Journal of Affective Disorders 109 (2008) 149–156www.elsevier.com/locate/jad

Research report

Heterogeneity in cognitive functioning among patientswith bipolar disorder

Diego J. Martino, Sergio A. Strejilevich ⁎, María Scápola, Ana Igoa,Eliana Marengo, Ezequiel D. Ais, Lila Perinot

Bipolar Disorders Program, Psychiatry Department, Neurosciences Institute, Favaloro Foundation, Buenos Aires, Argentina

Received 29 August 2007; received in revised form 12 December 2007; accepted 13 December 2007

Available online 30 January 2008

Abstract

Background: Nowadays it is not clear if in bipolar disorders (BD) cognitive impairments are heterogeneous and if so which are thevariables that determine it.Methods: Fifty patients with BD and thirty healthy controls were clinically evaluated including measures of obstetric complicationshistory. All subjects completed an extensive neuropsychological battery selected to asses premorbid IQ and different cognitivedomains.Results: Compared with standardized norms, 38% of patients had none cognitive domain affected, while 40% had 1 to 2, and 22%had 3 to 5. Patients with cognitive functioning within normal limits had higher psychosocial functioning and premorbid IQ, andlower history of obstetric complications.Limitations: The small sample size could limit the generalizability of the results; since these data should be taken as preliminaries.Conclusions: The extension and severity of cognitive impairments may be heterogeneous in patients with BD, and it mightcontribute to explain the variability in functional outcome. Bipolar patients with low premorbid IQ and history of obstetriccomplications may represent a subgroup with lower cognitive performance and psychosocial functioning.© 2007 Elsevier B.V. All rights reserved.

Keywords: Obstetric complications; Premorbid IQ; Cognitive reserve; Neuropsychology

1. Introduction

Cognitive impairments have been reported in euthy-mic patients with bipolar disorder (BD). Verbal memory,attention, and executive function impairments are themost consistent findings, although some studies showeddysfunction in working memory, psychomotor speed,

⁎ Corresponding author.E-mail address: sstrejilevich@ffavaloro.org (S.A. Strejilevich).

0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jad.2007.12.232

and general intelligence (for reviews see Quraishi andFrangou, 2002; Robinson et al., 2006). Indeed, quali-tative similar, though less severe, patterns of cognitivedeficits have been reported among patients with BD andschizophrenia (Dickerson et al., 2004a; Daban et al.2006). Likewise, cognitive functioning has been asso-ciated with different measures of functional outcome associal and occupational functioning or employment status(Zubieta et al., 2001; Martinez-Arán et al, 2004;Dickerson et al., 2004b).These findings conducted to

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propose cognitive impairments as prominent determi-nants of disability and poor outcome that affect a highpercentage of patients with BD even after syndromalremission (Huxley and Baldessarini, 2007). However,althoughmany patients pursue a chronic and deterioratingcourse, others maintain a high level of social and occupa-tional functioning throughout their illness (Coryell et al.,1998; Kusznir et al., 2000; Goldberg and Harrow, 2004).Moreover, it has been reported that a subgroup of patientswith BDmight have particular abilities in some aspects ascreativity (Goodwin and Jamison, 1990). It may resultparadoxical to suppose that these patients with “highfunctioning” have impairments in verbal memory, atten-tion, and executive functions. Alternatively, it may bepossible that a subgroup of patients has a cognitive func-tioning within normal limits, although our knowledgeabout this issue is scarce. Almost all studies comparedpeople with BD and healthy controls, because of thisnowadays it is unclear if extension or severity of cognitiveimpairments are heterogeneous among patients. Aprevious study that compared cognitive function betweenpatients with BD and schizophrenia found a bimodalpattern for executive functions in the bipolar cohort, withmany in the group indistinguishable from healthy controlsand many indistinguishable from the group with schizo-phrenia (Altshuler et al, 2004). These findings suggestthat studies reporting mean values of cognitive function-ing in BDmight be failing to recognize that a subgroup ofbipolar patients is demonstrating most of the impairment.

On the other hand, preliminary evidence from high-risk studies brings support to the hypothesis that subtleimpairments in verbal memory and executive functionsmay be endophenotypic markers for BD (Glahn et al.,2004; Robinson and Ferrier, 2006). In addition withthese genetic factors, it is not clear yet if other etio-logical factors contribute to cognitive impairments inBD. Earlier neuropsychological studies predominantlyfocused in the relationship between clinical variablesand cognitive impairments. A recent review showed thatthe most consistent finding was a negative associationbetween the number of episodes, especially manic ones,and the number of admissions with cognitive function-ing (Robinson and Ferrier, 2006), although the directionof causality is unclear. In fact, these results might meanboth that the experience of successive episodes isassociated with a progressive cognitive decline, or thatmore severe and static cognitive impairments are thecause of a poorer illness course. Other possible influ-ences on cognitive functioning were less consistent suchas age at illness onset or length of illness, or have to bestill sufficiently investigated such as history of psychoticsymptoms, rapid cycling, or comobility (Robinson and

Ferrier, 2006). A recent study (Torrent et al., 2006) wasthe first to compare neurocognitive performancebetween patients with bipolar disorder types I (BDI)and II (BDII), and revealed that BDI have lowerperformance than BDII suggesting that some grade ofcognitive impairments could rely in clinical subtype ofillness. In addition with clinical variables, other studiesreported that exposure to antipsychotic medications(Donaldson et al., 2003; Frangou et al., 2005) orenvironmental factors as alcohol dependence (van Gorpet al, 1998), infection with herpes simplex virus type 1(Dickerson et al, 2006), and history of obstetric compli-cations (Martino et al, 2006) have a detrimental effect incognitive functioning.

The aim of this study was to examine if the extensionand severity of cognitive impairments are homoge-neously distributed in people with BD. Taken into ac-count the high variability in functional outcome in BD,we hypothesize that a subgroup of patients would have acognitive functioning within normal limits while otherswould display significant cognitive impairments. Asecond aim was to compare these subgroups of patientsin order to identify which factors could contribute toexplain heterogeneity in cognitive functioning.

2. Methods

Fifty subjects with BD were consecutively selectedwith the following inclusion criteria: age between 18 and55 years old; diagnosis of BDI or BDII according toDSM-IVusing Structured Clinical Interview for DSM-IV(SCID) (First et al., 1996); euthymic (defined by HamiltonDepression Rating Scale ≤8 and Young Mania RatingScale ≤6) for at least 6 weeks. Exclusion criteria were:antecedent history of substance abuse; history of mentalretardation, neurological disease, or any clinical conditionthat could affect cognitive performance.Additionally, thirtyhealthy controls matched by age and years of educationwere included: these had no antecedence of neurologicaldisease, neither history of psychotic or affective disorders inthemselves or a first-degree family member, and they werenot taking psychotropic medication. The study was ap-proved by an independent Ethics Committee and allsubjects gave written informed consent for their participa-tion after receiving a complete description of the study.

2.1. Clinical and psychosocial assessment

In addition to SCID, all subjects were evaluated withtheHamiltonDepressionRating Scale (HDRS) (Hamilton,1960), and Young Mania Rating Scale (YMRS) (Younget al., 1978). Psychosocial functioning was assessed with

Table 1Clinical and demographical characteristics of bipolar patients andhealthy controls (values are expressed as mean, standard deviation isshown in brackets)

Bipolarpatients(n=50)

Healthycontrols(n=30)

Test

Age 42.0 (12.0) 40.2 (13.2) t=0.62 df=78Gender

(% female)70.0 66.6 χ2=0.01 df=1

Years ofeducation

14.0 (2.7) 13.3 (2.8) t=1.2 df=78

Premorbid IQ(T-Score)

54.1 (5.7) 54.6 (5.5) t=−0.34 df=78

Obstetriccomplications

1.0 (1.8) 0.3 (0.7) Z=−1.6 df=78

YMRS Score 1.1 (1.5) 0.7 (0.9) t=1.6 df=78HDRS Score 2.4 (2.3) 1.9 (1.8) t=0.87 df=78GAF Score 77.4 (10.3) 89.5 (4.9) t=−7.0 df=74.7 ⁎

IQ: Intelligence Quotient; YMRS: Young Mania Rating Scale; HDRS:Hamilton Depression Rating Scale; GAF: General Assessment ofFunctioning.⁎ pb0.001.

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the General Assessment of Functioning (GAF) (DSM-IV).The rater was instructed to use the GAF to measure func-tioning in the last month and not symptoms since othermeasures of mood symptoms were obtained as part of theevaluation. Exposition to antidepressants, mood stabili-zers, antipsychotics, and benzodiazepines was assessed byClinical Scale of Intensity, Frequency, and Duration ofPsychopharmacological Treatment (Peralta and Cuesta,2002). This scale provides a quantitative measure ofcurrent exposition to different groups of psychotropicmedications in a 0–5 points range (0 = no medication, 1 =sporadic lowdose, 2 = continue lowdose; 3 =middle dose,4 = high dose, and 5 = very high dose). History of obstetriccomplications was examined with the Obstetric Complica-tion Scale (Lewis et al., 1989). Additional clinical informa-tion was obtained from clinical charts and direct patientsinterview.

2.2. Neuropsychological assessment

Patients and healthy controls completed an extensiveneuropsychological battery selected to asses the follow-ing 6 cognitive domains: 1) Attention. Backward Digit-SPAN (Wechsler, 1955); Trail Making Test part A(Reitan, 1958); and an analogous Continuous Perfor-mance Test that includes 60 target stimuli that alter-natively appear in the PC monitor with other stimuli.When target stimulus appears, subjects have to pressthe space bar in the keyboard as quickly as possible.Measures of performance are number of hits, number offalse alarms, and latency in milliseconds of hits; 2)Verbal memory: Memory Battery of Signoret (Signoretand Whiteley, 1979); 3) Language: Boston Naming Test(Kaplan et al., 1983); 4) Psychomotor speed: Simpleand Complex Motor Speed. Simple Tapping requires thesubject to tap the space bar of the keyboard with thedominant and non-dominant index fingers (three trialsof 10.5 s of each hand). Complex Tapping requires thesubject to tap the left and right sides of the keyboardusing the two index fingers in alternating fashion (threetrials of 5.5 s); 5) Executive functions: Wisconsin CardSorting Test (Heaton, 1981); Trail Making Test part B(Reitan, 1958); and Semantic and Phonological Fluency(Benton et al., 1983); and 6) Facial emotion recognition:Ekman-60 (Young et al., 2002). In this test differentfaces appear in random order for 5 s each in the PCmonitor, and subjects have to recognize facial expres-sion of six basic emotions (anger, disgust, fear, surprise,happiness, and sadness). The test yields a score out of amaximum of 60 correct answers for recognition of allsix emotions, or scores out of 10 for recognition of eachbasic emotion.

Additionally, estimated premorbid IQ was calculatedby the WAIS vocabulary subtest (Wechsler, 1955). Inthis task the examiner ask the meaning of 40 words inorder of difficulty; results were expressed as T-Scores.Vocabulary has been identified as the single bestmeasure of premorbid IQ (Lezak, 1995).

One experienced psychiatrist (SAS) examined clini-cally all subjects. All neuropsychological tests wereadministered by other physician (DM) in a quiet testingroom according to a standardized order. The total pro-cedure was done in an interview of 3–4 h with one ortwo breaks to avoid fatigue.

2.3. Data analysis

Independent sample t-test was employed for between-group comparison on continuous variables. Nonpara-metric variables were compared by usingMann–Whitneytest or chi-squared test, as appropriate. In order to calcu-late the number of cognitive domains affected amongpatients, we considered that a cognitive domain wascompromised when performance in some test of thatdomainwas below 2 standard deviations ormore from themean of normative data of each test (psychomotor speedmeasures and hits and false alarms were not included inthis analysis because normative data was not available).Patients were considered with cognitive functioning with-in normal limits when any cognitive domain was affected.Partial correlation, as has been suggested by Clark et al.(2002), was used to assess the influence of sub-clinical

Table 2Medications at time of testing of bipolar patients

Medications N(%)

Mean dose(mg/daily)

Mood stabilizers 48 (96)Lithiun carbonate 21 (42) 985.64Valproate 16 (32) 937.42Lamotrigine 16 (32) 181.23Carbamazepine 5 (10) 1120.00Topiramate 1 (2) 200.00

Antipsychotics 16 (32)Risperidone 5 (10) 1.00Olanzapine 5 (10) 5.00Clozapine 4 (8) 225.00Quetiapine 3 (6) 183.33Typical (in haloperidol equivalents) 2 (5) 2.50

Antidepressants 13 (26)Bupropion 6 (15) 250.00Paroxetine or Fluoxetine or Citalopram 6 (12) 21.66Venlafaxine 1 (2) 150.00Clorimipramine 1 (2) 150.00

Benzopdiazepines (in clonazepam equivalents) 18 (36) 1.25

Table 3Neuropsychological evaluation of bipolar patients and healthy controls(values are expressed as mean, standard deviation is shown in brackets)

Bipolarpatients(n=50)

Healthycontrols(n=30)

Test/significance(df=78)

AttentionBackward Digit-SPAN 5.74 (1.2) 6.20 (0.9) Z=−1.8Trail Making Test Part A 45.28 (20.7) 31.37 (11.2) t=3.3⁎⁎⁎

Hits 58.72 (3.0) 59.80 (0.4) t=−2.5⁎Hits Latency 542.8 (75.3) 496.8 (39.9) t=3.5⁎⁎

False Alarms 3.34 (3.4) 0.90 (1.8) Z=−4.8⁎⁎⁎

Verbal memoryImmediate Recall 7.66 (2.0) 8.46 (1.2) Z=−1.8Delay Recall 7.21 (2.1) 8.46 (1.2) Z=−2.2⁎Serial Learning 10.06 (1.5) 10.40 (1.4) Z=−0.5Free Delay Recall 8.44 (2.1) 8.73 (1.9) Z=−0.6Recognition 11.80 (0.5) 11.83 (0.7) Z=1.0

LanguageBoston Naming Test 51.46 (4.9) 52.37 (3.9) t=−0.8

Psychomotor speedDominant Simple Tapping 28.74 (3.9) 33.11 (4.2) t=−4.1⁎⁎⁎Non-Dominant SimpleTapping

26.02 (5.5) 30.02 (4.1) t=−3.4⁎⁎

Complex Tapping 35.40 (11.2) 42.15 (8.5) t=−2.8⁎⁎

Executive functionsSemantic Fluency 19.60 (5.7) 21.33 (5.2) t=−1.3Phonological Fluency 15.72 (5.1) 18.33 (3.7) t=−2.4⁎Trail Making Part B 109.12 (52.7) 71.37 (17.1) t=3.7⁎⁎⁎

WCST—Categories 5.50 (1.1) 5.87 (0.3) Z=−1.1WCST—Total Errors 24.04 (18.1) 15.77 (11.4) t=2.2⁎

WCST—PerseverativeErrors

13.08 (10.6) 7.93 (4.9) t=2.9⁎⁎

WCST—PerseverativeResponses

14.82 (12.2) 8.03 (4.6) t=3.5⁎⁎

Facial emotion recognitionTotal 44.78 (6.9) 48.17 (3.5) Z=−1.3Sadness 7.02 (1.9) 6.47 (2.3) Z=−0.9Happiness 9.92 (0.2) 9.93 (0.2) Z=0.0Anger 6.94 (1.7) 7.40 (1.1) Z=−1.5Surprise 9.14 (1.4) 9.50 (0.6) Z=−0.7Disgust 6.88 (2.4) 8.10 (1.4) Z=−0.8⁎Fear 4.92 (2.8) 6.93 (1.9) Z=−3.1⁎⁎

WCST: Wisconsin Card Sorting Test. ⁎pb0.05 ⁎⁎pb0.01 ⁎⁎⁎pb0.001.

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symptoms (scores in YMRS and HDRS). ANCOVAwasused to covariate-out effect of psychotropic medicationsin cognitive performance. Pearson correlation coefficientswere calculated to asses the relationship betweendemographic, clinical, neuropsychological variables,and psychosocial functioning (in nonparametric variables,results were confirmed by the Spearman correlation).

3. Results

Clinical and demographical features of bipolarpatients and healthy controls are shown in Table 1.Patients (48% BDI and 52% BDII) were a mean age atonset of 29.0 (10.2) years, and had a length of illness of12.0 (6.9) years, 3.2 (2.1) manic/hippomanic episodes,3.4 (2.1) depressive episodes, and 0.8 (1.5) hospitaladmissions. All patients were receiving a mean of 2.26medications at time of testing (Table 2); currentexposure assessed with IFD scale to benzodiazepineswas 1.29 (1.3) points; to antidepressants was 0.95 (1.3)points; to mood stabilizers was 2.70 (0.8) points; and toantipsychotics was 1.25 (1.1) points.

Results of neuropsychological evaluation of bipolarpatients and healthy controls are shown in Table 3; dif-ferences between groups remain significant after con-trolling sub-clinical symptomatology. Psychosocialfunctioning correlated with performance in verbal memory(Free Delay Recall: R=0.31, pb0.05), attention (Hits:R=0.54, pb0.001; False Alarms: R=−0.28, pb0.05; Trail

Making Test Part A: R=−0.43, pb0.01; and BackwardDigit-SPAN: R=0.42, pb0.01), and executive functions(Semantic Fluency: R=0.39, pb0.05; Phonological Flu-ency: R=0.37, pb0.01; Trail Making Part B: R=−0.56,pb0.001; WCST Perseverative Errors: R=−0.32,pb0.05; WCST Perseverative Responses: R=−0.28,pb0.05). Regarding to current psychotropic drugs expo-sure assessed with the IFD, no association was found

Table 4Variables included in a regression model to predict the number ofcognitive domains affected

Β coefficients t Significance

Constant 3.013 0.005Age 0.136 1.257 0.216Years of education 0.142 0.791 0.434Length of illness −0.007 −0.153 0.879No. of previous manic/

hippomanic episodes0.115 0.305 0.762

Clinical subtype −0.331 −1.386 0.174Premorbid intelligence

quotient−0.485 −3.292 0.002

Antecedence of obstetriccomplications

0.330 2.174 0.036

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between exposure to antidepressants or antipsychotics andcognitive functioning, while exposure to mood stabilizersnegatively correlated with performance in verbal memory(Free Delay Recall: R=−0.29, pb0.05; Recognition: R=−0.34, pb0.05), and exposure to benzodiazepines withperformance inmeasures of psychomotor speed (DominantSimple Tapping: R=−0.32, pb0.05; Complex Tapping:R=−0.34, pb0.05), attention (TMT-A: R=0.37,pb0.01), and executive functions (TMT-B: R=0.38,pb0.01).

When we evaluated the number of cognitive domainsaffected in bipolar patients, 38% had none, while 40%had 1 to 2, and 22% had 3 to 5 (Fig. 1). However,compared with healthy controls, patients with cognitivefunctioning within normal limits had lower performancein verbal memory (Free Delay Recall: F(df1)=6.45,p=0.02) and a trend in psychomotor speed (DominantSimple Tapping: F(df1)=3.76, p=0.06; Non-dominantSimple Tapping: F(df1)=3.30, p=0.07) after control-ling for effect of mood stabilizers and benzodiazepines.No differences in the proportion of patients withcognitive functioning within normal limits were foundregarding clinical subtype (BDI: 37.5% vs. BDII:38.5%; χ2 =0.005, df=1, p=0.94). Patients withoutany cognitive domain affected had higher premorbidIQ [T-Score: 57.7 (4.6) vs. 52.0 (5.2); t=−3.8, df=48,

Fig. 1. a) Rate of patients showing impairments in none, 1 to 2, and 3 to5 cognitive domains. Patients without cognitive domains affected hadlower performance than healthy controls in Free Delay Recall;b) Patients with cognitive domains affected had lower psychosocialfunctioning than patients without.

pb0.001] and GAF scores [82.3 (8.2) vs. 74.4 (10.5);t=−2.8, df=48, p=0.007], and lower antecedence ofobstetric complications [0.3 (0.8) vs. 1.4 (2.1); Z=−2.1,p=0.02] than those with some cognitive domainaffected. No differences were found between patientswith and without cognitive domains affected in otherclinical–demographical variables neither in terms ofcurrent exposure to psychotropic drugs. In order toavoid uncorrected confounding bias, we run a regressionmodel including age, education, length of illness,number of previous episodes, and clinical subtype, andpremorbid IQ and history of obstetric complicationswere the only variables to predict independently thenumber of cognitive domains affected (F=3.63; gl=7;Adjusted R2 =0.29; p=0.004) (Table 4).

4. Discussion

In order to confirm that our sample of patients withBD was representative, we first conducted a compara-tive analysis of cognitive functioning between patientsand healthy controls and assessed their relationship withpsychosocial functioning. Our results closely reproducethe findings of previous studies regarding verbalmemory, attention, executive functions, and psychomo-tor speed impairments in euthymic bipolar patients(Quraishi and Frangou, 2002; Robinson et al., 2006), aswell as the impact of these cognitive deficits infunctional outcome (Zubieta et al., 2001; Martinez-Arán et al, 2004; Dickerson et al., 2004a,b). However,when bipolar patients were compared with standardizednorms, while 38% of the patients had no cognitivedomain affected, 40% had 1 or 2, and 22% had 3 to 5.Although 38% of the patients had a cognitive function-ing within normal limits, they showed lower perfor-mance than healthy controls in verbal memory even

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after controlling for effect of medication. These findingsmay mean that while some cognitive impairments arerelatively homogeneous in bipolar patients, the exten-sion and severity of these may be extensively hetero-geneous. In other words, some patients might show justsubtle impairments in verbal memory while othersmay suffer strong impairments in almost all cognitivedomains. Deficits in verbal memory in those patientswith cognitive functioning within normal limits supportprevious studies that have proposed this impairment asendophenotype for BD (Glahn et al., 2004; Robinsonand Ferrier, 2006). In addition, those patients withoutcognitive domains affected had higher psychosocialfunctioning than patients with cognitive domainsaffected (Fig. 1), which is consistent with the findingsof earlier studies that showed that higher cognitiveimpairments are associated with poorer functionaloutcome (Zubieta et al., 2001; Martinez-Arán et al,2004; Dickerson et al., 2004a,b). Taken together, theseresults bring strong support to the hypothesis thatcognitive heterogeneity might contribute to explain thevariability in functional outcome.

When we compared with patients without cognitivedomains affected, those patients with some cognitivedomains compromised had lower premorbid IQ andhigher history of obstetric complications. Our grouppreviously reported that BD patients with history ofobstetric complications have poorer cognitive function-ing than patients without history of obstetric complica-tions (Martino et al, 2006). In this analysis, history ofobstetric complications and premorbid IQ were the onlyindependent predictors of the number of cognitivedomains affected after controlling to demographical andclinical confounders. One could argue that the differ-ences in premorbid IQ between patients with andwithout cognitive domains affected could be an indirectresult of different rates of history of obstetric complica-tions. We cannot exclude absolutely this possibility,although no association was found between premorbidIQ and history of obstetric complications (R=−0.15,p=0.3), and they were independent predictors in ourregression model. Alternatively, it is possible to arguethat differences in cognitive functioning betweenpatients with and without cognitive domains affectedcould be caused by the same amount of cognitivedecline from different levels of premorbid IQ. However,a decline from higher levels would suggest that in thepremorbid state those patients without cognitivedomains affected performed above the level of healthycontrols in four of five domains, on which they nowequal controls, which is highly unlikely. Finally, thisfinding could suggest that a higher premorbid IQ could

have some protective effect in cognitive functioningwhich is in accordance with ‘cognitive reserve’ hypoth-esis (Satz, 1993) used in dementia research. Thishypothesis argues that because of genetic predisposi-tion, environmental factors or both, some individualsdevelop a cognitive reserve that may increase thethreshold for cognitive symptoms after acquired brainpathology. Indeed, premorbid intellectual function wasused as an indicator of cognitive reserve in otherneuropsychiatric diseases (Alexander et al., 1997). Arecent review of cognitive reserve in neuropsychiatrypointed out that the evidence about its role in BD islimited (Barnett et al., 2006). Further studies usingneuroimaging procedures, standardized measures ofeducational level and occupational status, and control-ling effects of obstetric complications could be useful toaddress the cognitive reserve hypothesis in BD.

Contrarily, we do not find any difference in thenumber of episodes/admissions between patients withand without cognitive domains affected, which is indisagreement with many previous studies (Robinson andFerrier, 2006). Although previous studies were correla-tional and our analysis was different, we cannot excludethat our negative result could be due to an error type IIand it should not be over-interpreted. Alternatively, amean of around 7 previous episodes in our sampleindicates a no severely ill patient cohort and mightexplain the equity in number of episodes in patients withand without cognitive domains affected. Likewise, wedid not find differences in the proportion of patients withcognitive functioning within normal limits when com-paring patients with BDI and BDII. However, theseresults are not necessarily discordant with the ones of theonly previous study that assessed influence of clinicalsubtype in cognitive functioning. In fact, the study ofTorrent et al. (2006) compared cognitive functioningbetween BDI and BDII while in our study we comparedthe number of cognitive domains affected. Moreover, inthe study of Torrent et al. patients with BDI had lowerperformance than those with BDII in all measures ofverbal learning and memory, in one of four measures ofexecutive function, and in any measure of attention, andwith small effect sizes for all positive findings. Thesesubtle differences in cognitive functioning between BDIand BDII could not be expressed as differences in thenumber of cognitive domains affected.

Certain methodological limitations of our studyshould be taken into account. First, our small samplesize could limit the generalizability of the results.Hence, these data should be taken as preliminaryfindings. Additionally, all patients included in thestudy were taking psychotropic medications and we

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cannot discount the influence of drugs in cognitivefunctioning. However, different to almost all studies weused a quantitative measure (IFD) in order to pair sub-groups in terms of exposure to medication and controlstatistically its effects when necessary. Finally, the cross-sectional design does not allow exploring static orprogressive nature of cognitive impairments in patientswith and without cognitive domains affected.

In summary, our study brings preliminary evidencethat extension and severity of cognitive impairments maybe heterogeneous in patients with bipolar disorder, and itmight contribute to explain the variability in functionaloutcome. Independent of clinical characteristics, bipolarpatients with low premorbid IQ and history of obstetriccomplications may represent a subgroup with lowercognitive performance and psychosocial functioning.Further studies are needed to reproduce our findings andto explore additional factors that could contribute toheterogeneity in cognitive functioning among patientswith bipolar disorder.

Role of funding sourceBipolar Disorders Program, Neurosciences Institute, Favaloro

Foundation, Buenos Aires, Argentina.

Conflict of interest

No conflict declared.

Acknowledgements

This project was supported by an Initiation Researchgrant to Dr. D. Martino from the National HealthMinistry, Argentina. The authors thank to Dr. V. Peraltafor his support.

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