Original Article

Cognitive impairment in euthymic bipolarpatients: implications for clinicaland functional outcome

Most previous research on neuropsychologicalperformance in bipolar disorder has examinedcognitive function in acute episodes. Cognitiveareas which seem to be more impaired duringactive periods of illness are attention, learning andmemory, psychomotor functioning and frontalexecutive functions (1–3).

It is unclear which of these cognitive dysfunctionsremain in remission states. Recent studies have

suggested that verbal learning and memory, atten-tion and executive function may also be impaired ineuthymic patients, but results are still contradictory(4). Van Gorp et al. (5) who employed a rigorousdefinition of euthymia and a control sample thatwas matched on general intellectual ability andyears of education, found executive and verbalmemory dysfunctions in euthymic patients. Somerecent studies have suggested that sustained atten-tion may constitute a vulnerability marker inbipolar disorder (6, 7). Other authors have alsopointed to impaired verbal learning and memory in

Martınez-Aran A, Vieta E, Colom F, Torrent C, Sanchez-Moreno J,Reinares M, Benabarre A, Goikolea JM, Brugue E, Daban C, Salamero M.Cognitive impairment in euthymic bipolar patients: implications forclinical and functional outcome.Bipolar Disord 2004: 6: 224–232. ª Blackwell Munksgaard, 2004

Objective: Cognitive impairment in bipolar disorder may be a stablecharacteristic of the illness, although discrepancies have emerged withregard to what dysfunctions remain during remission periods. The aim ofthis study was to ascertain whether euthymic bipolar patients wouldshow impairment in verbal learning and memory and in executivefunctions compared with healthy controls. Secondly, to establish if therewas a relationship between clinical data and neuropsychologicalperformance.

Methods: Forty euthymic bipolar patients were compared with30 healthy controls through a battery of neuropsychological testsassessing estimated premorbid IQ, attention, verbal learning andmemory, and frontal executive functioning. The effect of subsyndromalsymptomatology was controlled.

Results: Remitted bipolar patients performed worse than controls inseveral measures of memory and executive function, after controlling forthe effect of subclinical symptomatology, age and premorbid IQ. Verbalmemory impairment was related to global assessment of function scores,as well as to a longer duration of illness, a higher number of manicepisodes, and prior psychotic symptoms.

Conclusions: Results provide evidence of neuropsychologicalimpairment in euthymic bipolar patients, after controlling for the effectof subsyndromal depressive symptoms, suggesting verbal memory andexecutive dysfunctions. Cognitive impairment seems to be related to aworse clinical course and poor functional outcome.

A Martınez-Aran, E Vieta, F Colom,C Torrent, J Sanchez-Moreno,M Reinares, A Benabarre,JM Goikolea, E Brugue, C Dabanand M Salamero

Bipolar Disorders Program, Clinical Institute of

Psychiatry and Psychology, Hospital Clinic,

Barcelona Stanley Medical Research Institute

Center, University of Barcelona, IDIBAPS,

Barcelona, Spain

Key words: bipolar disorder – cognition –

functional outcome – mania – memory – psychotic

symptoms

Received 19 August 2003, revised and accepted

for publication 11 February 2004

Corresponding author: Eduard Vieta, MD, PhD,

Clinical Institute of Psychiatry and Psychology,

Hospital Clinic, University of Barcelona, Villarroel

170, 08036 Barcelona, Spain.

Fax: +34 93 2275477;

e-mail: evieta@clinic.ub.es

Each author declares that they have no potential conflict of interest.

Bipolar Disorders 2004: 6: 224–232Copyright ª Blackwell Munksgaard 2004

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remitted patients after controlling for subclinicalpathology (8, 9). Sapin et al. (10) assessed20 bipolar patients who had remained euthymicfor a month and were 2-week drug-free. Theseauthors observed facial recognition impairment inpatients compared with controls. Donaldson et al.(11) examined a large sample of remitted bipolar Ipatients and controlled for the effect of severalclinical features and medication on cognition. Inthis regard, they suggested that current antipsy-chotic medication, duration of illness, and familyhistory of affective disorder were the variables thatbetter predicted IQ and memory functioning.Chronic cognitive impairment has been reportedsuggesting that deficit may rather represent a traitthan a state (12, 13). Most studies have includedreduced samples, have not used restricted remissioncriteria or have not controlled the effect of subclin-ical symptoms. On the contrary, between 30 and50% of bipolar patients experience significant socialdisability that may be related to persistent cognitiveimpairment (14). In view of data commented before,the main hypotheses arised in the present studywere, firstly that bipolar patients would show verbalmemory as well as executive function impairmentseven after controlling for the effect of low levels ofaffective symptoms, secondly that some particularclinical features would be associated with cognitivedysfunction, and finally that some specific neuro-psychological measures, especially those related tomemory and executive function would be morestrongly associated with psychosocial functioningrather than clinical features.

Patients and methods

Subjects

Patients participating in the present study wereenrolled at the Bipolar Disorders Program atHospital Clınic, Barcelona. The clinical state ofthe patients was determined by a psychiatristresponsible for the follow-up of bipolar patientsin the Barcelona Bipolar Disorders Program usingDSM-IV criteria, and the Structured ClinicalInterview for Diagnostic Symptoms (SCID,DSM-IV), the Spanish version of the HamiltonDepression Rating Scale (HDRS, 17-item) (15, 16),and the Spanish version of the Young ManiaRating Scale (YMRS) (17, 18). Subjects with otherdisorders that could be related to neuropsycholog-ical impairment (significant physical or neurolog-ical illness, neurodegenerative disorder, substanceabuse or dependence in the last 12 months, mentalretardation, electroconvulsive therapy in the lastyear) were excluded. Patients and controls gave

informed consent after the procedures had beenfully explained. Ethical approval for the study wasgranted by the Ethics Committee.

Neuropsychological performance was assessed in40 euthymic bipolar patients (17 male and23 female, who met DSM-IV criteria for bipolardisorder, age range: 20–60). Patients euthymic statewas confirmed through YMRS £ 6 and HDRS £ 8during monthly visits over a 6-month period.Patients (62) were initially screened to arrive atthe current sample of patients. The reasons for notentering the study were current substance abuse,history of head injury, neurological illness, mentalretardation and subsyndromal fluctuations. Threepatients refused to participate in the study. Severalpatients met more than one exclusion criteria andwere not admitted into the present study. Withrespect to the comparison group, five subjects couldnot enter the study (two due to history of headinjury and three due to anxiety disorders).

Patients were treated according to the treatmentguidelines of the Barcelona Bipolar DisordersProgram. Two patients were off medication at thetime of testing. Most patients were receiving mood-stabilizing medication. The majority of patients(33 of 40) were treated with lithium carbonate,12 with carbamazepine and seven with valproate.Eleven patients were receiving more than one mood-stabilizer. Moreover, 23 patients were receivingantipsychotics (15 with atypical antipsychotics),eight antidepressants as maintenance treatment,and 17 were also medicated with benzodiazepines.Since patients were in remission, doses of antide-pressants and antipsychotics were low, and they didnot receive any anticholinergic medication. At thetimeof testing, dose of antipsychoticmedicationwas207.1 ± 121.1 chlorpromazine equivalents. Themean doses of mood-stabilizers were 1090.3 ±282.1 mg for lithium, 627.3 ± 155.5 mg for carb-amazepine and 1416.7 ± 204.1 mg for valproate.Patients were compared with 30 healthy controls(eight male and 22 female, age range: 22–60),withouthistoryofpsychiatric orneurological illness.Control subjects were screened through the SCID(DSM-IV) to exclude subjects with prior psychiatrichistory. Controls had no first-degree relatives withbipolar disorder or other psychiatric disorders whenasked in previous interview for selection of controls.The healthy comparison group was recruited from apool of normal volunteers of the Hospital Clınic ofBarcelona and from advertising.

Clinical and psychosocial assessment

Clinical variables were collected as part of theprotocol of the Bipolar Disorders Program.

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Psychosocial functioning was assessed throughthe General Assessment of Functioning (GAF)(19) as a measure of functional outcome. Theoriginal GAF instructions call for rating symptomsor functioning. As many other measures of moodsymptoms were obtained as part of the evaluation,the rater was instructed to use the GAF to measurepsychosocial functioning in the month prior torating.

The GAF was administered by a trained psychi-atrist, whereas the neuropsychological evaluationwas carried out by a neuropsychologist who wasblind to the results of the clinical and psychosocialassessments.

Neuropsychological assessment

A battery of neuropsychological tests was admin-istered to assess estimated premorbid IQ, attention,verbal learning and memory, and frontal executivefunctioning. Neuropsychological testing lastedapproximately 90 min and sometimes included asmall break halfway through the assessment. Teststhat are actually able to assess a single cognitivefunction are not generally available so the testsemployed were ascribed to broad cognitive cate-gories, despite the need for multiple cognitive skillsin their successful completion.

Estimated premorbid IQ. Vocabulary subtest(Wechsler Adult Intelligence Scale) (20): A meas-ure to estimate premorbid intelligence. In this task,the examiner asks the meaning of 40 words,arranged in order of difficulty. Vocabulary hasbeen identified as the single best measure of bothverbal and general mental abilities (21, 22).

Frontal executive functions. Wisconsin Card Sort-ing Test (WCST) (23): It measures concept forma-tion and cognitive flexibility. The number ofcorrectly completed categories (a measure of abilityto establish, maintain and change set) and thenumber of perseverative errors (ability to changeset, cognitive flexibility) were analysed.Stroop Colour-Word Interference Test (SCWT)

(24): It measures mainly selective attention andexecutive function. Part 1 of the test, which consistsof reading colour names in black ink, measuresverbal ability and attention. The part 2 requires thesubject to say the colour of coloured XXXs. In part3, the colour words are printed in incongruent inkcolours, and the subject is asked to name the colourinstead of reading the name. This situation gener-ates interference, and measures the ability to changedemands and suppress a habitual response infavour of an unusual one. The interference score,

which measures �resistance to interference� wascorrected for speed factors by using the formulaprovided by Golden (24).FAS (Controlled Oral Word Association Test)

(25): This test was used to evaluate verbal fluency,which is also a sensitive measure of frontalexecutive function, because it requires the subjectto generate their own strategy. The patient isrequired to generate as many words as possiblebeginning with the letters F, A and S, in three trialsof 1 min. Moreover, one category (animal naming)was used to assess semantic fluency. Total correctresponses were analysed.

Attention/concentration and mental tracking. Digitsubtest (Wechsler Adult Intelligence Scale) (20):The subject repeats a fixed random series ofnumbers of increasing length in direct order (digitsforward) and in reverse order (digits backward). Inaddition to auditory attention and short-termretention capacity, this test assesses the ability tomanipulate the information in verbal workingmemory. Raw scores for direct and reverse orderwere analysed.Trail Making Test (TMT) (26): Part A of the test

measures psychomotor speed. The results of part Breflect the ability to shift strategy and assessexecutive function and visuospatial working mem-ory. Part A and B were recorded in seconds.

Verbal learning and memory. California VerbalLearning Test (CVLT) (27): It assesses multipleaspects of how verbal learning occurs as well as theamount of verbal material learned. It comprises alist learning task (16 words, four words from eachof four semantic categories). There are five imme-diate free recall trials of list A which provides aglobal measure of learning performance. These fivetrials are followed by an interference list B that ispresented once. After this, short-delay recall of listA is tested in both free and cued forms. Cues aregiven in the form of the four categories. Following20 min of non-verbal tests, long delay-free andcued recall from list A are recorded. Recognitionhits were recorded.

Statistical analysis

Differences between groups were tested withANOVA. After that, ANCOVA was used tocovary for the effects of age, estimated premorbidIQ and subclinical symptomatology, which werethought to influence neuropsychological perform-ance, as previous studies have shown and on thebasis of correlations found between these variablesand cognitive measures. Since multiple-dependent

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variables were used and neuropsychological testsare naturally correlated, a prior protectiveMANOVA analysis was performed with the varia-bles mentioned above as covariates. This procedurewas considered better than Bonferroni correctionthat would increase type II error. The effect of othervariables such as the prior history of psychoticsymptoms were controlled using ANOVA. Rela-tionships between test scores that showed statisti-cally significant group differences (p < 0.05) andclinical variables related to the course and severity ofthe bipolar patients were tested with Spearmancorrelations, with a significance level of p < 0.05.Spearman correlations were also used to analyserelationships between neuropsychological perfor-mance and psychosocial functioning.

Results

Patients and controls did not differ with respect tosex, age, education level and estimated premorbidIQ (Table 1). Table 1 shows the characteristics ofthe two groups. Differences between groups werefound regarding HDRS scores but not with regardto YMRS, suggesting some degree of subclinicaldepressive symptomatology in the bipolar group,despite the narrow remission criteria defined forinclusion in the study. Table 2 gives the mean andSD of scores in each group for neuropsychologicaltests and the results of ANCOVA analysis.MANOVA analysis yielded a Pillai’s F15,46 ¼ 3.124(p ¼ 0.002) for the main effect, indicating thatthere were overall differences in neuropsychologi-cal performance between groups. After controllingfor covariates (subclinical symptoms, as measuredby HDRS scores, age, and estimated premorbidIQ), differences between groups were found asregard WCST perseverative errors, TMT, back-ward digit span and CVLT, whilst we did not findsignificant differences with respect to SCWTinterference and category fluency (animal naming)

scores. Furthermore, no significant impairmentwas found on immediate memory span (digitforward), verbal fluency (FAS) and the numberof categories achieved in the WCST. Impairedperformances in the patients were not explained bysex distributions in the two groups. When priorpsychotic symptoms were controlled for, weobserved that those patients with history ofpsychotic symptomatology in previous episodesshowed more verbal memory impairment in theCVLT, especially in the learning task (43.0 ± 11.6versus 52.5 ± 11.8; F ¼ 40.88; d.f. ¼ 1, 37;p ¼ 0.033), free long-delay recall (8.9 ± 3.6 versus11.9 ± 3.7; F ¼ 4.96; d.f. ¼ 1, 37; p ¼ 0.032) andcued long-delay recall (9.7 ± 3.1 versus12.4 ± 2.9; F ¼ 5.55; d.f. ¼ 1, 37; p ¼ 0.024).

In our bipolar group, performance in verbalmemory tasks was significantly correlated withchronicity, the number of previous manic episodes,hospitalizations and psychosocial functioning(Table 3). Moreover, measures related to executivefunction such as the TMT were correlated withduration of the illness and age of onset. Psycho-social functioning, as measured through the GAF,was related to measures of working memory(backward digit span) and learning, short- andlong-delay recall, and recognition (CVLT). Only12 of 40 patients were employed. The only clinicalmeasure that correlated negatively with GAFscores was the number of previous episodes(Spearman Rho ¼ )0.339, p ¼ 0.046). Withregard to correlations between depression measuresand cognitive performance, HDRS scores correla-ted with WCST perseverative errors (Rho ¼ 0.29,p ¼ 0.016); TMT-A (Rho ¼ 0.35, p ¼ 0.003);TMT-B (Rho ¼ 0.32, p ¼ 0.008); animal naming(Rho ¼ )0.36, p ¼ 0.002); forward digit span(Rho ¼ )0.39, p ¼ 0.001); backward digit span(Rho ¼ )0.28, p ¼ 0.023); CVLT learning task(Rho ¼ )0.43, p < 0.001); free short delay(Rho ¼ )0.42, p < 0.001); cued short-delay

Table 1. Demographic and clinical variables in the bipolar and control groups

Variable testedBipolar group (n ¼ 40) Control group (n ¼ 30)

Statistics

Mean (SD) Mean (SD) ANOVA p-value

Age 38.5 (10.1) 38.9 (12.4) 0.02 NSAge of onset 23.6 (7.1)Hospitalizations 2.6 (2.6)Chronicity (years) 15.0 (8.4)Total episodes 13.6 (11.1)Education (years) 13.0 (3.5) 12.5 (3.2) 0.36 NSEstimated premorbid IQ 109.9 (5.8) 113.0 (9.1) 2.81 NSHamilton Depression Rating Scale (HDRS) 2.8 (1.7) 1.2 (1.2) 19.44 <0.001Young Mania Rating Scale (YMRS) 1.4 (1.5) 0.9 (1.1) 1.65 NSGeneral Assessment of Functioning (GAF) 67.7 (12.8)

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recall (Rho ¼ )0.40, p ¼ 0.001); free long-delay recall(Rho ¼ )0.39, p ¼ 0.001); cued long-delayrecall (Rho ¼ )0.39, p ¼ 0.001), recognition hits(Rho ¼ )0.38, p ¼ 0.001). Finally, non-significantcorrelations were found between pharmacologicalvariables (doses of lithium and antipsychotics) andcognitive measures.

Discussion

Cognitive impairment in euthymic bipolar patients

After controlling for the effect of low levels ofaffective symptoms, in 10 of 15 neuropsychologicalmeasures, bipolar patients showed poorer perform-

ance compared with healthy controls. Patientsshowed lower scores than controls in tests ofverbal memory (CVLT). The bipolar groupretained less words than controls (learning task,trials 1–5), and had greater difficulty recallinginformation immediately (short recall) and after20 min (delay recall), in free and cued forms.Moreover, deficits in the recognition task were alsofound. These results suggest that encoding orconsolidation of information as well as retrievalwere impaired, which indicates that frontal andtemporo-hippocampal structures are involved inthese processes (28).

These findings replicate those of previous stud-ies (5, 13, 29) and point to verbal memory

Table 2. Neuropsychological performance in euthymic bipolar patients and healthy controls

Variables tested Euthymic group (n ¼ 40) Control group (n ¼ 30) ANCOVA p-value

Wisconsin Card Sorting Test (WCST)Categories 4.8 (1.8) 5.4 (1.4) 0.57 NSPerseverative errors 17.4 (14.6) 9.2 (7.2) 5.88 0.018

Controlled Oral Word Association Test, COWATFAS 34.9 (10.3) 39.8 (11.3) 2.41 NSAnimal naming 18.2 (4.3) 21.3 (4.7) 3.11 NS

Digit spanDigits forward 5.8 (1.2) 6.3 (1.2) 0.58 NSDigits backward 4.0 (0.9) 4.8 (1.1) 7.17 0.010

Trail Making Test (TMT, seconds)Trail A 45.3 (19.8) 30.1 (12.0) 13.53 0.001

Trail B 107.7 (65.5) 77.7 (39.1) 6.14 0.016

Stroop Colour-Word Interference Test (SCWT)Interference 0.6 (7.0) 4.9 (7.0) 2.91 NS

California Verbal Learning Test (CVLT)List A (total) 45.3 (12.2) 54.4 (9.6) 5.63 0.021

Free short-recall 8.9 (3.7) 11.6 (3.2) 4.62 0.036

Cued short-recall 10.5 (2.9) 12.8 (2.3) 9.42 0.003

Free delayed-recall 9.6 (3.8) 12.6 (3.0) 8.97 0.004

Cued delayed-recall 10.3 (3.3) 13.2 (2.4) 15.28 <0.001

Recognition 13.7 (2.2) 14.9 (1.3) 4.91 0.031

Data are given as the mean with SD in parentheses.ANCOVA with age, premorbid IQ and residual depressive symptomatology as covariates; d.f. ¼ 3,65. Values in bold are significantresults.

Table 3. Correlations between clinical, psychosocial variables and neuropsychological tests in bipolar patients

Neuropsychological measures Chronicity Age of onset Hospitalizations GAF Manic episodes

Digits backward )0.26 )0.12 )0.13 0.38* )0.13Trail Making Test (TMT-A) 0.44** 0.47** )0.07 )0.27 )0.03Trail Making Test (TMT-B) 0.19 0.37* 0.11 )0.25 0.15California Verbal Learning Test (CVLT)

List A (total) )0.29 0.12 )0.25 0.35* )0.21Free short-recall )0.36* )0.15 )0.38* 0.39* )0.34*Cued short-recall )0.33* )0.06 )0.32 0.36* )0.26Free delayed-recall )0.37* )0.03 )0.38* 0.46*** )0.35*Cued delayed-recall )0.34* )0.10 )0.32 0.45** )0.32Recognition )0.21 )0.06 )0.34* 0.46*** )0.24

Spearman correlations (statistical significance at *p < 0.05, **p < 0.01, ***p < 0.005).

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impairment as a trait abnormality as differencesremained significant after controlling for milddepressive symptoms, as other authors have alsosuggested (8, 9). In contrast, recent reports thatcontrolled subclinical symptomatology observedthat memory deficits seemed to depend on sub-threshold depression (6). Probably, differencesfound among studies on the relevance of subsyn-dromal features on cognition are because ofmethodological issues. These authors used, forinstance, partial correlations as statistical analysisinstead of ANCOVA, which would be moreconservative. Nevertheless, there are other reasonswhy this and other studies may not find a traitdeficit in verbal memory. Among methodologicallimitations, small sample sizes may not haveenough power to detect differences. In the Clarket al. (6) study, patients had a higher educationallevel and IQ than the patients in the presentstudy. Probably, in those patients with higher IQ,verbal memory deficits are more subtle or depend-ent on clinical symptoms. Chronicity may beanother of the reasons, so in samples with lesschronic patients less verbal memory impairmentcould be expected. Although the contribution ofsubclinical symptomatology should not be under-estimated, this is surely not the only explanationfor enduring cognitive dysfunctions in bipolarpatients. Some memory dysfunctions may repre-sent trait neurobiological markers and might bestudied through high-risk groups (first-degreerelatives, monozygotic twins etc.), so potentiallyconfounding variables such as medication or thenatural course of illness should be controlled. Inthis regard, some authors have reported delayedverbal recall impairment in healthy first-degreerelatives of bipolar probands (30). There is someevidence that cognitive impairment may precedethe onset of the illness and may worsen withillness progression. In a recent study comparingschizophrenic, schizoaffective and non-psychoticbipolar patients with regard to premorbid intel-lectual, language and behavioural functioning,normal intellectual functioning in future non-psychotic bipolar patients was found, comparedwith future schizophrenic patients (31). Therefore,controversial findings should lead to investigate ifthose cognitive deficits observed in remitted bipo-lar patients and their relatives constitute pheno-typic markers of vulnerability for bipolar disorder(12, 32, 33).

With regard to other tests, after controllingaffective symptoms, no differences were foundbetween patients and controls in verbal fluency(FAS, animal naming) and in SCWT interference,as other authors previously observed (8).

Subclinical symptomatology seemed to influenceon verbal fluency and interference. Likewise, wefound similar results to these authors� in severalmeasures of executive function. Hence, patientsshowed a poorer performance in TMT-B, back-ward digit span, and WCST perseverative errors,and deficits persisted when depressive symptomswere covaried for. Ferrier et al. (9) concluded thata deficit of working memory was observed inremitted bipolar patients when residual depressivesymptomatology was covaried for, and suggestedthat their findings may reflect frontal lobe damageor disruption of fronto-subcortical or mesolimbiccircuitry.

Viewing our results, memory and executivedysfunctions seem to represent a trait more thana state in bipolar disorder. These deficits appear tobe present independently of clinical state, evenwhen residual depressive symptomatology iscovaried for. Attentional dysfunctions are lessclear in our asymptomatic patients, probably dueto the lack of a wide attention assessment. Patientsshowed more impairment in TMT-A than controlsbut they did not differ with respect to forward digitspan or SCWT performance. With respect to this,recent reports have confirmed deficits in sustainedattention in remitted bipolar patients (6, 7, 34).

History of psychotic symptomatology

The presence of psychotic symptoms in previousepisodes was also controlled. In this regard, thosepatients with prior psychotic symptoms showedmore verbal memory impairment, especially in freeand cued long-delay recall. Albus et al. (35) alsofound that patients with history of psychosis, eitherschizophrenic or affective, performed much worsethan those without such a history on verballearning and memory. Several studies observedthat bipolar patients with psychotic features arelikely to have worse outcome and a more chronic,severe course of illness, suggesting that thesepatients may also experience greater deteriorationin cognitive function over time (36–38). Bipolarpatients in different clinical states with priorhistory of psychotic symptoms were found to showmore verbal memory deficits than those withoutsuch a history (13). However, Mojtabai et al. (39)in a larger, first-episode study of psychotic patientsnoted a significantly better verbal memory per-formance when using the Logical Memory subtestof the WMS-R in the affective groups, eitherbipolar or unipolar, than in the schizophrenicgroup. Some authors have associated cognitivedeficits to antipsychotic medication rather than topsychotic symptoms (11).

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Pharmacological treatment

All patients, except for two, were on medication.However, combined pharmacological treatments inthese patients, despite remitted state, make difficultto establish their real impact on cognitive function.However, cognitive dysfunctions observed in bipo-lar patients cannot be only justified by medication.In the present study, most patients were treated withlithium, although few of them in monotherapy. Otherstudies as well included primarily lithium-treatedpatients (5) whereas others included mostly divalp-roex sodium-treated patients (40). In our sample,cognitive dysfunctions seemed not to be related topharmacological variables. Regarding lithium, Stipet al. (41) observed that medium-term lithiumadministration did not impair explicit memory andattention of healthy subjects. Nevertheless, there iscontroversy regarding the effect of lithium and othermood-stabilizers on cognition, so several studieshave found impairments in memory, psychomotorspeed and attention (42), whereas others havereported no changes on cognition with long-termadministration (43). Donaldson et al. (11) observedthat antipsychotic medication may be a predictor ofIQ and memory function in bipolar I patients.However, improvements on cognitive functioninghave been reported using atypical antipsychotics atleast in schizophrenia although less information isavailable in bipolar disorder (44). One way toanalyse if the effect of treatment is so negative oncognition would be to study cognitive dysfunctionsin high-risk populations. Although the best way toelucidate medication-related versus psychopathol-ogy-related effects, would be to carry out studies onhealthy subjects (11). Other ways to establishwhether cognitive impairment is related to illnessand not to medication would be the inclusion ofdrug-free or drug-naive bipolar patients.

Implications for clinical and functional outcome

Clinical features and neuropsychological perform-ance. The analysis of relationships between clinicaland neuropsychological variables indicated thatthose patients with a longer duration of the illness,more manic episodes and hospitalizations showedmore verbal memory impairment. Other studieshave reported that chronicity or a longer durationof illness may have negative implications in cogni-tive function (5, 6, 8, 45). The impact of thenumber of previous manic episodes has also beenpointed by recent reports (5, 8, 13, 40). This findinghas important clinical implications, as preventionof manic episodes may lead to a reduction of theirnegative effect on cognitive function. Likewise, this

would represent less hospitalizations, which werehigher in patients showing more cognitive impair-ment. Moreover, prevention of mania may lead toavoiding psychotic symptoms at least in thesephases. Manic relapses should be early identifiedand treated to prevent negative consequences inpsychosocial and cognitive areas, which implies aprotective therapeutic intervention, pharmacologi-cal and psychological (46). Furthermore, HDRSscores correlated with several neuropsychologicalmeasures, so in some way subtle depressive symp-toms may be associated with a worse neuropsy-chological performance. In this regard, suitableprophylactic treatments should be applied in orderto improve not only subclinical symptoms but alsocognitive dysfunctions in remitted bipolar patients.Cognitive impairment may be related, partly, tothe effect of the disease process which implies thatbipolar disorder should be diagnosed and treatedearly. Chronicity and number of episodes are bothfeatures of illness severity so those more severepatients probably will show more cognitive deficits.The main goal of therapy should be a lifelongeffective treatment and the achievement of fullremission.

Neuropsychological performance and functional out-come. Psychosocial functioning was found to cor-relate more with neuropsychological measures thanwith clinical variables. Hence, functional outcomeonly correlated with total number of episodesamong clinical variables, whereas a poorer psycho-social functioning was associated with a poorerperformance in working memory (backward digitspan) and all measures of verbal learning andmemory (CVLT). A severe illness course probablyhas a negative impact on social and occupationalfunctioning as well as on cognition. Evidencesuggest that chronic multi-episode patients mayshow more cognitive dysfunctions, especially inverbal memory. Cognitive function may be medi-ating between illness process and functional out-come (32, 33). Cognitive impairments, particularlymemory difficulties, may have negative implicationsfor adherence to treatment and this may worsen thecourse of the illness and psychosocial adaptation ofthe patient (47). Moreover, stress-induced hyper-cortisolaemia during illness episodes may lead toneurotoxic effects on hippocampal and prefrontalstructures and this processmaybe partly responsiblefor cognitive impairment in bipolar disorder (5, 12).In this regard, we cannot discard a neurotoxic effectof episodes on cognitive functioning in bipolarpatients. Furthermore, structural abnormalitieshave been reported in adolescent and adult bipolarpatients compared with controls, although these

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findings do not contradict a potential role forglucocorticoids in the modulation of medial tem-poral function in already abnormal structures (48),in spite of contradictory findings (49).

Limitations

A larger sample size would allow more sophisticatedstatistical analyses and would show clearly signifi-cant differences between groups. Furthermore,bipolar patients were in clinical remission butresidual depressive symptoms had to be controlled,because differences were observed between patientsand healthy controls. On the contrary, attentionalfunctioning, especially with regard to sustainedattention, was not assessed, so our findings cannotroundly confirm deficits in attention. Sustainedattention deficits in remitted bipolar patients havebeen previously reported by other authors (6, 34, 50)by using mainly Continuous Performance Test(CPT) or other similar instruments. Sustainedattention in bipolar patients appear to be interme-diate between schizophrenic patients and healthycontrols (36). More recent reports suggest thatsustained attention may represent a vulnerabilitymarker for bipolar disorder that is shared withsubjects at risk of illness across the psychosisspectrum (6). A common problem in any neuropsy-chological study is the overlap of cognitive functionsassessed through the different neuropsychologicaltests. Another relevant issue is the potential effect ofmedication on cognitive functioning. Combinedtreatments and different dosages are very commonin most bipolar patients. Drug-free euthymicpatients, who would be the ideal study population,are scarce. Treating healthy subjects with similarmedications to assess long-term effects would likelybe unfeasible and unethical.

Finally, the study implications are limited by thecross-sectional nature of the design. A longitudinaldesign would allow evaluation of whether cognitiveimpairment is progressive and, in high-risk popu-lations, analyse whether some deficits are presentbefore illness onset.

Acknowledgements

This study was supported in part by grants from the Red CIENIDIBAPS-ISCIII RTIC C03/06, the Fundacio Marato de TV3(2510/01), Fundacio Roviralta and the Stanley MedicalResearch Institute, Bethesda, MD, USA.

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