University Department of Psychiatry, Warneford Hospital, Oxford
Department of Experimental Psychology, South Parks Road, Oxford
University Department of Psychiatry, Warneford Hospital, Oxford
Correspondence: Professor G. M. Goodwin, University Department of Psychiatry, Warneford Hospital, Oxford OX37JX, UK. Tel: +44 (0) 1865 226451; fax: +44 (0) 1865 204198; e-mail: guy.goodwin{at}psychiatry.oxford.ac.uk
See pp. 320326 and
editorial, pp. 293295,
this issue.
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ABSTRACT |
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Aims To characterise neuropsychological functioning in the euthymic phase of bipolar disorder with an emphasis on tasks of executive functioning.
Method Thirty euthymic patients with bipolar disorder were compared with thirty healthy controls on neuropsychological tasks differentially sensitive to damage within prefrontal cortex.
Results Bipolar I patients were impaired on tasks of attentional set shifting, verbal memory and sustained attention. Only sustained attention deficit survived controlling for mild affective symptoms. This deficit was related to progression of illness, but was none the less present in a subgroup of patients near illness onset.
Conclusions Sustained attention deficit may represent a neuropsychological vulnerability marker for bipolar disorder, providing a focus for further understanding of the phenotype and analysis of the neuronal networks involved.
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INTRODUCTION |
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METHOD |
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Patients were aged 18-60 years and described as euthymic by their consultants. Two subjects had received electroconvulsive therapy (ECT) in the past but not within the preceding year. Four subjects had a prior history of substance misuse (one polydrug, one alcohol, two polydrug and alcohol) but had been abstinent for at least 1 year. Comorbid anxiety disorders were not present in the patient group at the time of testing, as assessed by a truncated version of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID; First et al, 1995).
Five patients were off medication at the time of testing. The majority of patients were receiving mood-stabilising medication. For most patients (19/30) this was lithium carbonate (dose 400-1200 mg/day, mean 763 mg). Two patients were maintained primarily on carbamazepine, one patient on sodium valproate and one on a combination of the two. These mood-stabilising medications were taken typically in combination with a selective serotonin reuptake inhibitor (SSRI) (nine patients) or a neuroleptic (five patients). Two patients were receiving only SSRI medication. The present series was not, however, an excessively medicated group: 12/30 were on no treatment or on a monotherapy.
Thirty healthy controls were recruited using a psychology subject panel, advertisements and word of mouth. Controls had no prior psychiatric history and had no first-degree relatives with bipolar diagnoses.
Procedure
Neuropsychological testing lasted approximately 2 h. Subjects completed the
tests in a fixed order with a break half-way. Four tests from the Cambridge
Automated Neuropsychological Test Battery (CANTAB; CeNeS Ltd, Cambridge, UK)
were employed (see Elliott et al,
1996 and Purcell et
al, 1997, for fuller descriptions), as well as the California
Verbal Learning Test (CVLT; Delis et
al, 1987) and a computerised version of the Iowa Gambling
Task (Bechara et al,
1994). With the exception of the CVLT, all tasks were run on a
Datalux 486 PC with a 10-inch touch-screen monitor.
Subject mood was assessed formally using the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960) and the Young Mania Rating Scale (Young et al, 1978). A cut-off score of 8 was used on both scales to define euthymia, in addition to the prior judgement of the referring clinician. Level of intelligence was assessed in the two groups for the purposes of matching using three measures: years spent in education; the National Adult Reading Test (NART; Nelson & O'Connell, 1978), which is a measure of premorbid verbal IQ; and the Block Design sub-test of the Wechsler Adult Intelligence Scale Revised (WAISR; Wechsler, 1981).
Neuropsychological tasks
Spatial working memory
Spatial working memory is a self-ordered search task requiring subjects to
update the working memory continually to avoid returning to previously
searched locations. Dependent variables are between-search
errors (i.e. returning to boxes that previously have yielded tokens)
and a strategy score of how organised the search pattern is.
Between-search errors are employed in the correlational analysis.
Tower of London
The Tower of London is a problem-solving task demanding forward planning in
order to match the arrangements of coloured balls. There are a minimum number
of moves in which each problem can be solved (2, 3, 4 and 5) and the subject
has a maximum number of moves to solve each problem (5, 7, 9 and 12,
respectively). Dependent variables of interest are the average number of moves
taken to solve the 4- and 5-move problems and the overall number of problems
solved in the minimum number of moves (used in correlational analysis).
Intradimensionalextradimensional shift (IDED
shift)
The intradimensionalextradimensional shift is a visual
discrimination task requiring set learning, reversal learning and an
extradimensional set shift (EDS; similar to the Wisconsin Card Sort Test,
WCST). The task enables an impairment in attentional set shifting per
se to be separated from impairments in concept formation or reversing
reward associations, processes that are conflated in the WCST. Dependent
variables are summed errors on stages of reversal, errors at EDS stage and
summed errors across all stages. Errors at EDS are employed in the
correlational analysis.
Rapid visual information processing (RVIP)
Rapid visual information processing is a continuous performance test
lasting 7 min, requiring the detection of three-digit target sequences.
Dependent variables were the percentage of targets detected, the number of
false alarms and the latency to respond. Percentage of targets detected was
employed in the correlational analysis.
California Verbal Learning Test (CVLT)
The California Verbal Learning Test is an auditory verbal memory test using
a 16-item shopping list that is read to the subject five times. After each
trial subjects must repeat back as many items as they can remember (learning
score: trials 1-5 summed, used in the correlational analysis). Immediate and
delayed (20 min later) free recall also are assessed, followed by item
recognition (employing the 16 targets with 28 distractors).
Iowa Gambling Task
The Iowa Gambling Task is a decisionmaking task demanding a series of
choices from four decks of cards (A, B, C, D), each characterised by a
different rewardpunishment profile. Large wins on decks A and B are
paired with larger penalties, resulting in net loss. Smaller wins on decks C
and D are associated with smaller penalties, and hence net profit. Control
subjects typically acquire a bias towards deck C and D within about 40 trials.
The main dependent variable on the task is the summed number of choices from
the risky decks (A+B).
Statistical procedures
Independent-sample t-tests were performed on key demographic
variables (age and measures of intelligence) to determine whether the two
groups were adequately matched. MannWhitney U tests were
applied to the scores from the mood rating scales. Planned comparisons were
made for each of the neuropsychological variables with independent-sample
t-tests, with the exception of the IDED shift data, which were
non-parametric and consequently analysed with MannWhitney U
tests. Partial correlations controlling for score on the HRSD and Young Mania
Rating Scale were used to investigate the contribution of mild affective
symptoms to neuropsychological performance. Analysis of covariance (ANCOVA)
was used to achieve the same controlling procedure in the Ferrier et
al (1999) report.
However, ANCOVA should be used only where subjects are assigned randomly to
two (or more) experimental groups and are found to differ spuriously with
regard to a potentially confounding variable (e.g. age). The ANCOVA assumes
that the confounding variable would not be present in a sufficiently large
sample. This is clearly not the case here, because the groups of subjects are
selected on the basis of a psychiatric diagnosis where the confounds (mood
scores) are an inherent feature of one group. Keppell & Zedeck
(1990) recommend the use of
partial correlations to explore confounding effects in such situations.
With a sample size of 30 per group, this design has a power of 0.80 to
detect an effect size of approximately 1.0 with Cronbach's =0.05. From
previous research (Coffman et al,
1990; Morice,
1990; van Gorp et al,
1998) such an effect size was expected for at least the
attentional set shifting and verbal memory deficits. As an exploratory
exercise, partial correlations were calculated between neuropsychological and
psychiatric variables, controlling for age.
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RESULTS |
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Neuropsychological test data are shown in Table 2. The euthymic bipolar group performed very similarly to matched controls on Tower of London, spatial working memory and the Iowa Gambling Task. Group comparisons revealed three effects: impaired target detection and reduced psychomotor speed on RVIP; increased total errors at IDED shift and, more specifically, increased errors at the stage of EDS but not at stages requiring reversal; and impaired immediate recall on the CVLT. However, when controlling for HRSD and Young scores in these analyses the only effect to remain significant was impaired target detection on RVIP.
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Target detection on RVIP may be confounded by a tendency to respond impulsively on the task, and signal detection analysis can be applied to data to exclude this possibility. Signal detection analysis derives two independent measures of performance: target sensitivity and response bias (Grier, 1971). One-way analysis of variance (ANOVA) revealed a highly significant difference between the euthymic bipolar group and controls on target sensitivity (F(1,58)=15.4, P<0.001), and no difference on response bias (F(1,58)=1.16, P=0.286).
The RVIP data also may be examined over time: in tasks of sustained attention it is typical to find decreasing performance over the duration of the task. This vigilance decrement may be separable from the overall accuracy of responding across the whole task duration. This was examined using a repeated-measures ANOVA with one within-subject factor (seven levels; time on task) and one between-subject factor (bipolar group, controls). Apart from the established main effect of the group, there was a significant main effect of time (F=2.96, P=0.015) and the interaction of time x group approached significance (F=2.04, P=0.076). Post hoc t-tests revealed no significant difference between groups in the first minute of the task but a significant difference (P<0.05) at all subsequent time points. The euthymic bipolar group, therefore, showed a slightly more pronounced vigilance decrement than the controls did on a 7-min task of sustained attention (see Fig. 1).
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Relationship between neuropsychological performance and clinical
variables
To restrict the large number of correlations that could be computed from
these data, the most representative variable from each of the six tasks was
included (see Method). Nine clinical variables were examined: number of manic,
depressive and total admissions; number of manic and depressive episodes;
duration (in months) since first episode; duration (in weeks) since the start
of the most recent episode; duration (in months) ever treated with lithium
carbonate; and current dosage of lithium carbonate. Partial correlations,
controlling for age, are presented in Table
3. It is clear that performance on a number of tests, including
RVIP, is correlated with progression of bipolar disorder, as measured by
duration since first episode, and number of depressive episodes, in
particular.
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Post hoc analysis of the RVIP effect in euthymic patients
with bipolar disorder
The group difference between the euthymic bipolar group and controls on
RVIP accuracy remained highly significant when the four patients with a
history of substance abuse and the two patients with a history of ECT were
excluded from the analysis (F(1,52)=15.5, P<0.001). The
possibility that the RVIP deficit is related to medication status was examined
using correlational analyses (see Table
3). The RVIP accuracy was not associated with either current
dosage of lithium or the total duration of treatment. When the 11 patients not
receiving lithium medication were studied in isolation, the RVIP deficit
remained significant (F(1,39)=7.23, P=0.011).
The RVIP accuracy is inversely related to the number of manic episodes, the number of depressed episodes and the duration since the first episode. It is necessary to confirm whether the group difference between euthymic bipolars and controls on the RVIP test is still apparent at an early stage in the evolution of the illness trajectory. To examine this, the eight patients with the shortest illness durations and fewest episodes were identified: less than 40 months had elapsed since their first episode, they had been admitted no more than twice and had experienced no more than four affective episodes. These were compared with eight controls individually matched to the patients with regard to gender, age and IQ scores. Independent-sample t-tests revealed a significant difference between patients and controls on RVIP accuracy (bipolar mean, 61%; control mean, 84%; t=3.24, P=0.006). There were no significant differences on any of the other neuropsychological variables examined in Table 3. These data therefore suggest that RVIP accuracy deteriorates with illness progression but also is impaired in the early stages of bipolar disorder.
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DISCUSSION |
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Many of the patients in the present study were receiving lithium. Although a drug-free or drug-withdrawn cohort would be desirable, it would be hopelessly unrepresentative of clinically severe bipolar disorder. The present series was not an excessively medicated group: 12/30 were on no treatment or on a monotherapy. Previous research has suggested that lithium treatment can adversely affect cognitive functioning, with the most consistent effects in the mnemonic and psychomotor domains (Honig et al, 1999). In the current analysis, RVIP performance was not associated significantly with either current lithium dosage or duration of treatment (Table 3), but the small group sizes necessitate a degree of caution when interpreting the correlational analyses. Furthermore, bipolar patients on and off lithium performed similarly on the RVIP task, and the group not receiving lithium remained significantly impaired compared with controls. On these grounds, the persisting RVIP effect in the euthymic phase cannot be attributed to lithium treatment in this study.
The neural substrates of sustained attention are of ongoing research
interest. Functional neuroimaging studies in normal subjects have reported
right-lateralised activation in the prefrontal cortex during CPT performance
(Coull et al, 1996;
Paus et al, 1997).
Human lesion evidence also supports the view that the right prefrontal cortex
is critically involved in sustained attention
(Manly & Robertson, 1997).
A selective role for noradrenaline in target detection is based on the effects
of lesioning the dorsal noradrenaline bundle in rats
(Cole & Robbins, 1992) and
the effects of the 1/
2 agent clonidine on
RVIP performance in healthy volunteers
(Coull et al, 1995).
Low doses of clonidine impair RVIP accuracy without affecting impulsive
responding (Coull et al,
1995), which resembles the pattern of RVIP performance seen in
euthymic bipolar patients in the present study. The potential for innovative
pharmacological treatment strategies to improve attentional mechanisms has
been demonstrated already for attention-deficit hyperactivity disorder
(Arnsten et al,
1996).
Sustained attention deficit as a vulnerability factor for
psychosis
The failure to sustain attention is an obvious clinical feature of acute
mania and, indeed, distractivility is a criterion in DSM-IV for
the diagnosis of the condition. Measures of sustained attention are abnormal
and have even been reported to be correlated with frontal and hippocampal
volumes in patients with acute mania (Sax
et al, 1999). Changes in sustained attention from the
euthymic to the manic state will provide an interesting test of the idea that
neuropsychological measures can directly illuminate psychopathology. Sustained
attention in remitted bipolar patients was reported previously by Addington
& Addington (1997) to be
intermediate between patients with schizophrenia and controls. The calculated
effect size for the bipolarcontrol comparison was 0.59, representing a
medium effect (Cohen, 1988).
Their CPT paradigm required monitoring for only a single target digit, and may
not have placed sufficient demands on the attentional network optimally to
reveal the deficit in the bipolar group relative to controls.
In schizophrenia, sustained attention deficit is a robust effect during both symptomatic and asymptomatic phases (Nuechterlein et al, 1991). Furthermore, groups at high risk of developing the disorder, including first-degree relatives of subjects with schizophrenia (Chen et al, 1998) and non-clinical subjects with high schizotypy scores (Lenzenweger et al, 1991), also show impairment. Although the present finding in bipolar disorder must be confirmed initially in a larger sample of firstonset patients, further investigation of neuropsychological functioning in groups at high risk of developing bipolar disorder is clearly warranted. In schizophrenia and high-risk groups for schizophrenia there is usually a range of neuropsychological deficits in executive and mnemonic, as well as attentional, domains (Goldberg et al, 1990). A parallel but weaker effect might be expected for bipolar patients, given the difficulty in drawing a definitive boundary between the conditions in either genetic or phenomenological studies (Goldberg, 1999). Our findings support the possibility that sustained attention deficit may be a vulnerability marker for bipolar disorder that is shared with other individuals at risk of disorder across the psychotic spectrum.
Highly sensitive state markers in bipolar disorder
Our euthymic patients with bipolar disorder demonstrated impaired
performance on the ID-ED shift, (a measure of attentional set shifting) and
the CVLT (a verbal memory test). Both effects failed to reach statistical
significance after controlling for low levels of affective symptoms. These
results replicate but suggest a reinterpretation of previous studies in
bipolar patients using the WCST (Coffman
et al, 1990; Morice,
1990), and the CVLT (van Gorp
et al, 1998;
Krabbendam et al,
2000): the deficits may represent a depression-related state
effect rather than a trait abnormality. These findings are parsimonious in
light of research on acute unipolar depression detailing impairments in set
shifting (Purcell et al,
1997; Merriam et al,
1999) and verbal memory (Austin
et al, 1992; Brown
et al, 1994).
In the present study, euthymic patients with bipolar disorder were not impaired on a number of putative neuropsychological indicators of executive functioning: specifically, Tower of London, spatial working memory (two putative measures of dorsolateral prefrontal cortex function) and the Iowa Gambling Task (which has been reported to be sensitive to damage in more ventral aspects of the prefrontal cortex). Spatial working memory and the Iowa Gambling Task have not been used previously in patients with bipolar disorder. Ferrier et al (1999) included Tower of London in their neuropsychological investigation of euthymic bipolar patients, and similarly found no impairment when controlling for low levels of depression. Performance on the Iowa Gambling Task, unexpectedly, was also normal in schizophrenia (Wilder et al, 1998).
The present findings confirm the importance of controlling for low levels of affective symptoms when investigating remitted patients with mood disorder, and support the assertion that the planning and working memory deficits reported during depression are state-related markers of affective disturbance (Elliott et al, 1996). Why impairments on some tests (attentional set shifting, verbal memory) appear to develop at lower levels of symptoms than impairments on others (e.g. planning, working memory) remains unclear. Such deficits help to underline the need to improve the treatment of bipolar depression, a major problem accurately described recently as an underestimated challenge (Hlastala et al, 1997). Further research into the development of neuropsychological impairment with advancing symptoms may provide novel insights into the neural substrates of affective states. One intriguing possibility is that set shifting and memory in bipolar disorder patients are unusually sensitised to low-grade affective symptoms. This phenomenon and a persisting deficit in sustained attention in the euthymic state may help to explain the difficulties in psychological and occupational functioning in patients with bipolar disorder during remission, that served originally to cast doubt on the concept of full recovery between episodes.
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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 September 11, 2000. Revision received February 16, 2001. Accepted for publication February 16, 2001.
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