Stanley Research Centre, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, UK
Correspondence: Professor A. H. Young, Stanley Research Centre, School of Neurology, Neurobiology and Psychiatry (Psychiatry), University of Newcastle upon Tyne, Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. Tel: +44 (0)191 2824473; fax +44 (0)191 2275108; e-mail: a.h.young{at}ncl.ac.uk
Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To assess neurocognitive functioning in prospectively verified euthymic patients with bipolar disorder.
Method Sixty-three patients with bipolar disorder and a matched control group completed a comprehensive neurocognitive test battery. Euthymia was confirmed in the patient group by prospective clinical ratings over 1 month prior to testing. Saliva samples were collected to profile basal cortisol secretion.
Results Patients were significantly impaired across a broad range of cognitive domains. Across the domains tested, clinically significant impairment was observed in 3% to 42% of patients. Deficits were not causally associated with residual mood symptoms or hypercortisolaemia.
Conclusions Neurocognitive impairment persists in patients whose bipolar disorder is in remission. This may represent a trait abnormality and be a marker of underlying neurobiological dysfunction.
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INTRODUCTION |
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METHOD |
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Euthymia was prospectively defined as scores of 7 or below on both the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960) and the Young Mania Rating Scale (YMRS; Young et al, 1978) at initial assessment and after 1 month. Patients also completed the Beck Depression Inventory (BDI; Beck et al, 1961) and the Altman Mania Rating Scale (AMRS; Altman et al, 1997) each week during the euthymia verification month. Saliva samples collected at 08.00 h, 12.00 h, 16.00 h and 20.00 h on the day before testing confirmed that patients were eucortisolaemic (i.e. exhibited normal rhythm and secretion of cortisol), as measured by directed disequilibrium radioimmunoassay. With the exception of 3 patients who were taking no medication, all patients were stabilised on prophylactic medication at test; 40 were receiving combination treatment. Demographic and clinical characteristics of the sample are presented in Table 1.
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For the control group, 63 healthy volunteers were recruited from the community by local advertisement. Controls were matched on an individual basis with patients for age (±5 years), gender, race, handedness (Briggs & Nebes, 1975), years of education (±3 years), and premorbid IQ (±5 IQ points; Nelson, 1982). Controls were screened for significant medical conditions and were excluded if they had a current or past psychiatric illness (confirmed by SCID) or a family history of affective disorders in a first-degree relative, or were taking any medication other than the oral contraceptive pill. Control participants completed the same clinical ratings as patients on the study day, 1 week after completing a pre-screen AMRS and BDI.
For all participants, historic and current substance use was assessed using DSMIV criteria and a detailed inventory was derived from the major DSMIV substance classifications. To exclude people with current alcohol misuse, participants had to have a current alcohol intake of less than 28 units per week for men and 21 units per week for women. The Modified Mini-Mental State Examination (Teng & Chui, 1987) was administered on the study day to screen for dementia. The local ethics committee approved the investigation.
Neuropsychological measures
Participants completed a comprehensive battery of neurocognitive tests
spanning four broad cognitive domains. To control for the possible effects of
diurnal variation on performance, cognitive testing commenced at 14.00 h.
Tests were administered according to standard instructions and took about 2 h
to complete. The tasks were given in the same order to the whole sample. The
instruments administered for each domain were as follows:
The SOPT and CANTAB tasks were presented on a 486 microcomputer fitted with a high-resolution 38 cm touch-screen monitor. Detailed descriptions of the CANTAB tasks are provided in Robbins et al (1997) and further details regarding the pen-and-paper measures in Lezak (1995).
Statistical analyses
Analyses were conducted using the Statistical Package for the Social
Sciences, version 9 (SPSS,
1998). Data were first examined to see whether they fulfilled the
assumptions for parametric analyses. Variables fulfilling these assumptions
were analysed by independent samples t-test or analysis of variance
(ANOVA), with group (patient or control) as the between-subject factor. For
tests with more than one level and the cortisol data, an additional
within-subject factor of time or problem level was
added. Where sphericity was violated, within-subject degrees of freedom were
adjusted using GreenhouseGeisser or HuynhFeldt corrections as
appropriate. Adjusted P values are reported, although the original
degrees of freedom are also reported for clarity. Data not fulfilling the
assumptions of parametric analyses were either subjected to an appropriate
transformation or analysed non-parametrically
(Howell, 1997).
To calculate clinically significant performance impairments, the proportion
of patients scoring on or below the fifth percentile was determined (i.e.
1.64 standard deviations from the mean of the control sample).
Estimates of effect size were calculated for untransformed data using the
formula
(µpatientsµcontrols)/pooled
(Howell, 1999); the first part
of this equation was reversed for tasks where a high score indicates poorer
performance (i.e. µcontrolsµpatients) to
standardise the scoring schemes across tasks. All reported P values
are two-tailed. To examine the impact of illness severity on neurocognitive
performance, correlations between illness characteristics and neurocognitive
test variables were calculated using Spearmans method.
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RESULTS |
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Basal salivary cortisol measures
Basal salivary cortisol samples were collected from 54 people in the
control group and 56 patients. Comparison between patients and controls
illustrated the expected main effect of time
(F(3,324)=99.18, P<0.0001) but no main effect
of group (F(1,108)=1.13, P=0.29) or
groupxtime interaction (F(3,324)=0.54,
P=0.56). Overall cortisol output did not differ between the groups
(P>0.2).
Cognitive measures
Group mean performance and statistical comparisons for all cognitive
measures are summarised in Table
2. In tests comprising a delay or difficulty level variable, only
main effects and interactions involving group variables are reported below:
main effects of delay or difficulty level were significant in all cases
(excluding Vigil latency and omissions) but are not presented here. In
Table 3, outcome measures from
each test are sorted by effect size, with Cohens conventions used to
indicate small, medium and large effects
(Cohen, 1988). The proportion
of patients scoring at or below the fifth percentile of the control group is
also presented.
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Psychomotor performance
Patients response times were significantly slower than the control
group on the Vigil task. There was no groupxtime interaction
(F(3,369)=0.438, P=0.67), suggesting that
patients were impaired throughout the task. Patients were also significantly
slower than controls to complete part A of the Trail Making Test and produced
significantly fewer correct responses on the Digit Symbol Substitution
Test.
Attention and executive function
In contrast to the performance deficit on part A of the Trail Making Test,
patients and controls did not significantly differ on part B of this task. On
the Vigil task, patients made significantly more errors of omission than
controls; however, commission errors did not differ between groups. Analysis
of omission errors across time revealed that patients were impaired throughout
this task, indicated by the absence of a significant groupxtime
interaction (F(3,369)=0.833, P=0.471).
Patients performance was also significantly poorer than that of the
control group on the Stroop task and their response accuracy on the Tower of
London task was impaired. On the latter tasks latency measures,
patients motor initiation and motor execution times were significantly
greater than those of the controls, as were their overall initial and
subsequent thinking times. However, when the motor times were subtracted from
the thinking times to provide indices of planning times per se,
patients initial and subsequent response times did not differ
significantly from controls. No groupxlevel interaction was present
across any Tower of London index (P0.169). On the Controlled Oral
Word Association Test, patients generated significantly fewer correct
responses than controls, but made no more perseverative responses, and they
recalled significantly fewer digits on the Digits Backward test. On the SOPT,
there was a significant main effect of group, as patients made significantly
more errors than controls, but no groupxset-size interaction
(F(3,309)=0.632, P=0.586). For Spatial Working
Memory between-search errors there was a significant main effect of group,
with patients making significantly more errors than controls, but again no
groupxlevel interaction (F(2,248)=0.931,
P=0.387); however, on this tests strategy index,
patients scores were no different from controls.
Immediate memory
Unlike their performance on the Digits Forward task, patients CANTAB
Spatial Span scores were significantly below those of the controls.
Declarative memory
Patients performance was no different from that of controls on the
CANTAB Pattern Recognition Memory task, but they showed significant impairment
on the Spatial Recognition Memory task. On the CANTAB Matching to Sample tasks
there was no between-group difference when the stimuli were presented
simultaneously. On the delayed trials, however, patients performance
was significantly poorer than controls. The absence of a
groupxdelay interaction (F(2,240)=0.867,
P=0.422) suggests that the deficit is not delay-dependent. On the
Paired Associates Learning test patients required significantly more trials
than controls to complete the task. Patients also completed fewer sets
successfully and located fewer patterns correctly after a single
presentation.
Patients verbal learning was significantly poorer than that of controls (RAVLT trials A1A5). Patients performance was also impaired on the RAVLT distracter word list recall trial (list B), post-interference recall (trial A6), number of targets correctly identified on the recognition trial, and on the standard index of delayed recall (A7). However, when the delayed recall index was modified to control for the confounding effects of patients reduced encoding (see footnote 3 in Table 2), patients performance did not differ from controls, suggesting that retention in long-term memory per se is intact. Also, patients committed no more errors of commission than did controls on the RAVLT recognition trial and their immediate span (trial A1) was intact.
Post hoc multivariate analysis by neurocognitive domain
Studies of neurocognitive function are frequently at risk of type I error
because of the number of comparisons conducted in the analysis. Multiple
comparisons are a product of the need to use several tasks to profile the
range of different neurocognitive processes. One approach that has been
suggested to overcome this problem is to group together tests and outcome
measures that have some degree of theoretical overlap
(Stevens, 2002), i.e. apply to
a specific neurocognitive domain. This method was therefore adopted and it
confirmed that a significant multivariate statistic (Hotellings trace)
was present in each of the four domains (from
Table 2): psychomotor
performance (MANOVA=0.244, F=9.86, P<0.001), attention
and executive function (MANOVA=0.492, F=3.33, P<0.001),
immediate memory (MANOVA=0.061, F=3.63, P=0.029) and
declarative memory (MANOVA=0.2389, F=2.17, P=0.014).
Effects of residual mood symptoms
Residual mood symptoms have been found to impair cognition in affective
disorders (Ferrier et al,
1999; Clark et al,
2002). As patients mood scores on many of the clinical
rating scales used in this study were significantly higher than those of
controls, a series of analyses were performed to rule out this potential
confound on the observed deficits. Correlations between the clinical rating
scales and neurocognitive tests illustrating between-group differences were
first calculated, to establish which deficits might have been influenced by
mood. Partial correlations were subsequently performed on any cognitive index
that significantly correlated with the mood ratings, to examine whether the
previously observed between-group differences on these indices remained when
the effect of mood on performance was partialled out. These analyses
illustrated that 11 cognitive indices correlated significantly with the rating
scales. However, when the effects of mood on these variables were controlled,
all between-group effects remained significant (apart from subsequent thinking
time on the Tower of London task) when the BDI scores on the day of test and
at week 4 were partialled out (P=0.066).
Relationship between illness characteristics and neurocognitive function
To restrict the number of correlations computed between the illness
characteristics and the neurocognitive test variables, only those indices
illustrating between-group differences were examined. In addition, only the
most representative variable from each of the cognitive tasks was included.
The results of these analyses are presented in
Table 4.
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Relationship between basal cortisol levels and neurocognitive function
Correlations between cortisol area under the curve and neurocognitive
indices were also examined for patients and controls separately. In patients,
the only significant correlations observed were for the Stroop
colourword latency (rs=-0.330, P=0.015),
Tower of London excess moves (rs=-0.312, P=0.022)
and verbal fluency on the Controlled Oral Word Association Test
(rs=0.303, P=0.025). In controls, no significant
correlation was observed (data not shown).
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DISCUSSION |
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Previous neuropsychological findings in bipolar disorder
Our findings are consistent with a growing body of evidence that people
with bipolar disorder experience a range of cognitive deficits during disease
remission (van Gorp et al,
1998; Ferrier et al,
1999; Rubinsztein et
al, 2000; Clark et
al, 2002; Martinez-Aran
et al, 2004). Many studies have used structured
interviews and standardised rating scales to demonstrate the euthymic status
of patients, but generally their sample sizes were smaller than ours and
prospective follow-up or cortisol measurements were not recorded. The majority
of studies to date have typically defined patients as impaired on the basis of
a between-group difference (from controls) on an arbitrarily selected
significance level. However, although a result might be statistically
significant, this says nothing about the size of the effect, nor does it
guarantee that it is clinically important. Few studies have provided data on
the number of patients falling within the clinically impaired range on
particular tasks, despite normative data being readily available to do so (but
see Rubinsztein et al,
2000). We sought to address this by providing effect sizes
alongside statistical significance tests and by calculating the percentage of
patients falling below the fifth percentile on the measures employed.
Magnitude of the impairment: statistical v. clinical significance
Previous studies have reported deficits in up to 32% of people with bipolar
disorder (Astrup et al,
1959; Bratfos & Haug,
1968; Dhingra & Rabins,
1991; Martinez-Aran et
al, 2000). Our results demonstrate that the proportion
affected is extremely variable and is dependent upon the particular task
employed. For example, for tasks within a medium to large effect size, on
average 25% of patients scored at or below the fifth percentile, although on
some tasks (such as the Digit Symbol Substitution Test) the proportion was
over 33%. This figure averaged almost 15% for tasks falling in the small to
medium effect size range. Even for tasks with little or no between-group
difference (i.e. d<0.2), clinically significant deficits were
still evident in some individuals. This is of particular clinical importance
because these deficits were observed in a cohort of patients who had been
euthymic for an average of 27.3 months (median 14 months), suggesting that
neurocognitive impairment persists long beyond the point of symptomatic
recovery. The enduring nature of this impairment is also highlighted by the
absence of association between the length of time patients had been in
remission and the extent of neurocognitive impairment.
Factors affecting neurocognitive impairment in bipolar disorder
All but three of the patients in this study were receiving medication at
the time of testing, therefore the effects of psychotropic drugs on
neurocognitive functioning cannot be excluded. Lithium use, for example, has
been shown to have subtle but definite effects on several domains, including
psychomotor speed and possibly verbal memory. Similarly, antidepressants have
been shown to have cognitive effects, particularly those with anticholinergic
properties (Amado-Boccara et al,
1995). However, in their review, Bearden et al
(2001) suggest that the
cognitive impairments in bipolar illness are unlikely to be a primary effect
of medication. In a comparison study of euthymic patients with bipolar
disorder and controls, neurocognitive impairment was observed not only in
patients receiving mood-stabiliser monotherapy but also in those who were
drug-free (Goswami et al,
2002). None the less, many patients with this disorder take
several psychotropic medications at varying doses, and it is unknown what the
effects of combined therapy might be, particularly over time. Similarly,
although ECT may affect neurocognitive function in some patients, only half
the patients in our study had ever received ECT and a negative effect of the
number of previous treatments on performance was observed on a small number of
tests.
Different rates of neurobiological abnormalities among patients with bipolar disorder may also affect the pattern and magnitude of neurocognitive impairment. Elevated cortisol levels have been shown to impair specific domains of neurocognitive functioning, both in studies in which synthetic glucocorticoids were administered exogenously and in patient groups with chronically elevated endogenous cortisol levels (e.g. Cushings disease). As hypothalamicpituitaryadrenal axis dysfunction in bipolar disorder may also persist in a proportion of euthymic patients (Watson et al, 2004), in our study saliva samples were collected on the day prior to testing to provide a simple, non-invasive assessment of basal cortisol secretion. No difference between patients and controls was observed, potentially excluding this confound. However, basal cortisol profiling is relatively insensitive compared with activating challenges such as the dexamethasone/corticotrophin releasing hormone test, which might be more informative in future studies (Watson et al, 2004).
Several studies have reported that residual mood symptoms may affect the degree of neurocognitive dysfunction observed in euthymic patients with bipolar disorder (Ferrier et al, 1999; Clark et al, 2002). When residual mood symptoms were statistically controlled in our study, all between-group differences remained with the exception of one. As we recruited a larger cohort than in the earlier studies, residual symptoms may exert only subtle effects on performance and are less problematic when the statistical power of the study is increased. The observed impairment is therefore unlikely to be an epiphenomenon of mood.
Clinico-cognitive correlations: disease process or trait deficit?
Several studies have reported that patients with a more severe course of
prior illness and greater number of episodes suffer greater neurocognitive
decline (Kessing, 1998;
van Gorp et al, 1998;
Denicoff et al,
1999). In our study, examination of the correlation between
illness history characteristics and neurocognitive functioning revealed an
effect of several factors, particularly lifetime duration of illness and
number of hospitalisations, consistent with several previous reports
(Tham et al, 1997;
Denicoff et al, 1999;
Rubinsztein et al,
2000). Such associations have typically been interpreted as
indicating a progressive disease process. However, the direction of causality
cannot be determined from correlational analyses. These results may equally
indicate that patients with neurocognitive impairments are more vulnerable to
developing a severe and recurrent bipolar disorder. Preliminary evidence
indicates subtle neurocognitive impairments in high-risk groups,
i.e. first-degree relatives of patients with bipolar disorder
(Keri et al, 2001;
Chowdhury et al,
2002; Sobczak et al,
2002). Therefore, although some deficits might be the result of
disease progression, evidence that impairments occur both in euthymic patients
with bipolar disorder and their healthy first-degree relatives may represent
an endophenotypic marker of genetic vulnerability.
Implications and future research
Neurocognitive deficits are evident in euthymic patients with bipolar
disorder. These deficits are often a cause of considerable distress and can
lead to impairment of psychosocial and occupational functioning (e.g.
Martinez-Aran et al,
2004). Our study confirms that these deficits are of both
statistical and clinical significance, and persist independently of mood
symptoms. Early intervention may be particularly important in order to
ameliorate such impairments, as several studies including this one
indicate that the degree of dysfunction may increase with disease
progression. One of the most important aims of future research should
therefore be the identification of the underlying neurobiology of
neurocognitive impairment in euthymic patients, thereby providing a target for
therapeutic intervention. Cognitive and psychoeducational rehabilitation
programmes may be warranted to improve the long-term outcome for some
patients.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication February 25, 2004. Revision received September 9, 2004. Accepted for publication September 10, 2004.