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Original Article

Neuropsychological decits and functional

impairment in bipolar depression, hypomaniaand euthymia

Malhi GS, Ivanovski B, Hadzi-Pavlovic D, Mitchell PB, Vieta E,Sachdev P. Neuropsychological decits and functional impairment inbipolar depression, hypomania and euthymia.Bipolar Disord 2007: 9: 114–125. ª Blackwell Munksgaard, 2007

Objective: To examine whether patients with bipolar disorder (BD)have subtle neuropsychological decits that manifest clinically ascognitive and functional compromise, and this study attempted todetermine the pattern of such cognitive decits and their functionalimpact across all three phases of BD. We hypothesised that euthymiadoes not equate with normal neuropsychological function and that eachphase has a characteristic pattern of decits, with disturbance inattention and memory being common across all phases of the illness: (i)bipolar depression – psychomotor slowing and impairment of memory;(ii) hypomania by frontal-executive decits and (iii) euthymia – a milddisturbance of attention, memory and executive function.

Methods: Twenty-ve patients with a diagnosis of bipolar I disorderunderwent neuropsychological testing over a period of 30 months in thenatural course of their illness while hypomanic and/or depressed and/oreuthymic. The results from these assessments were compared withndings from neuropsychological tests conducted on 25 healthy controlsmatched for age, sex, education and handedness.

Results: Initial analyses revealed modest impairment in executivefunctioning, memory and attention in both hypomanic and depressedbipolar patients, with additional ne motor skills impairment in thelatter. Memory decits, also noted in euthymic patients, were non-signicant after controlling for confounding variables, although bipolardepressed patients remained signicantly impaired on tests of verbalrecall. Bipolar depressed and hypomanic patients differed with respect tothe nature of their memory impairment. Depressed patients were moreimpaired as compared with euthymic patients on tests of verbal recalland ne motor skills. Psychosocial functioning was impaired across allthree patient groups, but only in depressed and hypomanic patients didthis correlate signicantly with neuropsychological performance.

Conclusions: The mood-state-related cognitive decits in both bipolardepression and hypomania compromise psychosocial function whenpatients are unwell. In euthymic patients, subtle impairments in attentionand memory suggest that an absence of symptoms does not necessarilyequate to recovery . The possibility of persistent cognitive decits in BDis an issue of profound clinical and research interest that warrants furtherinvestigation; however, future research needs to adopt moresophisticated neuropsychological probes that are able to better denestate and trait decits and determine their functional impact.

Gin S Malhi a,b,c , BelindaIvanovski b,d , Dusan Hadzi-Pavlovic b,d Philip B Mitchell b,d ,Eduard Vieta e and PerminderSachdev d,f

aNorthern Clinical School, University of Sydney,bMood Disorders Unit, Black Dog Institute, Prince

of Wales Hospital, c Mayne Clinical ResearchImaging Centre, Prince of Wales Medical ResearchInstitute, d School of Psychiatry, University of NewSouth Wales, Sydney, Australia, e Bipolar DisordersProgram, Hospital Clinic, University of Barcelona,IDIBAPS, Stanley Research Medical Centre,Barcelona, Spain, fNeuropsychiatric Institute,Prince of Wales Hospital, Sydney, Australia

Key words: bipolar disorder – depression –euthymia – mania – neuropsychology

Received 17 January 2005, revised and acceptedfor publication 2 February 2006

Corresponding author: Gins S Malhi, AcademicDiscipline of Psychological Medicine, NorthernClinical School, University of Sydney, Sydney,NSW, Australiae-mail: [email protected]

The authors of this paper do not have any commercial or other conict of interest with respect to this article.

Bipolar Disorders 2007: 9: 114–125Copyright ª Blackwell Munksgaard 2007

BIPOLAR DISORDERS

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Until recently, bipolar disorder (BD) has beenregarded as an episodic illness with the assump-tion that between episodes of depression andmania, patients resume normality of mood andmake a complete functional recovery. Conse-quently, periods of illness and accompanyingimpairments have been generally viewed as wholly

reversible. However, it is increasingly apparent thatthis view is somewhat inaccurate and that euthymicpatients, although clinically in remission , continueto experience functional compromise (1–4). Theprecise nature and extent of this impairment is asyet unclear and investigations including neuroim-aging studies that have attempted in vivo to identifyits biological underpinnings have been less inform-ative than initially hoped. Structural and func-tional state and even trait (5) abnormalities havebeen reported, but a robust and reliable marker of the illness is yet to emerge. Therefore, the bur-geoning neuropsychological literature in BD is of particular interest, as it implicates subtle neuro-cognitive decits across each phase of the illness (6,7) such that even euthymia is neuropsychologicallyscarred (1, 6–10).

The cognitive decits in BD involve attention,mental exibility, decision making, verbal uencyand memory with some overlap between the twopoles (11, 12). The reported pattern of cognitiveimpairment in bipolar depression also overlapswith that in major depression especially withrespect to memory and executive functioning (13),and the decits observed in acute mania are shared

across a number of psychoses (14, 15). Of partic-ular interest, however, is the provocative sugges-tion that euthymic patients may also have subtlecognitive decits (16–18) irrespective of subsyn-dromal symptoms (19, 20).

The possibility of persistent neuropsychologicaldecits in BD is of profound importance bothbecause of its potential as a marker for the illnessand because of prognostic ramications forpatients. A number of recent studies have exam-ined bipolar patients during an episode and wheneuthymic, and compared them with healthy

controls. Thus far the ndings are inconclusiveprincipally because too few studies have beenconducted (21) for the many methodologicalissues to be addressed. Many of these investiga-tions have also been limited by cross-sectionaldesign, small sample sizes and the inclusion of patients with mixed diagnoses (for example,bipolar I and II). Confounds of medication andsubstance misuse are also difficult to eliminate(22). Clinically, psychosocial functioning is asophisticated construct that encompasses interac-tions and activities in personal, occupational and

recreational contexts. It is therefore not sur-prising that few studies have specically exam-ined functionality and its neuropsychologicalconcomitants.

In this study, we have attempted to characterisethe cognitive prole of BD and examine itscontribution to functional impairment by conduct-

ing clinical and neuropsychological assessmentsacross all three phases of the illness. We hypoth-esised that bipolar patients would have greaterfunctional impairment than controls in all phasesof the illness and that this would be associated withcognitive decits involving in particular attention,memory and executive function. Specically, bipo-lar depression would be associated with psycho-motor slowing and impairment of memory;hypomania would be associated with frontal-exec-utive decits; and euthymia would not equate to anormal neuropsychological prole by virtue of amild disturbance of attention, memory and exec-utive function.

Materials and methods

Subjects

Seventeen female and eight male patients aged19–59 years (mean 38.6 ± 11.0 years) with DSM-IV bipolar I disorder were recruited from ourSydney BD clinic, providing a second opinion forpatients currently receiving treatment. Researchpsychiatrists (GM, PM), using the Structured

Clinical Interview for DSM-IV (SCID-P) (23)supplemented by a case note review, made thediagnoses. Subjects were excluded if they had ahistory of ongoing substance misuse, neurologicaldisease or closed head injury or had an additionalAxis-I or Axis-II DSM-IV diagnosis or a medicaldisorder currently necessitating treatment.

Of the 25 bipolar patients assessed, 14 wereassessed during the depressive phase of their illness,15 when euthymic and 12 when hypomanic. Of the25 patients, 13 were assessed in one phase only(7 in euthymia, 4 in depression and 2 in hypoma-

nia). Of the remaining 12 patients, 4 were assessedin all three phases and 8 in two phases of BD (4 inhypomania and depression, 2 in hypomania andeuthymia and 2 in depression and euthymia).Patients were not assessed in the same phase of their illness more than once and several depressedor hypomanic patients were unable to undergomore than one assessment because of changes totheir medication, hospitalization or non-responseto treatment. It is important to note that thisnecessitates analysis of groups that clearly involveoverlap of subjects.

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Patients were compared with healthy volunteersrecruited via advertisement and matched for age(21–59 years; mean 34.0 ± 13.0 years), handed-ness (all right handed) and education (11–19 years;mean 14.8 ± 2.1 years). Comparison subjects werescreened for a history of neurological or psychi-atric disorder (with SCID-non-patient version) or

for a family history of the same. They wereadministered the same clinical and neuropsycho-logical assessments and self-report questionnairesas patients.

The Prince of Wales Hospital and University of New South Wales ethics committees approved thestudy and all participants provided writteninformed consent.

Clinical and neuropsychological assessment

Patients were instructed to monitor their symptomsand notify researchers of any signicant moodchange. The majority was able to reliably anticipatetheir episodes of illness. In addition, researchersmaintained telephone contact with patients andmonitored their mental state throughout the dura-tion of the 30-month study. Assessment involved astructured clinical interviewconductedby a researchpsychiatrist (GM) and a series of neuropsycholog-ical tests conducted by a research psychologist (BI).

Clinical assessment. Illness severity was assessedusing the 21-item Hamilton Depression RatingScale (HAMD) (24), the Montgomery-Asberg

Depression Rating Scale (MADRS) (25), theCORE measure for psychomotor disturbance (26)and, if currently manic or hypomanic, the Young

Mania Rating Scale (YMRS) (27). Patients werecharacterised as euthymic if they had been inremission for at least 1 month and scored £ 9 onthe HAMD and 16 on the HAMD; and hypomanic if they had a score of >10 on the YMRS.Psychosocial functioning was assessed using the

Global Assessment of Functioning (GAF) (28)rating the month prior to assessment. Patients alsocompleted the following questionnaires: the BeckDepression Inventory (BDI) (29), the SpielbergerState-Trait-Anxiety Inventory (30), the EysenckPersonality Inventory (EPI) (31) and the AnnettHandedness Inventory (32) (the latter two wereonly administered on the rst assessment).

Neuropsychological assessment. All subjects wereadministered a battery of neuropsychological teststailored to assess attention, working memory,learning and memory, executive functioning andpsychomotor speed. To minimise practice effects,repeat assessments used alternate forms of DigitSpan Backwards, Trail Making Test (TMT), Con-trolled Oral Word Association Test (COWAT),Rey Auditory Verbal Learning Test (RAVLT) andSymbol Digit Modalities Test (SDMT). A sum-mary of these tests is provided in Table 1.

Statistical analyses

Two-tailed paired t tests were conducted to gainmaximal advantage of high subject correlation.

Dependent variables were grouped into

cognitivedomains (executive functioning, memory, atten-tion and psychomotor abilities) and variables that

Table 1. Neuropsychological test battery

Description Dependent variables

Estimated premorbid IQNational Adult Reading Test (NART; 46) This measure estimates premorbid

intelligence using a list of words,arranged in order of difculty.Pronunciation and knowledge of wordsis a reliable measure of both verbal andgeneral mental abilities (44, 45).

1. Estimated WAIS-III (39) Full Scale IQscore, derived from NART score.

Frontal executive functionsWisconsin Card Sorting Test (WCST; 43) This computerized version assesses

concept formation and cognitiveexibility by measuring the ability toestablish, maintain and change set.

1. Total number of categoriescompleted.

2. Trials to complete rst category.3. Failure to maintain set.4. Percentage perseverative errors.

Stockings of Cambridge (SOC; 41) This test, a component of the CambridgeNeuropsychological Test AutomatedBattery (CANTAB), is a modiedversion of the Tower of London task andassesses spatial planning and motorcontrol.

1. Average number of moves taken tosolve four move problems.

2. Average number of moves taken tosolve ve move problems.

3. Total number of problems solved inminimum moves.

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were highly correlated with each other, and allother variables within each domain were identiedand removed as they appeared to measure similarconstructs and were thus deemed redundant. This

procedure was performed to reduce the totalnumber of variables within each domain and henceenhance statistical power. Potential confoundssuch as residual affective symptoms, anxiety and

Table 1. Continued

Description Dependent variables

Trail Making Test (TMT; 44): Part B This test in two parts measures attention,psychomotor speed and the ability toshift strategy. Part B assesses setswitching and visuospatial workingmemory.

1. Time taken to complete Part B.

Controlled Oral Word Association Test(COWAT; 40)

This test which requires the strategygeneration assesses verbal uency andis a sensitive measure of phonemicuency.

1. Total number of words generated.2. Total number of rule violations.3. Total number of repetition errors.

Animal Naming Test (47) A test of category verbal uency. 1. Total number of words generated.2. Total number of rule violations.3. Total number of repetition errors.

Attention, concentration and mental trackingStroop Colour-Word Interference Test

(SCWT; 42)This assesses mainly selective attention

and response inhibition. In particular,Part 3 of the test generates interferenceand measures the ability to changedemands and suppress a habitualresponse in favour of an unusual one.

1. Age-adjusted scores of the number ofitems read on the word-only trial.

2. Age-adjusted scores of the number ofitems read on the colour-only trial.

3. Age-adjusted scores of the number ofitems read on the word/colour trial.

4. Interference score.

Trail Making Test (TMT; 44): Part A This test in two parts measures attention,psychomotor speed and the ability toshift strategy. Part A assesses focusedattention.

1. Time taken to complete Part A.

Digit span from the Wechsler AdultIntelligence Test – Third edition (WAIS-III; 39)

This test assesses auditory attention andshort-term retention capacity and theability to manipulate information inverbal working memory.

1. Longest digit span backwards.

Symbol Digit Modalities Test (SDMT; 36) This test requires mental and motorspeed and mental exibility. It also tapsconcentration and visual perceptionand scanning.

1. Total number correct.

Verbal learning and memoryRey Auditory Verbal Learning Test

(RAVLT; 35, 37)The RAVLT assesses immediate and

delayed-memory span, new learningand susceptibility to interference andrecognition memory.

1. Recognition score.2. Learning slope.3. Total number of words recalled.4. Interference.5. Retroactive interference.6. Delayed recall.

Psychomotor functionReaction Time (RT) (41) This assesses simple reaction time,

which involves stimulus detection andresponse execution.

1. Mean reaction time.2. Mean movement time.

Purdue Pegboard (34) This test assesses nger and handdexterity.

1. Total number of pegs placedcorrectly, dominant hand.

2. Total number of pegs placedcorrectly, non-dominant hand.

3. Total number of pegs placedcorrectly, both hands.

Grooved Pegboard (33, 38) This test is also a measure ofmanipulative dexterity; however, thetask requires more sophisticatedmanipulation than that needed in thePurdue pegboard task and hencerequires more complex visuomotorcoordination.

1. Time taken to complete usingdominant hand.

2. Time taken to complete using non-dominant hand.


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neuroticism controlled for by between-group andwithin-patient analyses of covariance (ANCOVA)were severely limited by small sample size. As aconsequence of the latter (small n), p values havebeen reported for all comparisons and criticalvalues were not adjusted for multiple comparisons.Correlations between GAF and neuropsychologi-

cal test scores were also performed.

Results

Sample characteristics

Demographics of patients and controls are sum-marised in Table 2. The mean age of onset of depression was 24 ± 8.4 years and for mania25.2 ± 8.6 years. The mean duration of illnessfrom diagnosis was 15.2 ± 10.8 years and themean number of previous depressive episodes was11.5 ± 8.2 and manic episodes 8.2 ± 7.2. Of the25 patients, 11 fullled DSM-IV criteria for rapidcycling BD.

At the time of clinical assessment and neuropsy-chological testing, 21 patients were on moodstabilizing psychotropic medications only, withdosages unaltered over the preceding week. Twelvepatients were taking lithium (mean daily dose975.1 ± 213.2 mg) with a mean plasma level of 0.77 ± 0.1 mmol/L. Four of these patients andseven others were taking valproate (mean dailydose 1436.0 ± 590.4 mg), with a mean plasmalevel of 512.5 ± 89.2 l mol/L. Two patients

were taking carbamazepine (mean daily dose850 ± 636.4 mg), with a mean plasma level of 30.0 ± 14.1 l g/mL, one in combination withvalproate. The remaining ve patients were un-medicated. Importantly, they had been free of neuroleptic or antidepressant medication for2 weeks. Sixteen patients had at least one rst-degree relative with an affective disorder (5 BD, 10unipolar depression and 1 both). One patient had a

family history of schizophrenia and seven patientshad no family history of psychiatric illnesses. Eightpatients had a past history of regular substancemisuse including alcohol, amphetamines andcannabis.

Clinical assessments

Results from clinical and self-report measures aresummarised in Table 3. Predictably bipolarpatients and control subjects differed signicantlyon clinical scale scores. However, of particular noteis the signicant difference between scores on theHAMD ( t14 ¼ 3.57, p ¼ 0.003), MADRS ( t 14 ¼4.93, p ¼ 0.000) and BDI ( t13 ¼ 2.82, p ¼ 0.01),between euthymic bipolar patients (means 3.47,4.33, 8.21, respectively) and between healthycomparison subjects (means 1.43, 1.22, 3.22,respectively), indicating residual depressive symp-tomatology in patients. Relative to controls, hypo-manic patients also scored higher on the measuresof depression (HAMD: t11 ¼ 3.5, p ¼ 0.01;MADRS: t11 ¼ 2.79, p ¼ 0.02; BDI: t10 ¼ 2.51,p ¼ 0.03), suggestive perhaps of mild mixed moodstates in some patients. Depressed patients scoredsignicantly higher on the CORE, reecting greaterpsychomotor retardation than matched controls(t12 ¼ 8.74, p ¼ 0.00); however, euthymic andhypomanic patients did not differ signicantlyfrom controls on this measure, although thedifference for the hypomanic patients did approachsignicance ( t 10 ¼ 2.14, p ¼ 0.06). In addition, of

note are the signicantly greater state and traitanxiety levels in the depressed and euthymicpatients (depressed: t8 ¼ 3.67 and p ¼ 0.01, t9 ¼4.06 and p ¼ 0.00; euthymic: t13 ¼ 2.79 and p ¼0.02, t13 ¼ 5.42 p ¼ 0.00) but not in the hypoman-ic patients as compared with controls. Finally,patients scored higher on the Neuroticism scaleof the EPI than controls, irrespective of moodstate (euthymic: t13 ¼ 7.21, p ¼ 0.00; depressed:

Table 2. Demographic variables for bipolar and control groups

Variable Bipolar group, mean (SD) Control group, mean (SD)

Age 38.6 (11.0) 34.0 (13.0)Education (years) 14.7 (2.9) 14.8 (2.1)IQ score (derived from NART score) 113.8 (7.14) 115.4 (9.52)Age of onset of depression 24 (8.4) –Age of onset of mania 25.2 (8.6) –Duration of illness from diagnosis (years) 15.2 (10.8) –Number of depressive episodes 11.5 (8.2) –Number of manic episodes 8.2 (7.2) –

Mean scores are drawn from the t -test analyses and hence may not include all subjects within each group because of missing data.Mean scores for the control group are not drawn from the t -test analyses (as the n varies in each analysis) and hence reect total meanscores for this group (n ¼ 25). NART ¼ National Adult Reading Test.

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t9 ¼ 3.49, p ¼ 0.01; hypomanic: t10 ¼ 2.40, p ¼0.04), reecting personality differences between thegroups although patients did not formally meet thecriteria for personality disorders. However, it isimportant to note that confounds of medicationand subsyndromal symptoms, in all three patientgroups, may also have inuenced personalityassessment.

Global Assessment of Functioning scores forall three groups of patients (depressed52.5 ± 7.31; hypomanic 66.71 ± 13.34; euthymic

86.13 ± 6.96) were lower in comparison tocontrols (92.26 ± 2.92), and compared witheuthymic patients, scores for both depressed(t17 ¼ 11.39, p ¼ 0.00) and hypomanic ( t15 ¼0.04, p ¼ 0.00) patients were signicantly lower.Furthermore, GAF scores of depressed patientswere signicantly lower than the scores of hypo-manic patients ( t 14 ¼ 2.86, p ¼ 0.01). Signicantcorrelations between GAF scores and neuropsy-chological test performance are summarised inTable 4.

In bipolar depressed patients poor psychosocialfunction was associated with poor performance onthe Stroop word-reading task and slower reactiontimes, whereas in hypomanic patients poor psy-chosocial function was associated with poor work-ing memory and poor new learning. In euthymicpatients, there were no signicant correlationsbetween GAF scores and neuropsychological testperformance, but when the GAF scores for allbipolar patients were pooled together, poor psy-chosocial and executive function were signicantly

correlated on the Wisconsin Card Sorting Test,such that patients with lower GAF scores found itmore difficult to maintain set. However, inferenceof causality from such correlations is limited,especially as many neuropsychological tests scoresare highly correlated.

Neuropsychological assessments

Statistically signicant results from patient versuscontrol and within-patient group comparisons are

Table 3. Clinical variables for bipolar and control groups

Depressed (D)Mean (SD)

Euthymic (E)Mean (SD)

Hypomanic (H)Mean (SD)

Control (C)Mean* (SD)

Hamilton Depression Rating Scale (HAMD) 23.08 (4.25) 3.47 (2.29) a 5.5 (2.88) b 1.43 (1.95)Montgomery-Asberg Depression Rating Scale 28.25 (4.81) 4.33 (2.44) c 4.25 (2.49) d 1.22 (1.98)Beck Depression Inventory (BDI) 27.33 (14.99) 8.21 (5.81) e 8.18 (4.92) f 3.22 (2.70)Young Mania Rating Scale (YMRS) – – 20.67 (3.52) –

CORE 7.85 (3.24) g 0.13 (0.52) 1.09 (1.45) 0.04 (0.2)Global Assessment of Functioning (GAF) 52.5 (7.31) h,i 86.13 (6.96) 66.71 (13.34) j 92.26 (2.92)State-Trait Anxiety Inventory (State) 53.11 (15.80) k 36.43 (7.06) l 41.55 (14.34) 29.13 (8.17)State-Trait Anxiety Inventory (Trait) 57.2 (15.22) m 44.5 (8.78) n 41.55 (15.63) 31.52 (6.43)Extrovert Scale (EPI) 9.7 (4.72) 11.29 (4.83) 11.91 (8.24) 12.65 (3.6)Neuroticism Scale (EPI) 17.8 (4.211) o 12.86 (3.94) p 14.82 (5.71) q 6.30 (5.03)Lie Scale (EPI) 3.9 (0.88) 3.64 (1.55) 3.82 (2.27) 3.65 (1.72)

*Mean scores for the control group are not drawn from the t -test analyses (as the n varies in each analysis) and hence reect total meanscores for this group (n ¼ 25). EPI ¼ Eysenck Personality Inventory.a E versus C: t 14 ¼ 3.57, p ¼ 0.003; b H versus C: t 11 ¼ 3.5, p ¼ 0.01; c E versus C: t 14 ¼ 4.93, p ¼ 0.000; d H versus C: t 11 ¼ 2.79, p ¼0.02; eE versus C: t 13 ¼ 2.82, p ¼ 0.01; fH versus C: t 10 ¼ 2.51, p ¼ 0.030; g D versus C: t 12 ¼ 8.74, p ¼ 0.00; hD versus E: t 17 ¼11.39, p ¼ 0.00; iD versus H: t 14 ¼ 2.86, p ¼ 0.01; jH versus E: t 15 ¼ 0.04, p ¼ 0.00; kD versus C: t 8 ¼ 3.67, p ¼ 0.01; lE versus C:t 13 ¼ 2.79, p ¼ 0.02; m D versus C: t 9 ¼ 4.06, p ¼ 0.00; nE versus C: t 13 ¼ 5.42, p ¼ 0.00; o D versus C: t 9 ¼ 3.49, p ¼ 0.01; p E versus C:t 13 ¼ 7.31, p ¼ 0.00; q H versus C: t 10 ¼ 2.40, p ¼ 0.04.

Table 4. Signicant correlations between Global Assessment of Functioning (GAF) scores and neuropsychological tests in patients

Neuropsychologicalmeasures

Depressed groupGAF scores (N ¼ 10)

Euthymic groupGAF scores (N ¼ 10)

Hypomanic groupGAF scores (N ¼ 8)

Bipolar group (mixed states)GAF scores (N ¼ 28)

Stroop Task a 0.74 (p ¼ 0.015) – – –Reaction Time ) 0.72 (p ¼ 0.019) – – –Digit Span backwards – – 0.77 (N ¼ 8; p ¼ 0.027) –Trail Making Test, Part B – – ) 0.80 (N ¼ 7; p ¼ 0.033) –RAVLT–learning – – 0.81 (N ¼ 8; p ¼ 0.016) –WCST b – – – ) 0.42 (N ¼ 25; p ¼ 0.037)

RAVLT ¼ Rey Auditory Verbal Learning Test; WCST ¼ Wisconsin Card Sorting Test.a Word-only task.b Failure to maintain set.


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summarised in Tables 5 and 6, respectively. Incomparison to controls, the majority of differencesoccurred in depressed patients who were found tobe signicantly impaired across all cognitivedomains. They were limited in their ability togenerate phonemic words on the COWAT thatassessed verbal uency ( t12 ¼ 2.26, p ¼ 0.04); hadimpaired recall ( t12 ¼ 2.37, p ¼ 0.04) and recogni-tion ( t12 ¼ 2.63, p ¼ 0.02) memory on theRAVLT; had diminished attention by virtue of completing and reading fewer items on the SDMT

(t12 ¼ 2.90, p ¼ 0.01) and Stroop Word and Col-our Tasks ( t 12 ¼ 2.75, p ¼ 0.02; t12 ¼ 2.33, p ¼0.04) and were slower on motor tasks as assessedby the Purdue (non-dominant hand, t12 ¼ 3.37,p ¼ 0.01) and Grooved (dominant hand, t12 ¼2.39, p ¼ 0.03) pegboards.

Like depressed patients, hypomanic patientswere impaired on both recognition ( t11 ¼ 3.58,p ¼ 0.004) and recall ( t11 ¼ 4.84, p ¼ 0.001) com-ponents of the RAVLT, while euthymic patientswere only impaired on immediate recall ( t14 ¼ 2.11,p ¼ 0.05). Compared with controls, hypomanic

patients performed less well when generatingsemantic words in the COWAT and were slower(t11 ¼ 2.40, p ¼ 0.04) in performing Trails A of theTMT.

Within-patient group comparisons of partici-pants tested in more than one mood state revealedthat recall memory assessed using the RAVLT wasmore impaired in depression than in euthymia(t4 ¼ 3.64, p ¼ 0.02). Compared with hypomanicpatients, on this test depressed patients had greaterretroactive interference ( t 6 ¼ 5.46, p ¼ 0.002)although hypomanic patients had poorer

long-term memory recall/retention ( t6 ¼ 3.38,p ¼ 0.015). However, as compared with euthymicpatients, both depressed ( t4 ¼ 3.21, p ¼ 0.03) andhypomanic ( t5 ¼ 2.81, p ¼ 0.04) patients wereslower.

Within-patient and between-group ANCOVAsthat controlled potential confounds such asanxiety, neuroticism and residual affective symp-toms were constrained by small sample sizes andthe majority of signicant differences were lost.In depressed patients, only one memory decit

that was no longer signicant in euthymic andhypomanic patients remained signicant:depressed subjects ( t5 ¼ 2.75, p ¼ 0.04) recalledfewer words in total than control subjects. Inhypomanic patients relative to controls, nodifferences remained signicant, although differ-ences in recall ability ( t 7 ¼ 1.88, p ¼ 0.096) andattention (Trail A: t7 ¼ 2.09, p ¼ 0.07) didapproach signicance. In euthymic patients, con-trolling for depression, anxiety and neuroticismresulted in a signicant difference in completingPart A of the TMT ( t 9 ¼ 3.56, p < 0.01). How-

ever, it is important to note that these results arelimited by the small numbers of subjects in eachof these comparisons.

Discussion

Functional localisation based purely on neuropsy-chological impairment is potentially problematic asthere are few strict correlations. In most cases,neuropsychological decits imply network dys-functions that may or may not be regionallylocalised. However, broad inferences can be made

Table 5. Signicant comparisons between patient (depressed, euthymic and hypomanic) groups and the control group

Cognitive domain Test Depressed patients Euthymic patients Hypomanic patients

Executive (14 DVs) COWAT a

Animal Naming Test b

Memory (6 DVs) RAVLT c d e

Attention (7 DVs) SDMT f

Stroop Task g

Trail Making Test, Part A hMotor (9 DVs) Purdue Pegboard i

Grooved Pegboard j

DVs ¼ dependent variables; COWAT ¼ Controlled Oral Word Association Test; SDMT ¼ Symbol Digits Modalities Test; RAVLT ¼ ReyAuditory Verbal Learning Test.a Impaired ability to generate phonemic words ( t 12 ¼ 2.26, p ¼ 0.04).b Impaired ability to generate semantic words ( t 11 ¼ 2.35, p ¼ 0.04).c Impaired total recall ( t 12 ¼ 2.37, p ¼ 0.04) and recognition ( t 12 ¼ 2.63, p ¼ 0.02).d Impaired total recall ( t 14 ¼ 2.11, p ¼ 0.05).e Impaired recognition ( t 11 ¼ 3.58, p ¼ 0.004) and recall ( t 11 ¼ 4.84, p ¼ 0.001).fCompleted fewer items ( t 12 ¼ 2.90, p ¼ 0.01).g Read fewer items on the Word Task ( t 12 ¼ 2.75, p ¼ 0.02), Colour Task ( t 12 ¼ 2.33, p ¼ 0.04).hSlower ( t 11 ¼ 2.40, p ¼ 0.04).iSlower, non-dominant hand ( t 12 ¼ 3.37, p ¼ 0.01).jSlower, dominant hand ( t 12 ¼ 2.39, p ¼ 0.03).

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with reasonable condence of brain regions mostlikely implicated.

Verbal uency

Initial analyses from our study revealed evidence of impairment in verbal uency in both depressed andhypomanic patients but not in euthymic patients,corroborating the ndings of an earlier study thatspecically examined euthymic patients (48).Therefore, frontal lobe dysfunction in BD may bemood-state dependent; however, our subsequentanalyses revealed no decits in executive function-ing in any of the mood states although patients inboth poles of illness have been shown to performpoorly on decision making, problem solving andconcept formation tests (14, 49). The initial ndingof a decit in verbal uency is concordant with the

results of an early report that compared depressedbipolar and unipolar patients (50). In this study,depressed bipolar patients had a selective decit inverbal uency, that of semantic categories (50), incontrast to a more recent study in unipolardepressed patients in which both semantic andphonemic categories appear to be affected (51). It isinteresting to note that executive function decitsin euthymic patients have been reported even aftercontrolling subclinical depressive symptoms (1),implicating dysfunction of organisational andplanning abilities (52–54). A recent prospective

study that examined euthymic bipolar patientsdemonstrated enduring neurocognitive impairmentacross a broad range of domains (55).

Memory

Mnemonic decits are the most consistentlyreported neuropsychological decits in BD (1, 4,6–8), and it is therefore no surprise that all threegroups of patients in our study performed poorlyon tests of verbal immediate-recall and thatdepressed and hypomanic patients also had

impaired recognition memory. Subsequent analy-ses that controlled confounds pared these ndingsand revealed that the memory decit was speci-cally one of verbal recall and not recognition,suggesting a dysfunction of information retrievalas opposed to encoding. A previous study (56) alsoreported poor verbal recall and intact recognitionmemory in bipolar depression; however, in ourstudy because the decit only remained signicantin the depressed group, it is most likely a state-related decit rather than a bipolar trait. This isalso borne out to some extent by within-groupcomparisons in which depressed patients weremore impaired on recall as tested by the RAVLTthan euthymic patients. In keeping with our ndingthat differences in the performance of memorytasks between hypomanic patients and controlsapproached statistical signicance, depressed and

hypomanic patients when compared directly dif-fered in the nature of their memory decit, suchthat bipolar depressed patients had greater retro-active interference, and hypomanic patients hadpoorer long-term recall. Difficulties in acquisitionand retention in both verbal and non-verbaldomains in hypomanic patients have been reportedpreviously (49, 57). Such memory and learningdecits implicate temporal lobe and in particularhippocampal pathology, brain regions that alongwith the ventromedial prefrontal cortex subserveverbal uency (58). Persisting decits in these brain

regions may be responsible for the difficulties insocial and occupational functioning reported bybipolar patients (6, 7, 59, 60). However, the natureof cognitive impairment in BD especially withrespect to memory and the question of whetherverbal memory decits are a state or trait marker(1, 6, 7, 48, 61) awaits further clarication.

Attention

In initial analyses, depressed and hypomanicpatients in our study were impaired on tests of

Table 6. Signicant within-patient group comparisons: depressed and hypomanic compared with euthymic

Cognitive domain TestDepressed patients (DPs)versus euthymic patients

Hypomanic patients (HPs)versus euthymic patients

Depressed patientsversus hypomanic patients

Memory RAVLT a b

Motor Purdue Pegboard c

Reaction Time d

RAVLT ¼ Rey Auditory Verbal Learning Test.a DPs demonstrated impaired total recall ( t 4 ¼ 3.64, p ¼ 0.02).b DPs displayed greater retroactive interference than the HPs ( t 6 ¼ 5.46, p ¼ 0.002) and the HPs had poorer long-term recall/retentionthan the DPs ( t 6 ¼ 3.38, p ¼ 0.015).c DPs were slower when using their dominant hand ( t 4 ¼ 3.21, p ¼ 0.03).d HPs were slower ( t 5 ¼ 2.81, p ¼ 0.04).


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attention when compared with controls; however,subsequent analyses revealed no decits for eitherof these groups, contradicting the many reports of attention decits in BD (12). However, the litera-ture reporting evidence of decits in attention haslargely employed tests of sustained attention,whereas the tasks employed in our study were

measures of focused or selective attention. Thissuggests that attention decits in bipolar depres-sion or mania may be specic to sustained ratherthan selective attention. Interestingly, the impair-ment in sustained attention in bipolar depressedpatients is greater than that found in unipolardepression and is characterised by an inattentiveresponse pattern that results in errors of omission(62). In contrast, patients with mania manifest animpulsive response pattern that results in errors of commission (63). It is likely that had our samplesbeen larger, the initial state-related decits mayhave remained. This also explains to some extentthe unusual ndings in our euthymic group inwhich subsequent analyses demonstrated a signif-icant difference in focused attention on the TMTpart A as compared with controls. It is, however,noteworthy that initial analyses almost attainedsignicance (p ¼ 0.07) and failure to do so mayreect not only methodological limitations but alsothe effects of subsyndromal mixed affective symp-toms.

Motor function

Motor function was assessed in our study becauseof the greater preponderance of melancholia inBD (64) and the obvious heightened energydisplayed by patients when manic (2). As antici-pated, depressed patients performed poorly onmotor tasks as compared with controls, althoughthis difference did not remain signicant insubsequent analyses. However, within-patient a-nalyses partly support a state-related associationas depressed patients also performed poorly incomparison to euthymic patients and hypomanicpatients were slow to react in comparison to

euthymic patients.

Psychosocial function

In comparison to controls, psychosocial function-ing in patients was poorer across all three phases of the illness but especially in depression and hypo-mania. Correlating social function and neuropsy-chological performance in bipolar patientsimplicated poor executive functioning; however,when individual mood states were examined sep-arately, social functioning in euthymic patients did

not correlate with any of the neuropsychologicalmeasures. This is extremely important as it sug-gests that psychosocial impairment in euthymia isnot wholly attributable to cognitive impairment,although this must be tempered against the factthat the GAF is a composite assessment compris-ing symptoms and social adjustment and this may

also blur any association. It is also possible that theneuropsychological tests administered in this andmany other studies simply fail to capture the subtleneurocognitive impairment that patients experi-ence in their day-to-day lives. In other words, theassumption that cognitive testing relates to real-world functioning may well be erroneous (65). Thelikelihood remains that patients with BD evenwhen well have some degree of functional com-promise that may reect a persistent neuropsycho-logical decit. Clinically this has importantimplications not only for therapeutic interventionbut also for patients daily living. For instance,patients with BD even when well and functioningappropriately in terms of work often describedifficulties with decisions that require factoring of future consequences. A concrete example of this isthe need to balance current expenditure with theneed to pay off debts such as mortgage. This isimportant in the context of understanding theillness and adhering to medication as patients oftenstop treatment despite having had catastrophicconsequences in the past.

Such subtle compromise is necessarily difficult todetect and determine in terms of its immediate and

long-term impact; however, assessing this in thecontext of insight into the illness and its potentialconsequences, given a number of scenarios, forexample complying with medication versus notdoing so, may provide an indicator as to whetheran individual has a decit.

Clearly, good non-specic bedside markers areunsatisfactory and future research needs to focusmore on dening the extent and nature of any suchdecit. This requires the development of new teststhat are designed to identify subtle decits and aretailored to the individual. Longitudinal testing

is needed combining neuropsychological testswith imaging and electrophysiological measuresso as to achieve greater regional and temporallocalisation.

Limitations

The nal neuropsychological data set had someomissions largely because of patients being toounwell to complete the entire neuropsychologicaltest battery or self-report measures. As a conse-quence, the number of subjects in each analysis

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