specificity of cognitive deficits in bipolar disorder versus schizophrenia

13
Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com Special Article Psychother Psychosom 2006;75:72–84 DOI: 10.1159/000090891 Specificity of Cognitive Deficits in Bipolar Disorder versus Schizophrenia A Systematic Review Claire Daban a Anabel Martinez-Aran a Carla Torrent a Rafael Tabarés-Seisdedos b Vicent Balanzá-Martínez b Jose Salazar-Fraile b Gabriel Selva-Vera b Eduard Vieta a a Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, and b Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, University of Valencia, Valencia, Spain Conclusions: The neuropsychological differences re- ported between both groups could be due to the pres- ence of psychotic features, to environmental factors (stressful events, duration of the disease and number of hospitalisations) and could also be related to differences during the neurodevelopmental phase. Further studies should confirm whether these results are truly related to different neurobiological backgrounds. Copyright © 2006 S. Karger AG, Basel Introduction Comparing bipolar disorder (BD) to schizophrenia (SZ) is a relevant point since both disorders show consid- erable overlaps in many aspects. From a diagnostic point of view, bipolar patients with psychotic features give a very close phenomenological approximation to SZ and can often be misdiagnosed as schizophrenic [1]. At an- other level, genetic factors are known to play an impor- tant role in both disorders [2]. The risk of BD in first-de- gree relatives of patients is about 5%, similar to risk esti- mates for first-degree relatives of schizophrenic patients (7–10%) and a similar concordance rate for monozygotic twins in BD and in SZ (40–70% and 50%, respectively) [3] . Linkage studies have identified candidate regions for susceptibility genes for each BD and SZ, with regions for Key Words Bipolar disorder Schizophrenia Intellectual functioning Verbal memory Executive function Abstract Background: More and more epidemiological, genetic and neuroimaging studies show similarities between bi- polar disorder (BD) and schizophrenia (SZ). Cognitive functions are known to be highly impaired in SZ and are increasingly studied in BD. When both populations are compared, the conclusions appear to be contradictory. The purpose of this review is to help define the profile of cognitive deficits in BD and in SZ. Methods: A system- atic review of the literature of neuropsychological stud- ies comparing BD and SZ was made, beginning in Janu- ary 1990 and ending in January 2005. Thirty-eight studies met the required quality criteria and were included in this review. Results: Bipolar patients exhibit extensive cogni- tive abnormalities with a pattern of deficits that is not unique to this disease. However, when compared to schizophrenic patients, bipolar patients demonstrate a lesser degree of deficits, particularly concerning premor- bid and current intelligence quotient and perhaps atten- tion, verbal memory and executive functions. When looking into effect sizes, there seem to be different pro- files even in studies finding no significant differences. Eduard Vieta, MD, PhD Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona Villarroel 170 ES–08036 Barcelona (Spain) Tel. +34 93 227 5401, Fax +34 93 227 5477, E-Mail [email protected] © 2006 S. Karger AG, Basel 0033–3190/06/0752–0072$23.50/0 Accessible online at: www.karger.com/pps

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Page 1: Specificity of Cognitive Deficits in Bipolar Disorder versus Schizophrenia

Fax +41 61 306 12 34E-Mail [email protected]

Special Article

Psychother Psychosom 2006;75:72–84 DOI: 10.1159/000090891

Specifi city of Cognitive Defi cits in Bipolar Disorder versus Schizophrenia A Systematic Review

Claire Daban

a Anabel Martinez-Aran

a Carla Torrent

a Rafael Tabarés-Seisdedos

b Vicent Balanzá-Martínez

b Jose Salazar-Fraile

b Gabriel Selva-Vera

b Eduard Vieta

a

a Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona , and b

Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, University of Valencia, Valencia , Spain

Conclusions: The neuropsychological differences re-ported between both groups could be due to the pres-ence of psychotic features, to environmental factors (stressful events, duration of the disease and number of hospitalisations) and could also be related to differences during the neurodevelopmental phase. Further studies should confi rm whether these results are truly related to different neurobiological backgrounds.

Copyright © 2006 S. Karger AG, Basel

Introduction

Comparing bipolar disorder (BD) to schizophrenia (SZ) is a relevant point since both disorders show consid-erable overlaps in many aspects. From a diagnostic point of view, bipolar patients with psychotic features give a very close phenomenological approximation to SZ and can often be misdiagnosed as schizophrenic [1] . At an-other level, genetic factors are known to play an impor-tant role in both disorders [2] . The risk of BD in fi rst-de-gree relatives of patients is about 5%, similar to risk esti-mates for fi rst-degree relatives of schizophrenic patients (7–10%) and a similar concordance rate for monozygotic twins in BD and in SZ (40–70% and 50%, respectively) [3] . Linkage studies have identifi ed candidate regions for susceptibility genes for each BD and SZ, with regions for

Key Words Bipolar disorder � Schizophrenia � Intellectual functioning � Verbal memory � Executive function

Abstract Background: More and more epidemiological, genetic and neuroimaging studies show similarities between bi-polar disorder (BD) and schizophrenia (SZ). Cognitive functions are known to be highly impaired in SZ and are increasingly studied in BD. When both populations are compared, the conclusions appear to be contradictory. The purpose of this review is to help defi ne the profi le of cognitive defi cits in BD and in SZ. Methods: A system-atic review of the literature of neuropsychological stud-ies comparing BD and SZ was made, beginning in Janu-ary 1990 and ending in January 2005. Thirty-eight studies met the required quality criteria and were included in this review. Results: Bipolar patients exhibit extensive cogni-tive abnormalities with a pattern of defi cits that is not unique to this disease. However, when compared to schizophrenic patients, bipolar patients demonstrate a lesser degree of defi cits, particularly concerning premor-bid and current intelligence quotient and perhaps atten-tion, verbal memory and executive functions. When looking into effect sizes, there seem to be different pro-fi les even in studies fi nding no signifi cant differences.

Eduard Vieta, MD, PhDClinical Institute of Neuroscience, Hospital Clinic, University of BarcelonaVillarroel 170ES–08036 Barcelona (Spain)Tel. +34 93 227 5401, Fax +34 93 227 5477, E-Mail [email protected]

© 2006 S. Karger AG, Basel0033–3190/06/0752–0072$23.50/0

Accessible online at:www.karger.com/pps

Page 2: Specificity of Cognitive Deficits in Bipolar Disorder versus Schizophrenia

Cognition in Bipolar Disorder versus Schizophrenia

Psychother Psychosom 2006;75:72–84 73

SZ overlapping those for BD [4] , although no candidate genes are available yet. Array studies showed interesting results with oligodendrocyte and myelin dysfunctions in prefrontal cortices in both BD and SZ when compared to healthy controls [5] . Structural brain abnormalities in BD are similar to those of SZ especially in the frontal lobe [6, 7] with cerebellar atrophies [8] . Epidemiological charac-teristics are shared in both diseases, such as lifetime risk, course of illness, stress vulnerability and risk for suicide [9] . Finally, the literature suggests that bipolar patients have cognitive defi cits when compared to controls [10, 11] , with 32% of adults in remission having persistent cognitive defi cits [12] . However, when compared to schizophrenic patients, the results are contradictory. The purpose of this critical review is to report the studies deal-ing with the neuropsychology of BD with special atten-tion to the possible relationship with SZ. This paper at-tempts to defi ne the profi le of defi cits of bipolar patients by comparing it to the one existing in schizophrenic pa-tients. Therefore, we have selected relevant studies from the literature meeting the criteria included in this review. Many important factors can infl uence the result, such as the phase of illness at the time of testing, premorbid func-tioning, functional outcome, the presence of subsyndro-mal symptoms, the medication status and the number of previous episodes. All these points will be taken into ac-count in this review.

Methodology

The major databases (Medline, Psychological Abstracts, Cur-rent Contents) were consulted in order to conduct a comprehensive and objective review of the literature on the neuropsychology of bipolar and schizophrenic patients. Searches were made within the past 15 years by using different key words ( table 1 ). A large number of studies were identifi ed but only 38 studies met the criteria and thus were included in this review. The articles were selected if they met the following criteria: 1 comparison between bipolar patients and schizophrenic pa-

tients, 2 published between January 1990 and January 2005, 3 cross-sectional or longitudinal comparative studies, 4 including patients aged between 18 and 60, 5 including standardized diagnostic criteria and outcome mea-

sures, such as: DSM-III-R [13] , DSM-IV [14] , PANSS [15] , Young Mania Rating Scale [16] or Hamilton Depression Rating Scale [17] ,

6 selection of standardised or well-established cognitive tasks and

7 including clear descriptive and comparative statistical meth-ods. Finally, the references of the selected articles were also studied

in order to fi nd any additional studies not previously identifi ed.

Methodological Issues of Comparative Studies on Cognition Studies addressing cognition in these disorders may face a cer-

tain number of limitations. One major bias is the sample size. It should be noted that only 12 studies out of 38 have recruited a group of bipolar patients equal to or larger than 30 patients, while, in gen-eral, groups of schizophrenic patients are larger. Comparing a small sample to a larger sample is a problem, since the signifi cant results are more likely to emerge in the larger group than in the smaller one. Therefore, in order to have a better idea of the statistical weight of each study, we have calculated the effect size for most of the cognitive variables. Another limitation is related to the medication regimens. Comparing patients with different treatments can induce a bias. Indeed, bipolar patients usually receive mood stabilizers (lithium or anticonvulsants) or combined treatments, while schizo-phrenic patients usually take antipsychotics among others. In this case, the effect of pharmacological treatment on cognition could be diffi cult to determine. Some studies have shown a cognitive im-provement after antipsychotic treatments [18, 19] , in acute mania [20] , in euthymic bipolar patients [21] and in acute [22] or stable [23] schizophrenic patients. In contrast, negative impacts of neu-roleptics and other psychotropic treatments on cognition have also been demonstrated [24] . Some studies suggest that atypical anti-psychotics are safer than conventional neuroleptics with regard to cognition [20, 21] . Lithium is said to have a negative effect on memory and speed of information processing [25] , while other studies showed that it did not exert any negative or positive effect on cognition [19, 26] . Mood stabilizers such as carbamazepine or valproic acid/valproate possess adverse cognitive effects in healthy volunteers [27] . Among modern anticonvulsants, lamotrigine may be one of the safest and topiramate one of the worst with regard to their cognitive side-effects [28] . In general, antidepressants appear to have a benign profi le in depressed patients [29] . Cognitive defi -cits seen in either BD or SZ are not a primary effect of medication treatment. However, we cannot exclude that some of these phar-macological treatments could have an impact on cognitive func-tions, especially in cases of high doses and in cases of combined treatments [30] . Another methodological bias is the presence of both unipolar (UP) and bipolar patients in the same comparison group. Mixing UP and bipolar patients in the same group can mask the proper performance of the bipolar patients. In some studies, the absence of a healthy control group for comparison makes it diffi cult to assess the degree of patients’ cognitive impairment. Finally, re-sidual manic or depressive symptoms are scarcely measured, al-though these symptoms may have an impact on cognitive function-ing. Bearing these problems in mind, this narrative review will fo-cus on neuropsychological functions in BD and in SZ through the analysis of the most relevant comparative studies in this fi eld.

Table 1. Key words used for literature re-search (for BD and SZ)

+ Attention+ Memory+ Intellectual functioning+ Global functioning+ Cognitive function+ Neuropsychological function+ Executive function

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Daban et al.

Psychother Psychosom 2006;75:72–84 74

Results

Table 2 summarises the fi ndings of the studies includ-ed in this review.

Global Functioning A close relationship between impaired cognition and

poor functional outcome has been demonstrated in BD [31, 32] and in SZ [33] , indicating a possible link between these factors. In bipolar asymptomatic patients, defi cien-cies in visual and verbal memories are associated with poor psychosocial functioning [31, 32] . Likewise, in schizophrenic patients, defi ciencies in delayed verbal memory, in cognitive fl exibility and in sustained atten-tion are associated with all types of inadequate function-al outcomes such as diffi culties in social problem solving, in skill acquisitions or in community outcome [33] . Nev-ertheless, when compared to stabilised schizophrenic pa-tients, euthymic bipolar patients have a signifi cantly bet-ter psychosocial functioning [34, 35] .

In sum, bipolar patients have a better social function-ing than schizophrenic patients, but remain impaired when compared to healthy controls.

Intelligence Quotient Current Intelligence Quotient Generally, when measured with the Wechsler Adult

Intelligence Scale (WAIS) [36] , bipolar patients perform better than schizophrenic patients [37–43] . According to Goldberg et al. [41] , the intelligence quotient (IQ) is the most discriminating variable between SZ and BD, as shown by the signifi cant difference between the groups and the large effect size (d = 1.1). Three other studies have large effect sizes on measures of intellectual ability (range: d = 0.97–2.35) [38, 42, 43] . In contrast, only one study failed to fi nd any difference between schizophrenic pa-tients and bipolar patients, when evaluated on the WAIS-R [44] , but the effect size was quite large, suggesting that the absence of a difference between the diagnostic groups was more a matter of statistical power than the nature of neuropsychological fi ndings.

Authors Population Cognitive measures Effect size BD vs. SZ Results Comments

Hoff et al.,1990 [53]

35 BD vs. 30 SZ TMT; WMS (LM); BVRT(non-verbal memory);verbal IQ; CVLT

LM: 0.1verbal IQ: 0.2

BD = SZ BD were all acutely manic;CVLT; TMT A/B excluded from analysis

Morice,1990 [38]

20 BD vs. 60 SZ vs. 34 CONT

WCST; WAIS WAIS full IQ: 1WCST persev: 0.01

WAIS: SZ < BD = CONT WCST: BD = SZ < CONT

BD recovering from manic episode

Rund et al.,1992 [59]

19 BD vs. 28 SZ vs. 17 CONT

CPT NA BD = SZ < CONT mixed BD with 17 depressed partially remitted patients

Jones et al.,1993 [49]

49 BD vs. 100 SZ vs. 46 OP

NART NA BD > SZ

Goldberg et al.,1993 [41]

16 BD vs. 57 SZ vs.29 UP depressive

WAIS-R; TMT-B; WMS(LM, PAL); WRAT-R; WCST

WAIS full IQ: 1.1TMT-B: 0.58LM: 0.69, PAL:0.2WRAT: 0.01WCST persev: 0.66

BD = UP > SZ for IQ;WCST, LM, PAL BD = SZ: WRAT, TMT

absence of a normal control group

Landro et al.,1993 [76]

18 BD vs. 30 SZ vs. 18 CONT

short-term and long-term verbal memory; WCST

short-term 15 s: 0.53long-term: 0.77

SZ ^ BD = CONT; chronic SZ < non-chronic SZ

no available data for the WCST

Green et al.,1994 [88]

31 manic vs. 63 SZ vs. 48 CONT

VBM NA BD = SZ < CONT chronic patients

Metz et al.,1994 [81]

17 AD vs. 28 SZ vs. 5 SZAff

WCST WCST persev: 0.74 AD > SZ for categories and persev. errors

absence of a normal control group

Souza et al.,1995 [37]

19 BD vs. 26 SZ vs. 27 CONT.

NART; WAIS; VF; verbal recall

WAIS = 1NART = 0.75VF:1.82verbal recall: 0.9

BD > SZ: NART; WAIS; VF; verbal recall

P300 abnormal latency correlated to poor performance in VF for SZ

Table 2. Summary of studies comparing cognitive functioning between bipolar and schizophrenic patients

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Cognition in Bipolar Disorder versus Schizophrenia

Psychother Psychosom 2006;75:72–84 75

Authors Population Cognitive measures Effect size BD vs. SZ Results Comments

Tompkins et al.,1995 [75]

24 MD (BD or MDD) vs. 24 SZ

LM immediate, delayed (cue, no cue); WAIS-R (object assembly and picture arrangement; vocabulary)

LM imm. no cue: 0.89LM imm. cue: 0.26LM del. no cue: 0.52LM del. cue: 0.12

MD = SZ: voc WAIS-R; LM

two testing conditions: with and without cue: modest effect of cuing on both groups; small groups (n = 12)

Albus et al.,1996 [65]

17 BD vs. 10 UP (27 AD) vs. 27 SZ vs. 27 CONT

TMT A/B; Stroop; WCST; CVLT; VF; LM

NA SZ < AD without � = CONTSZ = AD with � < CONT

BD and UP included in a group of AD; with or without �

Docherty et al.,1996 [60]

24 BD vs. 48 SZ vs. 23 CONT

WM = TMT-B + VF; CPT WM index: 0.18VF: 0.17CPT: NA

BD = SZ many participants made no errors on the tests

Addington and Addington, 1997 [61]

40 BD vs. 59 SZ vs. 40 CONT

CPT degraded version CPT sensitivity: 0.23 SZ ^ BD ^ CONT patients evaluated inpartial remission; 12 weeks after discharge

Hawkins et al.,1997 [87]

22 BD vs. 46 SZ vs. 26 CONT

VF; TMT VF: NA,TMT-B: 0.54

BD > SZ SZ with negative symptoms perform worse

Mc Grath et al.,1997 [46]

18 BD (mania) vs. 36 SZ vs. 20 CONT

NART; TMT; VF; Stroop and WCST

VF: T1: 0.07; T2: 0.19;TMT B/A: T1: 0.3; T2:0.05WCST persev: T1: 0.43; T2: 0.17WCST cat: T1: 0.34; T2: 0.70Stroop interf.: T1: 0.01; T2: 0.04

NART: BD = SZ,T1: SZ < BD for Stroop; TMT; T2:BD = SZ < CONT for StroopBD improved for WCST (cat) but not SZ

patients were tested just after admission and 4 weeks after initial testing (subacute);BD tested while in manic phase

Tam et al.,1998 [62]

23 BD vs. 26 SZ vs. 10 CONT

WCST; VBM; CPT WCST persev: 0.63CPT: hits false alarm: 0.24; VBM: 0.19

SZ ^ BD < CONT: WCST; VBMBD = SZ = CONT: CPT

Young et al.,1998 [82]

21 BD vs. 108 SZ WCST; IQ WCST cat = 0.25IQ = 0.25

no group difference on IQ or WCST

no group control; half of the BD were currently experiencing psychosis

Zilh et al.,1998 [83]

100 AD (72 UP; 28 BD) vs. 100 SZ

TMT-A; short- and long-term verbal memory; WCST

WCST persev: 0.7TMT-A: 0.24short memo: 0.05long memo: 0.09

AD = SZ for all tests (<1 SD/normative data); except WCST, long memo:BD > SZ

no group control

Gard et al.,1999 [43]

20 BD vs. 20 SZ vs. 20 CONT

WAIS-R NI; VF, TMT B; WCST TMT-B: 2.3WCST persev: 1.91WAIS: 2.35VF: 1.28

BD > SZ; SZ < CONT absence of defi nition concerning the mood state of the manic patients

Hobart et al., 1999 [42]

23 BD vs. 23 SZ WAIS III; LM; WCST; TMT; WMS-R; Stroop; modifi ed CPT

WAIS full IQ: 0.65 verbal IQ: 0.97 LM: 0.63,Stroop: 0.67,WCST persev: 0.18,TMT-B: 0.11,CPT: 0.02

BD > SZ: voc, LM, StroopBD = SZ: TMTB, WCST, CPT

65% (SZ) and 72% (BD) of the patients had drug abuse

Motjabai et al.,2000 [54]

72 BD vs. 49 UP vs. 102 SZ

VF; Stroop; WMS-R; WAIS-R (VIQ); TMT

TMT-B: 0.8Stroop interf: 0.87imm. memo: 0.66VF: 0.7VIQ: 0.7

BD = UP > SZ : VF, VIQ, verbal memo, Stroop, TMT

patients tested while on fi rst episode in partial remission

Krabbendaum et al., 2000 [69]

21 BD vs. 22 SZ vs. 22 CONT

AVLT (imm; delayed memo); Stroop; modifi ed TMT; VF

Stroop interf: 0.40VF: 0.32imm. memory: 0.2delayed memo: 0.03modifi ed TMT-B: 0.03

SZ < CONT, BD = CONT, SZ = BD: Stroop interf and VF;BD = SZ < CONT: imm. and delayed memo, TMT

bipolar patients in remission;BD I = BD II on all cognitive measures

Table 2 (continued)

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Daban et al.

Psychother Psychosom 2006;75:72–84 76

Authors Population Cognitive measures Effect size BD vs. SZ Results Comments

Verdoux and Liraud, 2000 [70]

33 BD vs. 29 (non-SZ) with � vs. 20 SZ vs. 19 MDD

BEM-84 (verbal memo); Stroop test; WCST (cat)

Imm. verbal memory:0.69; WCST: 0.09; Stroop interf.: 0.19

BD > SZ for verbal memory; no group difference on WCST and Stroop

no normal group was included;subjects with history of alcohol and drug abuse were included

Gilvarry et al.,2000 [50]

66 AD (27 mania) vs. 91 SZ vs. 50 CONT vs. 65 BD Rel. vs. 85 SZ Rel

NART NART: 0.77 SZ < BD < CONT = fam

Rossi et al.,2000 [84]

40 BD vs. 66 SZ vs. 64 CONT

WCST WCST persev: 0.18WCST cat: 0.25

SZ < BD = CONT: categories BD = SZ: persev. errors

Dickerson et al., 2001 [35]

26 BD vs. 74 SZ RBANS (including immediate verbal memory); WAIS III (subtests)

Imm. verbal memo: 0.68

BD > SZ for immediate verbal memory

all patients were stable at the time of testing;no healthy control group

Gooding and Tallent, 2001 [89]

20 BD vs. 34 SZ vs. 30 CONT

visual working memory task; estimated IQ (SHT)

WM % correct: 1.27estimated IQ = 0.97

WM % correct: BD = CONT > SZ;.BD = CONT > SZ: IQ

all patients were clinically stable

Mc Grath et al., 2001 [47]

12 manic vs. 19 SZvs. 19 CONT

visual WM task; NART memory T1: 0.68,T2: 0.03NART: 0.1

Mania = SZ < CONT(T1 and T2);correlation with positivesymptoms

evaluated on admission and4 weeks later

Liu et al., 2002 [64]

22 BD without � vs. 46 BD with � vs. 22 MDD without � vs.41 SZ

CPT degraded and non-degraded version

CPT sensitivity: 0.97 (SZ vs. BD with �);1.16 (SZ vs. BD without �)

SZ < BD with � < BD without � < CONT

tested in acute phase and after remission; BD improve their performance in phase of remission; but not SZ

Martinez-Aran et al., 2002 [34]

49 BD vs. 49 SZ WAIS-R (vocabulary; digit); WCST; TMT; VF

WAIS voc: 0.1;WCST cat: 0.5; VF: 0.21; TMT-B: 0.26

BD = SZ: WAIS voc, VFand TMT-B;BD > SZ: WCST (cat)

all patients were stable;no healthy control group

Seidman et al., 2002 [39]

15 BD vs. 87 SZ vs. 94 CONT

WAIS voc; WRAT-R; WCST; TMTA/B; CPT; LM

WRAT-R: 0.11WCST persev: 0.67WAIS- oc: 0.53TMT: 1.03; LM: 0.34;CPT: 0.60

SZ < CONT: all except verbal abilities;BD < CONT: LM.SZ < BD: WCST; TMT; CPT.SZ < BD = CONT: IQ

patients clinically stable; BD with psychotic features

Arduini et al., 2003 [85]

22 BD vs. 42 SZ WCST WCST persev: 0.28 SZ = BD patients were evaluated while in remission

Seidman et al., 2003 [40]

14 BD vs. 79 SZ vs. 84 CONT

ROCF (visual memory)WRAT (premorbid IQ); IQ estimate (WAIS-R; vocabulary and block design)

WRAT: 0.01IQ estimate: 0.52Imm. visual memo: 0.47

Imm. visual memo, WART: SZ = BD < CONT;IQ: SZ < BD = CONT

BD patients with � features

Altshuler et al., 2004 [51]

40 BD vs. 20 SZ vs. 22 CONT

NART; CVLT; WCST; Verbal fl uency; TMT; Voc WAIS; Stroop.

Voc WAIS: 1.22NART:1.06WCST persev: 0.32WCST cat: 0.77CVLT total: 0.48VF: 0.46TMT B: 0.81Stroop Inter: 0.2

BD = CONT> SZ: NART, TMTB, Voc WAIS.BD=SZ< CONT: CVLT, WCST.BD = SZ = CONT: Stroop interf and VF.

Only men outpatients were included.

Dickerson et al., 2004 [77]

117 BD vs. 229 SZ vs. 100 CONT

RBANS: imm. memory; attention; delayed memory

imm. memo: 0.81delayed memo: 0.71

imm., delayed memo: BD > SZ

Table 2 (continued)

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Cognition in Bipolar Disorder versus Schizophrenia

Psychother Psychosom 2006;75:72–84 77

Premorbid IQ Using the National Adult Reading Test (NART) [45]

to evaluate premorbid IQ, similar scores were found be-tween manic patients, schizophrenics and healthy con-trols [46, 47] . A similar result has been reported using another reading test (Wide Range Achievement Test – Revised [48] ) in stable schizophrenic and bipolar patients [39–41] . In contrast, some studies have found that bipolar patients had a better premorbid IQ than schizophrenic patients, when measured with the NART [37, 49–51] . Three of these studies [37, 50, 51] have large effect sizes (range: d = 0.77–1.06) indicating powerful results. Using the vocabulary subtest of the WAIS-R to measure pre-morbid IQ, no signifi cant difference was found between bipolar patients (type I) and schizophrenic patients, but both groups signifi cantly differed from healthy controls [52] . This result was confi rmed in a comparison between stabilised bipolar and schizophrenic patients [34] and be-tween schizophrenic and manic patients [53] . In contrast, Hobart et al. [42] have found a signifi cant difference be-

tween both groups on the vocabulary subtest of the WAIS-III (p ! 0.005), with a large effect size (d = 0.97), making this variable one of the most discriminating of all the variables studied. A similar result was found in patients experiencing their fi rst psychotic episode, with bipolar patients being less impaired than schizophrenic patients on the vocabulary subtest of the WAIS-R [54] .

Finally, 3 longitudinal retrospective studies have eval-uated adolescents and youngsters with no evidence of ill-ness at the baseline assessment and later diagnosed with BD or SZ [55–57] . All studies have found that subjects with SZ performed signifi cantly worse on premorbid in-tellectual measures than those with a BD, who, in turn, did not differ from the comparison subjects.

The conclusions concerning the intellectual function-ing in BD and SZ are quite consistent concerning current IQ, which seems to be higher for bipolar patients. Regard-ing premorbid IQ, the results appear rather contradicto-ry. This could be due to the selection of different measures and to the inclusion of bipolar patients with or without

Authors Population Cognitive measures Effect size BD vs. SZ Results Comments

Tam and Liu, 2004 [63]

27 BD; 30 SZ+; 22 SZ –; 28 CONT

TR; WCST; VBM; CPT WCST persev:SZ+ vs. BD: 0.45SZ– vs. BD: 0.85CPT: SZ+ vs. BD: 0.58SZ– vs. BD: 0.08VBM: SZ+ vs. BD: 0.28SZ– vs. BD: 0.02

BD > SZ: WCSTBD = SZ: VBM, CPT

unmedicated patients for at least 1 month

Zalla et al.,2004 [44]

37 BD vs. 25 SZ vs. 33 BD Rel vs. 22 SZ Rel vs. 20 CONT

WAIS-R; VF; WCST; TMT-B, Stroop

WAIS-R: 0.58VF: 1.1; WCST persev: 0.45; WCST cat: 0.41TMT-B: 0.5Stroop interf: 0. 04

BD = SZ: IQ, Stroop; WCST; TMTB;BD > SZ: VF

the only signifi cant difference between SZ and BD: VF

Balanza-Martinez et al., 2005 [52]

15 BD I vs. 15 SZ vs. 26 CONT

WCST; TMT; VF; Stroop; verbal memory (Babcock Story Recall Test); WAIS-R (vocabulary)

T1 WAIS voc: 0.09T1/T2: WCST persev: 0.01/0.31 WCST cat: 0.1/0.32 VF: 0.33/0.03;Imm memo: 0.7/0.16TMT-B: 0.22/0.29; Stroop interf: 0.36/1.17

T1: BD = SZ < CONTT2: (3 years later) BD = SZ < CONT; for all except BD < SZ = Stroop interf

patients tested at T2 only if stable or euthymic

Table 2 (continued)

AD = Affective disorder; AVLT = Auditory Verbal Learning Task; BEM-84 = battery of memory effi ciency; BD I = BD type I; BVRT = Benton Visual Retention Test; COBLAT = control-based learning theory; CONT = healthy controls; CPT = Continuous Performance Test; HRD = Hebb’s Recurring Digits; LM = logical memory; MD = mood disorder; MDD = major depression disorder; NA = not applicable: effect size cannot be measured because of miss-ing data or incomparable data; OP = other pathology; PAL = paired associ-ated learning; Prem IQ = premorbid IQ; Rel = relatives; Raven SPM = Raven’s Standard Progressive Matrices Tests (problem solving); RBANS = Repeatable Battery for Assessment of Neuropsychological Status; ROCF = Rey-Osterrieth

Complex Figure; RT = reaction time; SAT = Span of Apprehension Test; SHT = IQ measure using the Shipley Hartfortd test; Stroop interf = Stroop interference; SZAff= schizoaffective disorder; T1 = fi rst evaluation; T2 = sec-ond evaluation; VF = verbal fl uency; VIQ = verbal IQ (vocabulary subtest); WAIS-R N I = Wechsler Adult Intelligence Scale -- Revised, neuropsycho-logical inventory; With � = with psychotic features; Without � = without psy-chotic feature; WCST cat = WCST categories; WCST persev = WCST perse-verative errors; WM = working memory; WMS = Wechsler Memory Scale; WRAT = Wide Range Achievement Test.

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psychotic symptoms [37, 39, 40] . The presence of psy-chotic symptoms in bipolar patients seems to worsen their performance on IQ measures (premorbid or current) leading to scores comparable with those of schizophrenic patients.

However, prospective longitudinal studies show that premorbid IQ may be well preserved in BD [55–57] . This attractive suggestion leads to the hypothesis of different models for the cognitive defi cits seen in both conditions. Indeed, an early childhood cognitive impairment could be specially associated with schizophreniform disorders and could predict psychotic symptoms in childhood and adulthood [58] .

Attention Sustained Attention The Continuous Performance Test (CPT) is a method

widely used to assess sustained attention or vigilance. Nine studies have compared bipolar to schizophrenic pa-tients using the CPT or a modifi ed version [39, 42, 59–65] . In four of them, bipolar patients performed equally to schizophrenics, and were moderately impaired when compared to controls [59–61, 63] . Docherty et al. [60] explain the absence of difference by the fact that the CPT version selected is relatively easy, yielding some problem-atic distributions. In contrast, two studies showed that schizophrenic patients performed worse than bipolar pa-tients (with or without psychotic features) who in turn performed worse than controls [39, 64] . Analysing this last study [64] , a large effect size (d = 1.17) was found, indicating powerful results and an important difference between the two groups of patients (p ! 0.001). The dis-crepancies between the studies may also be due to the different CPT versions selected (with or without working memory components) [63, 64] . The magnitude of the def-icit may be correlated to the clinical state of the patients, since bipolar patients in remission perform better than while in an acute phase [64] . However, when compared to controls, euthymic bipolar patients remain impaired, suggesting that these impairments may be a trait marker [66, 67] . It is important to note that in these two last stud-ies, low levels of affective symptoms were controlled for. Thus, defi cits in sustained attention do not seem to be specifi c to SZ and can be considered as a vulnerability marker for BD and other diseases with psychotic features [39, 64] .

Selective Attention The experimental task most commonly used to mea-

sure selective attention is the Stroop Colour and Word

Test [68] . Ten studies have compared bipolar and schizo-phrenic patients while performing this test [42, 44, 46, 50–52, 54, 65, 69, 70] . Six studies did not fi nd any differ-ence between the two groups [44, 46, 50, 51, 69, 70] . Both groups of patients were signifi cantly impaired when com-pared to controls [44, 46] . The disproportionate slowness seen in both groups of patients is interpreted as an in-creased susceptibility to the interference provoked by the test [44] . In one study, schizophrenic patients had more positive and negative symptoms when compared to bipo-lar patients [52] . Unfortunately, these variables were not used as covariates in the analysis, although negative symptoms, in particular, have a deleterious impact on cognitive functions [71] .

In contrast, three studies found that bipolar patients differed from schizophrenic patients [42, 52, 54] . Bipolar patients with psychotic features were found to perform better when compared to schizophrenic patients, on both the colour and word tests [42] . In the latter, the majority of the patients had a co-occurring substance abuse or de-pendence disorder at the time of testing, despite the fact that drugs have a negative impact on cognitive functions [72] . In another study, 102 schizophrenic and 72 bipolar patients were evaluated on their fi rst admission of psy-chotic disorder [54] . Both groups signifi cantly differed from each other, with bipolar patients having better scores of interference. An additional analysis has shown that there was no difference between patients (BD or SZ) with or without psychotic symptoms. In a recently published study [52] , the authors have investigated the cognitive performance of bipolar and schizophrenic patients at baseline and after 3 years, when stable for at least 2 months. At both points, bipolar and schizophrenic pa-tients showed similar defi cits on the Stroop Colour and Word Test compared to the controls. However, at time 2, the euthymic bipolar patients performed signifi cantly worse than the SZ group considering the interference score of the Stroop Colour and Word Test. This result remains an exception.

Finally, in the study by Albus et al. [65] , patients with affective disorder (n = 27: 10 UP, 17 BD) with psychotic features and schizophrenic patients were impaired on the Stroop Colour and Word Test, having scores 2 standard deviations (SD) below the normative data. On the other hand, patients with affective disorder without psychotic features differed from the schizophrenic patients but did not differ signifi cantly from normal controls.

Hence, concerning sustained and selective attention, bipolar patients have impaired performance persisting across mood states, with an apparent deleterious effect of

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the psychotic features on cognitive functions. Both schizo-phrenic and bipolar patients seem to have attentional dif-fi culties but comparative studies appear inconclusive or contradictory. However, importantly, the studies with the most powerful results seem to point out actual differ-ences between schizophrenic and bipolar patients, with schizophrenic patients being more impaired [54, 64] .

Memory Verbal memory is usually evaluated with word lists

and tests of story recall and recognition. The most com-mon verbal list task is the California Verbal Learning Test (CVLT) [73] . To our knowledge, two studies with avail-able data have compared bipolar to schizophrenic pa-tients on the CVLT [51, 65] . In both studies, bipolar and schizophrenic patients scored signifi cantly worse than control subjects but not signifi cantly different from each other. One study [69] has compared bipolar to schizo-phrenic patients using the Auditory Verbal Learning Task, a modifi ed version of the CVLT. Once again, both schizophrenic and bipolar patients had performance be-low the normal range. Identical results were found using another list of words with delayed or immediate recall [70] . Unfortunately, no group of healthy controls was in-cluded for comparison.

Verbal memory can also be evaluated using subtests issued from the Wechsler Memory Scale – Revised [74] , such as ‘logical memory’ or ‘paired associates’. Using these measures, three studies have found that bipolar and schizophrenic patients performed similarly [39, 53, 75] , but under the normal range [39] . In contrast, two studies have shown a difference between both groups of patients [41, 54] . Goldberg et al. [41] studied the contrasts be-tween UP, depressive bipolar and schizophrenic patients while performing cognitive tests. The results showed that, regarding logical memory and paired associate learning, the SZ group had signifi cantly lower performance than the two affective disorder groups. This defi cit seems to be present even in the early course of the disease, since Mot-jabai et al. [54] have found worse performance in patients with fi rst-admission SZ than in patients with fi rst-admis-sion psychotic affective disorder, especially in the short-term condition.

Other studies have selected modifi ed versions or new tests to measure verbal memory. Using the Babcock Sto-ry Recall Test, no difference was found between bipolar and schizophrenic patients [52] . Both groups had im-paired performance in verbal recall when compared to healthy controls, at baseline and after a 3-year follow-up (p ! 10 –3 ). In contrast, some studies have shown differ-

ences between the two groups of patients. Verdoux and Liraud [70] have studied cognitive performance in four groups of patients (SZ, non-SZ with psychotic symptoms, BD and major depression). While performing a test of immediate story recall, the subjects with SZ had lower performance than subjects with BD (p ! 0.01). This result was confi rmed by a high effect size (d = 0.69). Similar conclusions were given in other studies [35, 37, 42, 76, 77] . In three of these studies, the measure of immediate verbal memory was found to be among the most discrim-inating variable (range: d = 0.68–0.89) [35, 37, 77] . When compared to controls, both diseases are associated with signifi cant cognitive impairments, but those in SZ appear to be severer [77] .

The fact that verbal memory defi cits are present in pe-riods of partial remission, as well as in euthymic patients, suggests that these defi cits are a trait marker of BD, rath-er than linked to the clinical state. However, mild affec-tive symptoms should be controlled in order to establish their impact in verbal memory defi cits, since some au-thors have suggested that very subtle changes in mood may affect verbal memory performance [32, 78] .

Therefore, verbal memory and more especially imme-diate recall seem to differentiate the two groups of pa-tients. Several studies, unable to signifi cantly separate schizophrenic from bipolar patients, might actually lose their statistical power with regard to the bipolar sample [39, 52, 53, 75] . However, bipolar patients still perform below the standards. It appears that verbal memory defi -cits are not diagnosis specifi c, although there might be quantitatively signifi cant differences between SZ and BD. Moreover, the CVLT seems to discriminate very ef-fi ciently between patients and healthy controls, but much less so between schizophrenic and bipolar patients.

Executive Functions Cognitive Flexibility The Wisconsin Card Sorting Test (WCST) [79] is a

very popular task selected to measure executive function-ing, concept formation and cognitive fl exibility [80] . To our knowledge, nineteen studies with available data have compared bipolar patients to schizophrenic patients on this test. Nine studies did not fi nd any difference between the two groups, suggesting that cognitive infl exibility, linked to prefrontal cortical dysfunction, is not specifi c to SZ [38, 44, 46, 52, 65, 70, 82, 84, 85] . The small effect sizes (range: 0.10–0.44) confi rm that the differences be-tween the diagnostic groups are subtle. Hence, schizo-phrenic and bipolar patients, evaluated in the acute phase, had comparable performance. However, when the pa-

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tients were re-evaluated 4 weeks after the initial testing, while in the subacute phase, the schizophrenic patients did not improve the number of achieved categories, whereas the bipolar patients improved their performance, suggesting a different pattern of improvement between the two populations [46] .

In contrast, eight studies found that schizophrenic pa-tients performed worse than bipolar patients [34, 39, 41, 43, 62, 63, 81, 83] . Martinez-Aran et al. [34] have studied executive functions in remitted bipolar and schizophren-ic patients. The two groups only signifi cantly differed in the number of categories achieved (d = 0.70). Similar re-sults had previously been found, with both groups of pa-tients only being signifi cantly different on the WCST [81, 83] . Finally, according to Tam and Liu [63] , the presence of negative symptoms seems to worsen the performance. Indeed, a high effect size was found when comparing the schizophrenic patients with negative symptoms to the bi-polar patients (d = 0.85).

In addition, three studies have found a profi le charac-terised by similar results in perseverative errors but dif-ferent in the number of categories achieved [34, 42, 51] . For instance, Altshuler et al. [51] have compared stable bipolar to schizophrenic patients. The results showed that both groups had impaired performance on the WCST (cat-egories and perseverative errors). When compared to the schizophrenic patients, the bipolar patients made as many perseverative errors but achieved more categories. This suggests that bipolar and schizophrenic patients have im-paired cognitive fl exibility, but bipolar patients seem to perform better on abstraction and concept formation.

The Trail Making Test (TMT) part B [86] is also used as a measure of mental fl exibility. Many studies have compared the two groups on this test [34, 39, 41–44, 46, 51, 52, 54, 60, 65, 69, 87] . Eight studies did not fi nd any difference between the two groups [34, 41, 42, 44, 52, 60, 65, 69] . However, the limited sample size, particularly for bipolar patients, may again be an issue as refl ected by a large effect size in the absence of signifi cant differences [e.g. 41] . Bipolar patients with psychotic features were indistinguishable from schizophrenic patients, with per-formance at least 2 SD below the normal range. Bipolar patients without psychotic features had better scores than the schizophrenic patients but remained impaired (–0.5 SD) [65] .

Six other studies have found signifi cant differences be-tween the two groups, with bipolar patients performing better than schizophrenic patients [39, 43, 46, 51, 54, 87] . In one study, the largest effect size, which showed the greatest impairments in SZ compared to BD, was found

for the TMT (d = 1.03) [39] . A very large effect size (d = 2.30) was found in another study [43] , with schizophren-ic patients performing signifi cantly slower, confi rming their diffi culties in shifting context.

Working Memory Working memory implies functions considered as ex-

ecutive functions, such as the maintenance of relevant information and the processing of this information. The Visual Backward Masking (VBM) is a task evaluating the earliest phases of visual information processing. Three studies have compared schizophrenic patients to bipolar subjects using VBM, all showing that bipolar and schizo-phrenic patients have comparable results [62, 63, 88] . In one of these studies, the absence of data did not allow the measure of the effect size [88] and the two other studies had small effect sizes [62, 63] .

Using other tasks, impaired visual working memory was seen in schizophrenic patients when compared to sta-ble bipolar patients [89] or in both schizophrenic and manic patients during the acute and subacute phases [46] . Thus, working memory may differentiate SZ from BD when the patients are stable, but not in acute or subacute phases. Finally, neuroimaging studies have shown similar functional brain abnormalities in bipolar and schizo-phrenic patients, such as decreased size or hypoactivation in the prefrontal cortex, a region that is activated in work-ing memory tasks [90, 91] .

Verbal Fluency Tasks The generation of words is considered as an executive

task. Twelve studies have compared bipolar to schizo-phrenic patients on this task [34, 37, 43, 44, 46, 51, 52, 54, 60, 65, 69, 87] . In fi ve studies, bipolar and schizo-phrenic patients had comparable results [34, 46, 51, 52, 60] . An fMRI study has shown that, while performing a verbal fl uency task, bipolar patients have an extensive prefrontal activation during verbal fl uency that is signifi -cantly greater than in controls, whereas schizophrenic pa-tients have an attenuated frontal activation [92] . In con-trast, in six studies, schizophrenic patients were more im-paired than bipolar patients [37, 43, 44, 54, 69, 87] , with negative symptoms inducing severer impairments [87] . When compared to healthy controls, bipolar patients have similar results to schizophrenic patients [37, 43, 69, 87] . In one study, verbal fl uency was the only discriminat-ing test (d = 1.1), while many other executive functions had been studied (using the WCST, Stroop Colour and Word Test and TMT), for which both groups had similar scores [44] . Three other studies showed signifi cant differ-

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ences between the groups and high effect sizes for this measure (range d = 0.7–1.82) [37, 43, 54] .

In summary, concerning executive functions, it seems that both groups of patients are impaired, although the impairment profi le may be different. Moreover, neuro-imaging studies have found a hypoactivation of the pre-frontal cortex in both BD and SZ [11] , suggesting that impaired executive functions, associated with frontal lobe abnormalities, are present in both conditions.

Discussion

In the past, cognitive impairments in BD have been considered as infrequent and limited to the affective epi-sodes. More recently, some studies have shown the per-sistence of some defi cits during periods of euthymia [32, 93] . This review brings more evidence. When compared to schizophrenic patients, bipolar patients seem to be slightly less impaired, with broader differences with re-gard to both premorbid and current IQ and verbal mem-ory. Regarding attention and executive functions, minor differences or contradictory data appear. Schizophrenic patients, especially those with a predominant negative symptomatology, are the most severely impaired [34, 61, 87] . However, in some cases, the defi cits in patients with mania are indistinguishable from those in schizophrenic patients [46, 47] . Taken as a whole, it appears that cross-sectional neurocognitive defi cits are not diagnosis spe-cifi c. However, fi nding explanations to these impairments is like resolving a puzzle; multiple factors determine the answer. The small sample sizes, especially with regard to the bipolar groups, might have caused some type II errors in some studies not fi nding signifi cant differences be-tween schizophrenic and bipolar patients. Conversely, studies with small sample sizes fi nding large effect sizes and marginally signifi cant differences may show type I errors.

The differences seen between the two groups, in the intellectual functioning and in particular executive func-tions, may be due to differences at environmental levels. It appears that in SZ, the decline frequently begins before the onset of the psychosis and continues thereafter. In contrast, for bipolar patients, the decline seems to occur after the initial episode. Indeed, in BD, correlations were found between the number of previous episodes and poor cognitive performance, suggesting that severity and pro-gression of the illness are connected with the persistence of cognitive impairment [78] . If this was the case (longi-tudinal studies are scarce), there would in fact be a great

difference between SZ and BD, since generally, cognitive defi cits in SZ do not progress [94] . Early environmental risk factors for SZ also exist, such as an excess of births in winter/spring, fetal malnutrition, perinatal hypoxia and other obstetric complications [95] . Other environ-mental risk factors such as drug abuse, social adversity and isolation have also been identifi ed. Moreover, as seen earlier, a low IQ is also highly correlated with risk for SZ. On the other hand, neurodevelopmental alterations seen in SZ could explain neurocognitive defi cits. Indeed, struc-tural abnormalities, such as reduced brain volume, are more important in early-onset schizophrenic patients than in those with onset in adulthood [96] . If these abnor-malities are a marker of a general brain alteration, it could be postulated that cognitive defi cits seen in early-onset SZ are linked to these early neurodevelopmental abnor-malities. Therefore, it appears that both genetic and en-vironmental risk factors have impacts on the diagnosis and on the cognitive defi cits, although the literature on early neurodevelopmental injury is much more convinc-ing for SZ than for BD. Furthermore, three good-quality studies [55–57] suggest that there may be outstanding dif-ferences between BD and SZ with regard to premorbid IQ. This may mean that while neurodevelopmental ab-normalities would be the main reason for cognitive defi -cits in SZ, a neurotoxicity pattern related to recurring episodes and hypercortisolaemia might play a greater role in BD.

Future Directions Most of the studies previously mentioned employed

cross-sectional, between-subject designs comparing bipo-lar to schizophrenic patients. It seems that longitudinal, within-subject designs are more effective in assessing the outcome of cognitive performance. Therefore, in the near future, more studies of this type should be considered. Moreover, previously mentioned larger samples are also highly recommendable. Future studies should also con-sider manic or depressive residual symptoms, which are not frequently measured, since this subclinical psychopa-thology might possibly explain some persistent cognitive defi cits. A consensual defi nition of subclinical symptoms should also be made. Regarding the role of medication, studies in fi rst-episode unmedicated patients would be required. Although, as discussed, the cognitive impair-ments in BD are generally milder than those in SZ, they have a real negative impact on the quality of life and so-cial adaptation. These dysfunctions might improve with the aid of neuropsychological rehabilitation, which needs to be developed in this fi eld. Finally, as seen earlier, neu-

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ropsychological abnormalities such as impaired working memory or attentional defi cits may serve as endopheno-typic markers of genetic predisposition to SZ. Family studies have shown that impaired cognitive functioning was also present in unaffected relatives of SZ patients [97, 98] . However, very few family studies [44, 99] have fo-cused on BD and, in the near future, our interest should also be brought in this direction.

According to the conclusions of this systematic review, bipolar and schizophrenic patients share impairments in several cognitive domains, including attention, memory and executive functions, but subtle differences seem to

emerge with regard to IQ and premorbid adjustment. Further studies should explore the possibility that the neuropsychological similarities between these two condi-tions are related to converging pathways which not neces-sarily arise from the same neurobiological source.

Acknowledgments

This work was supported by grants from the Stanley Medical Research Institute (Bethesda, Md., USA), Glaxo-Smithkline (Spain) and Red CIEN IDIBAPS-ISCIII RTIC C03/06. Thanks to Jorge Capapey for statistical suggestions.

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