAT,
GIT (animal and occupational naming);
Mazes (1– 4) (WISC); Rule Shift Cards
(BADS)
Psychomotor Performance and Mental
Effor t: TMT- A; ASTM.
Visuo Constructional Ability: figure-
copying (ADS6) and Clock drawing.
Global: Premorbid IQ (NART) and
MMSE
CES- D: EOBD: 10.68 (6.6).
LOBD: 8.85 (7.8) HC: 8.33
(5.5)
YMRS: EOBD: 1.32 (1.6)
LOBD: 0.87 (1.6) HC: 0.6
(0.43)
Both groups (early and late onset) differ from
comparison group in all cognitive domains
except of visuoconstruction. Late onset is
more impaired than early onset.
7/9
8 Strejilevich and
Martino, 2013
24/20
Other group:
Y- B D: n =24
67. 46 ( 7.51)/ 70. 50 (7. 37) Cross- sectional To understand the evolution of cognitive
deficits in BD across life span comparing
the cognitive profile of older patients
with BD to their healthy counterparts
and to young euthymic patients with BD
Memory: Memory Battery of Signoret
Executive functions: WCST; phonological
fluency; Backward Digit Span
(WAIS- R)
Attention: Forward Digit Span (WAIS- R)
Language: BNT
Global: premorbid IQ vocabulary subtest
(WAIS- R)
HDRS: 1.63 (2.44)/2.23 (0.50)
YMRS: 1.08 (1.61)/0.45 (0.51)
Differences bet ween OABD and healthy controls
where found in verbal memory and executive
function. Differences between OABD and
Y- BD were found exactly in the same tests as
in the control group
7/9
9 Vaccarino et al.,
2018
35/30 65.7 (10.3)/66.4 (10.4) Cross- sectional To examine the relation between allostatic
load and cognitive function in BD and
differences with HC
Memory: logical memory (WMS- III);
ROCFc- memory (delayed); CVLT
(delayed free recall), WCST (errors).
Executive Functions: EXIT; TMT- B;
SCWT; category fluency
Processing speed: TM T- A
Visuospatial: block design (WAIS- III);
clock; ROCFc- copy, simple drawings.
Language: spot- the- word and speed of
comprehension (SCOLP), phonemic
(F- A- S from COWAT)
Visuomotor ability: block design from
WAIS- III, ROCF- copy, simple drawings,
Trails B / Trails A.
Global: BNT, clock drawing, digit span
(RBANS), finger tapping, and grooved
pegboard
HDRS: 3.0 (2.9)/1.6 (2.2)
YMRS: 1.6 (2.4)/0.3 (0.8)
Older patients with BD were
more impaired in processing speed/
executive functioning, delayed memory, language,
and visuomotor
ability
8/9
Abbreviations: ADS6, Amsterdamse Dementie Screening; ASTM, The Amsterdam Short- Term Memory Test; AVLT, Auditory Verbal Learning Test;
BADS, Behavioral A ssessment of Dysexecutive Syndrome; BD, Bipolar Disorder; BNT, Boston Naming Test; CES- D, The Center for Epidemiological
Studies Depression Scale; CERAD, Consortium to Establish and Registry for Alzheimer's Disease; COWAT, Controlled Oral Word Association Test;
CR- 48, Cued Recall 48 items; CPT, Continuous Performance Test; CTMT, Color Trail Making Test; CVLT, California Verbal Learning test; HC,
Healthy Control; HDRS, Hamilton Depression Rating Scale; IADL, Instrumental activities of daily living; E- BD, Elderly Bipolar disorder; EO,
Early onset; EOD, early onset depression; EXIT, Executive interview; GIT, Groningen Intelligence Test; GDS, Geriatric Depression Scale; LNS,
Letter Number Sequencing; LOBD, Late Onset Bipolar Disorder; MMSE, Mini- Mental State Examination; NART, New Adult Reading Test; NOS,
Newcastle Ottawa Scale; N/V, not valued; ROCF, Rey Osterrieth Copy figure; SCOLP, Speed and Capacity of Language Processing Test; SRT,
simple reaction time; SCWT, Stroop Color Word Test; SQZ, Schizophrenia; TMT- A , Trail Making Test part A; TMT- B, Trail Making Test part B; Y- BD,
Young Bipolar Disorder; YMRS, Young Mania Rating Scale; WAIS- R, Wechsler Adults Intelligence Scale- Revised; WAIS- III, Wechsler Adults
Intelligence Scale 3rd edition; WCST, Wisconsin Card Sor ting Test, WISC, Wechsler Intelligence Scale for Children; WMS, Wechsler Memor y Scale.
a This report only was included in the systematic review.
b Computerized version.
c Modified version.
TAB LE 1 (Continued)
|
123
MONTE JO ET al.
did not find impairment in verbal memory, but visual memory
was significantly impaired. Five studies detected poorer perfor-
mance of the OABD group in processing speed,31,81– 83,85 and,
finally, attention ability was impaired in the OABD group in two
studies.80,85 Martino et al.84 explored the heterogeneity of neu-
ropsychological performance within OABD and they identified
three subgroups based on the number of cognitive areas affected
(intact, selective deficits, and globally impaired). The subgroups
First author and
year Sample size BD/HC Age Mean (SD). BD/HC Study design Aim of the study Neuropsychological assessment battery
Mood scales.
Mean (SD) BD/HC Main results
Qualit y
assessment
(NOS scale)
7 Schouws et al.,
2009
119/78
EOBD: n =59
LOBD: n =60
EOBD: 68.41 (6.2) LOBD:
72.32 (7.5)
HC: 71.86 (8.0)
Cross- sectional To compare clinical and cognitive
characteristics between early onset BD,
late onset BD and comparison group
Memory: The 10 Words Test (AVLT)
Attention and Executive Functioning:
Digit
Span (WAIS- III); SCWTc; TMT- B; COWAT,
GIT (animal and occupational naming);
Mazes (1– 4) (WISC); Rule Shift Cards
(BADS)
Psychomotor Performance and Mental
Effor t: TMT- A; ASTM.
Visuo Constructional Ability: figure-
copying (ADS6) and Clock drawing.
Global: Premorbid IQ (NART) and
MMSE
CES- D: EOBD: 10.68 (6.6).
LOBD: 8.85 (7.8) HC: 8.33
(5.5)
YMRS: EOBD: 1.32 (1.6)
LOBD: 0.87 (1.6) HC: 0.6
(0.43)
Both groups (early and late onset) differ from
comparison group in all cognitive domains
except of visuoconstruction. Late onset is
more impaired than early onset.
7/9
8 Strejilevich and
Martino, 2013
24/20
Other group:
Y- B D: n =24
67. 46 ( 7.51)/ 70. 50 (7. 37) Cross- sectional To understand the evolution of cognitive
deficits in BD across life span comparing
the cognitive profile of older patients
with BD to their healthy counterparts
and to young euthymic patients with BD
Memory: Memory Battery of Signoret
Executive functions: WCST; phonological
fluency; Backward Digit Span
(WAIS- R)
Attention: Forward Digit Span (WAIS- R)
Language: BNT
Global: premorbid IQ vocabulary subtest
(WAIS- R)
HDRS: 1.63 (2.44)/2.23 (0.50)
YMRS: 1.08 (1.61)/0.45 (0.51)
Differences bet ween OABD and healthy controls
where found in verbal memory and executive
function. Differences between OABD and
Y- BD were found exactly in the same tests as
in the control group
7/9
9 Vaccarino et al.,
2018
35/30 65.7 (10.3)/66.4 (10.4) Cross- sectional To examine the relation between allostatic
load and cognitive function in BD and
differences with HC
Memory: logical memory (WMS- III);
ROCFc- memory (delayed); CVLT
(delayed free recall), WCST (errors).
Executive Functions: EXIT; TMT- B;
SCWT; category fluency
Processing speed: TM T- A
Visuospatial: block design (WAIS- III);
clock; ROCFc- copy, simple drawings.
Language: spot- the- word and speed of
comprehension (SCOLP), phonemic
(F- A- S from COWAT)
Visuomotor ability: block design from
WAIS- III, ROCF- copy, simple drawings,
Trails B / Trails A.
Global: BNT, clock drawing, digit span
(RBANS), finger tapping, and grooved
pegboard
HDRS: 3.0 (2.9)/1.6 (2.2)
YMRS: 1.6 (2.4)/0.3 (0.8)
Older patients with BD were
more impaired in processing speed/
executive functioning, delayed memory, language,
and visuomotor
ability
8/9
Abbreviations: ADS6, Amsterdamse Dementie Screening; ASTM, The Amsterdam Short- Term Memory Test; AVLT, Auditory Verbal Learning Test;
BADS, Behavioral A ssessment of Dysexecutive Syndrome; BD, Bipolar Disorder; BNT, Boston Naming Test; CES- D, The Center for Epidemiological
Studies Depression Scale; CERAD, Consortium to Establish and Registry for Alzheimer's Disease; COWAT, Controlled Oral Word Association Test;
CR- 48, Cued Recall 48 items; CPT, Continuous Performance Test; CTMT, Color Trail Making Test; CVLT, California Verbal Learning test; HC,
Healthy Control; HDRS, Hamilton Depression Rating Scale; IADL, Instrumental activities of daily living; E- BD, Elderly Bipolar disorder; EO,
Early onset; EOD, early onset depression; EXIT, Executive interview; GIT, Groningen Intelligence Test; GDS, Geriatric Depression Scale; LNS,
Letter Number Sequencing; LOBD, Late Onset Bipolar Disorder; MMSE, Mini- Mental State Examination; NART, New Adult Reading Test; NOS,
Newcastle Ottawa Scale; N/V, not valued; ROCF, Rey Osterrieth Copy figure; SCOLP, Speed and Capacity of Language Processing Test; SRT,
simple reaction time; SCWT, Stroop Color Word Test; SQZ, Schizophrenia; TMT- A , Trail Making Test part A; TMT- B, Trail Making Test part B; Y- BD,
Young Bipolar Disorder; YMRS, Young Mania Rating Scale; WAIS- R, Wechsler Adults Intelligence Scale- Revised; WAIS- III, Wechsler Adults
Intelligence Scale 3rd edition; WCST, Wisconsin Card Sor ting Test, WISC, Wechsler Intelligence Scale for Children; WMS, Wechsler Memor y Scale.
a This report only was included in the systematic review.
b Computerized version.
c Modified version.
TAB LE 1 (Continued)
124
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MO NTEJO E T al.
of selective and global deficits had lower psychosocial function-
ing. However, the group of global cognitive deficits had an illness
onset significantly higher compared with the cognitive intact
group. Alternatively, other studies investigated the association
between cognitive function and other variables. For instance,
in the study of Vaccarino et al.,30 allostatic load was associated
with delayed memory performance in the BD group. Gildengers
et al.31 found that processing speed and executive functions were
the two domains most related to daily living activities. Regarding
motor features, extrapyramidal symptoms were associated with
more severe cognitive impairment.83 Moreover, comparing cogni-
tive performance with other diagnoses distinct from BD in late life,
Besga et al.80 studied a group with Alzheimer's Disease (AD) with
late- onset bipolar disorder (LOBD) and found significantly poorer
performance in the memory domain of the AD group. Comparing
OABD group with young adults with BD, Strejilevich et al.86 did
not find significant differences in cognitive performance between
groups, suggesting no progression of cognitive deficits despite
OABD have a longer illness duration.
3.3 | Meta- analytic results
A total sample of 328 OABD patients and 302 HC were included
in the meta- analysis. The groups were overall well- matched for
age (mean range in BD samples = 63– 74 years, HC samples = 65–
73 years) and in education level (BD samples = 11– 16 years, HC
samples = 12– 15 years). The range of mean for IQ in the BD samples
was 103– 110 and of the HC samples was 103– 112. The mean age
at illness onset of our BD sample was 37.88 (15.25). For euthymia
criteria, all studies clearly specify that the samples comprised eu-
thymic patients at the time of neuropsychological assessment (mean
range HDRS: 1.56– 3; CES- D: 8.33– 10.68; YMRS: 0.3– 1.7), thus, we
concluded that all patients were euthymic at least at the assessment
time point.
The effect- sizes of the comparison between OABD and
matched controls, their confidence intervals and p- values, hetero-
geneity (I2), and the results of the Egger's test are given in Table 2.
The results provided by our meta- analysis indicate significantly
worse performance in the OABD group when compared with the
control group in almost all of the cognitive domains explored, as
well as in their subdomains, with moderate to large effect sizes
(from −0. 52to − 0.89). Specif ically, a large mag nitude of the ef-
fect sizes was found in two components of memor y: verbal learning
(Hedge's g =−0.89;p < 0.001) and visual and verbal delayed memory
(Hedge's g =−0.80 ;p < 0.001) followed by moderate effect size in
overall memory, including verbal and visual memory, as a primar y
cognitive domain (Hedge's g = −0.77;p < 0.001) and by immediate
memory (Hedge's g =−0.73;p < 0.001). Recognition achieved me-
dium effect size (Hedge's g =−0.53,p < 0.001). In the same way,
executive functions were also impaired in the OABD group with
medium effect size (Hedge's g =−0.67;p < 0.0 01) as well as com-
ponents of flexibility (Hedge's g =−0.72;p < 0.001), verbal fluency
(Hedge's g = −0.72;p < 0.001), and inhibition (Hedge's g =−0.52;
p < 0.001). Processing speed (Hedge's g =−0.76 ;p < 0.001), work-
ing memor y (Hedge's g =−0.74;p < 0.001), psychomotor function
(Hedge's g = −0 .67;p < 0.001), and attention (Hedge's g =−0.54;
p < 0.001) were also impaired with a medium effect size. Finally,
small effect sizes were found in the language (Hedge's g =−0.26;
p = 0.021) and visuoconstruction (Hedge's g =−0.25; p = 0.029)
domains; however, these did not remain significant after correct-
ing for multiple comparisons (Bonferroni correction: language
(p = 0.317) and visuoconstruction (p = 0.44)). Sub- domains of ex-
ecutive function such as planning and updating could not be ana-
lyzed due to the small sample size (k = 2). Figure 2 shows graphic
depiction of the cognitive profile according to the magnitude of
the impairment in OABD using the Hedge's g values. Appendix 1
shows the forest plots of BD patients and healthy controls for the
main cognitive domains analyzed.
There was high heterogeneity in some cognitive domains, spe-
cifically in verbal learning (I2 = 69.4%) and inhibition (I2 = 65.5%).
The remaining cognitive domains obtained a heterogeneity index
below 50%. The forest plots and the visual inspection of the funnel
plots showed that this heterogeneity could be caused by the data of
the sample focused on late- onset BD included in the study led by
Schouws et al.85 (see Appendix 2). To explore this possibility, a meta-
analysis excluding the data corresponding to late- onset sample was
carried out. Results are shown in Data S2. The verbal learning sub-
domain showed a more homogeneous distribution (I2 = 48.2%), with
similar overall moderate effect size (Hedge's g = −0.77;p < 0.001),
and the same effect was also observed in the inhibition subdo-
main (I2 = 36%) maintaining similar effect size (Hedge's g = −0 .41;
p = 0.003). This last finding displayed that the late- onset BD sample
was contributing to the presence of heterogeneity. However, this
second analysis, increased the heterogeneity noted in the visuocon-
struction domain (I2 = 61.7%), but this result had to be interpreted
with caution due to the small sample size. Overall, after exclusion
of late- onset BD data, the cognitive domains previously impaired
maintained similar trends of cognitive impairment with also similar
significantlarge andmoderateef fect sizes (−0.41to −0.77),where
OABD had worse performance compared with HC, and with an ho-
mogeneous effect size distribution.
3.4 | Publication bias
The Egger test and the visual inspection of the funnel plots re-
vealed indication of publication bias in the domains of learn-
ing (p = 0.049), inhibition (p = 0.001), and visuoconstruction
(p = 0.023). In the case of visuoconstruction, the Egger test was
statistically significant and the forest plot showed larger effect
sizes in smaller studies, indicating potential publication bias, al-
though this finding should be taken with caution because the plot
included only four studies. For learning and inhibition, the Egger
test was also statistically significant, but the forest plots showed
larger effect sizes in larger studies and this finding was possibly
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125
MONTE JO ET al.
TAB LE 2 EffectsizesofdifferencesbetweenBDandHCinneurocognitivevariables
Cognitive domain Subdomain Studies (k) Effect Sizea
CI (95%)
Zbp- value I2Egger tes t (p- value)lo up
Attention 8−0.54 − 0.70 −0.39 −6 .7 <0.001* 0.0 0.884
Processing speed 6−0 .76 −0.92 −0.59 −9. 0 <0.001* 0.0 0.677
Memory 9−0.77 −0.94 − 0. 61 −9.1 <0.001* 41.5 0.524
Learning 6−0.89 −1 . 24 −0.55 −5.0 <0.001* 69.4 0.049*
Immediate memory 3−0.73 −1 . 0 4 −0.42 −4.5 <0.001* 0.0 0.480
Delayed memory 9−0.80 −0.98 −0.62 −8 .7 <0.001* 34.7 0.941
Recognition 5−0.53 −0.72 −0.34 −5.4 <0.001* 0.0 0.144
Executive functions 9−0. 67 −0.83 −0. 51 −8.2 <0.001* 44.0 0.868
Inhibition 6−0.52 −0.84 −0.20 −3.2 0.001* 65.5 0.001*
Verbal fluency 8−0.72 −0. 89 −0. 55 −8.2 <0.001* 33.0 0.396
Flexibility 9−0.72 −0.89 −0 .55 −8.3 <0.001* 25.8 0.724
Working Memory 6−0 .74 −0.91 −0.57 −8.5 <0.001* 0.0 0.884
Language 4−0. 26 −0.49 −0.04 −2. 3 0.021 0.0 0 .714
Visuoconstruction 4−0.25 −0 .47 −0.02 −2.2 0.029 46.0 0.023*
Psychomotor speed 4−0. 67 −0.87 −0.47 −6.5 <0.001* 0.0 0.945
Abbreviations: BD, Bipolar Disorder; CI, confidence Interval; HC, Healthy Controls.
a Effect size (Hedge's g).
b Test of significance of effect size.
126
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MO NTEJO E T al.
more related to the heterogeneity caused by the inclusion of the
late- onset sample of Schouws et al.85 As expected, after carry-
ing out the meta- analysis excluding this late- onset data, the Egger
test p- value was not significant for learning (p = 0.171), indicating
absence of publication bias; however, this remained significant for
inhibition (p = 0.028) and for visuoconstruction (p = 0.022).
3.5 | Meta- regressions results
At a trend- level, the presence of psychosis history was associated
with worse memory (b = −1. 37 ; p = 0.047) and verbal and visual
delayed memory (b = −1.77 ; p = 0.014), and a lower estimated
intelligence quotient (IQ) was associated with worse perfor-
mance in delayed memory (b =−0.08;p = 0.016) and in flexibility
(b = 0.06; p = 0.040). Nevertheless, these relationships did not
remain after correcting for multiple comparisons (Bonferroni cor-
rection: p < 0.001). Meta- regression showed that the number of
hospitalizations, illness duration (in years), and educational level
were not significantly associated with any cognitive domain.
Meta- regressions by Newcastle- Ottawa Scale score were not
statistically significant. We could not conduct meta- regression
by medication burden due to the small number of studies that re-
ported these data.
4 | DISCUSSION
The present systematic review and meta- analysis are focused on
investigating the neuropsychological performance of a sample
of OABD aged over 50, as compared with HC. This is one of the
first meta- analytic studies to examine this relationship and, to our
knowledge, the first one which uses accurate neuropsychological
assessment criteria establishing a comprehensive assessment as
the main inclusion criteria. Effect sizes were calculated for a total of
15 cognitive domains and sub- domains. Of note are the clinical and
theoretical considerations that stem from the findings of the pre-
sent meta- analysis. This research makes a novel contribution to the
current literature with the input of a detailed and complete cogni-
tive profile specific to OABD, based on a comprehensive neuropsy-
chological assessment. In addition, the data analyses go beyond a
qualitative description, meaning the quantitative analysis provides
information not only about the number of cognitive domains af-
fected but also of the magnitude of the impairment, making it easier
to interpret its clinical significance.
Consequently, providing a detailed cognitive profile in OABD
allows clinicians to differentiate between cognitive deficits related
to bipolar disorder and deficits related to early stages of demen-
tia. Likewise, as shown by the results of the present meta- analysis,
cognitive impairment is also present in OABD, thus, a routine neu-
ropsychological assessment should be included in clinical prac-
tice to achieve a comprehensive understanding of BD in late- life.
Accordingly, results can be applied to design future intervention
programs focused on this age group. Considering the cognitive pro-
file yielded in our results, cognitive remediation interventions pro-
grams could be designed. In addition, due to the known link between
cognitive impairment and poor psychosocial functioning, interven-
tions in OABD should also be designed that would enhance psycho-
social functioning. Special attention should be paid to functioning in
older ages, since its impact could be greater than in younger patients
FIGURE 2 CognitiveprofileinOABDthrougheffectsizes(Hedge'sg value)
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127
MONTE JO ET al.
due to different factors related with older age such as comorbidities,
medication, etc.
OABD might be considered a population with different needs
when compared with young and middle- aged patients given to the
somatic comorbidities, different clinical features, illness burden, and
vulnerability to cognitive impairment. Consequently, interventions
should be tailored specifically for this age group. Inter ventions fo-
cused at improving or maintaining cognitive performance as well as
enhancing psychosocial functioning, taking into account the age, bi-
polar stage, and the specific needs might be designed. As a result, a
detailed OABD cognitive profile is provided, showing that, compared
with HC, OABD present deficits in most cognitive domains, with
large effects mainly in two components of memory (verbal learning
and visual and verbal delayed memor y) and moderate effects in pro-
cessing speed, working memory, psychomotor function, executive
functions, and, finally, attention. No significant patient- control dif-
ferences were detected in visuoconstruction and language domains.
Cognitive flexibility, verbal fluency, and inhibition components of ex-
ecutive functions also achieved moderate effect- sizes as well as two
components of memor y such as immediate memory and recognition.
On average, OABD performance ranged from 0.52 to 0.89 stan-
dard deviations below the HC group. Reviewing the results by cog-
nitive areas, in terms of memory function, we found that, in addition
of the impairment in overall memory as a main cognitive domain, all
components of memory reached significant differences, with these
more pronounced in verbal learning and visual and verbal delayed
memory where the largest effect sizes were found. It is important
to highlight that in the case of our results of delayed memory, the
recall of both verbal and visual stimuli contributed to that differ-
ence, because visual memory was assessed in only two studies.30,31
Consequently, we could not know for certain if this impairment is
due to verbal memory, visual memory, or both. Nevertheless, the
analysis of heterogeneity showed higher values (I2) in verbal learning
and in inhibition, suggesting that these results should be interpreted
with caution. The funnel and forest plots inspection revealed that
it could be caused by the sample focused in late- onset of Schouws
et al.85 study and secondary analyses confirmed this. As indicated
in the results, the heterogeneity disappeared in both cognitive do-
mains after running a second analysis excluding data of the late-
onset BD group. Furthermore, the heterogeneity was also reduced
in other cognitive domains when this group was removed. We hy-
pothesized that this sample is contributing to heterogeneity due to
the effect of the greater cognitive impairment usually observed in
this group,88 as was seen in our analyses. Besides, considering only
the data excluding late- onset group, we observed that the magni-
tude of the effect sizes was slightly decreased when we removed
late- onset data indicating that this group produced a bias in the anal-
ysis toward more pronounced cognitive impairment. This results are
consistent with the previous meta- analysis of OABD.11 Nevertheless
these cognitive deficits will be variable from one patient to another.
Both clinical practice and empirical research has shown that cog-
nitive and psychosocial functioning heterogeneity is present in BD,
while some patients are cognitively very impaired, others remain
intact or mildly affected.89,9 0 In this sense, OABD is a heterogeneous
group, composed by some patients presenting with early onset and
some with much later onset. Age of onset might be an important
clinical indicator of the heterogeneous presentation of the disease.91
There is strong evidence that early versus late onset BD patients dif-
fer according to clinical factors, cognitive performance, somatic co-
morbidities, and etiology, suggesting that these may represent two
different phenotypes.92,93 This has important clinical implications in
order to address specific approaches to allow for more application of
precise treatment approaches.
Furthermore, we did not find significant differences compared
with HC after correcting for multiple comparisons in language and
in visuoconstruction domains. However, the moderate significant
effect size found in verbal fluency could may have amplified the im-
pairments noted in the language domain if we had included it in this
last domain, as it is considered by some authors.94 In this sense, lan-
guage is an area that is rarely explored in BD and could be relevant
in late life according to previous results.95 Similarly, the visuocon-
struction domain did not reach significant differences in effect sizes,
indicating no cognitive impairment in the BD group compared with
HC, but this analysis included only four studies and it consisted of
screening tests, which have a lower discriminative power and may
not reflect the real performance level of this group. Finally, it also
included visuospatial tasks (for example, the clock test) and planning
test (ROCF), which are also considered to be part of executive func-
tion and do not specifically reflect visuoconstruction ability.
Within OABD group, there is one previous meta- analysis11 an-
alyzing cognitive performance but, in contrast to that study, in
addition to providing an updated review, we only included studies
that administered a comprehensive neuropsychological assessment
battery as a main inclusion criteria resulting in a different sample
analyzed with multiple cognitive domains analyzed. Comparing re-
sults with this previous report, we identified cognitive impairment in
OABD group in nearly the same cognitive domains (executive func-
tions, attention, delayed memory, and learning). In contrast, when
comparing effect sizes, we found greater impairment in the OABD
group mainly in the memory domain, but lesser impairment in the
executive functions and attention.
Aside from the heterogeneity of cognitive performance within
BD, previous meta- analyses have reported cognitive impairment in
middle- aged patients in attention, processing speed, verbal learning,
and executive functions.7– 9,96,97 On the contrary, our results indicate
significant large effects mainly in all components of memory, includ-
ing verbal learning, and also in processing speed, working memory,
executive functions, and attention with moderate effect sizes. In
addition, in secondary meta- regression analyses, our study found
no effect of illness duration or number of hospitalizations, although
the latter may not have been adequately evaluated as few studies
reported these data.
It is important to stress that the cognitive profile we found is
likely to be somewhat different from that seen in patients with a
neurodegenerative disorder (i.e Alzheimer`s dementia). Even though
our results identified cognitive impairment mainly in memory, the
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memory impairment in patients with dementia is more pronounced
and has a different profile (in AD for instance with great and rapid
recall impairment). Moreover, these differences may be a result of
the exclusion of comorbid dementia in the included studies. The
original studies included in this meta- analysis, for methodological
reasons, establish the presence of comorbid dementia as exclusion
criteria. This may be an obvious and overlooked source of poten-
tial bias, producing an underestimation of the presence of cognitive
impairment by excluding patients with greater cognitive impairment
and neuroprogression. Besides, visuoconstruction ability is often
impaired in dementia, but was preserved in the group of OABD. It is
thus possible that different pathological processes are contributing
to the cognitive deficits of OABD versus patients with a neurode-
generative disorder like AD.
Additionally, as specified above, one important aspect of study-
ing cognition in OABD is that it is an approach to understanding the
evolution of cognitive performance across the life- span. Previous
clinical studies which investigated the effects of age on neurocogni-
tion in BD have suggested a steeper cognitive decline over the adult
lifespan compared with their healthy peers. Lewandowski et al.104
found a decline in the BD group especially in processing speed do-
main, and Seelye et al.105 reported deficits in cognitive control pro-
cesses seen only in the older patients. These findings are in line with
findings from population- based studies showing strong evidence for
increased rates of developing dementia in patients with BD com-
pared with healthy peers18,19,21,22,10 6 and with other psychiatric
populations.23 Nevertheless, longitudinal clinical studies on the neu-
rocognitive course in OABD14,74,76 do not consistently support the
presence of greater cognitive dysfunction over time compared with
controls; however, these are studies with a relatively short follow- up
period (less than 5 years). Conversely, Gildengers et al.107 found that
OABD performed worse on the Dementia Rating Scale (DRS) both at
baseline and at 3- year follow- up compared with controls, showing
faster cognitive decline than the expected.
It has been shown that BD can reduce cognitive reserve,108
which consists of the brain's ability to compensate for cognitive im-
pairments caused by aging or neuropathology, which is measured
by combination of intellectual capacity, educational levels, and oc-
cupational status. When patients with BD age, they may thus have
lower capacity to compensate for illness- associated pathology and
therefore undergo an accelerated cognitive decline than the “nor-
mal” aging population.
A reduced life expectancy in BD is evident.110 Nevertheless, in
OABD, we may be studying a healthier cohort than average group,
given that those who reach old age have had lower rates of death
due to medical comorbidities or suicidal behaviors.111,112 Moreover,
in recent decades, many efforts has been made to develop inte-
gral treatments for chronic BD patients, dedicated not only to ad-
dress mental health, but also to optimize overall outcomes (physical
health, treatment of comorbid diseases, stress management, compli-
ance with pharmacological treatment, etc.) and this can contribute
to reaching older age with better prognosis. Therefore, these factors
may indicate that people with BD who reach old age could represent
a survivor cohort,93 such that those patients with the worst possible
outcomes (e.g., death by suicide or other severe medical comorbidi-
ties) are under- represented in an OABD cohort.
Higher heterogeneity in cognitive performance in BD has been
demonstrated.89, 109 There are dif ferent neurobi ological origin s of the
cognitive impairments for the previously observed distinct neuro-
cognitive subgroups of patients, which could explain such heteroge-
neity and the progression or not of the cognitive deficits. In addition,
comorbidities such as neurodevelopmental disorders (ADHD, learn-
ing disorders, etc.), personality disorders, substance use, etc. should
be also considered when assessing the neuropsychological perfor-
mance of OABD patients since these variables could interfere in
cognitive performance. In addition to that, medication may also be
considered as a confounding factor since the cumulative effects of
psychotropic medications over the life course of OABD are likely to
be of particular relevance to cognition and cognitive decline with
age. In one study focused in OABD, benzodiazepines were linked
to worse cognitive performance but no such effect was observed
with other medications (anticonvulsants, antipsychotics, or antide-
pressant).98 On the contrary, there is evidence that lithium has po-
tential long- term neuroprotective effects, increasing neuroplasticity
with changes observed in white matter,99– 1 02 reducing the oxidative
stress as well as increasing protective proteins such as neurotrophic
factor, among others.103 In fact, lithium has been identified as a po-
tential protective factor for the development of dementia.19 So that,
on one hand it is of special relevance to consider this variable as
a confounder factor when analyzing cognitive performance since
it may be producing a positive bias effect toward better cognitive
performance. On the other hand, in clinical practice, it can be con-
sidered as a preventive and compensatory strategy for patients who
present severe cognitive dysfunction or are in an early stage of cog-
nitive decline.
Despite the importance of the influence of illness- specific fac-
tors in cognitive function, the number of studies in OABD is still
limited. Schouws et al.,87 who included a sample of euthymic BD pa-
tients over 60 years old, found evidence that illness factors (such as
number of hospital admissions and age of onset), as well as medical
conditions (vascular risk factors), were related to poorer cognitive
functioning, specifically with verbal memory, executive functions,
and attention. Similarly, Murri et al.113 found that the diagnosis of
BD type I, lower level of education, and physical comorbidities were
predictors of cognitive dysfunction among elderly patients with BD.
In contrast, studies in middle- aged individuals, despite the heteroge-
neous evidence, suggest that the number of manic episodes, length
of illness, number of hospitalizations, and psychosis history are re-
lated with poorer cognitive function, especially concerning memory
and executive function domains.9,114,115 Contrary to reports in the
literature, in the present meta- regression analysis, none of the ill-
ness characteristics (number of hospital admissions and illness dura-
tion) or demographic variables (level of education and IQ) was found
to be associated with any of the cognitive domains analyzed. One
explanation for that could be that, from our meta- analysis, the num-
ber of the studies that reported illness factors data were limited,
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MONTE JO ET al.
thereby preventing us from carrying out a more detailed analysis
including more variables.
4.1 | Limitations
This study is not exempt of limitations that should be taken into
consideration. First, the high heterogeneity found in verbal learn-
ing and inhibition suggests that the inclusion of a study including
a late- onset BD group may have magnified effect sizes in those
domains.85 Even after excluding this sample from secondar y anal-
yses, an effect of late- onset may have been present, as some stud-
ies did not differentiate between early or late- onset and included
patients with a relatively late mean age of onset (i.e 38.86 ± 15.16)
and this may contribute to an overestimation of group differences.
In light of this, the cross- sectional design and the results of the
present meta- analysis do not allow for inferences about whether
bipolar disorder is a neurodevelopmental or neurodegenerative
disease. For that, longitudinal or cohort studies and some measure
of cognitive reserve would be necessary.116,117 Secondly, the small
sample size available for analyses within some cognitive domains
limits the interpretations of those results. Moreover, we detected
a potential publication bias with regard to the inhibition domain,
so this result should also be taken with caution. Additionally, al-
though it was a secondary analysis, the lack of data on clinical
variables prevented us from carr ying out meta- regressions to
analyze which clinical variables could be influencing cognitive per-
formance. The high heterogeneity found between cognitive tests
within a cognitive domain could decrease the overall statistical
power. Besides, the approach of including studies assessing three
or more cognitive domains has the disadvantage that it may have
led to exclude some studies, reducing the number of studies in-
cluded. Finally, the methodological quality of some of the included
studies was low (i.e. not all studies matched both groups), suggest-
ing that the results derived from these original studies could be
biased and should be interpreted with caution.
4.2 | Overall conclusions about cognitive profile
in OABD
In summary, our results show that OABD present lower perfor-
mance in most cognitive domains, especially in verbal learning and
visual and verbal delayed memory, with large effect sizes, as com-
pared with HC. To a lesser extent, processing speed, working mem-
ory, psychomotor function, and executive functions were also found
to be impaired. Finally, attention was the domain least significantly
affected when compared with HC and language, and visuoconstruc-
tion were found to be unimpaired. Our main findings reinforce the
idea that cognitive impairment persists in OABD, with some particu-
larities in the cognitive profile noted in middle- age BD. Late- onset
group exhibited a more pronounced cognitive impairment. These
data suggest that this group may benefit from different treatment
approaches than young and middle age patients, emphasizing the
need to consider age as a key component when considering assess-
ment and treatment approaches.
To conclude, our study provides evidence that cognitive im-
pairments are prevalent in OABD with multiple cognitive domains
affected. No significant correlations between clinical illness or de-
mographic variables and cognitive performance were found in our
study. The comprehensive cognitive profile of OABD detailed here
may provide a resource to consider when designing and developing
therapeutic interventions adapted for this population.
4.3 | Future considerations
Although a systematic cognitive screening in BD is highly recom-
mended and it is very useful for monitoring cognitive performance
throughout life- span,26 based on the present findings a compre-
hensive routine neuropsychological assessment should be highly
indicated in the evaluation of BD, especially in those patients with
older age (>50 years). The screening tools are not sensitive enough
to detect neurodegenerative process in early stages. It should be
considered by clinicians to explore cognition through a complete
neuropsychological battery because of the complexity of differen-
tiating the cognitive impairments in OABD from those found in vari-
ous types of dementia and also to avoid false negatives.
Our systematic search of the literature revealed that many stud-
ies either did not include a cognitive assessment or only used broad
screening tools. Given the heterogeneity found in the assessment
tools used in the studies, there is a need to create a consensus on
the best methods for neuropsychological assessment in OABD pa-
tients.2,118 The standardization of a reliable cognitive battery would
also improve comparative and meta- analyzable data. The results
from the complete neuropsychological profile should be the the-
oretical basis for the design of specific interventions in OABD. As
cognitive impairment is pronounced across many cognitive domains
in OABD, the design of specific interventions could be helpful to
improve the prognosis of the illness and should be conducted not
only in late- life but also in earlier stages of the disease to prevent
cognitive decline.119 Interventions aimed at enhancing cognitive re-
serve may be particularly helpful for those in whom neuroprogres-
sion is a reality120,121 and should be applied earlier for those at risk
for cognitive decline. In psychiatric illnesses, the study of AD PRS
constitutes an important tool with the potential for substantial clin-
ical utility in the disease risk detection, for specif ying subtypes of
disease, and even to assess treatment response.12 2 As patients with
BD has been shown to have an increased risk of dementia, the po-
tential use of AD PRS measures may help with differential diagnosis
with dementia and, joint with other clinical indicators, in making a
more precise treatment choice. Further, specific clinical and thera-
peutic approaches are needed for an older adult population because
the results derived from young and middle- age BD patients could
not be extrapolated to OABD.93 Further research is needed to in-
vestigate whether the characteristics of cognitive performance in
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MO NTEJO E T al.
OABD are due to a greater number of impaired cognitive domains, to
a greater severity of cognitive impairment, or both. In addition, it is
also necessary to examine the heterogeneity of neuropsychological
performance within OABD analyzing the characteristics of the dif-
ferent subgroups that might arise in order to delineate and prescribe
personalized treatments.
ACKNOWLEDGMENTS
AMA, CMB, CT, EJ, EV, and LM would like to thank the support
of the Spanish Ministr y of Science, the CIBER of Mental Health
(CIBERSAM); the Comissionat per a Universitats I Recerca del DIUE
de la Generalitat de Catalunya to the Bipolar Disorders Group
(2017 1365), the CERCA Programme/Generalitat de Catalunya,
and Instituto de Salud Carlos III for funding through the project
PI20/00060. AG declared having received grant Support from the
National Institute on Aging. BPF reports having received grant sup-
port from National Institute of Aging, Rogers Family Foundation,
Spier Family Foundation, Biogen and, Eli Lilly. HPB also has received
supported by National Institute of Mental Health of the National
Institutes of Health under Award Number R01MH113230. JR was
supported by the Spanish Ministry of Science, Innovation, and
Universities / Economy and Competitiveness / Instituto de Salud
Carlos III (CPII19/00009, PI19/00394), co- financed by ERDF Funds
from the European Commission ("A Way of Making Europe"). KWM
thanks the Lundbeck Foundation for her five- year Fellowship (grant
no. R215- 2015- 4121). LTE is supported by the VA Desert- Pacific
Mental Illness Research Education and Clinical Center. REP has re-
ceived grant support from National Institute of Aging, Rogers Family
Foundation, Biogen and Eli Lilly pharmaceuticals.
CONFLICTS OF INTEREST
BPF participated as a consultant of Biogen and Acadia
Pharmaceuticals. EV has received grants and served as consultant,
advisor or CME speaker unrelated to this work for the following en-
tities: AB- Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo
Pharma, Ferrer, GH Research, Gedeon Richter, Janssen, Lundbeck,
Otsuka, Sage, Sanofi- Aventis, Sunovion, and Takeda. JRG and REP
have received support from Biogen and Eli Lilly pharmaceuticals.
KWM has received consultancy fees from Lundbeck and Janssen-
Cilag in the past three years. LVK has been consultant during the last
3 years for Lundbeck and Teva. PC received Royalty from UpToDate
Wolters Kluwer Health.
DATA AVAI L AB ILITY STAT EM ENT
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
ORCID
Laura Montejo https://orcid.org/0000-0003-4407-9454
Carla Torrent https://orcid.org/0000-0003-0335-582X
Esther Jiménez https://orcid.org/0000-0001-6929-6207
Anabel Martínez- Arán https://orcid.org/0000-0002-0623-6263
Hilary P. Blumberg https://orcid.org/0000-0002-6363-4698
Katherine E. Burdick https://orcid.org/0000-0003-4417-4988
Annemieke Dols https://orcid.org/0000-0003-1964-0318
Lisa T. Eyler https://orcid.org/0000-0002-7783-8798
Jennifer R. Gatchel https://orcid.org/0000-0002-3892-9742
Ariel Gildengers https://orcid.org/0000-0001-9216-988X
Lars V. Kessing https://orcid.org/0000-0001-9377-9436
Kamilla W. Miskowiak https://orcid.org/0000-0003-2572-1384
Andrew T. Olagunju https://orcid.org/0000-0003-1736-9886
Sigfried Schouws https://orcid.org/0000-0003-0591-5405
Joaquim Radua https://orcid.org/0000-0003-1240-5438
Caterina del M. Bonnín https://orcid.org/0000-0002-1197-1596
Eduard Vieta https://orcid.org/0000-0002-0548-0053
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SUPPORTING INFORMATION
Additional supporting information may be found in the online
version of the article at the publisher’s website.
How to cite this article: Montejo L, Torrent C, Jiménez E,
et al; International Society for Bipolar Disorders (ISBD) Older
Adults with Bipolar Disorder (OABD) Task Force. Cognition in
older adults with bipolar disorder: An ISBD task force
systematic review and meta- analysis based on a
comprehensive neuropsychological assessment. Bipolar
Disord. 2022;24:115– 136. doi:10.1111/bdi .13175
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APPENDIX 2
