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Research report Neurocognitive and symptomatic predictors of functional outcome in bipolar disorders: A prospective 1 year follow-up study Diego J. Martino, Eliana Marengo, Ana Igoa, María Scápola, Ezequiel D. Ais, Lila Perinot, Sergio Adrian Strejilevich Bipolor Disorder Program, Neurosciences Institute, Favaloro Foundation, Buenos Aires, Argentina article info abstract Article history: Received 4 September 2008 Received in revised form 13 October 2008 Accepted 24 October 2008 Available online 25 November 2008 Background: The aim of this study was to estimate the predictive value of cognitive impairments and time spent ill in long-term functional outcome of patients with bipolar disorder (BD). Methods: Thirty ve patients with euthymic BD completed a neurocognitive battery to assess verbal memory, attention, and executive functions at study entry. The course of illness was documented prospectively for a period longer than 12 months using a modied life charting technique based on the NIMH life-charting method. Psychosocial functioning was assessed with the General Assessment of Functioning (GAF) and the Functioning Assessment Short Test (FAST)at the end of follow-up period when patients were euthymic. Results: Impairments in verbal memory and in attention, as well as subsyndromal depressive symptomatology were independent predictors of GAF score at the end of the study explaining 43% of variance. Similarly, impairments in attention and executive functioning were independent predictors of FAST score explaining 28% of variance. Limitations: We did not control factors that could affect functional outcome such as psychosocial interventions, familiar support and housing and nancial resources. Conclusions: Both cognitive impairments and time spent with subsyndromal depressive symptomatology may be illness features associated with poorer long-term functional outcome. Developing strategies to treat these illness features might contribute to enhance long-term functional outcome among patients with BD. © 2008 Elsevier B.V. All rights reserved. Keywords: Disability Verbal memory Attention Executive function Subsyndromal depression 1. Introduction Bipolar disorder (BD) has been identied by the World Health Organization as the sixth cause of disability among all medical illness (Murray and Lopez, 1996). Different studies found that patients with BD have reduced ability to regain premorbid levels of social and vocational functioning even after episodes remission suggesting that it exists a gap between syndromal recovery and functional recovery (Keck et al., 1998; Tohen et al., 2003; Strakowski et al., 1998). Research into this area is a critical issue to clarify which illness features produce disability and targeting treatments to enhance functional outcome. An illness feature related with the gap between syndromal and functional recovery might be cognitive impairments. Two meta-analyses concluded that euthymic patients with BD have impairments in verbal memory, attention, and executive functions (Robinson et al., 2006; Torres et al., 2007). Likewise, several studies showed a negative association between cognitive functioning and different measures of disability. Martinez-Arán et al. (2004) reported that impairments in verbal memory are associated with lower scores in measures of psychosocial functioning. Similarly, Zubieta et al. (2001) found a negative correlation between impairments in verbal memory and executive functions with social and occupational functioning, and Dickerson et al. (2004) reported a signicant Journal of Affective Disorders 116 (2009) 3742 Corresponding author. Congreso 2477 Dto. D (1428) Ciudad de Buenos Aires, Argentina. Tel./fax: +54 11 4833 2424. E-mail address: [email protected] (S.A. Strejilevich). 0165-0327/$ see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.10.023 Contents lists available at ScienceDirect Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

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Page 1: Neurocognitive and symptomatic predictors of functional outcome in bipolar disorders: A prospective 1 year follow-up study

Journal of Affective Disorders 116 (2009) 37–42

Contents lists available at ScienceDirect

Journal of Affective Disorders

j ourna l homepage: www.e lsev ie r.com/ locate / j ad

Research report

Neurocognitive and symptomatic predictors of functional outcome in bipolardisorders: A prospective 1 year follow-up study

Diego J. Martino, Eliana Marengo, Ana Igoa, María Scápola, Ezequiel D. Ais,Lila Perinot, Sergio Adrian Strejilevich⁎Bipolor Disorder Program, Neurosciences Institute, Favaloro Foundation, Buenos Aires, Argentina

a r t i c l e i n f o

⁎ Corresponding author. Congreso 2477 Dto. D (142Aires, Argentina. Tel./fax: +54 11 4833 2424.

E-mail address: [email protected] (S.A. St

0165-0327/$ – see front matter © 2008 Elsevier B.V.doi:10.1016/j.jad.2008.10.023

a b s t r a c t

Article history:Received 4 September 2008Received in revised form 13 October 2008Accepted 24 October 2008Available online 25 November 2008

Background: The aim of this study was to estimate the predictive value of cognitive impairmentsand time spent ill in long-term functional outcome of patients with bipolar disorder (BD).Methods: Thirty five patients with euthymic BD completed a neurocognitive battery to assessverbal memory, attention, and executive functions at study entry. The course of illness wasdocumented prospectively for a period longer than 12 months using a modified life chartingtechnique based on the NIMH life-charting method. Psychosocial functioning was assessedwith the General Assessment of Functioning (GAF) and the Functioning Assessment Short Test(FAST)at the end of follow-up period when patients were euthymic.Results: Impairments in verbal memory and in attention, as well as subsyndromal depressivesymptomatology were independent predictors of GAF score at the end of the study explaining43% of variance. Similarly, impairments in attention and executive functioning wereindependent predictors of FAST score explaining 28% of variance.Limitations: We did not control factors that could affect functional outcome such aspsychosocial interventions, familiar support and housing and financial resources.Conclusions: Both cognitive impairments and time spent with subsyndromal depressivesymptomatology may be illness features associated with poorer long-term functional outcome.Developing strategies to treat these illness features might contribute to enhance long-termfunctional outcome among patients with BD.

© 2008 Elsevier B.V. All rights reserved.

Keywords:DisabilityVerbal memoryAttentionExecutive functionSubsyndromal depression

1. Introduction

Bipolar disorder (BD) has been identified by the WorldHealth Organization as the sixth cause of disability amongall medical illness (Murray and Lopez, 1996). Different studiesfound that patients with BD have reduced ability to regainpremorbid levels of social and vocational functioning even afterepisodes remission suggesting that it exists a gap betweensyndromal recovery and functional recovery (Keck et al., 1998;Tohen et al., 2003; Strakowski et al., 1998). Research into thisarea is a critical issue to clarify which illness features produce

8) Ciudad de Buenos

rejilevich).

All rights reserved.

disability and targeting treatments to enhance functionaloutcome.

An illness feature related with the gap between syndromaland functional recovery might be cognitive impairments. Twometa-analyses concluded that euthymic patients with BDhave impairments in verbal memory, attention, and executivefunctions (Robinson et al., 2006; Torres et al., 2007). Likewise,several studies showed a negative association betweencognitive functioning and different measures of disability.Martinez-Arán et al. (2004) reported that impairments inverbal memory are associated with lower scores in measuresof psychosocial functioning. Similarly, Zubieta et al. (2001)found a negative correlation between impairments in verbalmemory and executive functions with social and occupationalfunctioning, and Dickerson et al. (2004) reported a significant

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38 D.J. Martino et al. / Journal of Affective Disorders 116 (2009) 37–42

association between impairments in verbal memory withemployment status. In addition with these cross-sectionalfindings, there is a paucity of information about if cognitiveimpairments would predict long-term functional outcome. Anotable exceptionwas a recent study by Jaeger et al. (2007) inwhich BD patients hospitalized for acute exacerbation under-went a neurocognitive battery after ‘initial stabilization’, andimpairments in attention and ideational fluency (a measureof executive functions) were associated with functionalrecovery assessed 12 months later.

However, some methodological issues must be consid-ered in studies assessing the predictive value of cognitiveimpairments in long term functional outcome. First, cogni-tive impairments have been associated with both syndromal(Martinez-Arán et al., 2004) and subsyndromal (Ferrier andThompson, 2002; Clark et al., 2002) symptomatology, as wellas with number of episodes (for a review see Robinson andFerrier, 2006). On the other hand, long-term follow upstudies showed high levels of sustained symptomaticmorbidity (around 50% of time) in patients with bipolar Iand II disorder, with a symptomatic structure fluctuatingalong the full range of severity and polarity within the samepatient over time (Judd et al., 2002; Judd et al., 2003). Finally,it has been reported that disability in BD fluctuates in parallelwith changes in affective symptoms severity, with exceptionof subsyndromal hypomanic symptoms that appear toenhance functioning (Judd et al., 2005). These inter-relation-ships between cognitive impairments, symptomatic status,and disability conduct to the question about potentialconfounders in studies assessing the predictive value ofcognitive impairments in long term functional outcome. Inother words, the association between cognitive impairmentsand long term functional outcome would be artificial andmediated by a higher number of episodes ormore time spentill during the follow up in those patients with poorercognitive functioning. A methodological design that wouldbe useful to avoid these potential confounders may consist inassess cognitive functioning and disability in euthymic BDpatients as well as the time that they spend ill along thefollow up period.

Fig. 1. Criteria for assigning mood

The aim of this study was to estimate the predictive valueof cognitive impairments in long-term functional outcome inpatients with BD. Taken into account the results of previousstudies mentioned above, we hypothesize that cognitiveimpairments would be independent predictors of long-termfunctional outcome.

2. Methods

Thirty five outpatients with BD were consecutivelyselected with the following inclusion criteria: 1) age between18 and 55 years old; 2) diagnosis of BD type I or II according toDSM-IV using Structured Clinical Interview for DSM-IV (SCID)(First et al., 1996); 3) euthymic (defined by HamiltonDepression Rating Scale ≤8 and Young Mania Rating Scale≤6) for at least 8 weeks at baseline; and 4) more than48 weeks of prospective follow up. Exclusion criteria were:antecedent history of substance abuse; history of mentalretardation, neurological disease, or any clinical conditionthat could affect cognitive performance. Additionally, thirtyhealthy controls matched by age and years of education wereincluded: these had not antecedence of neurological disease,neither history of psychotic or affective disorders in them-selves or a first-degree family member, and they were nottaking psychotropic medication. The study was approved bythe Hospital Ethics Committee and all subjects gave writteninformed consent for their participation after receiving acomplete description of the study.

2.1. Neurocognitive assessment

Patients and healthy controls completed a neurocognitivebattery selected to assess: 1) Attention. Forward Digit SPAN(Wechsler, 1955); and Trail Making Test part A (Reitan,1958);2) Verbal memory: Memory Battery of Signoret (Signoret andWhiteley, 1979). This test evaluates immediate and delayrecall of a short story, and the serial learning of a twelve wordlist of different semantic categories (3 trials), free delay recall,and recognition with semantic clues and multiple options ofthem; and 3) Executive functions: Wisconsin Card Sorting

state scores in life charts.

Page 3: Neurocognitive and symptomatic predictors of functional outcome in bipolar disorders: A prospective 1 year follow-up study

Table 1Medication of bipolar patients at time of neurocognitive assessment (valuesare expressed as mean, standard deviation is shown in brackets).

Medications N (%) Mean dose (mg/daily)

Mood stabilizers 35 (100)Lithium 17 (48.6) 1023 (276)Lamotrigine 12 (34.3) 183 (65)Valproate 7 (20.0) 928 (188)Carbamazepine 3 (8.6) 800 (400)

Antipsychotics 10 (28.6)Quetiapine 5 (14.2) 140 (108)Olanzapine 4 (11.42) 5 (0)Risperidone 1 (2.8) 1 (0)

Antidepressants 9 (25.7)Bupropion 7 (20.0) 214 (80)Venlafaxine 1 (2.8) 150 (0)Fluoxetine 1 (2.8) 40 (0)

Clonazepam 9 (25.7) 1 (0.8)

39D.J. Martino et al. / Journal of Affective Disorders 116 (2009) 37–42

Test (WCST) (Heaton, 1981); and Trail Making Test part B(Reitan, 1958). Neuropsychological tests were grouped inthese domains based in previous literature on BD (Martinez-Arán et al., 2004; Robinson et al., 2006; Torres et al., 2007).Additionally, estimated premorbid IQ was calculated by theWAIS vocabulary subtest (Wechsler, 1955). All neurocognitivetests were administered at baseline by one physician (DM) ina quiet testing room according to a standardized order.

2.2. Clinical and symptomatic assessment

In addition to SCID, all subjects were evaluated with theHamilton Depression Rating Scale (HDRS) (Hamilton, 1960),and Young Mania Rating Scale (YMRS) (Young et al., 1978)both at baseline and the end of follow-up. Additional clinicalinformation was obtained from clinical charts and directpatients interview. As a part of the routine clinical carepatients were assessed every 1 to 4weeks. During these visits,the course of illness was weekly documented for eachparticipant by his/her psychiatrist during the follow-up

Fig. 2. Neuropsychological evaluation of bipolar patients and healthy controls (valWisconsin Card Sorting Test—Perseverative Errors; TMT-B: Trail Making Test ParIntelligence Quotient. ⁎pb0.05 ⁎⁎pb0.01.

period using a modified life charting technique based on theNIMH life-charting method (Roy-Byrne et al., 1985) andanchored with scores from both the Hamilton DepressionRating Scale and Young Mania Rating Scale (Fig. 1). A similarapproach was used in previous studies (Joffe et al., 2004).

2.3. Functional assessment

Disability at the end of follow up period was assessedusing the General Assessment of Functioning (GAF) (DSM-IV)and the Functioning Assessment Short Test (FAST) (Rosa et al.,2007) when patients were euthymic (HDRS≤8 andYMRS≤6). The rater was instructed to use the GAF tomeasure functioning in the last month and not symptomssince other measures of mood symptoms (HDRS and YMRS)were obtained and end of follow up. The FAST comprises 24items that assess impairments or disability in the last 15 daysin six specific areas of functioning: autonomy, work function-ing, cognitive functioning, financial issues, interpersonalrelationships, and leisure time. Each item is scoring in a 0–3points range (0: no difficulty; 1: mild difficulty; 2: moderatedifficulty; 3: severe difficulty) with total score ranges from 0to 72 points. For the current analysis, the overall global ratingof the FAST was used.

2.4. Data analysis

Raw score of cognitive functioning were transformed tostandardized Z-score from the normative data of each test.Differences between groups in clinical and neurocognitivemeasures were compared using Student t-test or chi-squaredtest, as appropriate. Relationship between disability withcognitive functioning and symptomatic status in bipolarpatients was calculated with Spearman's correlation coeffi-cients. The variables with significant correlation with dis-ability measures (GAF and FAST) were considered as possibleexplanatory variables in a multiple linear regression model(variance provides as adjusted R2).

ues are expressed as Z-scores form normative data of each test). WCST-EP:t B; TMT-A: Trail Making Test Part A; SPAN-D: Backward Digit SPAN; IQ:

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40 D.J. Martino et al. / Journal of Affective Disorders 116 (2009) 37–42

3. Results

No differences between patients and healthy controls werefound in terms of age (43.0±13.8 vs. 40.2±13.2), gender(% female, 65.7 vs. 66.6), years of education (13.6±2.8 vs.13.3±2.8), and scores in YMRS (0.8±1.2 vs. 0.7±0.9) andHDRS (2.5±2.5 vs. 1.9±1.8) at study entry.Additionally, nodifferences were found in the group of patients betweenscores on YMRS (0.8±1.2 vs. 1.0±1.5) and HDRS (2.5±2.5vs. 2.3±2.2) at baseline and end of follow up. Patients (47%BDI and 53% BDII) were a mean age at onset of 30.0 (11.1)years, and had a length of illness of 13.4 (8.5) years, 3.3 (2.4)manic/hippomanic episodes, and 3.5 (2.21) depressive epi-sodes. All patients were receiving medication at time ofneurocognitive testing (Table 1). Results of neurocognitiveevaluation of bipolar patients and healthy controls areshown in Fig. 2; patients had lower performance thanhealthy controls in measures of verbal memory, attention,and executive function. Patients were followed-up a meanof 60.06 (21.3) weeks; the percentage of time spent illduring the follow-up is shownin Fig. 3.

A significant association was detected between GAF scoreat the end of follow up period with subsyndromal depressivesymptomatology (R=−0.54, p=0.001) as well as withimpairments in measures of verbal memory (free delay recall,R=0.37, p=0.030), attention (backward digit SPAN,R=0.46, p=0.006), and executive functions (WCST-perse-verative errors, R=0.35, p=0.041). When these variableswere included in a linear regression model, subsyndromaldepressive symptomatology (β=−0.33, t=−2.44,p=0.021), and impairments in attention (β=0.34, t=2.51,p=0.018), and in verbal memory (β=0.35, t=2.63,p=0.013) predicted GAF score accounting around 43% ofvariance (adjusted R2=0.430; F(3)=9.29, pb0.001). Theseresults were unmodified when scores in YMRS and HDRS atend of follow up were included in the model.

Similarly, FAST score at end of follow up period wassignificantly associated with subsyndromal depressive symp-tomatology (R=0.40, p=0.018) and with impairments in

Fig. 3. Percentage of time spent ill

measures of attention (backward digit SPAN, R=−0.43,p=0.010), and executive functions (WCST-perseverativeerrors, R=−0.34, p=0.047). When these variables wereincluded in a lineal regression model, impairments inattention (β=−0.40, t=−2.62, p=0.0138), and in execu-tive functions (β=−0.31, t=−2.07, p=0.047) were inde-pendent predictors of FAST score at the end of follow upperiod accounting around 28% of variance (adjustedR2=0.282; F(2)=7.49, p=0.002). These results wereunmodified when scores in YMRS and HDRS at end of followup were included in the model.

4. Discussion

The main finding of this study was that cognitiveimpairments were predictors of long term functional out-come. We assessed cognitive functioning in patients withstringent euthymia criteria at baseline, and impairments inmeasures of attention, executive function, and verbal memorywere independent predictors of level functional outcomeone year later. These results agree with previous cross-sectional studies that reported a relationship betweencognitive impairments and different measures of functionaloutcome as social and occupational functioning or employ-ment status (Zubieta et al., 2001; Martinez-Arán et al., 2004;Dickerson et al., 2004). Our results suggest that, in addition tocross-sectional relationship between cognitive impairmentsand functional outcome, cognitive functioning may be anindependent predictor in the long term too. A recent long-itudinal study also explored relationship between cognitiveimpairments and functional recovery from acute exacerbationleading to hospitalization (Jaeger et al., 2007). However, ourstudy differs from the one of Jaeger et al. in several importantways. First, we assessed both cognitive functioning as well asfunctional outcome taking into account stringent criteria ofeuthymia, to be sure both variables were core features of theillness and not influenced by clinical symptoms. Additionally,we assessed the time that patients spent ill along the followup period, and included it in our regression model when was

during the follow up period.

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necessary. Finally, in the previous study the sampling strategywould bias the study sample toward patients having a higherrisk of hospitalization and perhaps with poorer cognitivefunctioning and more disabled. Contrarily, we used asampling scheme more representative of ‘bipolar population’in a clinical ambulatory setting. In spite of these differences,our results closely reproduce and expand the ones of Jaeger etal., bringing additional support to the hypothesis thatcognitive impairments might be predictors of long termfunctional outcome, and that this association is not mediatedby syndromal or subsyndromal symptomatology.

Another interesting finding of our study was that the timespent with subsyndromal depressive symptomatology was anindependent predictor of long-term psychosocial functioningassessed with the GAF. These findings are particularly impress-ive, as we used low scores of HDRS to describe subsyndromaldepressive symptomatology (Fig. 1). Different to previousstudies our sample of patients was mildly lower symptomatic(around 30% of time) (Judd et al., 2002, 2003; Joffe et al., 2004;Paykel et al., 2006) and we did not find relationship betweendisability and syndromal symptomatology (Judd et al., 2005).These differences may be caused because of to the main aim ofthis study we included just euthymic patients at baseline.However, similarly to previous studies depressive symptoma-tology accounted the majority of the time spent ill during thefollow up. Our results are consistent with the ones of twoprevious small studies reporting that the persistence ofsubsyndromal depressive symptoms contributed substantiallyto disability (Altshuler et al., 2002; Morris, 2002). Moreover, ina recent study involving 759 outpatients, subsyndromaldepressive symptomatology was related with functional roleimpairments in multiple domains (Altshuler et al., 2006).Additionally, although previous cross-sectional studies havereported the association between subsyndromal depressivesymptomatology and functional impairment, the directionalityof this association is not clear nowadays. It has beenpointed outthat subsyndromal depressive symptoms may result in func-tional impairment, or alternatively that disability might con-tribute primarily to the development of subsyndromaldepressive symptoms (Altshuler et al., 2006). Our findingsmay contribute to enlighten this issue. While we did not findany relationship between scores in YMRS and HDRS at end offollow up with functional outcome, the time spent withsubsyndromal depressive symptomatology was an indepen-dent predictor of functional impairment, suggesting thatsubsyndromal depressive symptoms may be primary and thatdisability occurred as a consequence of these symptoms.

The results of this study have potentially importantclinical implications. Patients considered to have respondedto treatment may nevertheless continue to experiencecognitive impairments and subsyndromal symptoms. Sincecognitive impairments appear to be a core feature of illnessand since they may be independent predictors of long-termfunctional outcome, they can be considered rational treat-ment targets in bipolar disorder. Further researches focusedin strategies in the prevention or rehabilitation of cognitiveimpairments are needed in BD. Similarly, subsyndromaldepressive symptomatology may be another target of treat-ment to enhance functional outcome in BD. Paradoxically,despite the high morbidity of subsyndromal depressivesymptomatology mentioned above, nowadays it is not clear

which is the best way of treating it. Developing strategies fortreatment of subsyndromal depressive symptoms may alsocontribute to improve the overall functional outcome in BD.

Certain methodological limitations of our study should betaken into account. First, a higher sample size would allow usto construct more complex regression models includingother variables of interest (e.g. length of illness or number ofprevious episodes). Although we reported adjusted R2

statistics which account for the number of variables enteredin the models, they could be many to our sample size andmay have artificially inflated the fit of our overall models.Additionally, all patients included in the study were takingpsychotropic medications and we cannot discount theinfluence of drugs in cognitive functioning. However, wepreviously reported that cognitive impairments may be notentirely accounted by pharmacological factors (Martino etal., 2008). Finally, we did not control factors that could affectfunctional outcome such as psychosocial interventions,familiar support and housing and financial resources.

In summary, our findings bring further evidence that bothcognitive impairments as well as subsyndromal depressivesymptomatology are illness features associated with long-termfunctional outcome. These results point out the importance ofin which way developing strategies to improve cognitiveimpairments and subsyndromal symptomatology may lead tomore comprehensive treatments and contribute to enhance thelong-term functional outcome in patients with BD.

Role of the funding sourceThis project was partially supported by a fellowship for D. Martino from

National Council of Scientific and Technical Research (CONICET).

Conflict of interestNo conflict declared.

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