Deterioro Cognitivo en Bipolar II

8/2/2019 Deterioro Cognitivo en Bipolar II

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RCP S Y C HR OY AL C OL LE G E O FPSYCHIATRISTS

Th e B ritis h Jou rn al o f Ps ychia tr y

Coanitive impairment in bipolar II disorderCarlarorrent, Anabel Martinez-Aran, Claire Daban, Jose Sanchez-Moreno, Merce Comes, Jose ManuelGoikolea, Manel Salamero and Eduard VietaBJP 2006, 189:254-259.Access the most recent version at 001: 10.1192/bjp.bp.1 05.017269

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BRITISH JOURNAL OF PSYCHIATRY (2006), 189, 254-259. d o l : 10.1I92/bjp.bp.IOS.017269

Cognitive impairment in bipolar II disorderCARLA TORRENT, ANABEL MARTINEZ-ARAN, CLAIRE DABAN,JOSE SANCHEZ-MORENO, MERcE COMES, JOSE MANUEL GOIKOLEA,MANEL SALAMERO and EDUARD VIETA

Background Persistent impairments inneurocognitive function have beendescribed in bipolar disorder.Aims To compare the cognitiveperformance of patients with bipolar IIdisorder with that of patients with bipolar Idisorder and a healthy control group.Method The study included 71euthymic patients with bipolar disorder(38 bipolar 1,33 bipolar II), who werecompared on clinical and neuropsycho-logical variables (e.g. executive function,attention, verbal and visual memory) andcontrasted with 35 healthy controls oncognitive performance.Results Compared with controls, bothbipolar groups showed significant deficitsin most cognitive tasks including workingmemory (DigitS pan Backwards,P=0.002) and attention (DigitS panForwards, P=0.005; Trail Making Test,P=O.OOI).Those with type IIdisorders hadan intermediate level of performancebetween the bipolar Igroup and thecontrol group inverbal memory( P


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therapy in the past year. The 35 healthycomparison participants with no psy-chiatric or neurological history wererecruited through an advertisement andfrom a pool of healthy volunteers. Allparticipants were screened for Axis Ipsychiatric disorders using the StructuredClinical Interview for DSM-IV Axis IDisorders (SCID; First et al, 1997) and itwas ensured that none in the control grouphad a first-degree relative with bipolar dis-order. The control group included students,workers, homemakers and hospital staff.Ethical approval for the study was grantedby the ethics committee.

Clinical variables were collected as partof the Bipolar Disorders Programme proto-col of the University Hospital Clinic ofBarcelona. The clinical variables includedin this study were number and type of epi-sodes, duration of illness (chronicity); ageat onset of illness; number of hospitalisa-tions; suicide attempts; family history ofaffective disorders; history of psychoticsymptoms; and diagnostic type I or II.

Psychosocial functioning was assessedusing the Global Assessment of Functioningscale (GAF; American Psychiatric Associa-tion, 1994) as a measure of functional out-come. The original GAF instructions callfor rating symptoms or functioning. Asmany other measures of mood symptomswere obtained as part of the evaluation,the rater was instructed to use the GAF tomeasure psychosocial functioning in themonth prior to rating. Occupationaladaptation, as an additional measure offunctional outcome, was established as'good' when patients were working at agood or acceptable level of functioning or'poor' if they did not work at all or hadpoor occupational functioning during the3 years prior to the evaluation. This infor-mation was provided by the patient andconfirmed by a first-degree relative or apartner. The clinical interview, includingpsychosocial functioning, was conductedby a trained psychiatrist, and the neuro-psychological evaluation was carried outby a trained neuropsychologist, masked tothe results of the clinical and psychosocialassessments.

Neuropsychological measuresAn extensive review of previous literatureon this issue guided our choice of neuropsy-chological tests. To enhance replication,only tests frequently documented in theneuropsychological literature were used

(Lezak, 1995). Participants completed acomprehensive battery of tests spanning4 broad cognitive domains. Tests wereadministered according to standard instruc-tions and took about 90min to complete.The tasks were given in the same order tothe whole sample. The instruments admi-nistered for each domain are describedelsewhere (Martinez-Aran et al, 2004a):(a) Estimated premormid IQ: Vocabularysub-test from the Wechsler Adult Intel-ligence Scale (WAIS;Wechsler, 1955).Vocabulary has been identified as thesingle best measure of both verbal andgeneral mental abilities.

(b) Frontal executive functions: theWisconsin Card Sorting Test (WCST;Heaton, 1981), the Stroop Colour-Word Interference test (SCWT) andthe FAS task of the Controlled OralWord Association Test (Spreen &Strauss, 1998), including the animal-naming sub-tests.

(c) Attention/concentration and mentaltracking: the DigitSpan sub-test fromthe WAIS and the Trail Making Test(TMT; Reitan, 1958).

(d) Verbal learning and memory: theCalifornia Verbal Learning Test(CVLT; Delis et al, 1987).

Statistical analysesThe three groups (bipolar I, bipolar II andhealthy controls) were compared on clinicaland socio-demographic variables using ana-lysis of variance (ANOVA) and chi-squaredtests. Multivariate analysis of variance wasperformed to show overall differences inneuropsychological tests between groups.Since multiple dependent variables wereused, a prior protective analysis of covar-iance was performed with age as covariateand group as a main factor. The differencesshown between the scores on the YMRSand HRSD, when controlled for, did notsignificantly alter the results, so these vari-ables were not finally included as covari-ates. Since neuropsychological tests arenaturally correlated, this procedure wasconsidered better than Bonferroni inequal-ity correction, which would have increasedtype II error. Group differences between thebipolar I, bipolar II and control sampleswere tested in one-way ANOVA, followedby Tukey post hoc comparison procedurewhen significant main effects were present.The effects sizes have been calculated tofind the difference between the groups interms of standard deviation. Pearson

COGNITIVE IMPAIRMENT IN BIPOLAR DISORDER

correlations were used to analyse whichclinical and neurocognitive measures wererelated to psychosocial functioning, asmeasured by the GAF, taking into accountvariables that showed group differences(P


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TORRENT ET AL

Table I Demographic and clinicalcharacteristics of the study sample

Bipolar I (n=38) Bipolar II(n=33) Control (n=35) ANOVAF X 2

Age, years: mean (s.d.) 38.4 (8.7) 45.2 (9.0) 39.1 (12.0) 4.7Educational level, years: mean (s.d.) 13.2 (3.4) 13.0 (3.5) 12.9 (3.3) 0.05Estimated premorbid IQ, mean (s.d.) 112 (5.9) 110.2 (9.9) 113.9 (9.1) 1.66Age at onset, years: mean (s.d.) 23.5 (6.8) 30.9 (11.8) 4.54Chronicity, mean (s.d.) 14.7 (7.6) 13.4 (8.6) 0.16Total episodes, mean (s.d.) 10.2 (6.8) 13.5 (14.5) 0.64GAF score, mean (s.d.) 63.5 (14.2) 69.2 (15.4) 1.19HRSD score, mean (s.d.) 4.29 (2.51) 2.29 (2.29) 1.83 (1.25) 14.22YMRS score, mean (s.d.) 0.79 (1.19) 1.62 (2.12) 0.83 (0.98) 3.39Gender, n (% )

Male 13 (34) 17 (52) 13 (37) 2.44Female 25 (66) 16 (48) 22 (63)

Poor work adaptation, n (% ) 20 (53) 14 (44)' 0.54Prior psychotic symptoms, n (% ) 30 (81)' 5 (18)' 25.63Family history of affect ive disorder , n (% ) 17 (50)' 16 (62)' 0.79Medications, n (% )

lithium 29 (76) 15 (50)' 5.08Carbamazepi ne 8 (21) (3)' 5.49Valproate 3 (8) 4 (14)' 3.47Antidepressants II (29) 12 (40)' 0.91Anti psychotics 19 (50) 8 (27)' 3.81

ANOVA,analysisof variance; GAF,GlobalAssessment of Functioning;HRSD,Hamilton RatingScalefor Depression;YMRS,YoungManiaRatingScale.I. A fewpatients hadmissingdata for this variable.

learning and memory (CVLT learning task,cued short-delay and long-delay-recall andrecognition hits). Both bipolar disordergroups performed worse than the controlgroup on attention (TMT part A and Digit-Span Forwards) and working memory mea-sures (DigitSpan Backwards). In anothermeasure of working memory (TMT partB) only a trend towards a poorer perfor-mance was detected in patients comparedwith controls. Patients with type II disor-der, aswell as the bipolar I group, showeda trend towards a higher number of WCSTperseverative errors compared with healthycontrols (F=2.90. P=0.06). Tukey post hocanalysis showed that the bipolar I groupperformed worse on most measures thanthe bipolar II group, who in turn performedworse than the control group, so patientswith bipolar II disorder showed an inter-mediate cognitive profile between patientswith type I disorder and healthyparticipants.

The bipolar II group showed an inter-mediate level of performance, between thebipolar I and control groups, on the Stroopinterference task and on all measures ofverbal memory (CVLT). In this regard

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medium effect sizes were observed, asshown in Table 2 (Cohen's d values; Cohen,1988). Analysis of the effect sizes pointedto small differences between the patientgroups, suggesting that cognitive deficitsare present in both groups but these dys-functions are quantitatively more markedin bipolar I disorder. Cognitive dysfunctionwas present in the bipolar II group relativeto the control group but differences weremedium in terms of effect size. Pearsoncorrelations were also used in order to es-tablish which clinical variables correlatedwith the neuropsychological measures inthe patient groups. In the bipolar II groupwe found a correlation between psychoso-cial functioning as measured by the GAPand the age at illness onset (R= - 0.42,P=0.026), the HRSD (R= - 0.48,P=0.004) and the Trail Making Test partB (R=-0.45, P=0.009). Patients withlonger illness duration showed more slow-ness or diminished attention (TMT partA), more working memory dysfunctions(DigitSpan Backwards sub-test) and moredeficits in executive functions (animalnaming, and higher perseverative errorsfrom the WCST).

p

0.010.940.190.010.840.520.31


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Table 2 Performance on neuropsychological tests

Bipolar I (n=38) Bipolar II(n=33) Control (n=35) MANCOVA P Tukeypost Cohen's dMean (s.d.) Mean (s.d.) Mean (s.d.) F(2.103) hoc tests

Av.B Bv.C Av.CFrontal executive function

WCSTCategories 5.1 (1.3) 5.1 (1.6) 5.4 (1.3) 0.42 0.59 0 0.20 0.22Perseverative errors 14.5 (13.2) 16.0(14.9) 8.6 (6.7) 2.90 0.06 0.10 0.21 0.54

SCWTInterference 0.9 (6.1) 1.4 (7.2) 4.7 (7.0) 4.08 0.020 A


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had on average three more episodes thanthose with bipolar I disorder, but differ-ences did not reach statistical significanceowing to the higher standard deviation ofthe bipolar II sample.

Role of clinical and social factorsA severe illness course probably has anegative impact on social and occupationalfunctioning aswell ason cognition. The cor-relations found between psychosocial out-come and verbal memory in the bipolar Igroup are consistent with other findings byour research group (Martinez-Aran et al,2004a,b; 2006). Patients with type II disor-der initially showing a better clinical profilethan those with type I disorder may have aworse illness course because of the greaternumber of episodes, with significantly moremajor and minor depressive episodes andshorter inter-episode intervals (Vieta et al,1997; Judd et al, 2003). In bipolar II disor-der, patients experience more severe andlonger depressions than in bipolar I disorder(Ayuso-Gutierrez & Rarnos-Brieva, 1982)and havemore persistent residual depressivesymptoms (Cassano&Savino, 1997; Benaz-zi, 2001). Partial remission aswell as cogni-tive dysfunctions may lead to impairedpsychosocial functioning in bipolar disor-der. These subtle depressive symptomsmight explain why patients with bipolar IIdisorder have more cognitive complaintsand cognitive dysfunctions than healthyindividuals evenwhen the effect of subtle af-fective symptoms is controlled for. Rapid-cycling might carry higher risk of cognitiveimpairment, but as these patients wereequally split between the two groups, thereis a little chance that this factor could ex-plain the differences between type I and IIdisorder in our study. Other possible factorsinvolved when comparing executive func-tion between the two types of bipolar disor-der are prior psychotic symptoms andlithium treatment, which were both morefrequent in participants with bipolar I disor-der. However, looking at the effect sizeswecannot conclude that taking or not takinglithium would explain the differences incog-nitive performance between the two groups(P=0.023). In one study (Stipet al, 2000)it was observed that medium-term lithiumadministration did not impair explicit mem-ory and attention in healthy participants.

Regarding psychotic symptoms, theimportant reduction of the effect size (ap-proximately 50%) may mean that thehigher prevalence of psychotic symptoms

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in bipolar I disorder would partially explainthe differences in performance v. type II dis-order. The presence of psychotic symptomsis a baseline diagnostic difference betweenthe two diagnostic categories (Vieta et al,1997) and the specific effect of psychoticfeatures on cognitive function in bipolardisorder has not been adequately examined.A recent study did not reveal any correla-tion between prior history of psychoticsymptoms and cognitive impairment (Selvaet al, 2006). Frontal executive dysfunctions,specifically related to working memory im-pairment, may be related to a poorer psy-chosocial functioning ill bipolar IIdisorder. Working memory dysfunctionshave been found to be present in euthymicpatients with bipolar disorder, even whenresidual depressive symptoms were covar-ied for (Ferrier et al, 1999). Therefore,executive dysfunctions are likely toconstitute good predictors of social andoccupational difficulties in patients withtype II disorder, whereas problems in re-taining and recovering information maybe more relevant in type I disorder. Theseresults suggest that perhaps different ncuro-cognitive processes are involved in thepsychosocial difficulties of the two bipolarsubtypes. However, further research wouldbe required to clarify our findings.

Limitations of the studyOur study was cross-sectional, whereas alongitudinal follow-up might provide moreinformation about the progression of cogni-tivedysfunctions. Itremains unclear whethercognitive dysfunction is a premorbid issue oractually progressive in the course of theillness. A larger sample size would haveallowed more sophisticated analyses andmight have shown clearer differences be-tween the groups, for instance with respectto the executive functions. Another relevantissue is the baseline difference between pa-tients and controls in terms of medicationand history ofpsychotic symptoms. Inthe bi-polar Igroup therewas a significantly higherpercentage of patients with a previous his-tory of psychotic symptoms compared withthe bipolar II group, so the potential impactof this variable on cognition deserves specificattention in further research.

Clinical implicationsPersistent cognitive dysfunctions, includingdeficits in attention, executive function andverbal memory, exist in bipolar II disorder

as in type I disorder, so cognitive function-ing should be routinely examined in patientswith either subtype. In patients with bipolarII disorder, working memory dysfunctionseems to be a good predictor of functionalimpairment, after controlling for the effectof sub-syndromal symptoms. Rehabilitationinterventions should take into accountpotential cognitive differences between thetwo subtypes, especially regarding their im-pact on functioning. An early diagnosis oftype IIdisorder isimportant toprevent or rc-mediate as much as possible the cognitiveproblems of these patients.

ACKNOWLEDGEMENTS

The study was supported by grants from the Funda-cio Marat6 de TV3 (2510/01), the lnst.tuto Carlos IIIFIS051542 and Stanley Medica l Research Institute,Bethesda, Maryland, USA. The authors thank C.Corcherofromthe Universi ty Politecnica of Barcelonafor statist ical support .

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CARLA TORRENT, PhD, ANABEL MARTfNEZ-ARAN, PhD, CLAIRE DABAN, PhD, Bipolar DisorderProgramme, Cl inical Ins ti tute of Neuroscience, Universi ty Hospita l Clinic, Ins titut d' lnvest igacions BlomedlquesAugust P, i Sunyer (IDIBAPS), Barcelona; JOSE SANCHEZ-MORENO, Bipola r Disorder Programme, ClinicalIns titute of Neuroscience, Univers ity Hospi ta l Clinic , IDIBAPS, Barcelona and Psychiatry Depar tment,Unive rsidad Autonoma de Madrid; MERCE COMES, PsN, JOSE MANUELGOIKOLEA, MD, MANELSALAMERO, MD, PhD, EDUARD VIETA, MD, PhD, Bipolar Disorder Programme, Clinica l Institute ofNeuroscience, Universi ty Hospital Cl in ic , IDIBAPS, Barcelona, SpainCorrespondence: Dr Eduard Vieta, Clinical Institute of Neuroscience, University Hospital Clinic ofBarcelona, Villarroel 170,08036 Barcelona, Spain. Tel: +3493227540 I; fax: +34932275477; ema il:[email protected]

(First received 27 September 2005, final revision 8 May 2006, accepted 2 june 2006)

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Deterioro Cognitivo en Bipolar II