Cognitive impairment in bipolar disorder.
ABSTRACT Provide an overview of how bipolar disorder affects cognitive function in patients.
MEDLINE and PsycInfo data bases were searched for articles indexed by the combinations of MESH term or key word "bipolar disorder" with the following terms: "cognition", "memory", "neuropsychology", "neuropsychological tests", "lithium", "anticonvulsants", "antipsychotics", and "schizophrenia". Constraints limiting time period of publications or their language were not applied. Reference lists of publications identified by these procedures were hand-searched for additional relevant citations.
There is evidence of stable and lasting cognitive impairment in all phases of bipolar disorder, including the remission phase, particularly in the following domains: sustained attention, memory and executive functions. But research on the cognitive functions has yielded inconsistent results over recent years. There is a growing need for clarification regarding the magnitude, clinical relevance and confounding variables of cognitive impairment in bipolar patients. The impact of bipolar illness on cognition can be influenced by age of onset, pharmacological treatments, individual response, familial risk factors, and clinical features. In addition to the mood state, cognitive performance in bipolar patients is influenced by seasonality.
Previous optimistic assumptions about the prognosis of bipolar disorder were based on the success of the control of mood symptoms by pharmacotherapy. However, it is now clear that the "remitted" euthymic bipolar patients have distinct impairments of executive function, verbal memory, psychomotor speed, and sustained attention. Mood stabilizers and atypical antipsychotics may reduce cognitive deficits in certain domains and may have a positive effect on quality of life and social functioning.
- SourceAvailable from: David E VanceThe Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses. 04/2013; 45(2):77-87.
- Bipolar Disorders 06/2014; · 4.62 Impact Factor
- Comprehensive psychiatry 12/2013; · 2.08 Impact Factor
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011 Mar; 155(1):19–26. DOI 10.5507/bp.155.2011.003
© K. Latalova, J. Prasko, T. Diveky, H. Velartova
COGNITIVE IMPAIRMENT IN BIPOLAR DISORDER
Klara Latalovaa*, Jan Praskoa,b,c, Tomas Divekya, Hana Velartovaa
a Department of Psychiatry, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Czech
b Prague Psychiatric Centre, Ustavni 91, 181 03 Praha
c Centre of Neuropsychiatric Studies, Ustavni 91, 181 03 Praha
Received: June 17, 2010; Accepted with revision: November 16, 2010
Key words: Bipolar disorder/Cognitive impairment/Genetics/Mood stabilizers/Cognitive tests/Quality of life
Aim. Provide an overview of how bipolar disorder affects cognitive function in patients.
Methods. MEDLINE and PsycInfo data bases were searched for articles indexed by the combinations of MESH
term or key word “bipolar disorder” with the following terms: “cognition”, “memory”, “neuropsychology”, “neuropsy-
chological tests”, “lithium”, “anticonvulsants”, “antipsychotics”, and “schizophrenia”.
Constraints limiting time period of publications or their language were not applied. Reference lists of publications
identified by these procedures were hand-searched for additional relevant citations.
Results. There is evidence of stable and lasting cognitive impairment in all phases of bipolar disorder, including
the remission phase, particularly in the following domains: sustained attention, memory and executive functions. But
research on the cognitive functions has yielded inconsistent results over recent years. There is a growing need for
clarification regarding the magnitude, clinical relevance and confounding variables of cognitive impairment in bipolar
patients. The impact of bipolar illness on cognition can be influenced by age of onset, pharmacological treatments,
individual response, familial risk factors, and clinical features. In addition to the mood state, cognitive performance
in bipolar patients is influenced by seasonality.
Conclusion. Previous optimistic assumptions about the prognosis of bipolar disorder were based on the success
of the control of mood symptoms by pharmacotherapy. However, it is now clear that the “remitted” euthymic bipolar
patients have distinct impairments of executive function, verbal memory, psychomotor speed, and sustained attention.
Mood stabilizers and atypical antipsychotics may reduce cognitive deficits in certain domains and may have a positive
effect on quality of life and social functioning.
Cognitive impairment in bipolar disorder has been the
focus of intensive investigation during the past decade, fol-
lowing an earlier wave of similar studies in schizophrenia.
This delay was perhaps due to the fact that the impair-
ment in euthymic bipolar disorder patients is generally
less severe (and thus less obvious) than in schizophrenia1.
Several motivations for the recent interest in this topic
can be discerned. Psychiatric genetics has been search-
ing for endophenotypes for various disorders2,3, and cog-
nitive impairment is seen as a candidate for that role4.
Furthermore, there has been a controversy whether bi-
polar disorder and schizophrenia are best characterized
as separate disorders or along a continuum5. Differences
and similarities in cognitive impairments attending these
disorders have the potential to contribute to the resolution
of this controversy. Finally, it has been increasingly real-
ized that the impairments are clinically important since
they influence functional outcomes in bipolar patients.
The aim of the current review is to examine the pub-
lished evidence on cognitive impairment in bipolar dis-
order in terms of its description, assessment, effects of
the phase of illness, effects of medication, and impact on
functional outcomes. Finally, cognitive endophenotypes
in bipolar disorder will be discussed.
Cognitive domains studied in bipolar patients
Cognitive domains examined in bipolar patients in-
clude executive function, memory, attention, psychomo-
tor speed, and, more recently, social cognition. Executive
function includes the ability to move freely from one situ-
ation to another and to think flexibly in order to respond
appropriately (set shifting), response inhibition, concept
formation, working memory, emotional control, and other
aspects of mental control and self-regulation.
Short-term or immediate memory involves what one
can repeat immediately after perceiving it. Working mem-
ory is the executive and attentional aspect of short-term
memory involved in the interim integration, processing,
disposal, and retrieval of information.
Theory of mind (ToM) is a component of social cog-
nition. It refers to the ability to represent one’s own or
other’s mental states.
Cognitive assessment in bipolar patients
Executive function is assessed using Part B of the Trail
Making Test6 that focuses on set shifting, and the Stroop
K. Latalova, J. Prasko, T. Diveky, H. Velartova
test7 that can be seen as a test of response inhibition.
Wisconsin Card Sorting Test assesses the capacity for set
shifting and concept formation8.Verbal fluency is tested
by asking the subjects to name, as fast as they can, either
words from a certain category (e.g. animals), or words
beginning with certain letters9. Verbal fluency tests assess
capacity for organized thinking and memory.
Immediate verbal memory and learning are assessed
using word list learning (California Verbal Learning Test
(CVLT)10 or Auditory Verbal Learning Test (AVLT)11 or
Rey Auditory Learning Test (RAVLT) . Delayed recall
version of these tests is used to assess delayed memo-
ry. Working memory is tested using the Digit Span12.
Continuous Performance Test (CPT) assesses sustained
attention13. Trail Making Test part A (ref.6) and Digit
Symbol Substitution Test12 are used to measure psycho-
motor speed. Several tests of premorbid intelligence have
ToM testing uses stories or movies that are read or
shown to the subjects. The subjects are then asked about
the thoughts, emotions, and intentions of the characters
in the story or a movie.
Features of cognitive impairment in euthymic (remitted)
The most recent meta-analysis available used 45 stud-
ies comparing 1423 euthymic bipolar patients with 1524
healthy controls4. The results showed group differences
with medium to large effect sizes for measures of execu-
tive function, verbal memory, psychomotor speed, and
Meta-regression analyses were used to study the effects
of demographic variables, medication (percentage of pa-
tients using antipsychotics, antidepressants, and lithium),
and other variables. Medication effects will be discussed
Several ToM studies indicated impaired social cogni-
tion in bipolar disorder. One of the studies recorded the
fMRI response to ToM and control visual stimuli and
subsequent (off-line) subjects’ verbal rating of the same
stimuli16. The subjects were 20 euthymic bipolar patients
and 20 healthy controls. The results of verbal ratings in-
dicated that the patients were less able to assess intention
than the controls when viewing ToM stimuli. The fMRI
showed less activation in the patients than in controls in
a large number of anatomical areas.
Since it had been hypothesized that ToM deficits in-
crease vulnerability to psychosis, a study compared ToM
deficits in bipolar patients with and without a history of
psychosis17. The results were negative, thus ToM deficits
do not appear to be a trait marker for psychosis. A de-
tailed study of several ToM subtypes in bipolar disorder
has been published recently18. Impairments of social cog-
nition, including ToM, have a potential impact on func-
tional outcomes; more studies of ToM relating the results
to clinical variables are needed.
History of psychosis affects cognitive impairment in bipolar
Lifetime prevalence of hallucinations and delusions in
Bipolar Disorder I is perhaps 50% or more19, and psycho-
sis (and perhaps its treatment) may have enduring adverse
effects on cognition. Accordingly, research studies have
addressed this possibility in bipolar disorder.
Bipolar patients with a history of psychosis showed
greater impairments of executive functioning and working
memory (including spatial memory) than those without
such history20. In a large neuropsychological test battery,
the number of categories (i.e., the number of runs of 10
correct responses) on WCST was the only variable that
discriminated between euthymic bipolar patients with
(N=45) and without (N=20) a history of psychosis21.
However, these authors21 noted that there were other
clinical variables besides history of psychosis that affected
cognitive performance. Most patients (N=63) were treated
with lithium at the time of the neuropsychological assess-
ments, and plasma levels were determined. Higher lithium
levels, lower age of onset and lower level of education were
correlated with impairment of memory performance. In
a multiple regression analysis, this effect of lithium was
statistically independent of the severity of current depres-
Verbal memory was more impaired in bipolar patients
with a history of psychosis than in those without it22.
Another study aimed to determine whether the presence
of psychosis during inpatient hospitalization was asso-
ciated with greater cognitive impairment at the time of
hospital discharge23. Bipolar patients admitted with or
without psychosis completed a neuropsychological test
battery before discharge from the hospital. Patients ad-
mitted with psychosis had significantly poorer perform-
ance on the CVLT, logical memory subtest from Wechsler
Memory Scale-Revised, Stroop test, and the WCST than
those without psychosis. However, history of psychosis
had no effect on performance on a ToM test in bipolar
Thus, in summary, it appears that history of psychosis
affects executive functioning and various memory func-
tions in bipolar patients. Other clinical factors that may
interact with the history of psychosis influence cognitive
functioning. These factors include current lithium treat-
ment, history of early onset of bipolar disorder, and lower
level of education.
Cognitive dysfunction in bipolar disorder in manic,
depressed and euthymic states: state versus trait
A cross-sectional study compared 4 groups: manic or
hypomanic bipolar patients, depressed bipolar patients,
euthymic bipolar patients, and healthy controls using a
neuropsychological test battery24. Each of the three bi-
polar groups showed significant impairments in verbal
memory and executive functions in comparison with
controls. However, there were no substantial differences
among the bipolar groups. Similar studies of this type
were summarized in a review25. The principal conclusion
of these studies comparing various disease states within
bipolar disorder is that the cognitive impairment in eu-
Cognitive impairment in bipolar disorder
thymia is not substantially different from that in manic or
depressive state. In view of the persistence of cognitive im-
pairment, euthymia cannot be seen as a clinical recovery.
In a mixture of cross-sectional and longitudinal
prospective design, 25 patients with bipolar I disorder
underwent neuropsychological testing over a period of
30 months while hypomanic, depressed, or euthymic26.
Of the 25 patients, 13 were assessed in one phase only,
and 12 in two or three phases (hypomanic, depressed,
and euthymic). The results from these assessments were
compared with tests in 25 healthy controls. In this com-
parison, depressed patients showed impairments across
all cognitive domains tested (executive, memory, atten-
tion, and motor). Euthymic patients demonstrated only
impaired recall, and hypomanic patients had executive,
memory, and attention impairments. In comparisons
within the bipolar group, depressed patients had more
memory and motor impairment than euthymic patients,
and hypomanic patients had more motor impairments
than euthymic ones. Impairment on Global Assessment
of Functioning (GAF)27 was correlated with impaired per-
formance on WCST in the set of bipolar patients.
In addition to the mood state, cognitive performance
in bipolar patients is influenced by seasonality. Seasonal
variation of mood and behavior was assessed in a group
of bipolar patients, and a subgroup perceiving seasonal
fluctuations as a problem was identified28. These patients
showed impaired cognitive performance in a number of
domains in comparison with a subgroup without seasonal
variation. Furthermore, cognitive performance was in-
fluenced by the season when the testing occurred: the
results obtained in the winter were inferior to those ob-
tained during other seasons. The patients’ mood state
at the time of testing was not determined, so we do not
know whether this variable interacts with seasonal effects.
Interestingly, no effects of seasonality were detected in
a group of healthy controls28. These data were obtained
in Finland; it is not clear how they would generalize to
patients living at lower latitudes.
Thus, in summary, each of the disease mood states or
phases (mania, hypomania, depression, and euthymia) is
associated with cognitive impairments, particularly in the
domains of memory and executive function. It appears
that the euthymic state is associated with less impairment
than the other states; nevertheless, euthymic bipolar pa-
tients are still cognitively impaired in comparison with
healthy controls. Seasonality influences the results of
cognitive testing, and this effect should be accounted for
in future research.
Potencial deleterious effects of medication on cognition
in bipolar disorder
For clinical and ethical reasons, it is difficult to obtain
a sample of unmedicated bipolar patients. This compli-
cates the efforts at assessment of medication effects on
cognitive performance. One of the rare studies of unmedi-
cated patients compared 17 bipolar II currently depressed
unmedicated patients with healthy controls; a neuropsy-
chological test battery showed no significant differences29.
A somewhat similar study used 49 unmedicated bipolar
(11 bipolar I and 38 bipolar II) patients in depressed
phase and compared them with healthy controls30. The
patients performed worse on spatial working memory and
several other tests. In another study using similar subjects,
medicated (N=33) and unmedicated (N=32) bipolar dis-
order patients, all in depressed phase, were compared on
a neuropsychological test battery with each other and with
healthy controls31. The medication consisted of lithium
or valproate monotherapy. The medicated patients had
a significantly higher level of depressive symptoms than
the unmedicated ones.
As mentioned above, higher lithium plasma levels were
associated with impairment of memory performance in
bipolar patients21. On the other hand, bipolar patients
medicated with lithium (N=20) did not differ from those
who were unmedicated (N=20) in terms of their cognitive
performance32. This was an uncontrolled, open study; it
is unclear how the patients were assigned to their treat-
ment groups. Another small uncontrolled study suggested
that the cognitive impairment in lithium-treated bipolar
patients may depend on clinical response: the impairment
was greater in lithium non-responders33.
A meta-analysis of lithium effect on cognition sum-
marized 12 studies involving 276 lithium-treated and 263
similar or the same subjects who were lithium-free34. The
subjects included patients with bipolar disorder (who
comprised 44.2% of the entire sample), major depres-
sive disorder, schizoaffective disorder, other disorders,
and persons without mental illness. The results indicated
small but statistically significant deleterious effects on im-
mediate verbal learning and memory (ES = 0.24; 95% CI,
0.05–0.43) and creativity (ES = 0.33; 95% CI, 0.02–0.64).
In patients with affective disorders, there was additionally
a larger effect impairing psychomotor performance (ES
= 0.62; 95% CI, 0.27–0.97). It is not clear to what extent
these results apply specifically to lithium effects in bipolar
Meta-regressions of medication effects on cognitive
performance in bipolar patients were a part of a meta-
analysis discussed in a previous section4. Those meta-re-
gressions indicated that medication was associated with
impaired psychomotor speed and sustained attention:
Studies that reported higher proportion of patients an
antipsychotics reported lower psychomotor speed and
more omission errors, antidepressants were associated
with lower psychomotor speed and more impaired per-
formance on Trail Making Test A. These associations be-
tween medication and test performance of course do not
necessarily imply that medication had any direct causative
effect on the performance. It is possible, for example, that
the association was mediated by a third variable, such as
depression, that could cause psychomotor slowing as well
as trigger the prescription of an antidepressant.
In summary, lithium treatment was reported to be
associated with impairments in learning, memory, and
psychomotor performance. However, recent evidence
suggests that this effect may be limited to certain sub-
groups of bipolar patients (e.g, lithium non-responders).
Antipsychotic and antidepressant treatments were as-
sociated with impaired psychomotor performance and
K. Latalova, J. Prasko, T. Diveky, H. Velartova
various other impairments in bipolar patients. However,
these associations were observed in uncontrolled trials
(and their meta-analyses). Unmedicated patients that
are used as controls in some studies are typically bipolar
II patients in depressed phase. For clinical and ethical
reasons, such subjects are probably easier to recruit and
study than other unmedicated bipolar patients. However,
the results of studies focusing on such patients are dif-
ficult to generalize.
Potencial options of treatment/remediation of cognitive
impairment in bipolar disorder
Emerging evidence suggests that galantamine, a cog-
nitive-enhancing agent approved for the treatment of
Alzheimer disease, may alleviate some aspects of cog-
nitive impairment in bipolar disorder. A double-blind,
placebo-controlled study of this agent was conducted in
euthymic patients with bipolar disorder35. A total of 16 pa-
tients completed a neuropsychological test battery before
and after treatment in this 3-months study. Galantamine
treatment (but not placebo) was associated with a sta-
tistically significant improvement on CVLT (reflecting
improvement of memory and learning), but there were
significant improvements on several other tests that were
limited to the placebo group. Between-group statistical
tests showed no significant differences.
In another study, galantamine was administered for
4 months to 19 patients with bipolar disorder in remis-
sion, who reported subjective cognitive deficits36. Mood
and subjective cognitive questionnaires were administered
monthly in this open trial. At the beginning and the end of
the trial all subjects were administered neuropsychologi-
cal tests, including tests of attention (CPT) and memory
and learning (CVLT). The patients underwent proton
magnetic resonance spectroscopy (1H-MRS) before and
After treatment, the patients experienced significant
improvement of subjective cognitive scores and on CPT
as well as on CVLT. Spectroscopy demonstrated that in
the left hippocampus, N-acetyl aspartate increased and
choline-containing compounds decreased during treat-
ment. These changes suggested increases in neuronal vi-
ability and normalization of lipid membrane metabolism
in the left hippocampus36.
Taken together, these two small studies suggest that
galantamine merits further investigation as a potential
treatment of cognitive impairment in bipolar disorder. We
have not been able to locate any controlled randomized
double-blind trials of antipsychotics or mood stabilizers
for this indication.
An intensive psychosocial remediation program was
administered to bipolar depressed patients in a rand-
omized controlled trial37. The remediation enhanced re-
lationship functioning and life satisfaction. The authors
concluded that “Alternate interventions focused on the
specific cognitive deficits of individuals with bipolar dis-
order may be necessary to enhance vocational functioning
after a depressive episode”37.
This suggestion was followed by a recent study that
tried a new cognitive remediation (CR) treatment to im-
prove psychosocial and neuropsychological functioning in
patients with bipolar disorder38. The neuropsychological
test battery included the Frontal Systems Behavior Rating
Scale (FrSBe). The FrSBe is a 46-item behavior rating
scale that assesses behavioral changes commonly associ-
ated with frontal lobe pathology. It includes three sub-
scales: Apathy, Disinhibition, and Executive Dysfunction.
After a baseline neuropsychological and clinical assess-
ment, 18 bipolar patients received 14 CR sessions. At the
end of treatment, as well as at the 3-months follow-up,
patients showed a statistically significant improvement
of Executive Dysfunction, lower depressive symptoms,
and improved occupational, as well as overall psychoso-
cial functioning. Improvements in executive functioning
were associated with improvements in occupational func-
tioning. These results are encouraging, but the study was
small, open, and uncontrolled38. Replication is required.
In general, research into treatment of cognitive impair-
ment in bipolar disorder is lagging behind the similar ef-
fort in schizophrenia. Much more work needs to be done
in this area.
Cognitive impairment and functional outcomes
Functional disability in bipolar patients discharged
from the hospital is a serious problem. After a 30-year
follow-up, 33% of bipolar patients showed poor perform-
ance at work, and additional 24% were occupationally
incapacitated due to mental illness39. A 5-year follow-up
study of 148 bipolar patients detected a decline in job
status and income as well as deterioration in most areas
of psychosocial functioning in comparison with healthy
controls40. In a study of 3681 patients with acute mania,
there were only 11% of patients who showed no work
impairment in the previous year41. A review of 13 studies
involving a total of 813 bipolar patients found an unem-
ployment rate of 55% (ref.42).
Functional outcomes in bipolar disorder are affected
by various factors such as neuroticism and current level of
depressive symptoms43 as well as age, course of disorder
(single episode, multiple episodes, chronic deteriorating
course) insight into positive symptoms, family history of
schizophrenia, and lifetime substance use disorders44; oth-
er clinical and demographic factors have been described41.
However, there is increasing evidence indicating that cog-
nitive impairment contributes substantially to functional
Such contribution was demonstrated in a study testing
cognitive performance in 77 euthymic bipolar patients
with varying degrees of occupational functioning45. The
patients were divided into high-functioning and low-func-
tioning groups Tests of verbal recall and executive function
showed more impairment in the low-functioning group. In
another study using 25 bipolar patients in various mood
states, scores on Global Assessment of Functioning27 were
Cognitive impairment in bipolar disorder
correlated with performance on WCST26. Performance
on tests of attention and ideational fluency was reported
to predict functional outcome at a 12-month follow-up in
78 bipolar patients46.
In a study comprising 73 bipolar disorder patients,
verbal memory scores correlated with the GAF and with
a quality of life scale47.
A recent review identified 13 studies addressing rela-
tionship between cognitive impairments and functional
outcomes in euthymic (8 studies involving 316 patients
and 147 healthy controls) and non-euthymic (5 studies
involving 497 patients and 55 controls) bipolar patients
in comparison with healthy controls42. Significant rela-
tionships between cognitive impairments and functional
outcomes were reported in 12 of the 13 studies reviewed.
Thus, social and vocational outcomes in bipolar dis-
order are generally poor, and cognitive impairments play
an important role in this. The impairments and the poor
outcomes are enduring, being less dependent on current
mood states than was originally thought: even euthymic
patients show neurocognitive impairments and are likely
to be unemployed or show poor work performance as well
as inadequate social engagement.
Nevertheless, current therapeutic efforts in bipolar dis-
order are still focused on reduction of mood symptoms
and rely largely on pharmacotherapy. Cognitive behavio-
ral therapy, psychoeducation, and other psychosocial ap-
proaches have been tried with some success in improving
functional outcomes48, but this has attracted much less
interest than pharmacotherapy. This is an area that should
receive more attention in the future.
Bipolar disorder and schizophrenia
The Kraepelinian classification of “manic-depressive
insanity” and “dementia praecox” (schizophrenia) as
two separate categories has survived 150 years. However,
recent genetic, neurobiological, and clinical evidence
showing similarities between schizophrenia and bipolar
disorder5 has inspired a controversial view that these dis-
orders can be better conceptualized on a continuum than
as separate entities.
This controversy has inspired comparative investi-
gations of cognitive impairments. A neuropsychologi-
cal test battery was administered to 30 patients with
schizophrenia and 22 psychotic bipolar patients49. All
patients were experiencing the first episode of their ill-
ness. Schizophrenia patients showed impairments over all
domains tested. Bipolar patients had a similar test profile,
but the impairments were less severe. Bipolar patients
performed significantly better than schizophrenia patients
on verbal memory, reasoning and flexibility.
The underlying structures of neuropsychological func-
tioning in two sets of patients were determined using fac-
tor analysis50. The first set (N=250) was comprised of
schizophrenic and schizoaffective patients, the second set
(N=155) contained bipolar patients. The two sets had a
similar factor structure, but the bipolar patients performed
better on tests of attention and non-verbal functioning.
Another study compared 73 euthymic bipolar patients,
89 stabilized patients with schizophrenia and 67 normal
controls47. The battery tested executive functioning, sus-
tained attention, and verbal and visual memory. Patients
in both patient groups demonstrated impairments in all
domains in comparison with normal controls, Patients
with bipolar disorder performed significantly better than
patients with schizophrenia on executive functioning
(Trail Making Test (TMT) part B), sustained attention
(backward digit span), and verbal memory (CVLT). As
mentioned in a preceding section, verbal memory im-
pairment correlated with assessments of psychosocial
function, thus confirming the clinical relevance of neu-
In summary, both bipolar disorder and schizophre-
nia patients are cognitively impaired in comparison with
healthy controls. The two patient groups have a similar
profile of neuropsychological dysfunction, but the impair-
ments are more severe in schizophrenia. Thus, the dif-
ferences between the impairments in these disorders are
quantitative rather than qualitative.
Searching for cognitive endophenothypes: family studies of
Endophenotypes are subclinical quantitative traits that
are assumed to be located along the pathway between
the genotype and the phenotypic disease (in this case,
bipolar disorder or schizophrenia diagnosed by clinical
criteria). Endophenotypes are conceived as subcompo-
nents of the illness, providing an opportunity for a less
complex genetic analysis than the diagnostic phenotype.
Neurophysiological, anatomical, and neurocognitive
measures are among the candidate endophenotypes for
bipolar disorder and schizophrenia.
Endophenotypes should meet certain criteria: they
should be associated with illness, they should be her-
itable, and co-segregate within families with illness3.
Furthermore, they should be state-independent traits
present in illness as well as in remission, and they should
be more frequent in unaffected relatives of patients than
in general population4. The endophenotype criterion of
heritability has been met for certain neurocognitive func-
tions in a study of a population-based Finnish sample of
110 individuals from 52 families with bipolar disorder who
were administered a comprehensive test battery51. The re-
sults indicated high heritability of executive functions and
psychomotor processing speed, but not of verbal learning.
Searching for neurocognitive endophenotypes in bipo-
lar disorder, Finnish investigators administered a test bat-
tery to 32 familial bipolar I disorder patients, 40 of their
unaffected first-degree relatives and 55 controls52. The
relatives showed impairments in psychomotor perform-
ance speed and in executive function. Bipolar patients
were impaired in verbal learning and memory compared
with unaffected relatives and controls. They also differed
from controls in tasks of executive functions. The authors
suggest that impaired psychomotor performance speed
and executive function may represent endophenotypes
of bipolar disorder.
K. Latalova, J. Prasko, T. Diveky, H. Velartova
Another study by the same Finnish group53 examined
cognitive performance in two groups of bipolar patients:
those who came from families containing affected rela-
tives with bipolar disorder only (“bipolar families”), and
those coming from families with both bipolar I disorder
and schizophrenia or schizoaffective disorder (“mixed
families”). A neuropsychological test battery was admin-
istered to 20 bipolar patients and 36 unaffected relatives
from bipolar families, 19 bipolar patients and 28 relatives
from mixed families and 55 healthy controls. Irrespective
of the family group, patients and relatives were impaired
in psychomotor processing speed in comparison with
controls. Both patient groups were impaired in execu-
tive functioning, but the deficit was more severe in pa-
tients from mixed families. Patients from bipolar families
scored lower than controls on tests of verbal memory. All
relatives were slightly impaired in executive functioning.
Psychopathology in the family had no major effects on the
heritability of cognitive function. The authors concluded
that impaired psychomotor processing speed and execu-
tive functions may represent markers of susceptibility to
bipolar I disorder irrespective of psychopathology within
Another, somewhat similar study of bipolar patients
and their relatives showed deficits in verbal working mem-
ory and executive function in the relatives54. These deficits
were therefore proposed as candidates for neurocognitive
endophenotypes in bipolar disorder.
Meta-analyses of cognitive functioning in euthymic
bipolar patients and their first-degree relatives were im-
plemented55. Meta-analysis of bipolar patients and first-de-
gree relatives comprised, respectively, 28 and 14 studies.
In bipolar patients, comparisons with healthy controls
yielded large effect sizes (d>0.8) for executive functions
(working memory, executive control, fluency) and verbal
memory. Medium effect sizes (0.5<d<0.8) were reported
for other tests of executive function (concept shifting, ex-
ecutive control), mental speed, visual memory, and sus-
tained attention. In first-degree relatives, size effects were
small (d<0.5), but significantly different from healthy con-
trols for executive function and verbal memory in par-
ticular. The authors concluded that executive function
and verbal memory are candidate bipolar endophenotypes
given large deficits in these domains in bipolar patients
and smaller impairments in first-degree relatives.
Thus, in summary, family studies of bipolar disorder
suggest the existence of cognitive endophenotypes for this
disorder. Strong evidence supports executive function and
processing speed as endophenotypes marking the vulner-
ability to bipolar disorder. Some studies also provide sup-
port for verbal memory in that role.
Searching for cognitive endophenothypes: family studies
of bipolar disorder and schizophrenia
Genetic contribution to the risk of bipolar disorder
and schizophrenia has been generally accepted, and a
recent meta-analysis provided evidence for familial co-ag-
gregation of the two disorders56. Nevertheless, the genes
that underlie the predisposition to both disorders seem
difficult to find. It is possible that the somewhat arbitrary
categorical classification of these complex disorders devel-
oped by Kraepelin may not be the optimal way to define
the heritable phenotype. Endophenotypes may be more
useful for this purpose.
This line of reasoning led to a number of family stud-
ies of bipolar disorder and schizophrenia. A neuropsy-
chological test battery comprising tests of executive
function (Verbal Fluency Test, the Stroop Word Color
Test, the Wisconsin Card Sorting Test (WCST) and the
Trail Making Test (TMT)) was administered to 37 bipo-
lar disorder probands, 33 of their unaffected first degree
relatives, 25 schizophrenia probands, and 22 of their
unaffected first degree relatives were compared with
20 normal controls57. The unaffected relative groups did
not differ from the proband groups, implying familial re-
semblance. Bipolar and schizophrenic probands as well
as unaffected relatives showed impairment on the Stroop
test in comparison with the controls. The other tests did
not show this effect. The impairment on Stroop, imply-
ing enhanced susceptibility to interference and reduced
inhibition, could thus be a shared endophenotype that
marks a familial vulnerability common to bipolar disorder
The same French group of investigators who produced
the publication reviewed above57 used a similar design to
study 95 bipolar probands, 63 of their unaffected rela-
tives, 73 schizophrenia probands, 67 of their unaffected
relatives, and 48 normal controls58. The cognitive battery
included only 2 tests: WCST and TMT. In comparison
with the control group, both tests showed the greatest
impairment in schizophrenic probands, followed by bipo-
lar patients and then the two groups of relatives. Bipolar
probands did not differ from their relatives on the WCST
and part A and part B of the TMT, implying familial re-
semblance for the cognitive functions assessed by these
tests. However, familial resemblance was not observed in
schizophrenic probands and their relatives. The authors
conclude that “executive measures, as assessed by the
WCST or the TMT, should not be used as endopheno-
types in genetic studies of schizophrenia unless confound-
ers are identified and their effects eliminated” (p.131). It is
not clear why these authors did not use the Stroop test to
replicate the positive findings from their previous study57.
Unaffected relatives of bipolar patients were compared
with unaffected relatives of schizophrenic patients and
normal controls on several versions of the Stroop test59.
An emotional bias towards mood-related information
was detected in relatives of bipolar patients, and, in turn,
impairment in cognitive inhibition was found in the rela-
tives of schizophrenic patients. The findings suggest the
existence of different endophenotypes marking the vulner-
ability to bipolar disorder and schizophrenia.
Thus, in summary, there is some evidence for en-
hanced susceptibility to interference and reduced inhibi-
tion (assessed by the Stroop test) as a candidate cognitive
endophenotype shared by bipolar disorder and schizo-
phrenia. However, more research is needed in this area.
Cognitive impairment in bipolar disorder
Research into cognitive impairments in bipolar disor-
der has yielded results that lead to revisions of the clinical
approach to the illness. Previous optimistic assumptions
about the prognosis of bipolar disorder were based on
the success of the control of mood symptoms by phar-
macotherapy. However, it is now clear that the “remitted”
euthymic bipolar patients have distinct impairments of
executive function, verbal memory, psychomotor speed,
and sustained attention. Social cognition is also affected.
The severity of impairment is increased by history of
psychosis, history of early onset of bipolar disorder, and
lower level of education. Other factors such as current
pharmacological treatments are apparently involved, but
more research is needed in this area. Patients who are
currently manic or depressed are even more impaired than
those who are euthymic.
Cognitive impairments play a role in the generally
poor social and vocational outcomes in bipolar disorder.
Nevertheless, current therapeutic efforts in bipolar disor-
der are still focused on reduction of mood symptoms and
relies largely on pharmacotherapy. Cognitive behavioral
therapy, psychoeducation, and other psychosocial ap-
proaches have been tried with some success in improving
functional outcomes, but their study has attracted much
less interest than pharmacotherapy. This is an area that
should receive more attention in the future.
There is a controversy whether bipolar disorder and
schizophrenia are distinct categories separated from
each other, or whether they are better conceptualized on
a continuum without categorical separation of the two
entities. Cognitive research has therefore aimed at com-
parisons between these disorders. It has been established
that both bipolar disorder and schizophrenia patients are
cognitively impaired in comparison with healthy controls.
The two patient groups have a similar profile of neuropsy-
chological dysfunction, but the impairments are more
severe in schizophrenia. Thus, the differences between
the impairments in these disorders are quantitative rather
There are strong genetic influences on the risk for
bipolar disorder and schizophrenia, and cognitive impair-
ments have been proposed as potential endophenotypes
for these disorders. Family studies of bipolar disorder sug-
gest the executive function and processing speed as endo-
phenotypes marking the vulnerability to bipolar disorder.
Some studies also provide support for verbal memory in
that role. There may be a common cognitive endopheno-
type shared by bipolar disorder and schizophrenia, but
more data are needed in this area.
This paper was supported by the research grant NT11047
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