Cognitive functioning following stabilisation from first episode mania
Daglas et al. Int J Bipolar Disord
Cognitive functioning following stabilisation from first episode mania
Rothanthi Daglas 0 2
Kelly Allott 0 2
Murat Yücel 1
Lisa P. Henry 2
Craig A. Macneil 6
Melissa K. Hasty 6
Michael Berk 0 2 3 4 5
Sue M. Cotton 0 2
0 Centre for Youth Mental Health, University of Melbourne , 35 Poplar Road, Parkville, VIC 3052 , Australia
1 Brain and Mental Health Laboratory, School of Psychological Sciences & Monash Biomedical Imaging Facility, Monash University , Clayton , Australia
2 Orygen, The National Centre of Excellence in Youth Mental Health , 35 Poplar Road, Parkville, VIC 3052 , Australia
3 Florey Institute for Neuroscience and Mental Health , Kenneth Myer Building, Royal Parade, Parkville , Australia
4 Barwon Health and the Geelong Clinic, Swanston Centre , PO Box 281, Geelong, VIC 3220 , Australia
5 IMPACT Strategic Research Centre, School of Medicine, Deakin University , PO Box 281, Geelong 3220 , Australia
6 Orygen Youth Health- Clinical Program , 35 Poplar Road, Parkville 3052 , Australia
Background: The purpose of this study was to examine cognitive functioning in people following first-episode mania relative to a demographically similar healthy control group. Methods: Forty-one patients, who had recently stabilised from a first manic episode, and twenty-one healthy controls, were compared in an extensive cognitive assessment. Results: First-episode mania participants had significantly lower Full-Scale IQ (FSIQ) relative to healthy controls; however, this finding could be driven by premorbid differences in intellectual functioning. There were no significant differences between groups in Verbal IQ (VIQ) and Performance IQ (PIQ). First-episode mania participants performed significantly poorer than healthy controls in processing speed, verbal learning and memory, working memory, and cognitive flexibility with medium-to-large effects. There were no group differences in other measures of cognition. Conclusions: Participants following first-episode mania have poorer global intelligence than healthy controls, and have cognitive difficulties in some, but not all areas of cognitive functioning. This highlights the importance of early intervention and cognitive assessment in the early course of the disorder.
Bipolar disorder; Cognition; Depression; Manic; Remission
Cognitive impairments during euthymia in people in all
stages of bipolar disorder have been reported by several
meta-analyses, with findings of medium to large effect in
processing speed, verbal learning and memory,
non-verbal memory, working memory, verbal fluency, sustained
attention and executive functions
(Arts et al. 2008; Bora
et al. 2009; Bourne et al. 2013; Mann-Wrobel et al. 2011)
There has been limited research conducted on cognitive
functioning during the early stages of the illness, thus the
timing and onset of cognitive change remains unclear.
Recently, two meta-analyses on adults with first
episode bipolar disorder (including any polarity of illness)
have identified impairments in most cognitive domains
relative to healthy control (HC) participants
and Pantelis 2015; Lee et al. 2014)
. However, a recent
systematic review on first episode mania (FEM) that
included adolescents as well as adult samples, revealed
discrepancies between study findings across most
cognitive domains, apart from a consistently reported deficit in
working memory during remission, and that verbal
fluency and non-verbal memory remained intact (Daglas
et al. 2015). The literature regarding intelligence in FEM
has revealed that patients perform worse than HCs in
(Elshahawi et al. 2011; López-Jaramillo et al.
, and on measures of non-verbal intelligence
(Hellvin et al. 2012; Torres et al. 2010)
; however, the
studies in FEM (included in the systematic review) had not
controlled for the differences observed between FEM
and HC groups in IQ, which may have contributed to
the inconsistencies between study findings
(Daglas et al.
. This is in contrast to a meta-analysis that reported
preserved current IQ in people with established bipolar
(Bora et al. 2009)
. Moreover, there appears to
be a bi-modal pattern regarding school performance in
asymptomatic adolescents (aged 15–16 years) who later
develop bipolar disorder. Those with the highest school
grades displayed a nearly fourfold increased risk of
developing the disorder by age 31, whilst those with the lowest
school performance were found to have close to a twofold
(MacCabe et al. 2010)
. Predictors of lower
intellectual functioning in individuals with bipolar
disorder include an earlier age of onset, greater number of
prior episodes and hospitalisations
(Denicoff et al. 1999)
Although cognitive deficits have been identified during
remission in bipolar disorder, the effects of intelligence,
residual symptoms, medication use, number of
hospitalisations and number of past episodes may impact upon
(Bourne et al. 2013; Donaldson et al. 2003;
Nehra et al. 2006; Thompson et al. 2005; Torres et al.
. The first diagnostic episode for bipolar I disorder
enables the assessment of cognitive functioning prior to
the effects of covariates such as prolonged medication
use and recurrent manic episodes. Most of the studies
conducted to date have included adult samples with FEM
(Daglas et al. 2015)
and have not considered that the
incidence of FEM is greatest between 16 and 30 years
(Kennedy et al. 2005)
, and that there may be developmental
differences in cognition between younger and older
Thus, the aim of the current study was to examine
cognitive functioning of young people (15–25 years)
following FEM relative to a demographically similar HC
group. The cognitive domains considered were
processing speed, attention, sustained attention, verbal learning
and memory, non-verbal learning and memory, working
memory, verbal fluency and executive functions. Due to
diagnostic instability in the early phases of the illness,
and that an accurate diagnosis is on average delayed for
7.5 years in people with bipolar disorder, any
presentation of FEM will be considered in this study
et al. 1999; Schimmelmann et al. 2005)
. It was
hypothesised that FEM participants would perform significantly
worse than HCs in processing speed, attention, sustained
attention, verbal learning and memory, working
memory and executive functions; and that the groups would
not significantly differ in verbal fluency and non-verbal
memory. Furthermore, FEM participants were expected
to perform more poorly than HCs in full-scale IQ (FSIQ)
and performance IQ (PIQ), but that the groups would
have similar verbal IQ (VIQ).
This study involved secondary analysis of baseline
data from a single-blinded Randomised Control Trial
(RCT) conducted at Orygen, The National Centre of
Excellence in Youth Mental Health, Melbourne,
Australia. The focus of the trial was on the effectiveness of
quetiapine fumarate compared to lithium carbonate
monotherapy for the maintenance treatment of FEM
over a 12-month period. This trial was registered with
the Australian and New Zealand Clinical Trials Registry
ACTRN12607000639426. Neuropsychological data were
also collected on a separate HC group that was not part
of the RCT, using the same time-points and measures.
Sample and setting
The FEM patients were recruited between 2006 and 2013
from outpatient clinics of OYH and Monash Health,
located within the Western, North Western and South
Eastern suburbs of Melbourne, respectively. To satisfy
inclusion criteria for the RCT, the FEM patients were
required to have: (1) clinically stabilised from a first
treated manic episode on a combination of quetiapine
and lithium for a least 1 month prior to randomisation
(stabilisation of mental state was based on clinical
judgment by the treating clinicians on the basis of a global
clinical assessment); (2) met Diagnostic and
Statistical Manual of Mental Disorders-Fourth Edition-Text
Revision (DSM-IV-TR; APA, 2000) criteria for bipolar I
disorder, schizoaffective disorder-bipolar type, or a
substance-induced mood disorder; (3) scored a minimum of
20 on the Young Mania Rating Scale (YMRS) during the
first manic episode; and (4) been aged 15–25 years at the
time of recruitment.
FEM patients were excluded if they had a clinically
relevant systemic medical disorder, biochemical or
haematological abnormalities or unstable diabetes mellitus,
were pregnant or lactating, had a sensitivity or allergy to
components of lithium or quetiapine, were non-fluent in
English, had a history of epilepsy, were at immediate risk
of harm to self or others, or had an organic mental
disease including intellectual disability (FSIQ < 70). The use
of potent cytochrome P450 inhibitors and inducers was
also prohibited during the study.
HCs were matched as closely as possible to the FEM
group in age, sex and premorbid intelligence, and were
recruited from similar regions of Melbourne through
advertisements in a freely distributed newspaper at
inner-city metro stations of Melbourne, the Orygen
website, and by word of mouth. Due to recruitment
feasibility, FEM and HC participants were recruited at a ratio of
2:1. Individuals interested in participating contacted the
researchers and were given a detailed description of the
study. Prior to providing informed consent, the HCs were
assessed for current or past mental health disorders with
the screening tool of the Structured Clinical Interview
(Patient Edition) for DSM-IV-TR. HCs were excluded if
they had a history of, or current mental health disorder,
substance abuse or dependence, an FSIQ < 70, or were
not 15–25 years of age.
One assessor (RD) was trained in standardised
neuropsychological testing and clinical assessment of this clinical
population and conducted all assessment components of
the study. The neuropsychological battery was
administered in the same order for all participants and consisted
of psychometrically robust, valid and standardised tests.
Cognitive functions that were assessed included
intelligence, processing speed, attention span, sustained
attention, verbal learning and memory, non-verbal learning
and memory, working memory, verbal fluency and
To measure estimated premorbid intelligence, the
Wechsler Test of Adult Reading (WTAR) was used
Psychological Corporation 2001)
. As a measure of
current intelligence, the Wechsler Abbreviated Scale of
Intelligence (WASI) was utilised
. From the WASI, FSIQ, VIQ and PIQ
scores were derived.
Four tests of processing speed were administered,
including Trail Making Test—part A (TMT-A)
WAIS-III Digit Symbol Coding
computerised Go/No-Go test to assess the reaction time for
(see Takagi et al. 2011)
, and the CogstateTM
(see Hammers et al. 2011, 2012)
Attention span was assessed with WAIS-III Digit
. The computerised Stroop task
for congruent responses, Go/No-Go test for missed go
(see Takagi et al. 2011)
, and CogstateTM
Identification task were used as measures of focused attention
(see Hammers et al. 2011, 2012)
A shorter version of the original Attention Network Test
(ANT) was used to measure sustained attention
et al. 2005)
Verbal learning and memory
The Rey auditory verbal learning test (RAVLT) was
administered to test verbal learning and memory
1983; Rey 1958)
. The correct recall of words in trial 1 was
used as a test of immediate memory, and the total
correct recall of the same list of words in five consecutive
trials was used to measure verbal learning. Delayed
verbal recall was measured by the recall of the same list of
words after a 20-min interval.
Nonv‑erbal learning and memory
The computerised CogstateTM One-card leaning
(see Hammers et al. 2011, 2012)
CogstateTM Groton Maze Learning Test (GMLT)—
delayed recall were used as measures of non-verbal
learning and memory (see Snyder et al. 2005).
The WAIS-III Digit Span-backward was used to measure
working memory capacity
The Controlled Oral Word Association Test was used to
measure semantic (animal category) and phonemic (FAS)
(see Mitrushina et al. 2005)
The Trail Making Test—part B (TMT-B) was utilised to
measure cognitive flexibility
. To assess
inhibitory control, computerised versions of the Stroop
and Go/No-Go tasks were used
(see Takagi et al. 2011)
The CogstateTM GMLT was used as a test of spatial
(see Snyder et al. 2005)
The clinical scales used to assess psychiatric
symptomatology included: the YMRS
(Young et al. 1978)
Montgomery–Åsberg Depression Rating Scale (MADRS)
(Montgomery and Asberg 1979)
; the Brief Psychiatric
Rating Scale (BPRS), total scores and positive psychotic
scores (including the 4 subscales: unusual thought
content, hallucinations, suspiciousness and conceptual
(Overall and Gorham 1962)
; and the Clinical
Global Impression scale—modified for bipolar disorder
(Spearing et al. 1997)
The trial adhered to Good Clinical Practice guidelines,
and was approved by the Human Research Ethics
Committees of Melbourne Health (HREC 2006.644) and
Monash Health (06138B). All participants or legal
guardians (on behalf of participants under 18 years of age)
provided voluntary informed consent. Patients who were
treated with a combination of quetiapine and lithium for
their first acute episode of mania were referred to the
study by the treating psychiatrist or case manager. Once
patients had clinically stabilised and were transferred to
outpatient care, they were provided with a full
description of the study. Cognitive and clinical assessments
occurred once the patients had stabilised and had
commenced monotherapy. The clinical assessment was
conducted on the same day as the cognitive assessment for
most FEM participants (41%). Thirty-one percent of the
FEM participants had the clinical assessment within the
first week, 15% within the 2-weeks and 13% over 2-weeks
of cognitive testing. The time-point for the structured
clinical interview for DSM-IV-TR was within 2–4 weeks
of the cognitive testing.
All statistical analyses were conducted using IBM® SPSS®
Statistics Version 22.0. Descriptive statistics were
calculated for demographic variables, and illness
characteristics. Independent samples t test and Chi-square (χ2)
analyses were performed to assess for between-group
differences on demographic variables. Several outliers
were identified by box plots, and skewness and kurtosis
values revealed that the cognitive data were differentially
distributed within the two groups. Therefore,
non-parametric Mann–Whitney U tests were utilised to compare
groups for each cognitive measure. To control for the
effects of multiple comparisons, family-wise error
adjustments were made per cognitive domain (α =
.05/number of cognitive measures per domain). To determine
absolute values for effect size (r), z scores were divided
by the square root of N (r = Z/√N), as used for
(Fritz et al. 2012)
. According to Cohen’s
(1998) guidelines for r, a small effect size is 0.1, medium
effect size is 0.3 and a large effect size is 0.5
. The relationship between clinical symptom rating
(YMRS, MADRS, BPRS and BPRS—positive psychotic
scores) and cognitive functioning was assessed using
Pearson’s correlation on any measure that showed a
significant difference between FEM participants and HCs
following family-wise adjustment.
The cohort included sixty-one patients who had recently
stabilised from their first treated manic episode. Of the
61 FEM patients, 7 were excluded due to not adhering to
the randomised medication allocation, 2 were deemed
too unwell to participate by their treating psychiatrist,
5 relapsed prior to the first assessment, and 6 withdrew
consent or disengaged from the service. In total, 41 FEM
participants and 21 HCs were included in the study.
Demographic and illness characteristics are presented in
Table 1. The FEM and HC groups did not differ
significantly in age, sex and premorbid intelligence. However,
the difference observed between groups in premorbid
HC (n = 21)
intelligence was of moderate effect (d = 0.57). On average
the HC group had spent more years in education than
the FEM group. The largest percentage of FEM patients
had a diagnosis of bipolar I disorder (85%), 10% had a
substance-induced mood episode and 5% were diagnosed
with schizoaffective disorder-bipolar type. All FEM
participants had experienced a manic or mixed episode with
On average the FEM participants were in remission
from acute mania (YMRS, M = 2.51, SD = 3.57), did not
have positive psychotic symptomatology in the BPRS
(M = 4.63, SD = 1.64), and were rated normal/not ill in
mania severity on the CGI-BP (M = 1.15, SD = 0.573).
However, the FEM participants were on average mildly
depressed (MADRS, M = 7.39, SD = 8.95), as also
identified in the BPRS total psychopathology rating
(M = 33.24, SD = 9.32). FEM participants were
considered minimally ill in depression severity (M = 2.05,
SD = 1.56), and in overall bipolar disorder severity on the
CGI-BP (M = 2.02, SD = 1.49).
The median and minimum/maximum scores for each
group per cognitive measure and the associated test
statistics and effect sizes are presented in Table 2.
FEM participants had significantly lower FSIQ (p = .014)
and PIQ (p = .046) than HCs, with medium (r = .31)
and small to medium effect (r = .26), respectively.
However, PIQ did not remain significant after family-wise
adjustment (i.e. α/3). There was no significant difference
between groups in VIQ (p = .084).
A highly significant group difference was observed
between groups on the TMT-A (p < .001) and digit
symbol coding (p = .002), even after family-wise adjustment
(i.e. α/4). FEM patients performed substantially slower
than HCs with a large (r = .57) and medium (r = .40)
effect size, respectively.
There were no significant differences between groups
in ‘go’ reaction time (p = .480) or CogstateTM Detection
time (p = .668).
The groups did not differ significantly on Digit
Span-forward (p = .532), missed go responses (p = .753), Stroop
congruent total errors (p = .928) or in CogstateTM
Identification time (p = .487).
FEM and HC groups performed similarly in ANT
alerting (p = .785), orienting (p = .677) and executive control
(p = .081). There was no significant difference between
groups in total errors for the no cue (p = .593), spatial cue
(p = .351), double cue (p = .850), congruent (p = .248)
and incongruent (p = .432) conditions.
Verbal learning and memory
FEM patients recalled significantly fewer words in trial
1 of the RAVLT relative to HCs (p = .002), of medium
effect (r = .39). FEM patients recalled significantly fewer
words than HCs in trials 1–5 (p < .001) and in delayed
verbal recall (p < .001), which were both of a medium to
large effect size (r = .47). These differences remained
significant after family-wise adjustment (i.e. α/3).
Nonv‑erbal learning and memory
There were no significant group differences in the OCL
task (p = .609) or in the GMLT-delayed recall (p = .187).
FEM patients had poorer working memory capacity than
HCs, with a highly significant difference between groups
in Digit Span-backward (p = .001) with medium to large
effect (r = .44).
There was no significant difference between groups in
phonemic fluency (p = .122). FEM participants produced
significantly fewer words than HCs in semantic fluency
(p = .045), though, this difference did not remain
significant after family-wise adjustment (i.e. α/2).
A large difference was observed in cognitive
flexibility with FEM patients performing worse than HCs in
TMT-B (p = .004), even after family-wise adjustment (i.e.
α/5), with a medium effect size (r = .37).
Groups did not differ significantly with respect to
response inhibition in Go/No-Go false alarm responses
(p = .063), in Stroop incongruent total errors (p = .974),
or in Stroop effect (p = .794). Additionally, no significant
group differences were observed in spatial problem
solving as assessed by GMLT (p = .502).
Relationship between clinical symptomatology and cognition
A significant negative correlation was found between
rating scores on the YMRS and the RAVLT trial 1 (p = .033)
with a moderate effect size (r = − .333). There also
was a significant negative relationship between
symptom rating on the YMRS and scores on the RAVLT
trials 1–5 (p = .029), which was of a moderate effect size
(r = − .342). Furthermore, a significant negative
correlation was found between general psychopathology rating
(BPRS total) and the RAVLT trials 1–5 (p = .008), which
was of a moderate to large effect size (r = − .408). There
were no other significant correlations found between
clinical symptom rating scales and cognition.
The purpose of this study was to investigate cognitive
functioning in youth following FEM. FEM patients were
found to have lower FSIQ than HCs. While the groups
were statistically matched in estimated premorbid
intelligence, the difference in premorbid IQ was of medium
effect and so the difference in current FSIQ may be driven
by true pre-existing group differences or the inherent
difficulties encountered matching FEM and HC on
premorbid intelligence. Furthermore, FEM patients were still
within the average intelligence range when compared to
norms of people from a similar age group. Furthermore,
the groups did not significantly differ in verbal and
performance IQ after controlling for multiple comparisons.
Previous research has been mixed showing that patients
following FEM had poorer global intellectual functioning
compared to HCs
(Elshahawi et al. 2011; López-Jaramillo
et al. 2010)
and that FEM patients and HCs did not
differ in verbal IQ, though FEM patients performed more
poorly than HCs in subtests of performance IQ, including
Block Design (Hellvin et al. 2012) and spatial reasoning
(Hellvin et al. 2012; Torres et al. 2010)
Our findings indicate that FEM patients displayed
cognitive impairments in some, but not all areas of cognitive
functioning. First, as expected FEM patients performed
worse than HCs in tests of processing speed, verbal
learning and memory, working memory and cognitive
flexibility. Second, phonemic verbal fluency and
nonverbal learning and memory were not impaired relative
to HCs; and differences observed in sematic verbal
fluency were no longer apparent after family-wise
adjustment. Contrary to our hypothesis, there were no group
differences found in attention span, sustained attention
or in the computerised tests of psychomotor speed and
response inhibition. Although findings in the literature
examining cognitive functioning in the early stages of
bipolar disorder is somewhat mixed
(Daglas et al. 2015)
the results from the current study are generally
comparable to the majority of research findings in FEM.
Regarding processing speed, Elshahawi et al. (2011) also
revealed impairments in FEM patients relative to HCs as
assessed by TMT-A and Digit Symbol Coding.
Additionally, Hellvin et al. (2012) found that FEM patients
performed worse than HCs in Digit Symbol Coding, whilst
reporting no difference between groups in Stroop
performance. On the other hand, Torres et al. (2010) found that
FEM patients and HCs performed alike in both Stroop
and in TMT-A. Another study by López-Jaramillo et al.
(2010) reported a similar performance between FEM
patients and HCs in TMT-A and in Digit Symbol
Coding; however, this study had recruited relatives of the
FEM patients as HCs, which may have influenced their
findings. It has been reported that first-degree relatives
of people with bipolar I disorder have a slower ability to
process information than those without a family history
of psychiatric illnesses
(Antila et al. 2007)
Deficits in working memory have been reported by
most first episode studies across the bipolar disorder
spectrum relative to HCs
(Barrett et al. 2009; Elshahawi
et al. 2011; Hellvin et al. 2012; Hill et al. 2009;
LópezJaramillo et al. 2010)
. However, two studies that assessed
working memory using the letter–number sequencing
(LNS) task failed to find a significant difference between
(Torres et al. 2010; Zanelli et al. 2010)
explanation for this may be that FEM patients may have a
weaker activation of the phonological loop required for
verbal memory encoding (as in the Digit Span task), but
may have maintained the ability to process more complex
information, such as the interaction required between
visuospatial functions, processing speed, and working
memory when switching between letters and numbers in
(Crowe 2000; Haut et al. 2000)
Our study revealed that FEM patients had deficits
in verbal learning and memory, but spared non-verbal
learning and memory. Notably, when either mania or
general psychopathology symptoms increased, verbal
learning and memory performance decreased. Similar to
our findings, Torres et al. (2010) reported that patients
who had recently experienced a first episode of mania
recalled significantly fewer words than HCs. Whilst,
another study failed to find a significant difference
between groups in total words recalled (trials 1–5), there
were a significantly higher percentage of FEM patients
(24%) who had clinically impaired verbal learning on the
task (1.5 standard deviations below the mean of the HC
group) than HCs (5%)
(Hellvin et al. 2012)
in delayed verbal recall have also been reported by
previous studies in people with bipolar disorder experiencing
their first episode of mania or psychosis
(Hellvin et al.
2012; Zanelli et al. 2010)
Most research on first episode patients across the
bipolar spectrum has revealed that non-verbal learning
and memory remains intact
(Hellvin et al. 2012;
LópezJaramillo et al. 2010; Torres et al. 2010; Zanelli et al.
. Only one study of patients with bipolar disorder
in remission from their first episode of psychosis
identified a deficit in non-verbal memory
(Barrett et al. 2009)
Furthermore, a study on individuals at ultra-high risk for
psychosis identified impaired visual reproduction relative
to HCs, in patients who later developed a first episode
(Brewer et al. 2005)
. A deficit in non-verbal
memory has also been identified in patients with
recurrent bipolar disorder
(Arts et al. 2008)
dysfunction in non-verbal memory may reflect a deficit primarily
related to psychosis or more chronic forms of bipolar
disorder that appears to remain unaffected following FEM.
Our finding that attention was not impaired is
consistent with the majority of first episode studies in bipolar
(Hellvin et al. 2012; Hill et al. 2009;
López-Jaramillo et al. 2010; Torres et al. 2010)
. Although one study
identified impairment in attention span in FEM patients
relative to HCs, this study was limited by their
recruitment of hospital employees from the same hospital as the
FEM patients for the HC group, and therefore may not
have been truly representative of the general population
(Elshahawi et al. 2011).
Furthermore, our finding of no deficit in sustained
attention is contrary to a previous study by Torres et al.
(2010), who found that FEM patients performed
significantly worse in this domain than HCs. The inconsistency
between these study findings may be largely attributed
to the different tests that were administered. The
sustained attention task used in the current study required
the unique activation of alerting, orienting and executive
control pathways, which is a variation from more
commonly used tests of sustained attention such as the rapid
visual information processing task. However, as there has
only been one previous study that has assessed sustained
attention in FEM, further studies are required in respect
to this domain.
In accordance with the recent systematic review on
(Daglas et al. 2015)
, both phonemic and semantic
verbal fluency remained intact in the current study of
FEM patients. Whilst a recent meta-analysis in the first
episode bipolar disorder identified deficits in verbal
fluency, these were of small effect and were observed in
only two studies
(Lee et al. 2014)
. However, these studies
had compared adult FEM patients to a poorly matched
HC group in age, sex and/or education level
(Nehra et al.
2006; Zanelli et al. 2010)
Furthermore, we identified that there were no
impairments in most domains of executive function, except
for cognitive flexibility. Cognitive inflexibility has been
reported in the acute state of FEM
(Fleck et al. 2008)
Most studies on patients following FEM have reported
that cognitive flexibility remained intact relative to HCs
(Hellvin et al. 2012; López-Jaramillo et al. 2010;
Torres et al. 2010)
, with the exception of Elshahawi et al.
(2011) who identified deficits in cognitive flexibility
during remission in patients who had FEM with psychotic
features relative to HCs. Most studies in FEM
during the acute state
(Lebowitz et al. 2001)
(López-Jaramillo et al. 2010; Torres et al. 2010)
in support of our finding that response inhibition is not
impaired following FEM. The deficits in response
inhibition identified by one study of FEM patients who were
predominantly depressed at the time of testing may have
been reflective of the ongoing mood symptoms (Hellvin
et al. 2012). A study by
Malhi et al. (2007
) identified that
depressed patients with bipolar disorder had significantly
poorer response inhibition than HCs, a finding that
was not observed for either the euthymic or hypomanic
The decline in cognitive functioning with illness
progression has been elucidated by studies comparing FEM
patients to those with multiple episodes
(Elshahawi et al.
2011; Hellvin et al. 2012; López-Jaramillo et al. 2010;
Torres et al. 2010)
. Relative to findings of widespread
cognitive impairments in people with chronic forms of
bipolar disorder, our findings suggest that specific deficits
in processing speed, verbal learning and memory,
working memory and cognitive flexibility might occur from
the early stages of the illness. It may be postulated that
the impairments reported in attention, sustained
attention, non-verbal memory, verbal fluency and other
executive functions may result from recurrent episodes
et al. 2009; Bourne et al. 2013; Mann-Wrobel et al. 2011;
Torres et al. 2007)
, as reported deficits in these domains
are largely inconsistent in studies in FEM
(Daglas et al.
. Neuroimaging studies have provided evidence in
support of neuroprogression in bipolar disorder, with
findings of prefrontal, cerebellum volume and
ventricular abnormalities seen in patients with recurrent
episodes relative to first episode patients or HCs
et al. 1999; Mills et al. 2005; Strakowski et al. 2002)
structural brain abnormalities pertaining to the
subgenual prefrontal cortex, have also been identified early in
the course of the illness, which may reflect the cognitive
deficits in the specific domains observed by studies in
(Strakowski et al. 2005)
Amongst the strengths of this study is the
relatively large sample size of a specified group of
psychiatric patients recruited from a naturalistic treatment
environment. Given the sample size, post hoc power
analyses indicated that we had sufficient power at .80 to
detect moderate to large effects when α was set at .05.
Additionally, in this study we administered an
extensive cognitive battery, which covered several cognitive
domains and included computerised cognitive testing to
increase sensitivity in identifying deficits. Importantly,
the FEM participants were matched as closely as
possible to the HC group in age and sex. We also attempted
to match the groups as closely as possible on
premorbid intelligence; however, the FEM group had an
average premorbid intelligence score 6.8 lower than the HC.
Although the between-group difference in premorbid
intelligence was not statistically significant, it was of
moderate effect and might have explained the differences
between groups in specific cognitive domains. It was not
possible to control for premorbid intelligence and other
factors (e.g. education) in non-parametric analyses.
However, it is argued, that clinically such a difference is not
necessarily meaningful and both groups had mean
premorbid intelligence scores that would be considered in
the average or normal range. Also highlighted are the
difficulties matching patient and healthy control groups on
Other limitations included that stabilisation from acute
mania was based on clinical judgment without use of an
objective mania cut-off score, and on average the FEM
participants were mildly depressed. Medication effects
may have influenced cognitive functioning; it would
be methodologically ideal but ethically questionable to
include a medication-naive group. Although this study
utilised a catchment area service, the generalisability of
our results is limited to individuals who had stabilised
from a FEM with psychotic features, representing the
more severe end of the bipolar spectrum. The findings of
this study are also not generalisable to people following
stabilisation from first episode mania on other
medications. Additionally, this study did not exclude FEM
participants with comorbidities such as substance abuse
disorders, which may have impacted the findings. Also,
due to the cross-sectional nature of this study, it is not
possible to assess whether cognitive deficits existed prior
Our findings revealed lower global intelligence in people
following FEM may be evident prior to the onset of FEM,
as well as specific cognitive deficits in processing speed,
verbal learning and memory, working memory, and
cognitive flexibility. These findings highlight the necessity of
cognitive testing early in the course of the disorder. Amid
the clinically relevant findings of this study, the
differences observed in verbal learning and memory compared
to non-verbal learning and memory may inform tailored
interventions to address potential difficulties in
functioning in people with FEM. Future research on the
trajectory of cognitive functioning following FEM and the
associated effects of treatment medications over time is
MB, MY, MKH, CAM, SMC and LPH were involved in the original study design
and conduct of the project. RD, was a PhD candidate who collected the data,
analysed the data and prepared the first draft of the paper; SMC was her
principal supervisor and MB, KA,\ and MY were co-supervisors. All authors read
and approved the final manuscript.
Sue Cotton is supported by a NHMRC Career Development Fellowship
1061998. Kelly Allott is supported by a Ronald Philip Griffiths Fellowship,
The University of Melbourne. Murat Yücel is supported by a NHMRC Senior
Research Fellowship 1021973. Michael Berk is supported by a NHMRC Senior
Principal Research Fellowship 1059660, and has received Grant/Research
Support from the NIH, Cooperative Research Centre, Simons Autism Foundation,
Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC,
Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol
Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon,
Novartis, Mayne Pharma, Servier and Woolworths, has been a speaker for
Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag,
Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth, and
served as a consultant to Astra Zeneca, Bioadvantex, Bristol Myers Squibb,
Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck Merck and Servier. For the
remaining authors, none were declared. This article is the authors’ original
work, has not received prior publication, and is not under consideration for
Availability of data and materials
Data are available on request to MB.
Consent for publications
There are no individual person’s data in this article.
Ethics approval and consent to participate
This study was granted institutional approved by the Melbourne Health
Human Research and Ethics Committee (MHREC 2006.044) and Southern
Health Human Research and Ethics Committee (06138B).
This study involved baseline analyses from an RCT that received an
investigator-initiated grant by AstraZeneca. This funding source had no influence on
the study design and was not involved in data collection, data analysis and
interpretation of the results.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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