Rev neurocogniciòn en TB II

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Review

Meta-analytic review of neurocognition

in bipolar II disorder

Introduction

The clinical profile of bipolar II disorder andits relationship with bipolar I disorder and uni-polar disorder remains an area of active explo-ration. Endophenotypes, such as cognition, area potentially valuable differentiating marker.A substantial number of studies have found

cognitive dysfunction in bipolar disorder (BD)(16). As confirmed by several meta-analyses,cognitive deficits in BD persist even in euthymicpatients (79). In addition to findings fromstudies in remitted patients, evidence regardingcognitive deficits in relatives of affected patientssuggests that cognitive deficits could be traitcharacteristics of BD (8, 10, 11).

Bora E, Yu cel M, Pantelis C, Berk M. Meta-analytic review ofneurocognition in bipolar II disorder.

Objective: The clinical distinction between bipolar II disorder (BD II)and bipolar I disorder (BD I) is not clear-cut. Cognitive functioningoffers the potential to explore objective markers to help delineate thisboundary. To examine this issue, we conducted a quantitative reviewof the cognitive profile of clinically stable patients with BD II incomparison with both patients with BD I and healthy controls.

Method: Meta-analytical methods were used to compare cognitivefunctioning of BD II disorder with both BD I disorder and healthycontrols.Results: Individuals with BD II were less impaired than those with BDI on verbal memory. There were also small but significant difference invisual memory and semantic fluency. There were no significantdifferences in global cognition or in other cognitive domains. Patientswith BD II performed poorer than controls in all cognitive domains.Conclusion: Our findings suggest that with the exception of memoryand semantic fluency, cognitive impairment in BD II is as severe as inBD I. Further studies are needed to investigate whether more severedeficits in BD I are related to neurotoxic effects of severe manicepisodes on medial temporal structures or neurobiological differencesfrom the onset of the illness.

E. Bora1

, M. Ycel1,2

, C. Pantelis1

,

M. Berk2,3,4

1Melbourne Neuropsychiatry Centre, Department of

Psychiatry, The University of Melbourne and Melbourne

Health, Carlton, 2Orygen Research Centre, Melbourne,3Department of Clinical and Biomedical Sciences,

Barwon Health, The University of Melbourne, Geelong

and4Mental Health Research Institute, Melbourne and

Deakin University, Geelong, Vic., Australia

Key words: bipolar disorder; type II; cognition;

neuropsychology; meta-analysis

Emre Bora, Melbourne Neuropsychiatry Centre,

Department of Psychiatry, The University of Melbourne

and Melbourne Health, Alan Gilbert Building NNF level

3, Carlton, Vic. 3053, Australia.

E-mail: [email protected]; [email protected]

Accepted for publication October 25, 2010

Summations

The most important cognitive difference between BD I and BD II is poorer memory performancein BD I.

Clinical, demographic, and antipsychotic use do not explain these cognitive differences. Individuals with BD II are also cognitively impaired outside depressive episodes.

Considerations

Some studies do not report data for meta-regression analyses.

More studies are needed to make a more definitive neurocognitive comparison between BD I and BDII.

Acta Psychiatr Scand 2010: 110All rights reservedDOI: 10.1111/j.1600-0447.2010.01638.x

2010 John Wiley & Sons A/S

ACTA PSYCHIATRICASCANDINAVICA

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One of the weaknesses in neurobiologicalresearch in a psychiatric context is the neglect ofheterogeneity within the various syndromes. This isalso the case with regard to the investigation intocognitive dysfunction in BD, because the majorityof neuropsychological studies have examined BDas a homogeneous category. In fact, heterogeneity

of BD has been acknowledged in DSM-IV bydividing the disorder into subtypes: bipolar Idisorder I (BD I), bipolar II disorder (BD II),bipolar NOS, and cyclothymia. The main diagnos-tic difference between BD I and BD II is theseverity of elevated mood; while BD II involves lesssevere hypomanic episodes, BD I involves moresevere manic episodes with greater functionalimpairment. Depression, which is the majorburden in both BP I and BP II, is equally severe.Neglecting subtypes of BD might be relativelyunimportant if BD II is just a milder form of BD.

In that case, we would expect to find less pro-nounced but qualitatively similar neurobiologicalfindings in BD II. However, BD II cannot beunderstood simply as a milder form of BD I,because there are other clinical differences betweenthese syndromes. BD II is a more chronic conditioncharacterized by more frequent depressive episodeswith shorter euthymic periods than BD I (1216).The clinical profile of BD II is spectrally related tounipolar depression, because BD II is characterizedby recurrent depressions and relatively mild epi-sodes with elation in mood. Moreover, familystudies also suggest that BD II is the most common

diagnosis among the relatives of patients with BDII (13, 1719).

To date, most cognitive studies have focused onBD I, and in some of these studies, patients withBD II have been included together with patientswith BD I. However, a number of recent studieshave compared the cognitive profiles of BD I andBD II. The findings from these studies have beenlargely contradictory; some found better cognitiveabilities in BD II (20, 21), while others foundgreater impairment in BD II (22, 23). Thesecontradictory findings might be related to small

samples sizes and differences in the clinical char-acteristics of cohorts. Clinical state is particularlyimportant, because unlike the studies in stablepatients, studies in depressive episodes reportedmore severe cognitive impairment in BD II. Meta-analytical methods offer the means to help over-come these limitations.

Aims of the study

Our primary aim was to compare the neurocogni-tive profiles of clinically stable bipolar I disorder

and bipolar II disorder (BD II) using meta-analyt-ical methods. We also systematically reviewedstudies comparing the cognitive abilities of clini-cally stable individuals with BD II with healthycontrols.

Material and methods

Study selection

Potential articles were identified through a litera-ture search using Pubmed, Scopus, and Psychinfoduring the period between 1987 and July 2009. Forthe literature search, combinations of the followingkeywords were used: bipolar disorder, manic-depress*, mania, cognit*, neuropsycholog*. Thereference lists of the published articles were alsocross-referenced and reviewed.

The following criteria were used to select studiesfor review: i) articles assessed the cognitive abilitiesof patients with BD II using reliable neuropsycho-logical testing methods and were published inEnglish peer-reviewed journals; ii) included BD Ior healthy subjects as controls; iii) reported testscores (mean and SD) of both groups or effect sizesof group comparisons, and iv) patients are clini-cally stable (sample is entirely in remission orincludes stable patients with minimal symptoms).While our initial literature search revealed over1000 articles, there were only 19 studies (2038)that met the first three inclusion criteria (Table 1),and five of these studies were excluded because

assessment was conducted in depressive phase (22,23, 25, 36, 37) (criterion 4). Furthermore, anothertwo of these studies were not used in the meta-analytic calculations because they were based onoverlapping samples with other studies (35, 38)leaving 12 studies in the current meta-analysis.

In addition to cognitive data, we recordedinformation concerning the sample characteristicsand potential moderator variables. The clinicalvariables included depression and mania scales,history of psychosis, percentage of antipsychoticuse, age of onset, and duration of illness. We also

coded studies into two groups depending onwhether they used strict criteria for euthymia todefine clinical stability. Demographic variablesincluded mean and SD of age and years ofeducation for both groups. Gender was coded aspercentage of males. These variables are used in themeta-regression and subgroup analyses describedlater.

Similar to other meta-analyses in BD, wecombined data across very similar tests in someinstances. For example, we combined differenttasks of list learning such as the Rey Auditory

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Table1.

CharacteristicsofstudiesthatcomparecognitiveabilitiesofBDIIwithBDIandorhealth

ycontrols

Sample

Clinicalfeatures

Historyofpsychosis

Antipsychotics

Cogn

itivemeasures

Studiesincludedin

meta-analyses

Glahnetal.(24)

21BDI

10BDII

17HC

Pediatricsample

Clinicallystableout-patientslivingwithpa

rents

Mixtureofpatientsinremissionandpatie

ntswith

depressiveandmanicsymptoms

Noinformation

57%

BDI

10%

BDIIareon

atypicals

CVLT,

PM

Torrentetal.(20)

38BDI

33BDII

35HC

Euthymic

81%

BDI

18%

BDIIpsychosis+

50%

BDI

27%

BDIIareon

atypicals

WCST,Stroop,

TMT-A

,TMT-B,

Digitsforward,

digits

backward,semantic

fluency,phoneticfluency,

CVLT

Anderssonetal.(26)

25BDII

28HC


ntswith

mildtomoderatedepressivesymptoms

Noinformation

8%

BDIIareonatypicals

PASAT,Stroop,symb

olcoding,

CVLT,

Reycomplex

figurerecall,phone

ticfluency

Dittmannetal.(27)

65BDI

38BDII

62HC

Euthymic

72%

BDI

26%

BDIIpsychosis+

51%

BDI

24%

BDIIareon

atypicals

TMT-A,symbolcodin

g,

digitsforward,

figurerecall,

storyrecall,

listrecall,

LNS,

TMT,semanticfluency

Savitzetal.(29)

49BDI

19BDII

44UD

Euthymic

Noinformation

N

oinformation

Digitsforward,

digits

backward,

Stroop,phonetic

fluency,

RAVLT,

WCST,Reycomplexfigurerecall

Simonsenetal.(21)

42BDI

31BDII

124HC


ntswith


62%

BDI

32%

BDIIpsychosis+

81%

BDI

16%

BDIIareon

atypicals

WMSlogicalmemory,CVLT,

2-back,

digitsforward,

digitsbackward,Stroop,phoneticfluency,

semanticfluency

Derntletal.(30)

26BDI

36BDII

62HC

Euthymic

58%

BDI

28%

BDIIpsychosis+

58%

BDI

42%

BDIIareon

atypicals

PM,

facerecognition

memory

Haetal.(31)

22BDI

29BDII

29HC


ntswith


Noinformation

N

oinformation

CVLT,

WMSlogicalm

emory,

Reyfigurerecall,

CPT,

phoneticfluency,se

manticfluency,

WCST,TMT-B,

ToL

Hsiaoetal.(28)

30BDI

37BDII

22HC

Euthymic

73%

BDI

16%

BDIIpsychosis+

N

oinformation

TMT-A,

TMT-B,

digit

symbol,WMS-III:logical

memory,

VPA,

listrecognition,

faceandpicture

delayedrecall,spatialspan,

digitspan

Kungetal.(32)

22BDI

29BDII

20HC

Remission

Unclear

Unclear

Conners

CPT

Ancinetal.(33)

115BDI

28BDII

Euthymic

Unclear

Unclear

VisualCPT

Morieraetal.(34)

36BDI

24BDII

60HC

Euthymic

Unclear

Unclear

Reycomplexfigurer

ecall

Studiesexcludedfrom

meta-analyses

Martinez-Aranetal.(35)

108BD

30HCpost-hoc

analysis

forBDIvs.B

D

II

Manic,

depressedandeuthymicpatients

Unclearforsubgroups

Unclearforsubgroups

Post-hoc

analysisfor

CVLT

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Table1.

Continued

Sample

Clinicalfeatures

Historyofpsychosis

Antipsychotics

Cogn

itivemeasures

HarvakyFriedmanetal.(23)

32BDI

19BDII

58HC

Suicideattempters,allwereindepresse

depisode

Noinformation

N

oinformation

Symbolcoding,

TMT-

A,

TMT-B,

CPT,Stroop,

Nback,

Buschke,

BentonVR

T,phoneticfluency,

finger

tapping,

AnotBre

actiontimetask,reactiontime

tests,GoNogo,tim

eestimation

Summersetal.(22)

25BDI

11BDII

Comparedw

ith

Normatived

ata

MoredepressedpatientsinBDII(4565%)thanBD

I(2032%)

Noinformation

N

oinformation

Facerecognition,

PAL

,Reyfigurerecall,shapestest,

TMT-B,

SWM,

Nod

ataforothertestsinthestudy

TaylorTavaresetal.(25)

17BDII

22UD

25HC

Depression

Noinformation

U

nmedicated

CANTABtests:PRM,

SRM,spatialspan,

SWM,

DMTS,

IDED

Holmesetal.(36)

65BD(5265BD

II)

52HC

Depressed

Noinformation

3

2unmedicated0%

anti-

p

sychotics

CANTABtests:PRM,

SWM,

RVIP

Roiseretal.(37)

49BD(3849BD

II)

55HC

Depressed

2%

historyofpsychosisin

mania,

fordepressionno

information

U

nmedicated

CANTABtests:PRM,

SRM,spatialspan,

SWM,

DMTS,

IDED,

RVIP,

reversalLearning

Simonsenetal.(38)

80BDI

61BDII

280HC

Mixtureofpatientsinremissionandpatientswith


80%

BDI

30%

BDIIpsychosis+

U

nclearforsubgroups

WMSlogicalmemory,CVLT,

2-back,

digitsforward,

digitsbackward,Stroop,phoneticfluency,

semanticfluency

CVLT,

Californiaverballearningtest;TMT,trailmakingtest;PAL,pairedassociateslearningtest;LN,

letternumbersequencingtest;PM,progressivematrices;ToL,towerofLondontest;PRM,patternrecognitionmemory;SRM,spatial

recognitionmemory;SWM,spatialworkingmemory;DMTS,

delayedmatchingtosample;VPA,verbalpairassociates;BDI,bipolarIdisorder;BDII,

bipo

larIIdisorder;UD,unipolardepression.

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Verbal Learning Test and the California VerbalLearning Test. In addition to meta-analysesfor individual tasks, we also combined indi-vidual tasks under six cognitive domains ofthe MATRICS (Measurement and TreatmentResearch to Improve Cognition in Schizophrenia)because there were not a sufficient number of

studies for some individual tasks (3940).Domain scores were calculated by averagingeffect sizes of individual tasks under each cate-gory. The cognitive tasks that were not part ofMATRICS were categorized on relevant domainbased on agreement between authors. We alsocalculated a summary measure, global cognition,by averaging the effect sizes from each cognitivedomain. This measure was only calculated forstudies that at least included two domains. Inaddition to MATRICS domains and summaryscore, we conducted meta-analyses for individual

tasks when there were three or more studies thatexamined these tasks. In Table 2, classification ofindividual cognitive tasks used in the reviewedstudies according to MATRICS domains isshown (4153).

Meta-analytical procedure

For each cognitive test, an effect size and standarderror was calculated. Effect sizes for each cognitivevariable from each study were calculated as themean difference between two groups divided by thepooled standard deviation (Cohens d). Effect sizes

were weighted using the inverse variance method.We used a random effects model. Homogeneity ofthe resulting mean weighted effect sizes was testedusing the Q-test. The Q-test is computed bysumming the squared deviations of each studyseffect estimate from the overall effect estimate,weighting the contribution of each study by itsinverse variance. Publication bias was assessed byEggers test. Meta-analyses were performed usingmix software (54). Effects of moderator variables on

observed between-group differences were analyzedby meta-regression analyses. Meta-regression anal-yses were conducted using spss 11.0 (SPSS Inc.,Chicago, IL, USA). These weighted generalizedleast squares regressions were performed using themacros written by David B. Wilson (http://mason.gmu.edu/~dwilsonb/ma.html). Meta-regres-

sion analyses with random effects modelling wereperformed using the restricted-information maxi-mum likelihood method with a significance level setat P < 0.05.

Results

BD I vs. BD II

Eleven studies that met our inclusion criteria inves-tigated cognitive differences between BD I and BDII. These studies included 444patientswith BD I and285 patients with BD II. The BD I and BD II groupswere well matched for age (d =

)0.01), duration of

education (d = )0.05), duration of illness(d = )0.03), and gender (RR = 1.04). Patientswith BD I tended to have a younger onset of illness;however, the between-group difference was notsignificant (d = 0.15, CI = )0.18 to 0.47.z = 0.89, P = 0.37). There were no significantbetween-group differences in depressive (d = 0.12,CI = )0.23 to 0.47, z = 0.69, P = 0.49, k = 8)and manic symptoms (d = )0.14, CI = )0.34 to0.05, z = 1.44, P = 0.15, k = 6). More patientswith BD I were using antipsychotics than patients

with BD II (RR = 1.80, CI = 1.362.39,Z = 4.05, P < 0.001, k = 5). Five studiesreported data regarding history of psychosis andfound more patients with a history of psychosis inBD I (RR = 3.33, CI = 2.384.67, Z = 6.99,P < 0.001, k = 5).

Global cognition

There was a small (d = 0.26) but significantdifference in global cognition between the BD Iand BD II groups: patients with BD II performed

better than patients with BD I (Table 3). Excludingthe only study with a pediatric sample (20) did notchange the observed findings (d = 0.27). Therewas no evidence of publication bias or heteroge-neous distribution of effect sizes.

Processing speed

There was a small but significant difference inprocessing speed, with BD II being better than BDI. The distribution of effect sizes was homoge-neous. Eggers test did not show evidence for

Table 2. NIMH-MATRICS cognitive domains

Cognitive domain Cognitive tests

Processing speed Phonetic fluency (41), semantic fluency (41),

TMT (42), Stroop (41), symbol coding (43)

Attention Continuos performance test (44)

Working memory Digit span (43), LNS (43), spatial span

(41), PASAT (45)

Reasoning and problem solving WCST (46), ToL (47), progressive matrices (48)

Verbal learning and memory WMS logical memory (49), CVLT (50), RAVLT (51)

Visual learning and memory Rey complex figure (52), shapes test (53), face

memory (41)

CVLT, California verbal l earning test; RAVLT, Rey auditory verbal learning test; TMT,

trail making test; PRM, pattern recognition memory; SRM, spatial recognition

memory; SWM, spatial working memory; DMTS, delayed matching to sample.

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publication bias. Individual analyses were con-ducted for TMT-A, TMT-B, phonetic fluency,semantic fluency, and the Stroop interference task.Patients with BD I performed significantly poorerthan patients with BD II only in semantic fluency(d = 0.31). There was no evidence for publicationbias or heterogeneity of effect size distributions forthe individual tests.

Attention

There was no significant difference in sustainedattention abilities of people with BD I or BD II.Individual task analyses for omission and commis-sion errors were not significantly different either.There was no evidence for significant heterogeneityor publication bias for any of sustained attentionmeasures.

Visual memory

Individuals with BD II performed significantlybetter than BD I (d = 0.38) on visual memory.The distribution of effect sizes for visual memorywas heterogeneous. Patients with BD II performedbetter on the complex figure recall task (d = 0.66).There was no evidence for publication bias for thevisual memory domain score and figure recall task.

Verbal memory

Patients with BD II performed significantly betterthan BD I in the verbal memory domain. The

between-group difference had a medium effectsize (d = 0.52). The distribution of effect sizesbecame homogenous (Fig. 1). Individual taskanalyses for list learning, recall, and recognitiontasks showed significantly worse performance forindividuals with BD I (d = 0.480.53). Distribu-tions of effect sizes were homogenous for indi-vidual tasks. There was no evidence forpublication bias for verbal memory domain and

any individual tasks.

Working memory

Working memory (WM) did not differentiatebetween BD I and BD II groups. Distribution ofeffect sizes was homogenous. Egger test was alsonon-significant, indicating that there was no evi-dence for publication bias. Individual task analysesfor digits backward and forward did not reveal anysignificant difference between BD I and BD II.

Planning and reasoning

There was no significant between-group differencein planning abilities. The distribution of effect sizeswas homogeneous, and there was no evidence forpublication bias. We were able to undertakeindividual task analysis for the WCST (persevera-tion and number of categories achieved scores),and these analyses similarly did not reveal anysignificant between-group differences. The distri-bution of effect sizes was homogeneous for theseindividual task analyses.

Table 3. Mean weighted effect sizes for cognitive differences between BD I and BD II

Test Study BD I BD II D 95% CI Z P Q-test P Bias

Global cognition 8 293 233 0.26 0.080.44 2.88 0.004 0.85 0.90

Processing speed 6 246 187 0.28 0.080.48 2.81 0.005 0.54 0.81

Phonetic fluency 4 151 112 0 )0.25 to 0.25 0.01 0.99 0.86 0.87

Stroop interference 3 129 83 0.26 )0.05 to 0.58 1.62 0.10 0.29 0.10

TMT-A 3 130 98 0.08 )0.18 to 0.34 0.59 0.56 0.99 0.50

TMT-B 4 152 131 0.25)

0.05 to 0.53 1.65 0.10 0.21 0.69Semantic fluency 4 167 131 0.31 0.080.55 2.59 0.01 0.94 0.43

Visual memory 6 218 183 0.38 0.080.68 2.45 0.01 0.05 0.12

Complex figure recall 3 107 72 0.66 0.340.97 4.07


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Moderator factor analyses

Meta-regression analyses were conducted for theclinical (duration of illness, age of onset, between-group differences in depression mania symptoms,relative ratio for patients with psychotic of psy-chosis, and antipsychotic use) and demographic(age, education, and sex) variables. These analysesdid not find any significant association betweenconfounder variables and the magnitude of cogni-tive differences between BD I and BD II.

BD II vs. controlsNine studies that compared the cognitive abilitiesof patients with BD II with healthy controls wereincluded into the meta-analysis. These studiescompared the cognitive performances of 263patients with BD II and 415 healthy controls. Inthese studies, there were no significant between-group differences in age, years of education, andgender composition.

We were unable to conduct a meta-analysis forattention because less than three studies examinedcontrol vs. BD II differences. Meta-analysis of the

other five cognitive domains (d = 0.290.55) andglobal cognition (d = 0.43) found significant cog-nitive deficits for all measures (Table 4). Excludingthe only study with a pediatric sample (20) did notchange the results (d = 0.45). According to meta-regression analyses, clinical and demographic vari-ables did not significantly influence the cognitivedeficits in BD II. The Q-test did not reveal anyheterogeneity for distribution of effect sizes for anyof these measures, nor was there any evidence forpublication bias. We were able to conduct individ-ual meta-analyses for processing speed (phonetic

fluency, semantic fluency, symbol coding, Stroopinterference, TMT-A, and TMT-B), verbalmemory (list learning, list recall, and list recogni-tion), visual memory (figure recall), and WM(digits forward) measures. In all individual taskanalyses for processing speed (d = 0.460.72) andvisual memory (d = 0.60), patients with BD IIperformed significantly worse than healthy con-trols. There was no evidence for publication bias orheterogeneous distribution of effect sizes for thesedomains. Individual task analyses for three mea-sures of verbal memory showed less pronounceddifferences between patients with BD II and

healthy controls (d = 0.220.39) and patientswith BD II were significantly more impaired thancontrol subjects only on tasks of list learning. Thedistribution of effect sizes was heterogeneous forlist recall.

Discussion

To our knowledge, this is the first meta-analyticstudy of cognition in BD II. In general, ourfindings suggest that BD II is associated withsimilar cognitive deficits as have been reported in

BD I. However, verbal memory, visual memory,and semantic categorization deficits seem to bemore specifically associated with BD I.

There could be several potential explanations fora relatively specific impairment of memory in BD I.First, diagnosis-associated secondary features likepsychosis, age of illness onset, and treatment ratherthan diagnoses itself might explain the between-group difference in this cognitive domain, becausethese factors are associated with more cognitivedeficits in BD (6, 5562). However, cognitivedifferences between the BD I and BD II were

Fig. 1. Forest plot for showing verbal memory differences between BD I and BD II.

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more selective for memory, and the only study thatcontrolled for the effect of a history of psychosis stillfound more impaired verbal memory functioning inBD I (21). Our meta-regression analyses did notfind any relationship between the relative ratio ofhistory of psychosis, age of onset, antipsychotic use,and cognition in BD I and BD II. However, thesemeta-regression analyses are limited because only asmall number of studies reported these variables.Additional studies examining the effect of theseconfounding factors on cognitive deficits in BD I

and BD II are necessary for further clarifying theseissues. Also, potential effect of other medicationslike lithium, antiepileptics, and antidepressantsshould also be further examined.

Second, more pronounced memory deficits inBD I could be related to differences in the course ofBD II and BD I. BD I is characterized by moresevere manic mood episodes, and previous studieshave found a relationship between the number ofmanic episodes and verbal memory impairment(61, 62). There is a suggestion that mania is moreneurotoxic than depression and associated with a

more accelerated process of neuroprogression (63).Recurrent and severe manic episodes might there-fore be associated with progressive deficits inmedial temporal regions, and this could lead tomemory deficits specific to BD I. However, it isalso possible that there might be verbal memorydifferences from the onset of the illness. However,the available evidence is too limited to concludedefinitively whether pronounced verbal memorydeficits in BD I are a result of neurodevelopmentalor neurodegenerative differences between BD I andBD II.

Outside of memory, a semantic fluency deficitwas the only other cognitive measure that differedbetween BD I and BD II, with worse performancein the former group. This difference is unlikely tobe related to slower processing speed in BD I,because there were no group differences in phoneticfluency. While processing speed is an importantfactor in semantic fluency performance, otherfactors like semantic knowledge and organizationalso contribute to semantic fluency performance.Because temporal lobe, including medial temporal

lobe, function is important for semantic fluency(64, 65), there might be a common pathophysiol-ogy for verbal memory and semantic fluencydeficits in BD I.

Our findings suggest that executive functions,attention, and WM might be potential endophe-notypes for both BD I and BD II. These deficitsmight be associated with structural abnormalitieslike anterior cingulate cortex (ACC) volume reduc-tion, which is a consistent finding in BD (66). Ourresults also suggest that memory deficits associatedwith medial temporal lobe abnormalities might be

a potentially specific endophenotype for BD I.These findings are consistent with a recent studysuggesting that ventromedial frontal and anteriorlimbic gray matter abnormalities are sharedbetween BD I and BD II, and there are additionalgray matter abnormalities in other regions of brainincluding temporal and parahippocampal corticesin BD I (67).

In conclusion, our findings revealed a differentprofile for certain cognitive deficits between BD Iand BD II, suggesting that there might be someneurobiological differences that underpin these

Table 4. Mean weighted effect sizes for cognitive differences between controls and BD II

Test Study HC BD II D 95% CI Z P Q-test P Bias

Global cognition 8 379 239 0.43 0.250.60 4.87


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subtypes of BD. More work is needed tounderstand the relationship between cognitivedeficits and depressive symptoms in BD II.Brain imaging studies might be relevant tofurther demonstrate neurobiological similaritiesand differences between BD I and BD II. Studiesin relatives of patients with BD II and follow-up

studies are also important to ascertain whethercognitive dysfunction is a trait characteristic ofBD II.

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