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Carla Torrent, Anabel Martínez-Arán, Claire Daban, Jose Sánchez-Moreno, Mercè Comes, José Manuel Goikolea

, Manel Salamero and Eduard Vieta BJP 2006, 189:254-259. Access the most recent version at DOI: 10.1192/bjp.bp.105.017269

Cognitive impairment in bipolar II disorder


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Deckersbach et al. Fava. particularly memory difficulties. 1994) and were euthymic. 2004a 2006). CLAIRE DABAN. All patients provided written informed consent. although more so in the bipolar I group. 1995. al. ¤ ' ¤ JOSE SA NCHEZ-MORENO. As far as we know. 2002. Martinez-Aran et al. 1997. both bipolar groups showed significant deficits in most cognitive tasks including working memory (DigitSpan Backwards. Ramos-Brieva & Cordero-Villafafila. Young et al.Those an intermediate level of performance between the bipolar I group and the control group in verbal memory (P50. Kravariti et al. al. attention. 2004a. that have been reported to influence negatively cognitive functioning in bipolar disorder.B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 6 ) . Martinez-Aran et al. 2004a. 2005). the number of hospitalisations. 11 9 2 / b j p . The remission criteria were prospectively assessed euthymia during monthly visits over a 6-month period. early onsetof illness and poor performance on a measure related to executive function. al. al. 2001. but again al. To date investigations on neurocognitive functioning have not distinguished between bipolar subtypes. al. Zubieta et al.Those with type II disorders had 0.020). Cognitive impairment. al. Furthermore. who were compared on clinical and neuropsychological variables (e. Method The study included 71 euthymic patients with bipolar disorder (38 bipolar I. Hamilton. et al. Aran et al. 2004. however. All patients met DSM–IV criteria for bipolar disorder type I or II (American Psychiatric Association. 1 0 5 . al. attention and abstraction (McKay et al.g. employing a rigorous definition of euthymia. Dickerson et al. Clark et al. 0. 2004a. Thompson et al. The clinical state of the patients was determined by a psychiatrist responsible for the follow-up of patients in the Barcelona programme. this is the first study to evaluate specifically cognitive dysfunctions in bipolar II disorder. There is increasing evidence that several cognitive areas are impaired during the acute phases of bipolar illness and that this impairment persists even in the euthymic periods (van Gorp et al. may also have negative implications in the functional outcome of patients with bipolar disorder (Martinez-Aran et al. 2 5 4 ^ 2 5 9 . Martinezal.Trail MakingTest. We predicted that the bipolar II group would exhibit an intermediate profile between the bipolar I group and the healthy controls with an emphasis on domains of verbal memory. 2005). with a negative impact on the performance of tasks on memory. MARTINEZ-ARAN. The bipolar II population has not been assessed in this aspect.020). 2000. al. al.001).b. al.005. MERCE COMES. d o i : 1 0 . These factors have not.b). 1999. are the number of episodes (espe2004a cially manic episodes). Ten patients had a history of rapid cycling (n¼5 bipolar (n 5 I. al. 1999. et al. n¼5 bipolar II). Declaration of interest None. verbal and visual memory) and contrasted with 35 healthy controls on cognitive performance. None of the patients had a concomitant medical illness or substance misuse. 2002). 1960. 2004. Altshuler et al. 2002. the occurrence of psychotic symptoms and chronicity defined as duration of the illness. 2002. Additionally. test battery was administered to 33 patients with bipolar II disorder. al. Fleck al. executive function. 2004. 1998.005. 2002). 1988) and 6 or less on the Young Mania Rating Scale (YMRS. Cavanagh et al. who were compared with 38 patients with bipolar I disorder and 35 healthy individuals. Balanza-Martinez al. 2003. al.005) and executive functions (Stroop interference task. Ferrier et al. Altshuler et al. Conclusions Cognitive impairment exists in both subtypes of bipolar disorder. Aims To compare the cognitive performance of patients with bipolar II disorder withthatof patients with bipolar I disorder and a healthy control group. P¼0. in recently published studies only patients with bipolar I disorder were investigated (Donaldson et al. 2004).Trail P¼0. Factors al. The best predictors of poor psychosocial functioning in bipolar II disorder were subclinical depressive symptoms. SANCHEZ-MORENO. attention and executive functions. 2001. 0. Benazzi. METHOD Participants Patients participating in this study were enrolled in the Bipolar Disorders Programme of the University Hospital Clinic of Barcelona. Patients with learning 5 difficulties were excluded as well as patients who had received electroconvulsive 254 . mainly because of the small number of patients with type II disorder included in these studies. P¼0. 33 bipolar II). with scores of 8 or less on the Hamilton Rating Scale for Depression (HRSD. A neuropsychological al. been specifically investigated in bipolar II disorder. subsyndromal features may have a negative impact in neuropsychological impairment and psychosocial functioning (Cassano & Savino. these studies are not specifically focused on bipolar II disorder. Dixon et al. 0 1 7 2 6 9 Cognitive impairment in bipolar II disorder ¤ CARLA TORRENT. al. Funding detailed in Acknowledgements. al. b p . which are the most common cognitive deficits in bipolar illness in general. ANABEL MARTI¤NEZ-AR AN. with a design involving two control groups: one comprising patients with bipolar I disorder and the other healthy participants. 2005.002) and attention (DigitSpan 0.001). 2005. 2004a al. Clark et al.002) Forwards. P¼0. A further hypothesis was that neuropsychological performance would also influence psychosocial functioning in patients with bipolar II disorder. The main aim of our study was to identify the cognitive performance in patients with bipolar II disorder in comparison with those with bipolar I disorder and a healthy control group. MANEL SALAMERO and EDUARD VIETA Background Persistent impairmentsin neurocognitive function have been described in bipolar disorder.b. al. al. JOSE MANUEL GOIKOLEA. Colom et al. 1 8 9 . Between 30% and 50% of patients with bipolar disorder experience significant social disability that may be related to persistent cognitive impairment (Zarate et al. Results Compared with controls. 2005. 1978.

The variables included in the analysis were the same as in the multiple linear regression model. Psychosocial functioning was assessed using the Global Assessment of Functioning scale (GAF.C O G NI T I V E I M PA I R M E N T IN B I P OL A R D I S O R D E R IN therapy in the past year. correlations were used to analyse which clinical and neurocognitive measures were related to psychosocial functioning. 1987). bipolar II and healthy controls) did not differ with respect to gender. The 35 healthy comparison participants with no psychiatric or neurological history were recruited through an advertisement and from a pool of healthy volunteers. which would have increased type II error. including psychosocial functioning. results are shown in Table 2. As many other measures of mood symptoms were obtained as part of the evaluation.39 v. 1994) as a measure of functional outcome. bipolar II and control samples were tested in one-way ANOVA.05). Ethical approval for the study was granted by the ethics committee. 30. 0. the rater was instructed to use the GAF to measure psychosocial functioning in the month prior to rating. The clinical and neuropsychological variables that correlated with the GAF were introduced in the model using a hierarchical stepwise method: clinical variables were introduced in block 1 and neuropsychological variables in block 2. 1995). version 10. The control group included students. when controlled for. patients with type II disorder performed poorly on most neuropsychological measures compared with healthy controls. educational level. and the neuropsychological evaluation was carried out by a trained neuropsychologist.1). 0. 1981). (c) Attention/concentration and mental tracking: the DigitSpan sub-test from the WAIS and the Trail Making Test (TMT. duration of illness (chronicity). especially on measures related to semantic verbal fluency (animal naming) and verbal Statistical analyses The three groups (bipolar I. Patients with type I disorder more commonly had a history of psychotic symptoms and a greater percentage of them were taking lithium (Table 1). Data analyses were performed using the Statistical Package for the Social Sciences. In gener(P al. This information was provided by the patient and confirmed by a first-degree relative or a partner. effect sizes were similar to those of the combined bipolar I and II groups. d. for example in measures of verbal memory such as recognition (0. A logistical regression test was also performed to identify predictive variables of occupational adaptation. (P 0. (Lezak. as measured by the GAF.45 v. as an additional measure of functional outcome.¼30. To enhance replication. Pearson Neuropsychological measures An extensive review of previous literature on this issue guided our choice of neuropsychological tests. The tasks were given in the same order to the whole sample. Heaton. The effects sizes have been calculated to find the difference between the groups in terms of standard deviation. Tests were administered according to standard instructions and took about 90 min to complete.952. the Stroop Colour– Word Interference test (SCWT) and the FAS task of the Controlled Oral Word Association Test (Spreen & Strauss. as defined above. The original GAF instructions call for rating symptoms or functioning. which were lower in the bipolar I group. masked to the results of the clinical and psychosocial assessments. workers. Occupational adaptation. was established as ‘good’ when patients were working at a good or acceptable level of functioning or ‘poor’ if they did not work at all or had poor occupational functioning during the 3 years prior to the evaluation.952.f. history of psychotic symptoms.28). was conducted by a trained psychiatrist. 1955). bipolar II and healthy controls) were compared on clinical and socio-demographic variables using analysis of variance (ANOVA) and chi-squared tests. In patients with bipolar II disorder. The differences shown between the scores on the YMRS and HRSD.33) or free short recall (0. The instruments administered for each domain are described elsewhere (Martinez-Aran et al.0 for Windows. Clinical variables were collected as part of the Bipolar Disorders Programme protocol of the University Hospital Clinic of Barcelona. They differed on age and age at illness onset. only tests frequently documented in the neuropsychological literature were used 255 . followed by Tukey post hoc comparison procedure when significant main effects were present.004) for the main effect. indicating that there were overall differences in neuropsychological performance between groups. age at onset of illness.f. Group differences between the bipolar I. Multivariate analysis of variance was performed to show overall differences in neuropsychological tests between groups. number of hospitalisations. First et al. family history of affective disorders. 170 (P¼0. d. cued delayed recall (0. 1958). suicide attempts. With regard to neuropsychological variables. taking into account variables that showed group differences (P50. American Psychiatric Association. functional outcome and total number of episodes (Table 1). (b) Frontal executive functions: the Wisconsin Card Sorting Test (WCST. 1997) and it al. Participants completed a comprehensive battery of tests spanning 4 broad cognitive domains. RESULTS The three groups (bipolar I. Reitan. 1998). For the subgroup of patients who were taking lithium. Multivariate analysis of covariance yielded Pillai’s F¼1. 0.43). this procedure was considered better than Bonferroni inequality correction. 2004a): al. Since neuropsychological tests are naturally correlated. The clinical variables included in this study were number and type of episodes. al. so these variables were not finally included as covariates. (d) Verbal learning and memory: the California Verbal Learning Test (CVLT. Since multiple dependent variables were used. 2004a (a) Estimated premormid IQ: Vocabulary sub-test from the Wechsler Adult Intelligence Scale (WAIS. Delis et al. Wechsler. For 12 of 15 comparisons the differences reached statistical significance (P50.32 v. The clinical interview. All participants were screened for Axis I psychiatric disorders using the Structured Clinical Interview for DSM–IV Axis I Disorders (SCID. including the animalnaming sub-tests. Owing to the small sample size there was insufficient statistical power to perform a subanalysis through the groups.004) 1. and diagnostic type I or II. did not significantly alter the results. homemakers and hospital staff. a prior protective analysis of covariance was performed with age as covariate and group as a main factor. was ensured that none in the control group had a first-degree relative with bipolar disorder. we used a multiple linear regression model to identify the variables that would be good predictors of psychosocial functioning. Vocabulary has been identified as the single best measure of both verbal and general mental abilities.

more working memory dysfunctions (DigitSpan Backwards sub-test) and more deficits in executive functions (animal naming.25) 0.55.12) (52) (48) (44)1 (18)1 (62)1 (50)1 (3)1 (14)1 (40)1 (27)1 39.d. The TMT part B 9. Patients with (R 7 0. YMRS. stepwise multiple linear regression analysis showed that the variables that best predicted psychosocial functioning.9) (6.06 0.90. as well as the bipolar I group.0 110.7%) of the variance (F¼9. Cohen.06).37. showed a trend towards a higher number of WCST perseverative errors compared with healthy controls (F¼2. P¼0. mean (s. longer illness duration showed more slowness or diminished attention (TMT part A). free (R 0. Analysis of the effect sizes pointed to small differences between the patient groups.36.52 0.05 1.16 0.) Chronicity.02 0.Y YMRS.32.90. P50. 0.009). 0.55.98) 13 22 (37) (63) 14.35.) Estimated premorbid IQ.d. Global Assessment of Functioning. mean (s.32.7 10. In the bipolar I group psychosocial functioning was related to some frontal executive functions such as the FAS (R¼0.2 13.83 (1.4) (2.4 13.19 0.001).8) (14. accounted for nearly 18% of the variance after controlling for the effect of the clinical variables (b¼70.8) (7.009). learning and memory (CVLT learning task. were higher HRSD score.6) (14.7) (3. 0.08 (2. Hamilton Rating Scale for Depression. GAF.019).45. n (%) Male Female Poor work adaptation. P¼0.9 13. In this regard medium effect sizes were observed. mean (s. mean (s.001 0. mean (s.013) and (R 0. P¼0.TO R R E N T E T A L T Table 1 Demographic and clinical characteristics of the study sample able Bipolar I (n¼38) (n 38) Bipolar II (n¼33) (n 33) Control (n¼35) (n 35) F ANOVA w2 P Age. who in turn performed worse than the control group.4) (5.31 50. P¼0.79 13 25 20 30 17 29 8 3 11 19 (8.9 (12.29 1.54 0. as measured through the GAF.027).) Total episodes. Both bipolar disorder groups performed worse than the control group on attention (TMT part A and DigitSpan Forwards) and working memory measures (DigitSpan Backwards).025).48 50.62 17 16 14 5 16 15 1 4 12 8 (9.5) (15.6) (6. logistical 256 .007).81 0. 0.47 0.Young Mania Rating Scale.045) measures from (R 0. suggesting that cognitive deficits are present in both groups but these dysfunctions are quantitatively more marked in bipolar I disorder.) Age at onset. so patients with bipolar II disorder showed an intermediate cognitive profile between patients with type I disorder and healthy participants. Cognitive dysfunction was present in the bipolar II group relative to the control group but differences were medium in terms of effect size. years: mean (s.2 30.001 0.39. n (%) Prior psychotic symptoms. (R¼0.5 69.) Educational level. In another measure of working memory (TMT part B) only a trend towards a poorer performance was detected in patients compared with controls. (R 0.22 3. well as the learning (R¼0.39 ANOVA.1) 4. P¼0.01 0.93. and higher perseverative errors from the WCST).d. 1988).019). In the bipolar II group.84 0. Pearson correlations were also used in order to establish which clinical variables correlated with the neuropsychological measures in the patient groups. wards sub-test (R¼0.51) (1.) HRSD score. P¼0. years: mean (s. P¼0.48.41.29 0. HRSD. as shown in Table 2 (Cohen’s d values. (b 7 7 0.37. analysis showed that the bipolar I group performed worse on most measures than the bipolar II group. 0.025).004) and the Trail Making Test part 0.2 63. analysis of variance.013). between the bipolar I and control groups.d. cued short-delay and long-delay-recall and recognition hits).63 0.) Gender.9) (11.4 13.007).29) (2.29 0. P¼0.009). the DigitSpan Back0.39. 0.027).d.0) (3.d.009).19) (34) (66) (53) (81)1 (50)1 (76) (21) (8) (29) (50) 45. Consistently with these results.39.0) (3.66 4.d.54 25.045) the CVLT. n (%) Family history of affective disorder.49 3.d. 0.1 12.79 5.026).37.06). 0.37. as (R 7 0. years: mean (s. Patients with type II disorder. after selecting all the variables that were correlated with the GAF.44 0. On the other hand.004) B (R¼70.013).19 0.42.9 113. P¼0.) GAF score. n (%) Lithium Carbamazepine Valproate Antidepressants Antipsychotics 38. the HRSD (R¼70.021) and recog0. Tukey post hoc (F 2. t¼72.5 14.41. In the bipolar II group we found a correlation between psychosocial functioning as measured by the GAF and the age at illness onset (R¼70.037 2. TMT part B score and the age at illness onset.43 0.91 3. oung 1.026).8) (8. 14 of 33 patients showed poor occupational adaptation. (R 0.01 0.94 0. (R 7 P¼0.3) (9. P¼0.021) nition (R¼0.08 5. and cued long-delay recall (R¼0.5 4.17 0. mean (s.64 1. This model accounted for nearly half (49.83 (0.5) (9.7 0.2 112 23. The bipolar II group showed an intermediate level of performance. (R 0. A few patients had missing data for this variable. short-delay recall (R¼0.d.013) the TMT part B (R¼70. (R 7 P¼0.44 0. n (%) Medications. on the Stroop interference task and on all measures of verbal memory (CVLT).2 2.41. P¼0.) YMRS score.

57 0.20 0. Wisconsin Card SortingTest. but all studies so far have been crosssectional.9 (6. regression analysis also showed that higher TMT part B scores appear to be nearly significant as an indicator of poor occupational adaptation (Exp(B)¼1.75 0. the bipolar I and II groups had a worse performance than the control group on working memory measures (DigitSpan Backwards and TMT part B) and attention (TMT part A).6) 16.001 A5B5C 50.9) 6. Kieseppa et al.001 A5B5C 0.9) 10.001 A5B5C 0.) Bipolar II (n¼33) (n 33) Mean (s.81 4.7) 30.5 (2. 2004a.32 0.3 (11.2) 18.54 5. California Verbal LearningTest.1) 1.74 0.7 (2. particial. pants with bipolar II disorder in this study 2 57 .59 0.6 (6.06 0 0. 2004a al.B5C A.2) 5.4 (1.058).95 0.9 (17.B5 0.74 0.9) 9.7 (7.77 0.59 6. Trail MakingTest.98 2. (Exp(B) 1.0 (14.5) 10.2) 5.9) 9.4 (7.3) 12.08 0.1 (1. Balanza-Martinez et al.0) 4. 1999.6 (37.4 (2.) MANCOVA F(2.4 (3.021.41 0.72 0. TMT.48 0.3) 48.C O G NI T I V E I M PA I R M E N T IN B I P OL A R D I S O R D E R IN Table 2 Performance on neuropsychological tests Bipolar I (n¼38) (n 38) Mean (s.54 CVLT.d.B5C A.4 (1.56 0.3 (3.1 (1.06 0.67 0.d.45 0.7) 10. Vieta et al.5) 14.22 0.52 0.10 0. 2005).9) 11. the bipolar I group showed quantitatively more dysfunctions than the bipolar II. This suggests that working memory may be correlated with illness severity.0) 1. but a particularly malignant subtype with regard to frequency of episodes (Vieta et al.8 (3.4 (1.1 (4.5) 74.60 9.1) 10.9) 11.42 2.71 41.2) 4.0 (1. Our findings indicate that euthymic patients with type II disorder also show (although to a lesser degree) the persistent cognitive deficits seen in patients with a type I diagnosis.02 0. patients with type II disorder seem to make more perseverative errors in the Wisconsin Card DISCUSSION To the best of our knowledge. Sorting Test. C Frontal executive function WCST Categories Perseverative errors SCWT Interference Subtest Digits (WAIS) Digits forward Digits backward TMT Trail A Trail B Verbal fluency FAS Animal naming Verbal learning and memory CVLT List A (total) Free short-recall Cued short-recall Free delayed-recall Cued delayed-recall Recognition 44.2) 12.6 (1.) Control (n¼35) (n 35) Mean (s.3) 5.021.36 0.B5 A.0) 5.4 (1.5 (2.56 0. MANCOVA.058).1) 100.5) 15 (1.B5 0.B5C A.2) 36. After controlling for age.0 (55.6) 99.1 (11.2) 13.0 (6.020 A5B5C 0.28 0.9) 5.5) 40. Our study suggests that cognitive dysfunctions in bipolar disorder are not limited to the traditional bipolar I subtype.4 (11.3 (9.0) 4.6) 19.73 0. C A v.50 0. Perseverative errors may also be related to greater impulsivity. 1997).8 (2.3 (3. In fact.0 (2.2 (0. When compared with bipolar I patients. Wechsler Adult Intelligence Scale.7) 0. A longitudinal study al.90 0.3) 4.55 0. Stroop Colour^Word InterferenceTest. 0. 2005.6 (2. Martinez-Aran et al.06 A.0) 13.3 (3.24 0.5 (9.07 0.1) 5.39 0. 2002) and was confirmed with this study. Cognitive performance in bipolar II disorder Patients with bipolar II disorder had many verbal memory deficits compared with healthy controls.8) 39.5 (13.40 0.22 0.d. none of the previous cognitive studies in bipolar disorder focused on neuropsychological dysfunction in type II disorder.010 A5B5C 50.45 0. This is consistent with a growing body of evidence that people with bipolar disorder experience impairment in verbal learning and memory which persists during the euthymic state (Cavanagh et al.001 A5B5C 0. B Cohen’s d B v.74 0. WCST.1) 6. 2004.66 0. WAIS.46 6.80 0. Glahn et al. al. bipolar II disorder has been reported to be not just a milder form of bipolar illness.005 0.B5C A.12 0.8) 22.27 0.73 35. P¼0.82 0.5 (52.15 0.6 (11. However.002 A. multivariate analysis of variance.004 A5B5C 0. so this could be related to a higher comorbidity related to the impulsivity spectrum in type II disorder (Goldberg & Harrow.3) 14. 2000).001 0. al.103) P Tukey post hoc tests A v.83 8.002 A. 2002.26 0.8 (14.10 0. This was already anticipated as a clinical observation (Vieta et al.5 (2.32 0. Regarding executive functions. SCWT.3) 8.1 (1.85 0. Patients in the bipolar II group showed an intermediate level of performance between the bipolar I and control groups in verbal memory and executive functions (Stroop interference task). would better address the differences in cognitive performance in hypomania and mania.89 7.4) 53.b.B5 0. al. al.48 7.2 (10.50 0. al.55 Attention/concentration and mental tracking 5.0 (3.5) 11.21 0.

Another relevant issue is the baseline difference between patients and controls in terms of medication and history of psychotic symptoms.Washington. L. The course of manic-depressive illness. type II disorder. C. 2000) 0. The presence of psychotic symptoms is a baseline diagnostic difference between the two diagnostic categories (Vieta et al. ACKNOWLEDGEMENTS The study was supported by grants from the Funda¤ de TV3 cio Marato deTV3 (2510/01). A recent study did not reveal any correlation between prior history of psychotic symptoms and cognitive impairment (Selva et al.. Medicina Clinica. R. Hillsdale.V. 119. (1982) Limitations of the study Our study was cross-sectional. executive dysfunctions are likely to constitute good predictors of social and occupational difficulties in patients with type II disorder. whereas problems in retaining and recovering information may be more relevant in type I disorder. 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