Skip to main content Accessibility help
×
Home
Hostname: page-component-99c86f546-66nw2 Total loading time: 0.78 Render date: 2021-12-04T13:52:18.322Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true, "newUsageEvents": true }

Neurocognitive impairment in euthymic patients with bipolar affective disorder

Published online by Cambridge University Press:  02 January 2018

Jill M. Thompson
Affiliation:
Stanley Research Centre, School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne, UK
Peter Gallagher
Affiliation:
Stanley Research Centre, School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne, UK
John H. Hughes
Affiliation:
Stanley Research Centre, School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne, UK
Stuart Watson
Affiliation:
Stanley Research Centre, School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne, UK
John M. Gray
Affiliation:
Stanley Research Centre, School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne, UK
I. Nicol Ferrier
Affiliation:
Stanley Research Centre, School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne, UK
Allan H. Young*
Affiliation:
Stanley Research Centre, School of Neurology Neurobiology and Psychiatry University of Newcastle upon Tyne, UK
*
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@ncl.ac.uk
Rights & Permissions[Opens in a new window]

Abstract

Background

Persistent impairments in neurocognitive function have been described in patients with bipolar disorder whose disease is in remission. However, methodological issues such as the effect of residual mood symptoms and hypercortisolaemia may confound such studies.

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.

Type
Papers
Copyright
Copyright © 2005 The Royal College of Psychiatrists 

Converging evidence suggests that people with bipolar disorder exhibit persistent cognitive impairment across a range of tasks of attention, memory and executive function during remission (Reference van Gorp, Altshuler and Thebergevan Gorp et al, 1998; Reference Ferrier, Stanton and KellyFerrier et al, 1999; Reference Rubinsztein, Michael and PaykelRubinsztein et al, 2000; Reference Clark, Iversen and GoodwinClark et al, 2002; Reference Tavares, Drevets and SahakianTavares et al, 2003; Reference Martinez-Aran, Vieta and ColomMartinez-Aran et al, 2004). However, small sample sizes, the effects of residual mood symptoms and different rates of biological abnormalities such as hypercortisolaemia may confound such studies. Importantly, few studies have examined the magnitude of impairment in a meaningful way, i.e. as effect sizes or in terms of the proportion of patients with ‘clinically significant’ impairment. This study sought to address previous limitations by testing a large sample of well-characterised, prospectively verified euthymic patients with bipolar disorder on a comprehensive neuropsychological test battery. We predicted that patients would demonstrate clear neurocognitive impairment compared with healthy controls.

METHOD

Participants

Sixty-three people with a DSM–IV diagnosis of bipolar affective disorder (American Psychiatric Association, 1994) were recruited from out-patient clinics in secondary and tertiary care in the north-east of England; 54 had bipolar type I disorder, 9 had type II and 5 were rapid-cycling. Diagnoses were confirmed using the Structured Clinical Interview for DSM–IV (SCID; Reference First, Spitzer and GibbonFirst et al, 1997). Illness characteristics were derived from retrospective life charts constructed from patient interview and hospital medical records (Reference Leverich and PostLeverich & Post, 1996). Patients were excluded if they were taking corticosteroids or antihypertensive medication, had any other current Axis I diagnosis or had a neurological or medical condition. A history of substance or alcohol misuse in the past 6 months (6 patients met DSM–IV criteria for a previous history of alcohol dependence, 4 met criteria for a previous history of substance dependence and 1 patient met criteria for previous substance and alcohol dependence) or electro-convulsive therapy (ECT) in the past year also led to exclusion.

Euthymia was prospectively defined as scores of 7 or below on both the Hamilton Rating Scale for Depression (HRSD; Reference HamiltonHamilton, 1960) and the Young Mania Rating Scale (YMRS; Reference Young, Biggs and ZieglerYoung et al, 1978) at initial assessment and after 1 month. Patients also completed the Beck Depression Inventory (BDI; Reference Beck, Ward and MendelsonBeck et al, 1961) and the Altman Mania Rating Scale (AMRS; Reference Altman, Hedeker and PetersonAltman 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.

Table 1 Demographic and clinical characteristics

Variable Control group (n=63) Patient group (n=63) Inferential test statistic P
Demographic characteristics
    Gender (female:male), n:n 26:37 26:37
    Age, years: mean (s.d.) 45.4 (9.1) 44.4 (8.6) 0.61 0.540
    Education, years: mean (s.d.) 14.2 (3.1) 14.24 (3.0) -0.12 0.906
    Pre-morbid IQ: mean (s.d.) 110.0 (9.2) 109.6 (10.2) 0.22 0.824
    MMSE score: mean (s.d.) 29.8 (0.6) 29.6 (0.7) 3236.5 0.013
    Handedness (right:left:mixed), n:n:n 58:5:0 56:4:3
Mood rating scores: mean (s.d.)
    HRSD initial assessment 2.1 (1.7)
    YMRS initial assessment 1.4 (2.0)
    BDI
       Week 1 6.1 (5.8)
       Week 2 5.1 (5.4)
       Week 3 4.6 (5.6)
       Week 4 1.9 (2.3) 4.8 (5.4) 1396.0 0.003
    AMRS
       Week 1 3.2 (3.3)
       Week 2 2.3 (2.4)
       Week 3 2.1 (2.6)
       Week 4 1.6 (2.0) 2.2 (2.6) 1788.5 0.313
    HRSD post-month assessment 0.7 (1.1) 1.4 (1.6) 1336.0 0.001
    YMRS post-month assessment 0.3 (0.8) 0.8 (1.5) 1654.0 0.031
    BDI post-month assessment 1.8 (2.2) 4.0 (4.9) 1384.0 0.003
    AMRS post-month assessment 1.6 (1.9) 1.9 (2.5) 1912.5 0.713
Clinical characteristics
    Age at illness onset, years
       Mean (s.d.) 25.3 (7.2)
       Range 12-42
    Duration of illness, years
       Mean (s.d.) 19.5 (10.0)
       Range 0.58-39
    No. of hospital admissions
       Mean (s.d.) 5.0 (6.1)
       Range 0-40
    No. of depressed episodes
       Mean (s.d.) 12.0 (16.4)
       Range 0-88
    Lifetime months of depression
       Mean (s.d.) 29.5 (40.3)
       Range 0-242
    No. of manic episodes
       Mean (s.d.) 10.3 (17.4)
       Range 1-98
    Lifetime months of mania
       Mean (s.d.) 9.8 (16.4)
       Range 0.5-121
    Duration since last episode, months
       Mean (s.d.) 27.3 (40.9)
       Range 1-192
Medication
    Mood stabilisers, n 56
    Antidepressants, n 18
    Anticholinergics, n 3
    Benzodiazepines, n 4
    Antipsychotics (typical:atypical), n:n 11.6
    Dosage (CPZeq per day), mg1
       Mean (s.d.) 181.6 (146.0)
       Range 50-533
       No. of previous ECT treatments (n=30)2
          Mean (s.d.) 18.1 (26.4)
          Range 2-120
       Time since last ECT treatment, years2
          Mean (s.d.) 17.2 (10.3)
          Range 2-37

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 (Reference Briggs and NebesBriggs & Nebes, 1975), years of education (±3 years), and premorbid IQ (±5 IQ points; Reference NelsonNelson, 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 DSM–IV criteria and a detailed inventory was derived from the major DSM–IV 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 (Reference Teng and ChuiTeng & 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:

  1. (a) Psychomotor performance: the Vigil test (response latency) (Reference Cegalis and BowlinCegalis & Bowlin, 1991), Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale – Revised (WAIS–R; Reference WechslerWechsler, 1981) and the Trail Making Test part A (Reference ReitenReiten, 1958).

  2. (b) Attention and executive function: Trail Making Test part B, Vigil (errors of omission and commission), Stroop Neuropsychological Screening Test (Reference Trenerry, Crosson and DeboeTrenerry et al, 1989), the Tower of London task from the Cambridge Neuropsychological Test Automated Battery (CANTAB, Cambridge Cognition Ltd, Cambridge, UK), the Controlled Oral Word Association Test (Reference Benton and HamsherBenton & Hamsher, 1976), the Digits Backward sub-test from the WAIS–R, a computerised version of the Abstract Designs Self-Ordered Pointing Task (SOPT; Reference Petrides and MilnerPetrides & Milner, 1982) and the CANTAB Spatial Working Memory test.

  3. (c) Immediate memory: the Digits Forward sub-test from the WAIS–R and the CANTAB Spatial Span.

  4. (d) Declarative memory (visual and verbal): the CANTAB Pattern Recognition Memory and Spatial Recognition Memory tasks, CANTAB Simultaneous and Delayed Matching to Sample, CANTAB Paired Associates Learning test and the Rey Auditory Verbal Learning Test (RAVLT; Reference ReyRey, 1964).

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 (Reference Robbins, James, Owen and Rabbit1997) and further details regarding the pen-and-paper measures in Lezak (Reference Lezak1995).

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 Greenhouse–Geisser or Huynh–Feldt 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 (Reference HowellHowell, 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 (μpatients–μcontrols)/σpooled (Reference HowellHowell, 1999); the first part of this equation was reversed for tasks where a high score indicates poorer performance (i.e. μcontrols–μpatients) 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 Spearman's method.

RESULTS

Demographic and mood data

There was no significant between-group difference across the demographic variables. On the clinical rating scales patients exhibited few symptoms during the euthymia verification period, although their scores were still significantly higher than the controls on most of the measures completed by both groups (Table 1).

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 group×time 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 Cohen's conventions used to indicate small, medium and large effects (Reference CohenCohen, 1988). The proportion of patients scoring at or below the fifth percentile of the control group is also presented.

Table 2 Cognitive performance comparisons (untransformed means are reported for clarity)

Measure Control group (n=63) Mean (s.d.) Patient group (n=63) Mean (s.d.) Inferential test statistic P
Psychomotor performance
    Vigil latency, ms 371.6 (55.1) 402.8 (67.3) 9.42 0.003
    Digit Symbol Substitution Test 61.2 (10.0) 50.5 (13.2) 5.15 0.000
    Trail Making Test part A, s 32.1 (8.8) 37.4 (13.1) -2.67 0.009
Attention and executive function
    Trail Making Test part B, s 65.6 (24.5) 71.4 (26.3) -1.27 0.206
    Vigil total omissions 1.7 (2.3) 5.4 (8.0) 13.72 0.000
    Vigil total commissions 1.7 (2.2) 2.6 (3.1) 2.44 0.120
    Stroop colour-word trial correct, ms 100.2 (12.0) 90.8 (19.4) 3.23 0.002
    Tower of London task1
       Minimum move solutions 8.8 (1.6) 7.9 (1.9) 2.88 0.005
       Number of excess moves 3.1 (1.8) 4.2 (2.5) 7.50 0.007
       Motor initiation time, ms 1535.3 (497.8) 2074.5 (997.5) 14.17 0.000
       Motor execution time, average ms per move 1350.4 (488.2) 1566.1 (580.2) 8.90 0.003
       Initial thinking time, ms 8888.5 (3175.1) 1023.2 (4499.6) 4.03 0.047
       Subsequent thinking time, average ms per move 2346.6 (1172.4) 2929.4 (1361.6) 7.10 0.009
       Initial planning time, ms 7353.2 (2963.0) 8157.9 (4330.8) 1.51 0.222
       Subsequent planning time, average ms per move 1100.3 (960.37) 1457.8 3.82 0.053
    Controlled Oral Word Association Test
       Total correct 44.8 (10.7) 40.9 (11.1) 1.98 0.050
       Perseverations 1.4 (2.0) 1.4 (1.5) 0.03 0.975
    Digits Backward span 5.2 (1.3) 4.7 (1.4) 2.23 0.027
    SOPT total errors 10.2 (4.1) 14.3 (5.6) 14.29 0.000
    Spatial Working Memory
       Total between-search errors1,2 29.1 (17.7) 40.6 (24.2) 6.88 0.010
       Strategy score2 34.2 (5.6) 35.4 (5.9) -1.11 0.267
    Immediate memory
       Digits Forward span 7.0 (1.2) 6.94 (1.4) 0.29 0.775
       Spatial Span 5.9 (1.2) 5.30 (1.3) 2.80 0.006
    Declarative memory (LTM)
       Pattern Recognition, total % correct 90.1 (9.3) 85.2 (12.9) 1.79 0.076
       Spatial Recognition, total % correct 82.0 (10.3) 74.4 (13.1) 3.67 0.000
       Matching to Sample
          SMTS % correct 96.2 (6.4) 96.2 (6.1) 0.00 1.00
          DMTS average % correct1 87.8 (7.2) 81.0 (12.5) 13.94 0.000
       Paired Associates Learning
          Sets successfully completed 7.9 (0.3) 7.8 (0.5) 2.52 0.014
          Completed sets first trials memory score 19.4 (3.7) 17.3 (4.0) 3.05 0.003
          Trials to success 14.1 (5.0) 16.6 (6.1) 2.57 0.011
       RAVLT
          Trial A1 6.5 (1.6) 6.1 (1.5) 1.21 0.229
          Learning (Trials A1 to A5) 51.7 (7.9) 46.7 (9.1) 3.23 0.002
          List B 6.4 (1.8) 5.6 (1.5) 2.80 0.006
          A6 10.7 (2.2) 9.3 (3.0) 2.96 0.004
          A7 10.6 (2.7) 9.1 (3.0) 2.94 0.004
          Retention % (A5-A7)3 94.3 (11.0) 92.1 (12.2) 1.05 0.300
          Recognition correct 13.3 (1.6) 12.1 (2.6) 3.23 0.002
          Recognition commissions 1.6 (2.3) 2.2 (2.9) -1.33 0.187

Table 3 Cognitive performance: effect sizes and percentage of patients scoring below the fifth percentile of the control group

Measure Domain1 Effect size2 Patients below 5th percentile (%)
Digit symbol substitution PsychM 0.84 35.5
Mean 0.84 35.5
SOPT total errors Att/Exec 0.78 34.0
ToL motor initiation time, ms Att/Exec 0.65 24.6
DMTS average % correct DeclarM 0.64 23.0
Spatial recognition total % correct DeclarM 0.62 27.0
Vigil total omissions Att/Exec 0.58 30.7
Stroop colour-word trial correct, ms Att/Exec 0.56 26.2
RAVLT learning (trials A1 to A5) DeclarM 0.56 19.4
RAVLT recognition correct DeclarM 0.55 22.6
SWM total between-search errors Att/Exec 0.53 31.8
PAL completed sets 1st trials memory score DeclarM 0.53 19.7
ToL number of excess moves Att/Exec 0.52 23.0
ToL minimum move solutions Att/Exec 0.51 26.2
RAVLT A6 DeclarM 0.51 25.8
RAVLT A7 DeclarM 0.51 21.0
Mean (range) 0.58 25.4 (19.4-34.0)
Vigil latency, ms PsychM 0.49 19.4
Spatial span ImmedM 0.49 11.5
RAVLT List B DeclarM 0.49 4.8
Trail Making Test part A, s PsychM 0.47 41.9
ToL subsequent thinking time (average ms per move) Att/Exec 0.45 16.4
PAL sets successfully completed DeclarM 0.44 21.0
Pattern recognition total % correct DeclarM 0.43 15.9
ToL motor execution time (average ms per move) ATT/Exec 0.40 11.5
Backward digit span Att/Exec 0.39 25.8
ToL subsequent planning time (average ms per move) Att/Exec 0.35 13.1
FAS total correct Att/Exec 0.35 11.3
ToL initial thinking time, ms Att/Exec 0.34 11.5
Vigil total commissions Att/Exec 0.32 16.1
RAVLT recognition commissions DeclarM 0.24 11.3
Trail Making Test part B, s Att/Exec 0.23 11.3
ToL initial planning time, ms Att/Exec 0.22 8.2
RAVLT trial A1 DeclarM 0.22 3.2
SWM strategy score Att/Exec 0.20 3.2
Mean (range) 0.36 14.3 (3.2-41.9)
RAVLT % retention (A5-A7) DeclarM 0.19 11.3
Digits Forward span ImmedM 0.05 16.1
PAL trials to success DeclarM 0.05 22.6
SMTS % correct DeclarM 0.00 6.6
FAS perseverations Att/Exec -0.01 3.2
Mean (range) 0.06 12.0 (3.2-22.6)

Psychomotor performance

Patients’ response times were significantly slower than the control group on the Vigil task. There was no group×time 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 group×time 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 task's 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 group×level interaction was present across any Tower of London index (P≥0.169). 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 group×set-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 group×level interaction (F (2,248)=0.931, P=0.387); however, on this test's 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 group×delay 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 A1–A5). 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 (Reference StevensStevens, 2002), i.e. apply to a specific neurocognitive domain. This method was therefore adopted and it confirmed that a significant multivariate statistic (Hotelling's 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 (Reference Ferrier, Stanton and KellyFerrier et al, 1999; Reference Clark, Iversen and GoodwinClark 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.

Table 4 Correlations between illness characteristics and impaired neurocognitive performance in patients with bipolar disorder

Measure Months clinically euthymic Duration of illness (years) No. of hospital admissions No. of depressed episodes Lifetime months of depression No. of manic episodes Lifetime months of mania No. of previous ECT treatments1 Time since last ECT treatment1 Age at onset (years)
Vigil omissions 0.060 0.283* 0.482*** 0.121 0.126 0.168 0.107 -0.013 0.041 -0.035
Trail Making Test part A -0.061 0.283* 0.201 0.073 0.056 0.000 -0.091 0.258 0.197 0.001
Stroop CW trial 0.022 0.009 0.114 0.010 -0.110 -0.084 -0.001 0.208 0.004 0.016
ToL excess moves 0.036 0.135 -0.058 -0.053 -0.118 -0.061 -0.067 -0.066 0.083 -0.034
FAS total correct 0.231 -0.090 -0.320* 0.008 -0.070 0.050 0.095 0.149 0.033 0.034
Digits Backward span 0.057 -0.156 -0.165 0.145 0.096 0.349** 0.294* 0.054 0.245 -0.081
Spatial Span -0.062 0.050 0.100 -0.089 -0.077 0.114 0.104 0.046 0.064 -0.167
SWM errors -0.037 0.217 0.278* 0.197 0.161 0.091 -0.018 0.386* -0.102 0.008
SOPT total errors -0.181 0.381** 0.430** 0.298* 0.293* 0.024 -0.034 0.136 -0.247 -0.148
Vigil latency 0.003 0.135 0.030 -0.171 -0.133 -0.033 0.033 -0.058 0.366 0.075
DSST -0.004 -0.306* -0.479*** -0.189 -0.230 -0.174 -0.121 -0.153 -0.199 -0.020
Spatial Recognition 0.017 -0.140 -0.023 -0.157 -0.154 0.005 0.089 -0.147 -0.006 -0.120
DMTS 0.085 -0.224 -0.324* -0.221 -0.261* 0.016 0.157 -0.136 0.130 -0.027
PAL sets completed 0.061 -0.299* -0.240 -0.124 -0.236 -0.042 0.094 -0.480** 0.257 -0.074
RAVLT (A1-5) -0.206 -0.231 -0.167 0.025 -0.063 0.045 -0.097 -0.262 0.090 -0.084

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 colour–word 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).

DISCUSSION

Our study demonstrates significant neurocognitive impairment in a prospectively verified sample of euthymic patients with bipolar disorder, compared with a well-matched control group. Patients were impaired across a range of cognitive domains, including attention and executive function, immediate (spatial) memory and verbal and visuospatial declarative memory. Significant psychomotor retardation was also evident. These impairments were not attributable to hypercortisolism, because basal salivary cortisol profiling revealed no difference between patients and controls. Also, dysfunction was still evident after controlling for the effects of residual mood symptoms post hoc using a partial correlational analysis.

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 (Reference van Gorp, Altshuler and Thebergevan Gorp et al, 1998; Reference Ferrier, Stanton and KellyFerrier et al, 1999; Reference Rubinsztein, Michael and PaykelRubinsztein et al, 2000; Reference Clark, Iversen and GoodwinClark et al, 2002; Reference Martinez-Aran, Vieta and ColomMartinez-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 Reference Rubinsztein, Michael and PaykelRubinsztein 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 (Reference Astrup, Fossum and HolmboeAstrup et al, 1959; Reference Bratfos and HaugBratfos & Haug, 1968; Reference Dhingra and RabinsDhingra & Rabins, 1991; Reference Martinez-Aran, Vieta and ColomMartinez-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 (Reference Amado-Boccara, Gougoulis and LittreAmado-Boccara et al, 1995). However, in their review, Bearden et al (Reference Bearden, Hoffman and Cannon2001) 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 (Reference Goswami, Gulrajani and MooreGoswami 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. Cushing's disease). As hypothalamic–pituitary–adrenal axis dysfunction in bipolar disorder may also persist in a proportion of euthymic patients (Reference Watson, Gallagher and RitchieWatson 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 (Reference Watson, Gallagher and RitchieWatson 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 (Reference Ferrier, Stanton and KellyFerrier et al, 1999; Reference Clark, Iversen and GoodwinClark 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 (Reference KessingKessing, 1998; Reference van Gorp, Altshuler and Thebergevan Gorp et al, 1998; Reference Denicoff, Ali and MirskyDenicoff 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 (Reference Tham, Engelbrektson and MatheTham et al, 1997; Reference Denicoff, Ali and MirskyDenicoff et al, 1999; Reference Rubinsztein, Michael and PaykelRubinsztein 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 (Reference Keri, Kelemen and BenedekKeri et al, 2001; Reference Chowdhury, Thompson and WatsonChowdhury et al, 2002; Reference Sobczak, Riedel and BooijSobczak 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. Reference Martinez-Aran, Vieta and ColomMartinez-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.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

  1. Patients with bipolar disorder are impaired across a range of neurocognitive domains. This is evident in terms of both statistical and clinical significance.

  2. These deficits persist in the euthymic state and suggest that neurocognitive impairment persists long beyond the point of symptomatic recovery.

  3. These deficits are not simply related to basal hypercortisolaemia.

LIMITATIONS

  1. The patients in the study were stable on medication, but were not drug-free.

  2. The study design was cross-sectional and the longitudinal course of these deficits remains to be fully demonstrated.

  3. Basal cortisol levels do not fully characterise hypothalamic–pituitary–adrenal dysfunction.

Acknowledgements

This project was made possible by the generous support of the Stanley. Medical Research Institute and the Mental Health Foundation. We thank Mr M. Leitch, Ms S. Dodds, Mrs M. Smith and Ms M. Watson for technical assistance. and Dr B. S. Wilkinson and Mrs C. L. Harrison for assistance with data. collection.

Footnotes

Declaration of interest

None. Funding detailed in Acknowledgements.

References

Altman, E. G., Hedeker, D., Peterson, J. L., et al (1997) The Altman Self-Rating Mania Scale. Biological Psychiatry, 42, 948955.CrossRefGoogle ScholarPubMed
Amado-Boccara, I., Gougoulis, N., Littre, M. F. P., et al (1995) Effects of antidepressants on cognitive functions: a review. Neuroscience and Biobehavioral Reviews, 19, 479493.Google ScholarPubMed
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM–IV). Washington, DC: APA.Google Scholar
Astrup, C., Fossum, A. Holmboe, R. (1959) A follow-up of 270 patients with acute affective psychoses. Acta Psychiatrica Scandinavica, 34, 165.Google ScholarPubMed
Bearden, C. E., Hoffman, K. M. & Cannon, T. D. (2001) Theneuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disorders, 3, 106150.CrossRefGoogle ScholarPubMed
Beck, A. T., Ward, C. H., Mendelson, M., et al (1961) An inventory for measuring depression. Archives of General Psychiatry, 4, 561571.Google ScholarPubMed
Benton, A. L. & Hamsher, K. (1976) Multilingual Aphasia Examination. Iowa City, IA: University of Iowa.Google Scholar
Bratfos, O. & Haug, J. O. (1968) The course of manic-depressive psychosis. A follow up investigation of 215 patients. Acta Psychiatrica Scandinavica, 44, 89112.CrossRefGoogle ScholarPubMed
Briggs, G. G. & Nebes, R. D. (1975) Patterns of hand preference in a student population. Cortex, 11, 230238.CrossRefGoogle Scholar
Cegalis, J. & Bowlin, J. (1991) Vigil: Software for the Assessment of Attention. Nashua, NH: Forthought.Google Scholar
Chowdhury, R., Thompson, J. M., Watson, S., et al (2002) Working memory architecture in first-degree relatives of patients with bipolar affective disorder. Bipolar Disorders, 4, S119.Google Scholar
Clark, L., Iversen, S. D. & Goodwin, G. M. (2002) Sustained attention deficit in bipolar disorder. British Journal of Psychiatry, 180, 313319.CrossRefGoogle ScholarPubMed
Cohen, J. (1988) Statistical Power Analysis for the Behavioral Sciences (2nd edn). Hillscale, NJ: Erlbaum.Google Scholar
Denicoff, K. D., Ali, S. O., Mirsky, A. F., et al (1999) Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder. Journal of Affective Disorders, 56, 6773.CrossRefGoogle ScholarPubMed
Dhingra, U. & Rabins, P. V. (1991) Mania in the elderly: a5–7 year follow-up. Journal of the American Geriatrics Society, 39, 581583.CrossRefGoogle Scholar
Ferrier, I. N., Stanton, B. R., Kelly, T. P., et al (1999) Neuropsychological function in euthymic patients with bipolar disorder. British Journal of Psychiatry, 175, 246251.CrossRefGoogle ScholarPubMed
First, M., Spitzer, R., Gibbon, M., et al (1997) Structured Clinical Interview for DSM–IV Axis I Disorders, Research Version. New York: Biometrics Research.Google Scholar
Goswami, U., Gulrajani, C., Moore, P. B., et al (2002) Neurocognitive decline in bipolar mood disorder: role of mood stabilizers. Journal of Psychopharmacology, 16, A45.Google Scholar
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 5662.CrossRefGoogle Scholar
Howell, D. C. (1997) Statistical Methods for Psychology (4th edn). Belmont, CA: Duxbury Press.Google Scholar
Howell, D. C. (1999) Fundamental Statistics for the Behavioral Sciences (4th edn). Pacific Grove, CA: Brooks/Cole.Google Scholar
Keri, S., Kelemen, O., Benedek, G., et al (2001) Different trait markers for schizophrenia and bipolar disorder: a neurocognitive approach. Psychological Medicine, 31, 915922.CrossRefGoogle ScholarPubMed
Kessing, L. V. (1998) Cognitive impairment in the euthymic phase of affective disorder. Psychological Medicine, 28, 10271038.CrossRefGoogle ScholarPubMed
Leverich, G. S. & Post, R. M. (1996) Life charting the course of bipolar disorder. Current Review of Mood and Anxiety Disorders, 1, 4861.Google Scholar
Lezak, M. D. (1995) Neuropsychological Assessment (3rd edn). New York: Oxford University Press.Google Scholar
Martinez-Aran, A., Vieta, E., Colom, F., et al (2000) Cognitive dysfunctions in bipolar disorder: evidence of neuropsychological disturbances. Psychotherapy and Psychosomatics, 69, 218.Google ScholarPubMed
Martinez-Aran, A., Vieta, E., Colom, F., et al (2004) Cognitive function across manic or hypomanic, depressed and euthymic states in bipolar disorder. American Journal of Psychiatry, 161, 262270.CrossRefGoogle ScholarPubMed
Nelson, H. E. (1982) National Adult Reading Test, NART. Windsor: Nelson.Google Scholar
Petrides, M. & Milner, B. (1982) Deficits on subject-ordered tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia, 20, 249262.CrossRefGoogle ScholarPubMed
Reiten, R. M. (1958) Validity of the Trail Making Test as an indicator of organic brain damage. Perceptual and Motor Skills, 8, 271276.CrossRefGoogle Scholar
Rey, A. (1964) L'Examen Clinique en Psychologie. Paris: Press Universitaire de France.Google Scholar
Rey, M. J., Schulz, P., Costa, C., et al. (1989) Guidelines for the dosage of neuroleptics. I: Chlorpromazine equivalents of orally administered neuroleptics. International Clinical Psychopharmacology, 4, 95104.CrossRefGoogle ScholarPubMed
Robbins, T. W., James, M., Owen, A. M., et al (1997) A neural systems approach to the cognitive psychology of ageing using the CANTAB battery. In Methodology of Frontal and Executive Function (ed. Rabbit, P.), pp. 215238. Hove: Psychology Press.Google Scholar
Rubinsztein, J. S., Michael, A., Paykel, E. S., et al (2000) Cognitive impairmentin remission in bipolar affective disorder. Psychological Medicine, 30, 10251036.CrossRefGoogle Scholar
Sobczak, S., Riedel, W. J., Booij, I., et al (2002) Cognition following acute tryptophan depletion: difference between first-degree relatives of bipolar disorder patients and matched healthy control volunteers. Psychological Medicine, 32, 503515.CrossRefGoogle ScholarPubMed
SPSS (1998) SPSS for Windows version 9. Chicago, IL: SPSS Inc.Google Scholar
Stevens, J. P. (2002) Applied Multivariate Statistics for the Social Sciences (4th edn). Mahwah, NJ: Erlbaum.Google Scholar
Tavares, J. V., Drevets, W. C. & Sahakian, B. J. (2003) Cognition in mania and depression. Psychological Medicine, 33, 959967.CrossRefGoogle Scholar
Teng, E. L. & Chui, H. C. (1987) The Modified Mini-Mental State (3 MS) examination. Journal of Clinical Psychiatry, 48, 314318.Google Scholar
Tham, A., Engelbrektson, K., Mathe, A. A., et al (1997) Impaired neuropsychological performance in euthymic patients with recurring mood disorders. Journal of Clinical Psychiatry, 58, 2629.CrossRefGoogle ScholarPubMed
Trenerry, M. R., Crosson, B., Deboe, J., et al (1989) Stroop Neuropsychological Screening Test. Odessa, FL: Psychological Assessment Resources.Google Scholar
van Gorp, W. G., Altshuler, L., Theberge, D. C., et al (1998) Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence: a preliminary study. Archives of General Psychiatry, 55, 4146.CrossRefGoogle ScholarPubMed
Watson, S., Gallagher, P., Ritchie, J. C., et al (2004) Hypothalamic–pituitary–adrenal axis function in patients with bipolar disorder. British Journal of Psychiatry, 184, 496502.CrossRefGoogle ScholarPubMed
Wechsler, D. (1981) WAIS–R Manual, Wechsler Adult Intelligence Scale – Revised. Cleveland, OH: Psychological Corp.Google Scholar
Young, R. C., Biggs, J. T., Ziegler, V. E., et al (1978) A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429435.CrossRefGoogle ScholarPubMed
Figure 0

Table 1 Demographic and clinical characteristics

Figure 1

Table 2 Cognitive performance comparisons (untransformed means are reported for clarity)

Figure 2

Table 3 Cognitive performance: effect sizes and percentage of patients scoring below the fifth percentile of the control group

Figure 3

Table 4 Correlations between illness characteristics and impaired neurocognitive performance in patients with bipolar disorder

Submit a response

eLetters

No eLetters have been published for this article.
You have Access
278
Cited by

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Neurocognitive impairment in euthymic patients with bipolar affective disorder
Available formats
×

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Neurocognitive impairment in euthymic patients with bipolar affective disorder
Available formats
×

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Neurocognitive impairment in euthymic patients with bipolar affective disorder
Available formats
×
×

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *