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Cognitive deficits in bipolar disorder: from acute episode to remission

Article in European Archives of Psychiatry and Clinical Neuroscience · April 2016

DOI: 10.1007/s00406-015-0657-2

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Eur Arch Psychiatry Clin Neurosci
DOI 10.1007/s00406-015-0657-2
ORIGINAL PAPER
Cognitive deficits in bipolar disorder: from acute episode
to remission
J. Volkert1 · M. A. Schiele2 · Julia Kazmaier2 · Friederike Glaser2 · K. C. Zierhut2 ·
J. Kopf1 · S. Kittel‑Schneider1 · A. Reif1
Received: 31 July 2015 / Accepted: 12 November 2015
© Springer-Verlag Berlin Heidelberg 2015
Abstract Considerable evidence demonstrates that neu-
ropsychological deficits are prevalent in bipolar disorder
during both acute episodes and euthymia. However, it is
less clear whether these cognitive disturbances are state-
or trait-related. We here present the first longitudinal study
employing a within-subject pre- and post-testing examin-
ing acutely admitted bipolar patients (BP) in depression
or mania and during euthymia, aiming to identify cogni-
tive performance from acute illness to remission. Cogni-
tive performance was measured during acute episodes and
repeated after at least 3 months of remission. To do so, 55
BP (35 depressed, 20 hypo-/manic) and 55 healthy con-
trols (HC) were tested with a neuropsychological test bat-
tery (attention, working memory, verbal memory, executive
functioning). The results showed global impairments in
acutely ill BP compared to HC: depressed patients showed
a characteristic psychomotor slowing, while manic patients
had severe deficits in executive functioning. Twenty-nine
remitted BP could be measured in the follow-up (dropout
rate 48 %), whose cognitive functions partially recovered,
whereas working memory and verbal memory were still
Electronic supplementary material The online version of this
article (doi:10.1007/s00406-015-0657-2) contains supplementary
material, which is available to authorized users.
* J. Volkert
julia.volkert@kgu.de
1
Department of Psychiatry, Psychosomatic
Medicine and Psychotherapy, Goethe-University,
Heinrich‑Hoffmann‑Straße 10, 60528 Frankfurt am Main,
Germany
2 all illness phases, with a moderate worsening of a subset
Department of Psychiatry, Psychosomatics
and Psychotherapy, University of Wuerzburg,
Fuechsleinstrasse 15, 97080 Würzburg, Germany
impaired. However, we found that subthreshold depressive
symptoms and persisting sleep disturbances in euthymic
BP were associated with reduced speed, deficits in atten-
tion and verbal memory, while working memory was cor-
related with psychotic symptoms (lifetime). This result
indicates working memory as trait related for a subgroup
of BP with psychotic symptoms. In contrast, attention and
verbal memory are negatively influenced by state factors
like residual symptoms, which should be more considered
as possible confounders in the search of cognitive endophe-
notypes in remitted BP.
Keywords Bipolar disorder · Cognition ·
Neuropsychological functioning · Depression · Mania ·
Remission
Introduction
Bipolar disorder (BD) is a recurrent and highly disabling
affective disorder characterised by mood swings as well as
cognitive disturbances. Impairments in psychomotor speed,
attention, working memory, long-term memory, and execu-
tive functions have been consistently reported both dur-
ing acute episodes of depression and mania [1] as well as
during euthymia, albeit in a milder form [2]. In contrast
to extensive investigations of neurocognitive functioning
in euthymic bipolar patients (BP), relatively few studies
have characterised changes in cognition across different
phases of the illness. A meta-analysis of cognitive function-
ing in euthymic, manic/mixed, and depressed BP revealed
severe impairments across neuropsychological domains in
of deficits in acute states [1]. Cross-sectional studies dem-
onstrated that manic, mixed, and depressed BP perform
13

worse (especially in verbal memory and executive func-
tioning) compared to healthy controls (HC), whereas no
or only marginal differences have been reported between
depressed and (hypo-)manic BP [3–5]. This is surprising
regarding the clinical presentation of cognitive patterns in
the two phases: during mania, hyperactivity, thought rac-
ing, flight of ideas, disinhibited behaviour and pressure
of speech predominate, whereas depression is typically
accompanied by psychomotor slowing, fatigue, egocentric
restriction of thinking, and ruminations, all of which impair
cognitive speed. Several neuropsychological studies aimed
to objectify cognitive dysfunctioning during acute episodes
of BD and found similar deficits in attention, memory, and
executive functions in bipolar and unipolar depression [6,
7], while cognitive deficits in acute mania seem to overlap
with impairments found in psychosis [8, 9].
In addition, an emerging body of research demonstrates
that cognitive disturbances in BD persist during remission
[10], at least in a subgroup of BP [11–13]. However, up
to now studies in euthymic BP are inconsistent and have
failed to report cognitive deficits specific to euthymic BD.
The identification of trait-related variables, however, would
be helpful in studies on the pathophysiology of BD. Fur-
thermore, stable trait markers could help to identify persons
with high risk of the disease and thus could facilitate early
diagnosis, prevention, and treatment options. Furthermore,
cognitive disturbances that persist in the absence of clinical
symptomatology may point to a genetically driven neuro-
cognitive endophenotype [14]. Within-subject longitudinal
studies across different mood states are the gold standard
to determine whether cognitive deficits in BD are trait- or
state-dependent. However, so far there is little systematic
research on the longitudinal course of cognitive functioning
in different clinical states in BD patients. Chaves et al. [15]
investigated clinically stable but symptomatic BD outpa-
tients in a pre- and post-testing over a period of 3 months.
The authors assessed changes in mood symptoms in rela-
tion to cognitive test performance at baseline and follow-
up. They found that BP showed persistent impairments in
psychomotor speed and attention over time. Neuropsycho-
logical measures were not influenced by variations in affec-
tive symptoms with the exception of verbal fluency and
verbal long-term memory, both of which were influenced
by depressive symptoms. In contrast, Malhi et al. [16]
investigated mood state-related cognitive deficits in BD
over a period of 30 months across all three phases of the ill-
ness. Due to the small sample size, only four patients could
be followed up in all three phases (depression, mania, and
euthymia), and eight patients in two phases of the disorder.
The authors found modest impairments in attention, mem-
ory, and executive tasks in depressed and manic patients,
while cognitive functions were largely normal during
euthymia, showing only subtle impairments in attention
13
Eur Arch Psychiatry Clin Neurosci
and memory. Similarly, a recent longitudinal study by Xu
et al. [17] compared 223 bipolar patients and 293 unipolar
depressed patients at baseline and after 6 weeks of treat-
ment. In comparison with healthy controls (HC), bipo-
lar and unipolar depressed patients were characterised by
similar patterns of cognitive impairment (reduced speed,
memory, verbal fluency, and executive functioning). During
clinical remission, test performance in both patient groups
improved, with the exception of deficits in speed and visual
memory, which points to trait-like cognitive impairments in
those domains. However, it should be noted that patients in
this study were in a relatively unstable state as follow-up
took place immediately after remission.
In summary, longitudinal studies on the course of cog-
nitive impairments in BD are rare, inconsistent, depend on
small samples and interpretation is limited due to meth-
odological issues. The aim of the present study was there-
fore to detect changes in cognitive performance from acute
episodes to euthymia in BD. We investigated BP suffer-
ing from acute depression or (hypo-)mania longitudinally
(follow-up after at least 3 months of remission). Based on
previous findings, we expected cognitive impairments in
acutely ill BP compared to a sample of HC [1]. Specifi-
cally, we hypothesised that depressed BP would show psy-
chomotor slowing and attentional deficits [7], while (hypo-)
manic BP would be impaired in frontal-executive functions
like working memory, cognitive flexibility, and response
inhibition [8]. Regarding cognitive functioning over time,
we assumed BP to improve during remission in all cogni-
tive domains, but to still show mild cognitive disturbances
compared to HC. Neuropsychological performance in HC
should be stable over time. Furthermore, based on previous
findings, we hypothesised that only a subgroup of remitted
BP show cognitive deficits [11]. Finally, we were interested
in the relationship between cognitive performance and
demographic, clinical, and treatment variables of the bipo-
lar sample.
Materials and methods
This study was performed at the Bipolar Disorder Program
of the Department of Psychiatry, Psychosomatics and Psy-
chotherapy, University Hospital Wuerzburg. All procedures
followed the Declaration of Helsinki in its latest version
and were approved by the ethical committee of the medical
faculty at the University of Wuerzburg. Written informed
consent was obtained from all participants.
Participants
A total of 55 inpatients with BD (diagnosed according to
DSM-IV criteria by an experienced psychiatrist) and 55
Eur Arch Psychiatry Clin Neurosci
HC participated in the study. Groups were matched for sex,
age, and years of education. Participants were 18–55 years
old and native German speakers. Intellectual abilities
were estimated via the German multiple-choice word
test (MWT-B) [18]. BP were initially assessed (baseline)
during an acute episode of depression (N = 35), mania
(N = 15), or hypomania (N = 5), all leading to inpatient
treatment. Within the acutely depressed sample, 20 patients
were diagnosed with BD type I and 15 with BD type II.
Of the (hypo-)manic patients, 15 were diagnosed with BD
type I and 5 with BD type II. Follow-up assessment took
place the first time 3 months after discharge. Patients had
to be euthymic for at least 3 months before the follow-up
testing was conducted. If patients were not fully remitted
at this 3-month mark, they were frequently contacted until
they reported having been euthymic for at least 12 weeks.
On average, follow-up took place after 21.1 ± 5.3 weeks.
At both, baseline and follow-up, affective symptoms of BP
were measured with clinical interviews and questionnaires.
We applied the observer-rating scales Montgomery–Asberg
Depression Ratings Scale (MADRS) [19], the Young
Mania Rating Scale (YMRS) [20], and the self-rating
questionnaire Beck Depression Inventory, Second Edition
(BDI-II) [21]. Criteria for euthymia were rating scores of
MADRS < 12, BDI-II < 15 and YMRS < 5 points. Further-
more, patients had to be on a stable medication for at least
4 weeks at follow-up to qualify for follow-up assessment.
Exclusion criteria for BP were previous head trauma, neu-
rological illnesses, schizoaffective disorder, or present sub-
stance abuse. Patients who had received electroconvulsive
therapy (ECT) in the preceding 6 months were excluded as
well. HC (N = 55) were recruited via Web-based announce-
ments. They were screened for history of DSM-IV Axis I
disorder by the Mini International Neuropsychiatric Inter-
view, German Version 5 [22]. Furthermore, persons with
a history of substance abuse/taking of psychotropic drugs
and neurological diseases were excluded. Similar to BP,
HC were tested in an initial and a follow-up assessment of
approximately 3-month interval (13.3 ± 1.3 weeks).
At the follow-up testing, 26 of 55 BP could not be
retested in a euthymic mood state for the following reasons:
7 BP (27 %) did not reach full remission during the full
observation period, 9 BP (35 %) had relapsed, 6 BP (23 %)
were lost during follow-up, and 4 BP (15 %) did not wish
to participate at follow-up. Comparison of completers and
non-completers revealed that patients who did not take part
again were characterised by a higher number of episodes
in their life (t = −1.79, p = .079), especially of depressive
phases (t = −2.34, p = .024). Furthermore, they displayed
higher MADRS scores at the initial assessment (t = 1.90,
p = .063), indicating a higher load with depression. Groups
did not differ in other clinical variables.
Clinical assessment
The following clinical characteristics (lifetime presence)
of BP were recorded via structured interviews with the
patients, their relatives, and clinical records: number of
episodes (depression, mania/hypomania, mixed episodes),
bipolar subtype, age at illness onset, number of hospitalisa-
tion, polarity of the first episode, attempted suicides, sub-
stance abuse, psychotic symptoms, medication, ECT, fam-
ily history of mental disorders, and comorbid somatic (e.g.
thyroid diseases) or mental illnesses, especially anxiety dis-
orders and attention deficit disorder (ADHD). Patients were
asked whether they had persistent sleep disturbances (ini-
tial or middle insomnia) in the week preceding the inter-
view. Additionally, MADRS item 4 (reduced sleep) was
analysed separately in order to assess sleep disorder in our
sample. Furthermore, current mood of all participants was
recorded using the self-report Positive and Negative Affect
Scale (PANAS) [23] prior to neuropsychological testing. In
order to assess psychosocial functioning, all patients were
evaluated by the clinician with the Global Assessment of
Functioning Scale (GAF) [24].
Neurocognitive assessment
We conducted a 60-min neuropsychological testing
(including a 5-min break). Five standardised tests were
administered in a fixed order by the same trained, expe-
rienced clinical psychologist (JV). Except the California
Verbal Learning Test, all tests were computerised and par-
allel forms were used for the follow-up testing. Tests were
selected based on evidence of sensitivity to cognitive defi-
cits in bipolar disorder (see Table 1).
Statistical analysis
All statistical tests were performed using the Statistical
Package for Social Sciences (SPSS), version 22.0 (IBM
Corporation, Armonk NY, USA). For all tests, the signifi-
cance level was set at p < .05 and Bonferroni–Holm cor-
rection for multiple testing was applied. Chi-square tests
and analyses of variance (one-way ANOVAs) were used
to compare demographic variables and current mood by
group. In case of a significant F test, post hoc t tests were
calculated. Neurocognitive and clinical variables were
checked for outliers and normal distribution (Kolmogorov–
Smirnov test). Given that all test measures (except compat-
ible trials of Stroop Test) were not normally distributed, we
conducted nonparametric tests. We used the Kruskal–Wal-
lis one-way analysis of variance to test whether the three
groups [depressed BP, (hypo-)manic BP, and HC] dif-
fered from each other on the baseline assessment. In case
13
 Eur Arch Psychiatry Clin Neurosci

Table 1  Neuropsychological tests

Cognitive domain Test Dependent variables

Psychomotor speed Compatible trials of the Stroop Test [66] Reactions times (RT) in ms
Attention Subtest Divided Attention, Test battery of Attentional Number of omissions
Performance (TAP) [67]
Short- and long-term memory California Verbal Learning Test (CVLT) [68] Scores of total verbal learning, immediate and delayed
recall
Executive functioning Subtest Working Memory (n-back task of the TAP) Number of omissions
Cognitive Flexibility (shifting task of the TAP) Number of errors
Incompatible trials of the Stroop Test [66] Response inhibition (interference score)

of significant group differences, we conducted post hoc our sample of euthymic BP was very small, and the corre-
Table 2  Demographic characteristics of depressed and (hypo-)manic bipolar patients (BP) and healthy controls (HC)
Depressed BP (N = 35) Manic BP (N = 20) HC (N = 55) F/χ2 p value Post hoc t tests
N/Mean (SD) N/Mean (SD) N/Mean (SD)

Age 37.1 (11.7) 43.9 (9.7) 39.5 (9.6) 2.82 .064 –

Gender f/m 17/18 14/6 35/25 2.44 .296 –
Years of education 11.1 (1.7) 10.6 (1.6) 11.1 (1.5) 0.68 .505 –
Verbal IQa 104 [13] 109 (12) 106 (12) 3.18 .080 –
PANASb PAc (baseline) 20.9 (6.4) 33 (7.9) 32.8 (5.3) 45.5 <.001*** M > HC > D
PANAS NAd (baseline) 16.9 (5.8) 15.3 (5.3) 11.1 (1.4) 25.1 <.001*** HC < D&M
PANASPA (follow-up) 28.5 (7.9) 30.9 (6.2) 32.1 (5.5) 2.59 .081 HC > D
PANAS NA (follow-up) 13.5 (3.9) 13.7 (2.2) 11 (1.8) 10.60 <.001*** HC < D&M
a
Verbal IQ via multiple-choice word test (MWT-B)
b
Positive and Negative Affect Scale [momentary mood prior the testing at baseline and follow-up]
c
Score positive affect
d
Score negative affect

Mann–Whitney U tests.
In a subsequent step, Wilcoxon signed-rank tests were
used to check for differences in the repeated measurements
of each group. In order to check the test–retest reliability
of the neuropsychological tests, we examined performance
of HC over time and calculated Pearson correlation coef-
ficients for each test between the initial and follow-up
assessments. Test–retest reliability was considered good
if baseline and follow-up were significantly correlated
(p < 0.01).
Furthermore, we compared the clinical characteristics of
completers and non-completers (dropout analyses) using
Student t tests. Finally, exploratory correlational analyses
(Pearson coefficients) were conducted to assess associa-
tions between test performance and demographic/clinical
and treatment variables of BP. In order to control the influ-
ence of age on cognitive measures, we calculated partial
correlations with age as the covariate. We did not apply a
correction of p values in this exploratory analysis, because
lational analysis was not the main hypotheses of the paper.
Results
Sample characteristics
Demographic characteristics and current mood at base-
line and follow-up of depressed/(hypo-)manic BP and HC
are presented in Table 2. There were no group differences
regarding age, gender, verbal IQ, and years of education
between groups. Mood ratings (measured by PANAS score)
at the initial assessment showed a significantly reduced
positive and increased negative affect in depressed patients
compared to (hypo-)manic patients and HC. At follow-up,
BP showed reduced positive and increased negative affect
compared to HC, despite being euthymic.
Depressed and (hypo-)manic BP did not differ from
each other in their drug regimen with the exception of

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Eur Arch Psychiatry Clin Neurosci

Table 3  Mood ratings and medication of depressed and (hypo-)manic bipolar patients at baseline (acute) and follow-up (euthymic)
Depressed BP (Hypo-)manic BP
2
Baseline (acute) Follow-up (euthymic) t/X p Baseline (acute) Follow-up (euthymic) t/X2 p
(N = 35) (N = 20) (N = 20) (N = 9)

Mood ratings
MADRS 24.3 (5.8) 7.5 (2.9) 15.6 <.001*** 7.6 (4.8) 4.2 (2.7) 4.1 .003**
BDI-II 22.4 (10.1) 8.4 (5.7) 3.7 .002** 5.6 (4.8) 6.2 (3.7) −0.4 .709
YMRS 2.5 (1.5) 0.7 (0.9) 5.9 <.001*** 11.6 (2.7) 1.4 (2.6) 9.6 .000***
Medication
Antidepressants 27 (77.1 %) 15 (75 %) 4.4 .073 3 (15 %) 1 (11.1 %) 5.9 .154
Antipsychotics 25 (71.4 %) 13 (65 %) 12.1 <.001*** 16 (80 %) 6 (66.7 %) 5.1 .083
Lithium 19 (54.3 %) 12 (60 %) 16.3 <.001*** 11 (55 %) 4 (44.4 %) 5.7 .040*
Other MSa 10 (28.6 %) 7 (35 %) 12.4 .001** 5 (25 %) 1 (11.1 %) 9.0 .111
Benzodiazepines 6 (17.1 %) 2 (10 %) 2.1 .284 2 (10 %) 0 (0 %) – –

BP bipolar patients, MADRS Montgomery–Asberg Depression Rating Scale, BDI-II Beck Depression Inventory, YMRS Young Mania Rating
Scale
a
Mood stabilisers: valproate, carbamazepine, lamotrigine

antidepressant add-on therapy, which was prescribed sig-
nificantly more often in acutely depressed patients (see
Table 3). Overall, 11 (37.9 %) of patients had an altered
drug regimen at follow-up as compared to the initial meas-
urement. HC were completely medication free. At follow-
up, patients reported being in a euthymic state over a period
of 15.4 (SD 2.8) weeks. Mood ratings in the acute and
remitted sample are demonstrated in Table 3. GAF scores
indicated a marginal reduced psychosocial functioning in
euthymic BP (M = 76.5; SD 9.9).
Comparison of cognitive performance between acutely
ill bipolar patients and healthy controls (baseline
testing)
Acutely depressed and (hypo-)manic BP showed a sig-
nificantly reduced test performance compared to HC in
the test measures. However, some group differences did
not reach level of significance after the correction of the p
value according to Bonferroni–Holm method for multiple
testing. The results in Table 4 demonstrate that depressed
BP showed a significantly reduced psychomotor speed and
a lower response inhibition (reading colours, Stroop Test)
compared to HC. (Hypo-)manic BP showed a significantly
reduced performance in Working Memory. Both patient
groups were characterised by more omission errors in the
test assessing divided attention (trend). No significant dif-
ferences in total verbal learning (CVLT) and Cognitive
Flexibility were observed between depressed, (hypo-)manic
BP, and HC (for more detail, see Table 4). In the acutely
admitted bipolar sample, 51 BP (92.7 %) showed cogni-
tive deficits (cut-off score: at least one test measure 1.5 SD
below the average of normative data group), while only
four (depressed) BP (7.3 %) showed a test performance in
the normal range of the normative data group. These four
patients without cognitive deficits differed not in clinical or
demographic variables compared to acutely ill patients with
cognitive deficits.
Comparison of cognitive performance
between euthymic bipolar patients and healthy controls
(follow‑up testing)
At follow-up, euthymic BP differed significantly from HC
in Working Memory and delayed verbal memory. Although
we found marginal reduced performances in the other test
measures in euthymic BP compared to HC, differences did
not reach level of significance (see Table 5). In comparison
with the normative data of each test, 17 (58.6 %) euthymic
BP performed below the average in at least one test meas-
ure (cut-off score: 1.5 SD below the average of normative
data group), while 12 BP (41.4 %) showed no cognitive
deficits at all. The extent of cognitive deficits during remis-
sion was not associated with the test performance during
the acute episode.
Change in cognitive performance (baseline to follow‑up)
in bipolar patients and healthy controls
Differences in repeated measurements of each group
were analysed using the Wilcoxon signed-rank test.
Depressed BP showed an improvement from baseline
to follow-up in the compatible trials of the Stroop Test
Reading (Z = −2.98, p = .003) and Naming (Z = −2.49,
p = .013), a marginal improvement in the immediate verbal
recall (Z = −1.71, p = .088) and the Stroop Test Naming

13
 Eur Arch Psychiatry Clin Neurosci

Table 4  Group analyses of cognitive performance (baseline) in acutely depressed, (hypo-)manic bipolar patients and healthy controls
Cognitive domain Depressed BP baseline Manic BP baseline HC baseline Analysis of group differences
(N = 35) Mean (SD) (N = 20) Mean (N = 55) Mean Kruskal–Wallis p valuea Post hoc Mann–Whit-
(SD) (SD) X2 test ney U test

Psychomotor speed
Stroop Reading compatible 799 (119) 772 (107) 725 (72) 17.94 .001** HC > D
(RT)
Stroop Naming compatible 770 (118) 720 (116) 673 (81) 12.57 .016* HC > D
(RT)
Attention
Divided Attention (Omis- 2.1 (2.1) 2.2 (1.4) 1.2 (1.3) 9.34 .054 HC > D&M
sions)
Memory
CVLT (total verbal learn- 60.2 (10.1) 57.8 (11.2) 61.2 (7.2) 1.44 .488 –
ing)
CVLT (immediate recall) 11.7 (2.3) 11.7 (2.8) 13.1 (1.8) 7.02 .120 –
CVLT (delayed recall) 11.2 (2.5) 11.8 (2.6) 13.3 (2) 6.67 .180 –
Executive functions
Working Memory (Omis- 2.9 (3) 4.9 (4.3) 1.6 (1.9) 13.5 .009** HC > M
sions)
Cognitive Flexibility 3.1 (5.1) 4.8 (7.6) 1.5 (1.9) 5.5 .128 –
(Errors)
Stroop Reading incompat- 225 (152) 181 (104) 134 (78) 10.58 .028* HC > D
ible (RT)
Stroop Naming incompat- 121 (71) 183 (102) 119 (66) 6.19 .135 –
ible (RT)

BP bipolar patients, HC healthy controls, D depressed patients, M (hypo-)manic patients, CVLT California Verbal Learning Test, RT reaction
time in ms
a
p value corrected by Bonferroni–Holm method

(Z = −1.77, p = .077). (Hypo-)manic patients showed an
improvement in the Working Memory task (Z = −2.67,
p = .008) and the Stroop Test Naming (Z = −2.07,
p = .038). A detailed table of the test statistics of changes
in cognitive performance can be found in the supplemen-
tary material (table S1). Figure 1 illustrates z score trans-
formation of the test scores (healthy controls as reference)
of acutely depressed, (hypo-)manic, and euthymic patients
in order to facilitate comparison of the cognitive profile of
the different clinical states of illness.
Performance of HC improved in the same tests as BP,
namely the compatible trials of the Stroop Test (Z = −4.82,
p < .001), the immediate recall of the CVLT (Z = −3.16,
p = .002), and the Working Memory task (Z = −2.09,
p = .036). This indicates learning and practice effects in
these subtests. Thus, we calculated test–retest reliability by
Pearson correlations, which revealed that with the exception
of Cognitive Flexibility, initial and follow-up performance
scores were highly correlated, indicating good test–retest
reliability for the compatible trials of Stroop Test Reading
(r12 = .887, p < .001) and Naming (r12 = .815, p < .001),
Divided Attention (r12 = .490, p < .001), CVLT total verbal
learning (r12 = .577, p < .001), CVLT immediate recall
(r12 = .664, p < .001), CVLT delayed recall (r12 = .579,
p < .001), Working Memory (r12 = .556, p < .001), Cogni-
tive Flexibility (r12 = .152, p = .246), and the incompatible
trials of the Stroop Test Reading (r12 = .654, p < .001) and
Naming (r12 = .531, p < .001).
Association of cognitive performance and clinical
variables in BP
In order to test for associations between clinical variables
and cognitive functioning in the euthymic BP, exploratory
correlational analyses were conducted. We found signifi-
cant influences of subthreshold depressive symptoms and
sleep disturbances on cognitive deficits in BD after con-
trolling for age (see Table 6). Psychomotor speed (compat-
ible trials of Stroop Reading) was associated with MADRS
score (p = .036) and reduced sleep (p = .015); Stroop Test
Naming was correlated with reduced sleep (p = .018).
Divided Attention was associated with BDI-II depression
score (p = .036) and reduced sleep (p = .039). Total verbal
learning (CVLT) was correlated with MADRS (p = .013),

13
Eur Arch Psychiatry Clin Neurosci

Table 5  Group analyses of cognitive performance (follow-up testing) in euthymic bipolar patients and healthy controls
Cognitive domain Euthymic BP follow-up HC follow-up Analysis of group differences
(N = 29) Mean (SD) (N = 55) Mean (SD) Mann–Whitney U test p valuea

Psychomotor speed
Stroop Reading compatible (RT) 749 (115) 697 (75) 584.5 .315
Stroop Naming compatible (RT) 717 (129) 656 (84) 597.5 .360
Attention
Divided Attention (Omissions) 1.5 (2.1) 0.9 (1.3) 674.5 .872
Memory
CVLT (total verbal learning) 58.2 (9.1) 59.8 (8.4) 711.5 .836
CVLT (immediate recall) 12.3 (2.1) 13.4 (2.5) 550.0 .152
CVLT (delayed recall) 11.9 (2.5) 13.6 (2.2) 469 .020*
Executive functions
Working Memory (Omissions) 2.0 (1.7) 1.1 (1.4) 500.5 .027*
Cognitive Flexibility (Errors) 2.4 (2.6) 1.6 (1.8) 655.5 .855
Stroop Reading incompatible (RT) 165 (145) 130 (59) 738.5 .579
Stroop Naming incompatible (RT) 139 (113) 107 (64) 693.5 .984

BP bipolar patients, HC healthy controls, CVLT California Verbal Learning Test, RT reaction time in ms
a
p value corrected by Bonferroni–Holm method

Fig. 1  Mean z score trans- 2

formations of test scores of
depressed, (hypo-)manic, and 1.8 *
euthymic bipolar patients (z
scores were calculated using 1.6
mean and SD values of sample Depressed BP
of healthy controls) (*signifi- 1.4
cant differences after Bonfer-
(Baseline)
1.2 * *
roni–Holm correction; for
details, see Tables 4 and 5) 1 ** Manic BP
(Baseline)
0.8 *
* Euthymic BP
0.6
(Follow-up)
0.4
0.2
0

BDI-II (p = .006), and reduced sleep (p = .001), and with YMRS (p = .030). Furthermore, higher BDI-II scores
delayed recall in the CVLT was associated with MADRS were associated with more errors in the Cognitive Flex-
(p = .025), BDI-II (p = .021), and reduced sleep ibility test (p = .019). Therefore, impairment in most test
(p = .009). Interestingly, short-term recall was correlated measures was associated with subclinical depression and/

13
 Eur Arch Psychiatry Clin Neurosci

Table 6  Association (rpartial) of clinical characteristics and test performance (follow-up testing) of euthymic bipolar patients
Pearson correlation (rp, age as covariate)
MADRS BDI YMRS Sleep Age at onset Duration Total epi- Depressive Manic Psychotic Anti-psy-
illness sodes episodes episodes symptoms chotics

Psychomotor speed
Stroop .450* .308 .137 .453* −.104 .104 .099 .037 .089 −.166 −.041
Reading
compatible
(RT)
Stroop .322 .367 .232 .445* .046 −.046 −.042 −.124 −.036 −.094 .118
Naming
compatible
(RT)
Attention
Divided .302 .391* .271 .385* .251 −.085 .160 .117 .137 −.245 .160
Attention
(Omis-
sions)
Memory
CVLT (total −.481* −.520** −.033 −.596** −.028 .043 −.185 −.123 −.217 .322 −.364
verbal
learning)
CVLT −.276 −.332 −.427* −.166 −.310 .305 .365 .113 −.016 .221 −.067
(immediate
recall)
CVLT −.438* −.452* −.181 −.502** −.203 .199 −.057 −.079 −.159 .337 −.144
(delayed
recall)
Executive functions
Working .313 .337 .171 .268 .213 −.099 −.048 .006 .091 .432* −.104
Memory
(Omis-
sions)
Cognitive .101 .434* .075 .353 .303 −.295 −.210 −.101 .016 −.140 .125
Flexibility
(Errors)
Stroop .066 .260 .064 −.092 .258 −.258 −.266 −.312 −.188 −.144 .047
Reading
incompat-
ible
Stroop .229 .127 −.139 .160 .185 −.095 −.036 −.071 .012 .027 −.029
Naming
incompat-
ible

Significant correlations are indicated in bold

MADRS Montgomery–Asberg Depression Rating Scale, BDI-II Beck Depression Inventory, second edition, YMRS Young Mania Rating Scale,
CVLT California Verbal Learning Test, RT reaction time in ms
* p < .05; ** p < .01

or sleep disturbances except for Working Memory, which
was significantly associated with psychotic symptoms
(lifetime) (p = .015). There was no association of cogni-
tive performance and other clinical characteristics indicat-
ing disease severity such as number of previous episodes
or age of onset. Given these results suggesting that mood
symptoms have a negative effect on cognition in euthymic
BP, we expected to see the same pattern in acutely ill BP.
However, the performance in the test measures was not cor-
related with depression scores in acutely depressed BP or
YMRS scores in (hypo-)manic patients, respectively.
Psychosocial functioning was assessed using the GAF.
In euthymic BP, we found negative correlations between
GAF score and omission errors in the Working Memory

13
Eur Arch Psychiatry Clin Neurosci
task (r = −.454, p = .013) and reaction time in compat-
ible trials of the Stroop Test (r = −.562, p = .002). Fur-
thermore, reduced mnestic performance was highly associ-
ated with low psychosocial functioning, as indicated by a
positive correlation between GAF score and verbal learning
(CVLT) (r = .529, p = .003).
Discussion
The present within-subject longitudinal study investigated
the neurocognitive performance of bipolar inpatients in an
acute episode of depression or (hypo-)mania and during
remission. We found broad impairments in cognitive speed,
attention, working memory, verbal memory, and execu-
tive functioning in acutely admitted BP compared to HC.
As expected, depressed and (hypo-)manic patients showed
a different cognitive profile, in that depressed patients had
slowed reaction times while (hypo-)manic patients were
more impaired in executive functioning. However, the dif-
ferences were marginal and only the performance in the
Stroop Test (Naming of colour words with incongruent ink)
differed significantly between depressed and (hypo-)manic
BP. After at least 3 months of remission BP performance
generally improved, albeit we found persisting impairments
in working memory and delayed verbal memory. Further-
more, we confirmed previous data in that at least some cog-
nitive measures were associated with subthreshold depres-
sive symptoms and sleep disturbances of euthymic BP, but
not with clinical variables indicating severity of illness
[11]. In addition, we found strong associations between
worse cognitive performance and reduced daily life func-
tioning (GAF score). This is in line with previous investiga-
tions demonstrating that neuropsychological performance
predicts functional adjustment [25].
Cognitive impairments in acutely ill bipolar patients
In detail, we specified the clinical presentation of cogni-
tive disturbances in acutely depressed BP, in that patients
suffered of reduced psychomotor speed compared to
(hypo-)manic patients and HC. Furthermore, patients
were impaired in divided attention and response inhibi-
tion (Stroop Test Reading). This is in line with previ-
ous studies which demonstrated a cognitive slowing and
attentional deficits in acutely depressed BP [7, 26–28],
and also in executive functioning [29–31]. However, atten-
tion and cognitive speed are very basic processes which
underlie other cognitive functions, and deficits in atten-
tion can thus lead to greater distractibility and interference
effects [32]. Therefore, deficits in executive functioning in
depressed BP could be secondary to attentional deficits.
Similarly to the depressed sample, (hypo-)manic patients
showed considerable deficits in divided attention and work-
ing memory. Accordingly, previous investigations found
impaired cognition in manic patients, especially regarding
deficits in frontal-executive measures [8, 33, 34]. There-
fore, we confirmed a different cognitive profile during
depression and (hypo-)mania, in that the test performance
of depressed BP was comparable to the cognitive deficits
found in major depression [6, 7], and the cognitive per-
formance of (hypo-)manic patients was similar to deficits
found in psychosis [8, 9]. Interestingly, our results showed
that the differences between depressed and (hypo-)manic
BP were only marginal, and with the exception of the
Stroop Test, they did not reach significance. Possibly, the
neuropsychological tests are not sensitive enough to depict
the marginal differences of a depressive and hypomanic
symptomatology.
Cognitive deficits in remitted bipolar patients
Due to these difficulties in interpreting cognitive abilities
in acutely ill BP regarding the pathophysiology of the dis-
order, it is important to investigate the long-term course
within subjects. Unfortunately, longitudinal studies about
cognitive deficits in BD are rare and our study is one of
the few performing a follow-up measurement after stable
remission. We found that patients’ neurocognitive perfor-
mance improved after 3 months of remission. Particularly,
depressed BP no longer displayed a reduced psychomotor
speed compared to HC. (Hypo-)manic patients improved
significantly in the Working Memory task. However, even
in an euthymic mood state, our sample of BP showed sig-
nificant deficits in working memory and delayed verbal
memory compared to HC. This coincides with previous
studies which demonstrated an impaired verbal memory
[35–37] and working memory [5, 38, 39] as prominent
deficits of BD. Furthermore, we found that 58.6 % of our
sample showed cognitive impairments, while 41.4 % had a
test performance within the average of the normative data
group. Therefore, we confirmed previous study results that
only a subgroup of euthymic BP seems to have cognitive
deficits [11, 12].
We found that performance in working memory was exten-
sively reduced in patients with acute (hypo-)mania and in
remitted patients who reported psychotic symptoms (lifetime).
Working memory deficits have been demonstrated as core
impairment in psychotic disorders, and BP were suggested to
have comparable deficits to schizophrenic patients, albeit less
severe [40, 41]. Interestingly, Simonsen [42] showed that neu-
rocognitive dysfunction in BD and schizophrenia was deter-
mined more by the history of psychosis than by the diagnos-
tic category or subtype. These results indicate that deficits in
working memory may be related to neuronal changes related
to the psychotic spectrum. In addition, there is evidence of
13

structural abnormalities in brain regions associated with work-
ing memory in BD [43]. Neuroimaging studies have shown
altered neuronal activation within the brain network involved
in working memory tasks [44]. Most imaging studies in
BD reported a loss of connectivity in prefrontal and parietal
networks, structures that are well known to be involved in
working memory [45]. Taken together, there is evidence that
working memory is a trait biomarker in BD although being
aggravated by acute symptomatology in our study. Also our
correlational analyses are in favour of this hypothesis: psycho-
motor speed, attention and verbal memory were significantly
associated with residual symptoms (MADRS, BDI-II, and
sleep disturbances). On the contrary, working memory was not
correlated with any actual mood symptoms, which is in agree-
ment with a recently published study about predictors of cog-
nition in euthymic BP [11]. In line with these results, impair-
ments in executive functions including working memory were
considered as salient endophenotypic components of cogni-
tion in BD as they persist in remission, appear to be heritable,
and hence co-segregate within families [46, 47]. Therefore,
our study provides further evidence that working memory
could serve as a potential neurocognitive endophenotype in
remitted BP.
Association between cognition and clinical variables
Regarding the clinical characteristics of our bipolar sam-
ple, we found no relationship between test measures and
disease characteristics indicating severity of the disorder
(e.g. number of episodes, age of onset, bipolar type). How-
ever, subclinical mood symptoms and sleep disturbances
were associated with cognitive speed, attention, and verbal
memory. Although patients with bipolar disorder have his-
torically been characterised as returning to full remission
between affective episodes, recent studies demonstrated
that some residual symptoms may persist [48, 49]. It has
been previously demonstrated that subthreshold mood
symptoms are associated with impairments in attention
and verbal memory [11, 50–52]. In a study by Bonnin et al.
[53], the degree of cognitive functioning was best predicted
by subdepressive symptoms, and a meta-analysis reported
that more rigorously defined euthymia goes along with
smaller cognitive impairments [2]. Therefore, it seems that
the neuronal circuitry activated in the modulation of emo-
tions overlaps with brain regions involved in neurocogni-
tion. Besides subclinical depressive symptoms, 37 % of our
remitted bipolar sample reported sleep disturbances like
initial or middle insomnia or an abnormal increased sleep-
ing time. Rates of sleep disturbances are usually very high
in remitted BP [54, 55], and BD is highly associated with
sleep and circadian rhythm abnormalities [49, 56, 57]. It is
well known that sleep deprivation in healthy people causes
cognitive deterioration [58, 59]. Furthermore, it has been
13
Eur Arch Psychiatry Clin Neurosci
demonstrated that sleep and circadian rhythms are involved
in the cognitive deficits in BD through overlapping neuro-
biological systems [60]. In our bipolar sample, sleep distur-
bances were associated with impairments in psychomotor
speed, divided attention, and verbal learning. In a recently
published study, we reported accordingly that several cog-
nitive impairments in euthymic BP were predicted by sleep
disorder [11]. Taken together this underscores the need
for more extensive research on the influence of sleep dis-
turbances on cognitive deficits in BD. In conclusion, our
results suggest that residual symptoms negatively affect
cognitive functioning in BD. Therefore, an optimised
antidepressant treatment and sleep regulation should be
enforced in patients complaining about cognitive impair-
ments. Even though our results do not disprove the idea of
neurodegenerative processes in BD [1], our data underscore
the importance of residual symptoms. This also has impli-
cations for future research and calls for the improvement of
treatment options for cognitively impaired BP.
Comparable to the influence of subdepressive symptoms
on test performance of euthymic BP, we expected a relation-
ship between severity of depression and test performance
in acutely ill BP. Very surprisingly though, we did not find
associations between the severity of depression or (hypo-)
mania and neurocognitive measures in acutely admitted
BP. This might well be due to a ceiling effect of the effect
on affective measures on neuropsychological impairment.
Finally, it has to be discussed how much time patients need
to fully recover after an acute episode. We defined a period
of 3 months of euthymia preceding neurocognitive assess-
ment in order to ensure a relatively stable state. Neverthe-
less, some of the remitted BP reported residual symptoms.
Interestingly, in a recent study, Torres et al. [61] investigated
first-episode patients three times within the first year follow-
ing their initial manic episode. Patients’ cognitive function-
ing was improved 6 months after discharge and even further
at follow-up after 1 year. Therefore, it seems that it takes a
long time to fully cognitively recover after an acute episode,
and we recommend more research on BP who have been
remitted for a period of at least a year although these studies
are inherently difficult to conduct.
Limitations
Among the limitations of the present study is the rela-
tively small sample size, especially at follow-up, which is
inherent to these types of studies. This nevertheless raises
the possibility of selective attrition and whether non-sig-
nificant findings can be related to insufficient statistical
power. Indeed, we found that patients who dropped out
had a higher load with depression (more number of pre-
vious depressive episodes and higher depression scores at
baseline). Therefore, the study completers may have a less
Eur Arch Psychiatry Clin Neurosci
severe progress of disease. Due to the naturalistic nature
of the study, we had only limited control of pharmacologi-
cal effects on cognition. Although there were no statistical
differences between depressed and (hypo-)manic groups
on that regard, the effects of medications for bipolar disor-
der on cognition are not totally understood [62]. As some
BP had changes in drugs and dosing within the interval
between baseline and follow-up, interpretation of changes
in cognitive performance is limited. In particular, (hypo-)
manic patients received antipsychotics at baseline and
drugs were tapered at follow-up. A methodological prob-
lem which has to be addressed is to determine the extent of
practice effects in the pre-post-testing. We thus included a
sufficient sample size of HC to calculate test–retest reliabil-
ity allowing to control for practice effects.
Summary and conclusions
Although these limitations warrant attention, the results of the
present study add the existing literature to cognitive function-
ing in BD. To our knowledge, this is the first study present-
ing within-subject pre- and post-testing with acutely admit-
ted BP in depression or (hypo-)mania and during euthymia.
We found that cognitive deficits in BD are exacerbated dur-
ing acute episodes and partially recover during remission.
Working memory and verbal memory were still impaired in
euthymic BP compared to HC, indicating these two cogni-
tive domains as trait-related. The present study demonstrated
that “state” factors like subclinical symptoms and persisting
sleep disturbances contribute to cognitive impairment and are
potential confounders in the search of cognitive endopheno-
types in BD. Furthermore, our results implicate the need for
interventions that improve cognitive dysfunctions in remitted
BP. In the clinical setting, an optimised antidepressant treat-
ment and sleep regulation could improve cognitive deficits
which are caused by residual symptoms. Moreover, some
studies demonstrated promising results in that euthymic BP
benefit from a cognitive training with regard to neurocog-
nitive and psychosocial functioning [63–65]. However, to
clarify trait versus disease process effects in cognition in BD,
more studies with a prospective design, especially with high-
risk groups and first-episode patients, are needed.
Acknowledgments We acknowledge all participants who took
part in the present study. JV was supported by a grant of the German
Excellence Initiative to the Graduate School of Life Sciences, Uni-
versity of Wuerzburg. JK and AR received support by the DFG and
Laender funds RTG 1253/2 “Gk emotions”, AR and KZ received sup-
port by the DFG-funded study “earlyCBT” (BA 1504/7-1), AR and
MAS received support by the DFG-funded study SFB TRR 58 Z02,
and AR was supported by the Comprehensive Heart Failure Center
Wuerzburg funded by the BMBF (project 01EO1004).
Author contributions JV and AR designed the study and wrote the
protocol. JV assisted the literature searches and analyses, undertook
the statistical analysis, and wrote the first draft of the manuscript. All
authors contributed to and have approved the final manuscript.
Compliance with ethical standards
Conflict of interest None of the authors have conflict of interest with
the contents of this paper or financial ties to disclose.
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