Two-year follow-up of treated adolescents with early-onset bipolar disorder: Changes in neurocognition

Two-year follow-up of treated adolescents with early-onset bipolar disorder: Changes in neurocognition

Journal of Affective Disorders 172 (2015) 48–54 Contents lists available at ScienceDirect Journal of Affective Disorders journal homepage: www.elsev...

476KB Sizes 0 Downloads 33 Views

Journal of Affective Disorders 172 (2015) 48–54

Contents lists available at ScienceDirect

Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Research report

Two-year follow-up of treated adolescents with early-onset bipolar disorder: Changes in neurocognition Sara Lera-Miguel a,n, Susana Andrés-Perpiñá a,b,d, Mar Fatjó-Vilas b,c,e, Lourdes Fañanás b,c,e, Luisa Lázaro a,b,d,f a

Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic, Barcelona, Spain CIBERSAM, Spain c Institut de Biomedicina, Universitat de Barcelona, IBUB, Spain d Institut d'Investigació en Biomedicina August Pi i Sunyer, IDIBAPS, Spain e Department of Animal Biology, Universitat de Barcelona, Spain f Department of Psychiatry and Clinical Psychobiology, Universitat de Barcelona, Spain b

art ic l e i nf o

a b s t r a c t

Article history: Received 24 June 2014 Received in revised form 19 September 2014 Accepted 21 September 2014

Background: Few studies have analyzed the course of neurocognition in treated children and adolescents with early-onset bipolar disorder (EOBD) and shown improvements in attention, working memory, and verbal memory after treatment. The aim of this study was to determine the progress over two years in neuropsychological performance of a sample of medicated adolescents with EOBD compared to healthy controls (HC). Methods: Twenty adolescents, diagnosed in clinical setting as DSM-IV bipolar disorder, treated for two years, euthymic, and 20 gender and age-matched HC were assessed at two moments in reasoning, verbal and visual memory, working memory, speed, visual-motor skills and executive function. Multivariate analyses of variance was carried out to analyze the differences between groups over time, and to monitor the influence of psychotic symptoms and type of mood-stabilizer. Results: The entire sample improved on verbal and visual memory tests (verbal recall p o0.01; visual recall p o0.001). Moreover, patients improved more than controls in verbal reasoning (po 0.01), working memory (po 0.01), processing speed (po0.01) and visual-motor skills (po0.001). Psychotic symptoms and treatment with lithium were associated with poorer development in executive control tasks. Limitations: Sample size was small and groups were re-evaluated in slight different follow-up periods. Doses of antipsychotics drugs over time were not controlled. Conclusions: Processing speed and visual-motor skills in the EOBD group normalized during follow-up. Executive functioning, working memory, and verbal and visual memory remained impaired in patients versus controls. The knowledge of cognitive deficits due to normal course of illness or to drug effects allows better therapeutic strategies. & 2014 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder Adolescent Cognition Control group Follow-up study

1. Introduction Early-onset bipolar disorder (EOBD) defines the first appearance of this disorder in adolescence or childhood. It affects up to 2% of this age group and its premature course has been associated with a worse life outcome and higher rates of comorbidity (Carlson et al., 2009; Lazaro et al., 2007). A very early onset of the disorder, i.e., before 13 years of age, is associated both with a poorer clinical outcome than the onset before 18 and with a longer

n Correspondence to: Department of Child and Adolescent Psychiatry and Psychology. Hospital Clínic. C/Villarroel, 170, 08036 Barcelona, Spain. Tel.: þ 34 932279974; fax: þ34 932279172. E-mail address: [email protected] (S. Lera-Miguel).

http://dx.doi.org/10.1016/j.jad.2014.09.041 0165-0327/& 2014 Elsevier B.V. All rights reserved.

delay before the first treatment for mania and depression (Perlis et al., 2009; Post et al., 2010). Widespread neuropsychological deficits in relation to attention, working memory, executive functions, and verbal memory and learning have repeatedly been described in patients with EOBD (Doyle et al., 2005; Joseph et al., 2008; Karakurt et al., 2013; LeraMiguel et al., 2011; Nieto and Castellanos, 2011; Udal et al., 2012). Moreover, medium effect sizes have also been observed on lower performance of EOBD in verbal fluency, visual perceptive skills, and visual memory, compared to healthy controls (HC), as well as more consistent impairments. The presence of psychotic symptoms and a longer treatment with mood stabilizers have been related to the most severe cognitive deficits in adult populations with BD (Martinez-Aran et al., 2008; Gualtieri and Johnson, 2006; Holmes et al., 2008). Similar evidence has been recruited about the cognitive

S. Lera-Miguel et al. / Journal of Affective Disorders 172 (2015) 48–54

impairment related to psychotic symptoms in children and adolescents (Arango et al., 2014; Zabala et al., 2010). These data raise questions that need additional study in EOBD populations. The search is now underway for a common cognitive impairment for individuals with EOBD, adults with BD and their relatives (Cahill et al., 2009; Bora et al., 2009). Young adults with BD have shown impairment in executive functions during adolescence before the first appearance of the illness, as reflected in lower scores on the Wisconsin Card Sorting Test (Meyer et al., 2004). Studies with patients and relatives show common deficits in working memory, visual memory, and executive functions, while the role of verbal memory is inconsistent (Doyle et al., 2009; Frangou et al., 2005). Previous longitudinal studies have documented the maintenance of cognitive deficits for some years in adult patients with BD (Samamé et al., 2014; Santos et al., 2014). Long-term follow-up studies of young patients with BD are also needed to confirm the presence of permanent, specific deficits. Very few studies have compared the course of neurocognition in treated child and adolescents with BD. In the short term, adolescents and young adults medicated with aripiprazole for 24 weeks improved in sustained attention and cognitive flexibility (Wang et al., 2012). Children treated with lamotrigine for 14 weeks have also shown improvement in working memory and verbal memory, although deficits in attention and executive functions persisted in comparison with healthy controls (Pavuluri et al., 2010). To our knowledge, only one study has reported longer-term outcomes for neuropsychological performance in treated children with EOBD, finding an overall improvement in most cognitive functions, particularly in attention tasks; however, the performance of EOBD subjects lagged behind that of HC three years after baseline (Pavuluri et al., 2009). The main aim of this study was to increase knowledge about the course of neurocognitive function in adolescents with EOBD, assessing their performance in a wide battery of neuropsychological tests at two points in time, separated by more than two years of treatment. We focused on the comparison between euthymic states of adolescents diagnosed as type I or II BD in contrast with a control sample of healthy adolescents. Our secondary aim was to observe the influence on cognitive performance, during follow-up, of the presence of psychotic symptoms and the different outcome due to mood-stabilizer treatment (lithium or valproate). Our hypotheses were: (a) EOBD individuals would improve their performance in attention, working memory, and verbal memory from baseline to follow-up; (b) EOBD individuals would continue to show deficits in executive functions; (c) the EOBD neuropsychological profile would be worse than the HC profile; (d) patients with psychotic symptoms would show a worse cognitive outcome than patients without; and (e) no differences would be observed between lithium and valproate.

2. Methods This is a naturalistic, prospective, and controlled study of the cognitive outcomes of a sample of treated adolescents with EOBD. Preliminary results of baseline data of a portion of the sample have previously been published (Lera-Miguel et al., 2011). 2.1. Sample Twenty adolescents with a diagnosis of EOBD, type I or type II, were recruited for this follow-up study, part of a wider-ranging study on the clinical and neuropsychological characteristics of EOBD patients and their relatives. All patients started naturalistic pharmacological treatment between 2007 and 2009 and were followed for at least two years, at the Department of Child and Adolescent Psychiatry and Psychology, Hospital Clínic, Barcelona, Spain. The

49

diagnosis was established according to DSM-IV criteria and treatment was applied following internal guidelines, based on the recommendations of the American Academy of Child and Adolescent Psychiatry (McClellan et al., 2007). Neuropsychological evaluation was carried out once euthymia had been guaranteed for one to three months. The re-test sample was recruited from participants who had been diagnosed and had been in treatment for at least two years. From 25 subjects in that situation, 20 agreed to be reevaluated, three declined, one could not be contacted and another was in an unstable state due to drug abuse and was removed from the study. The inclusion criteria included: type I or II diagnosis of BD, age between 12 and 17 years old, beck depression inventory raw score o18, young mania rating scale raw score o8. The exclusion criteria included: no otherwise specified forms of BD, schizoaffective disorders, eating disorders patients in low weight (body mass index o17), drug dependence disorder or current abuse, psychosis induced by drugs, autism spectrum disorders, organic or neurologic diseases, and mental retardation. Twenty healthy adolescents were recruited from another study conducted in the same department at the same time and formed the control group. Healthy controls (HC), matched for gender and age with the EOBD sample, were selected from that study and asked to participate in our study in order to retest the same neurocognitive functions. Both assessments of patients and controls were done between 2007 and 2011. All patients and parents gave informed consent to participate. Healthy controls also received financial compensation for their participation. Institutional Review Boards of Hospital Clinic approved the project. Table 1 includes baseline clinical data for the EOBD sample. Forty percent of patients came from upper or middle–upper socioeconomic status, another 40% from middle class and the remaining

Table 1 Clinical data of EOBD sample at baseline. N (%) DSM-IV-TR diagnosis at recruitment Bipolar disorder type I Bipolar disorder type II Comorbidity Externalizant (ADHD/substance abuse/opossitional defiant) Internalizant (obsessive-compulsive disorder)

18 (90%) 2 (10%) 5 (25%) 4 (20%) 1 (5%)

Type of first episode Manic/hypomanic Depressive Mixed/unspecified

8 (40%) 3 (15%) 9 (45%)

Duration of illness4 1 year

5 (25%)

Previous hospitalizations One Two or more Suicidal ideation/suicide attempts Psychotic symptoms Drug therapies Mood-stabilizers monotherapy Combined therapy Anticonvulsivants/mood-stabilizers Atypical antipsychotics Antidepressants Age at onset of first unspecified symptoms Age at onset of specified BD symptoms YMRS score BDI score

Mean (sd)

16 (80%) 7 (35%) 9 (45%) 4 (20%)/1(5%) 6 (30%) 2 18 20 17 3

(10%) (90%) (100%) (85%) (15%) 12.9 7 2.6 14.17 2.2 1.5 7 1.8 9.3 7 5.9

50

S. Lera-Miguel et al. / Journal of Affective Disorders 172 (2015) 48–54

20% belonged to lower or middle-lower class; 75% of patients were living with both parents and siblings and almost all (95%) were studying in high school or college. All EOBD patients were medicated with anticonvulsivants (14 with lithium and 6 with valproate); antipsychotics prescribed were risperidone, quetiapine, olanzapine, and aripiprazole; the antidepressant treatment was with sertraline or venlafaxine. From baseline to follow-up, no EOBD subject required hospitalization. Only one suffered hypomanic symptoms at the time of the second assessment and was not evaluated until affective restoration, two months after the episode. At follow-up, four adolescents were not receiving any drug therapy. 2.2. Measures and instruments A structured psychiatric interview, the Spanish version of the Schedule for Affective Disorders and Schizophrenia, Past and Lifetime Version for Children (Kaufman et al., 1997; Ulloa et al., 2006), was administered to EOBD and HC participants at baseline. The beck depression inventory (BDI; Beck et al., 1961, Vázquez and Sanz, 1978) and the young mania rating scale (YMRS; Young et al., 1978; Colom et al., 2002) were administered to patients at baseline and to patients and controls at follow-up. A wide battery of neuropsychological tests served to assess the cognitive functions of patients and controls at baseline and at follow-up. It was administered by two clinical psychologists (S.L., S.A.), with more than five years of experience on clinical and neuropsychological assessment of children and adolescents. Between both of them, the inter-rater reliability ranges 0.80–0.99. The functions evaluated in all cases were: verbal and visual-spatial reasoning, auditory attention and working memory, verbal logical memory, verbal fluency, visual-spatial memory, visual-motor skills, processing speed, inhibition or executive control, and setshifting. Different instruments were administered to each sample to test verbal memory. To homogenize the scores of both tests, a new index was calculated for them: the percentage of correct hits over the total possible score. The tests used in this battery came from the following instruments: Wechsler intelligence scales. For participants under 17 years of age, the Wechsler intelligence scale for children 4th edition (WISCIV; Wechsler, 2004, 2006) was administered; for older participants, the Wechsler adult intelligence scale 3rd edition (WAIS-III; Wechsler, 1997a, 1999) was used. The tests for vocabulary and block design were selected to estimate intellectual level, and digits and letters-numbers were chosen to assess attention and auditory working memory. Test results are presented as standard scores (mean 10 and standard deviation 3). Wechsler memory scale, 3rd edition (WMS-III; Wechsler, 1997b) is a battery of tests to assess different attention processes and memory in people older than 16. Logical memory tests for the immediate and delayed recall of stories were selected to measure verbal memory, while the immediate and delayed recall of visual reproduction served as a measure of visual memory. Visual reproduction was administered to both samples, and data are presented as raw scores because standard scores were unable for age under 16. WMS-III logical memory was administered only to the EOBD sample; scores are presented as the percentage of hits over the total possible score. Rey–Osterrieth complex figure test (ROCF; Rey, 1980). This is an instrument to assess the perceptive ability to organize a complex visual stimulus, the visual-motor skills to copy it, and immediate visual memory. Data are presented as raw scores. Test of memory and learning (TOMAL; Reynolds and Bigler, 1994, 2001) is a standardized battery to test verbal and non-verbal attention processes and memory in children and adolescents 5–19 years of age. Immediate and delayed logical memories were only

administered to the HC sample. Scores are presented as a percentage of hits over the total possible score. Stroop word and color test (Golden et al., 1975; Golden, 2005) is an instrument to measure processing speed when reading words and naming colors, and also the executive control or verbal inhibition when visual stimuli are incongruent. Data are presented as raw scores. Wisconsin card sorting test (WCST; Heaton, 1981; Heaton et al., 1997). This is an instrument to test cognitive set-shifting in resolving logical tasks of classification. Index of total errors, perseverative and non-perseverative errors, and number of completed categories are presented as raw scores. Benton controlled oral word association test, phonemic fluency FAS (COWAT; Benton, 1969). This is a simple test of verbal fluency to measure speed in generating words that begin with the letters F, A, and S, in a minute. It was designed by Benton to assess aphasia. Data are presented as raw scores or total number of words generated. 2.3. Data analysis Multivariate analyses of variance (MANOVA) were calculated for each neuropsychological variable to observe the change over time between both groups. MANOVA F-statistics and p-values are presented in the text. Subsequent MANOVA was carried out by co-varying for mood-stabilizer treatment (lithium versus valproate) and for the presence of psychotic symptoms. Significant posthoc MANCOVA comparisons are presented in the text. The t-test for independent samples was applied to compare the means for age and months of follow-up between the two groups, and the t-test for repeated measures was applied to compare the mean scores for clinical tests. The type I error for all analyses was stated at 0.05. Data were processed with SPSS 15.0.

3. Results 3.1. Clinical and demographic data Because of the matching process, there were no differences at baseline between the two groups either for age (16.271.5 for the EOBD group, 16.371.9 for the HC group) or for gender distribution (12 girls in each group). There was a significant difference in the length of time between assessments, which was greater for the HC group than for the EOBD group (33 months versus 28 months, respectively, po0.001), which explains the mild difference, not a significant one, for age between the groups at follow-up (19.171.9 in HC versus 18.671.5 in EOBD). There were no significant differences in the EOBD cases for YMRS and BDI scores between baseline and follow-up, in spite of a slight increase in the mean score for mania symptoms at follow-up. YMRS and BDI were not administered to HC group at baseline, therefore those data are not displayed. At follow-up there was a significantly higher number of manic and depressive symptoms in the EOBD group than in the HC group (YMRS: EOBDfollow-up: 3.173, HCfollow-up: 0.170.2, po0.001; BDI: EOBD follow-up: 8.577.6, HCfollow-up: 1.972.3, po0.001). 3.2. Neuropsychological outcome Fig. 1 shows the performances of both samples at baseline and at follow-up in respect of a normalized HC baseline profile. Table 2 includes means and standard deviations for both samples at both moments. The MANOVA detected a significant change over time in several variables: ROCF copy accuracy (F39 ¼23.05, po0.001), ROCF immediate recall (F39 ¼ 15.77, po0.001), immediate logical verbal memory (F36 ¼10.06, po0.01), delayed logical verbal memory

S. Lera-Miguel et al. / Journal of Affective Disorders 172 (2015) 48–54

51

2 1 0 -1 -2 -3 -4 -5

Reasoning Attention/ Processing speed Execu ve Func ons Verbal Visual - Working Verbal Visual-Motor Control Set-shifting Motor Memory

Memory Verbal Visual-spatial

-6 -7

HC Baseline

EOBD Baseline

EOBD Follow-up

HC Follow-up

Fig. 1. Neuropsychological performance and change at baseline and follow-up, in relation to HC baseline performance.

Table 2 Means (standard deviation) for EOBD and HC samples at baseline and follow-up, and significant post-hoc comparisons. Measure

Early bipolar Baseline

Onset disorder Follow-up

Healthy Baseline

Control Follow-up

Vocabulary Block design Digits Letters/numbers Total FAS Stroop word Stroop color Stroop interference ROCF copy accuracy ROCF Imm recall ROCF copy time WCST total errors WCST perseverative WCST non-perseverative WCST no. categories Imm LogVerb memo Del LogVerb memo WMS-III Imm vis memo WMS-III Del vis memo

7.9 9.4 7.8 6.8 33.6 95.9 63.6 53.1 28.8 16.6 155.9 32.2 10.1 20.6 4.8 0.41 0.40 77.1 50.7

9.6 10 8.5 9 35.2 101.6 71 54.6 33.9 20.7 137.9 26.6 10.5 18.5 5.2 0.5 0.5 88 73

12.3 11.8 9.6 11.7 34.8 105.6 71.8 54.5 32.8 23 133.6 18.2 8.8 9.6 5.8 0.55 0.41 99.6 50.1

11.7 12.2 9.2 10.7 34.6 98.4 71.8 57.6 33.4 27 120.4 16 4.6 11.5 5.9 0.61 0.54 96.3 87.5

(0.3) (3.2) (3.4) (3.5) (7.8) (15.8) (13.2) (7.8) (4.9) (7.8) (47.4) (17) (1.9) (10.8) (1.9) (0.2) (0.2) (21.6) (29.1)

(0.4) (2.6) (2.7) (3.1) (10.1) (11.1) (11.6) (10.1) (3.6) (6.7) (33.2) (19) (2.6) (12.6) (1.7) (0.2) (0.2) (12.2) (21.3)

(2) (2.6) (2.6) (3.1) (8.5) (16.4) (6.7) (9.3) (2.5) (5.1) (38.5) (15.6) (7.4) (9) (0.7) (0.1) (0.1) (3.9) (33.5)

(1.9) (3.5) (3.3) (3.2) (9.7) (13) (7.6) (9) (3.3) (5.2) (34.1) (11.9) (4.4) (9) (0.5) (0.1) (0.1) (6.3) (14.7)

EOBDfu 4 EOBDbl

EOBDfu 4 EOBDbl EOBDfu 4 EOBDbl EOBDfu 4 EOBDbl EOBDfu 4 EOBDbl EOBDfu 4 EOBDbl; HCfu 4 HCbl

EOBDfu 4 EOBDbl; EOBDfu 4 EOBDbl; EOBDfu 4 EOBDbl; EOBDfu 4 EOBDbl;

HCfu 4 HCbl HCfu 4 HCbl HCfu o HCbl HCfu 4 HCbl

EOBD: early-onset bipolar disorder, HC: healthy controls, BL: baseline, FU: follow-up; YMRS: young mania rating scale; BDI: beck depression inventory; ROCF: Rey–Osterrieth complex figure test; WCST: Wisconsin card sorting test; Imm: immediate recall; Del: delayed recall; LogVerb Memo: logical verbal memory; WMS-III Vis Memo: visual memory of Wechsler Memory Scale, 3rd edition. Vocabulary, block design, digits and letters–numbers are presented as standard scores (mean 10, sd 3); the remaining measures as raw scores.

(F35 ¼20.5, po0.001), delayed visual memory (F36 ¼41.47, po 0.001), and stroop color naming (F34 ¼6.92, po0.05). These data indicate that the whole sample improved in visual organization and visual-motor skills, in verbal and visual memories, and in processing speed. Significant group  time interactions were observed in some variables, but most of them did not coincide with the variables mentioned above. The results indicated that the change between assessments was different between groups on: vocabulary (F38 ¼ 9.09, po0.01), letters–numbers (F38 ¼ 9.12, po0.01), stroop word reading (F33 ¼8.25, po0.01), and immediate visual memory (F35 ¼12.66, po0.001). Furthermore, the significant change reflected

for the whole group on ROCF copy accuracy was due to a significant improvement achieved by the EOBD cases (F38 ¼ 13.79, po0.001), while the change in stroop color naming is explained by the sharp increase in processing speed among the EOBD patients (F33 ¼ 6.92, po0.05). Thus, the EOBD group experienced greater improvement than the HC group in verbal reasoning, working memory, processing speed, visual-motor skills, and immediate visual recall. If EOBD patients with comorbid psychiatric conditions were excluded from the analyses, the results did not change. No measure of executive functions changed significantly over time. Some indexes, such as the FAS total score and WCST total errors, reflected improvement at follow-up for the EOBD sample,

52

S. Lera-Miguel et al. / Journal of Affective Disorders 172 (2015) 48–54

but this effect was far from reaching statistical significance EOBD performance in these cognitive functions remained lower than HC performance (Fig. 1). 3.3. Neuropsychological change, psychotic symptoms, and lithium MANCOVA were calculated to observe the differential effect of two variables. The first analysis reflected a time  group  presence interaction of psychotic symptoms only on the Interference index of the stroop test (F34 ¼7.93, p o0.05). The second showed another significant time  group  mood-stabilizer interaction on the same test (F34 ¼10.42, po 0.01). In this sense, the presence of psychotic symptoms and the use of lithium were related to a smaller improvement in executive control.

4. Discussion The aim of this naturalistic, prospective study was to observe the course of cognitive functions in euthymic adolescents with types I or II EOBD in mid-term psychiatric treatment, for at least two years. The interest was to observe whether changes in neuropsychological performance were similar to those achieved by healthy adolescents. Studies with children and adolescents need to consider the maturation and development of cognitive functions and control for the possible effect of learning in repeated assessments. Our results show that both groups, euthymic patients and controls, improve through time on some measures, such as visual and verbal memory. This may be due to a process of maturation involving the development of brain systems to increase their ability to process and store information, or also to a possible effect of maintained long-term recall (Roalf et al., 2014). Moreover, there were some neuropsychological tests in which patients with BD have improved from baseline to follow-up more than healthy adolescents or in which patients have improved while controls have declined. This differential effect appeared in verbal reasoning, working memory, processing speed, visual-motor skills, and some measures of visual memory; even, processing speed and visual-motor skills both normalized in EOBD sample at follow-up. We had hypothesized that EOBD would experience improvements in attention, working memory, and verbal memory while continuing to show general deficits with regard to healthy controls. However, only an improvement in working memory has been observed. The increase in attention scores was not great enough to be significant, while follow-up scores did not differ between EOBD and HC. EOBD scores in set-shifting and executive control did not improve, and rather remained lower than HC performance at follow-up, as did visual-spatial reasoning. In spite of the general increase in verbal and visual memory scores for both groups, the EOBD scores were lower than HC scores. By contrast, other unexpected performance increases occurred in EOBD, including better verbal reasoning, processing speed, and visual tasks. Turning to previous literature, our results corroborate those obtained by Pavuluri et al. (2009) in a 3-year follow-up study with treated children with pediatric bipolar disorder, in which cases improved in some cognitive domains, such as attention, visual memory, and working memory, but the whole neuropsychological profile remained impaired, particularly the executive functions and verbal memory. In a shorter follow-up study, patients treated with lamotrigine showed improvements in working memory and verbal memory compared with matched HC, and even appeared to be no longer impaired (Pavuluri et al., 2010); these findings are only partly observed in our study. Although the mean age of those samples is lower than our sample of adolescents, the outcomes evolved similarly. To our knowledge, there are no other controlled studies of cognitive

follow-up in samples with EOBD and the present study appears to be the first to assess adolescent patients in an euthymic state both at baseline and at follow-up. This difference in the initial affective state could explain the lack of significant improvement in attention and executive functions over the two years of follow-up in our study. Previous literature is controversial about cognitive impairment associated to disorder course. Some controlled, long-term followup studies with adults, diagnosed and treated as BD, have shown continued impairment of executive functions, while the course of attention is not consistent across the studies (Mur et al., 2008; Torrent et al., 2012). However, a recent meta-analysis of longitudinal studies has not found significant differences between patient and control neuropsychological outcomes, which remained stable for five years (Samamé et al., 2014). For several authors, executive dysfunction and memory deficits are the core endophenotypic traits present throughout the life of a subject with BD; they are even seen prior to the first appearance of the illness and can affect healthy relatives of patients with BD (Meyer et al., 2004; Schulze et al., 2011). However, other authors have not found consistent endophenotypic executive dysfunction. In this sense, only a third of young patients with type I BD have shown widespread executive deficits (Biederman et al., 2011) and unaffected relatives of BD patients have not always presented clear patterns of impaired performance (Arts et al., 2008; Jabben et al., 2010). Patients with EOBD need to be divided into subgroups according to the presence or absence of executive deficits, and then followed-up over time and across affective episodes. Patients with psychotic symptoms in our study did not evolve so differently from patients without a history of psychosis. In this respect, the sole finding relates to a lesser change in executive control in the presence of psychotic symptoms; however, for other cognitive functions, both subgroups behaved the same between assessments. Literature on adults with BD and psychoses have not consistently presented deficits; some studies show impairment in executive function, verbal memory or visual-spatial working memory (Martinez-Aran et al., 2008; Glahn et al., 2007), while others fail to detect differences between psychotic and nonpsychotic bipolar patients (Brissos et al., 2011). One work has found the same executive deficit on the Stroop test, but after co-varying with current psychopathologic symptoms, the deficit disappeared (Selva et al., 2007). In EOBD samples, reduced intellectual quotient was observed at the time of the first psychotic episode, similar to early onset schizophrenia (Arango et al., 2014; Zabala et al., 2010). In our study, differences in performance between EOBD with or without psychotic symptoms have not been analyzed, only their influence on change was observed. On the other hand, there were no clear significant differences between EOBD patients according to their mood-stabilizing treatment. Only one measure, the executive control, reflected a lower score in patients being treated with lithium compared to valproate. No other published studies have found differences in cognitive performance in BD patients treated with lithium or other moodstabilizers (Gualtieri and Johnson, 2006; Lopez-Jaramillo et al., 2010). Nevertheless, treatment with atypical antipsychotics seems to impair cognitive performance. Atypical antipsychotic drugs promote poorer cognitive performance in adults with BD and in healthy controls than in untreated patients in terms of verbal memory, attention, and processing speed (Torrent et al., 2011). We did not investigate the effect of antipsychotics because almost the entire sample was being treated with them. 4.1. Clinical implications This study increases the still limited knowledge of the cognitive development of adolescents once diagnosed as EOBD. After two years of psychiatric treatment certain cognitive functions presented

S. Lera-Miguel et al. / Journal of Affective Disorders 172 (2015) 48–54

improvement and performance on some tests reached normal levels. These findings of enhanced functions argue in favor of psychosocial and cognitive treatments in earlier phases of the illness. 4.2. Limitations The principal limitation of this study is the small sample size. For this reason, analyses of subgroups had not statistical power and are not conclusive. A second limitation was the different follow-up periods for each group, reflecting an older age of controls at follow-up that could explain better scores on memory, intellectual reasoning, and executive functions. Nevertheless, differences were not significant in several of these domains. A third limitation was the possible effect of long-term memory on outcomes that has not been controlled with the administration of parallel forms on memory tests at baseline and at follow-up. A final limitation is the absence of any analysis of doses for the antipsychotic drugs over time. Probably, initially higher doses could interfere in some of the functions that subsequently improved.

Role of funding source This research has been possible thanks to the grants obtained from CIBERSAM (Madrid, Spain) and Alicia Koplowitz Foundation (Madrid, Spain).

Conflict of interest All authors declare that they have no conflict of interest.

Acknowledgments We thank Ms. Alejandra Raventós, Ms. Montse Pàmias, and Mr. Samuel LópezAlcalde, who partially participated in the protocol adjustments and the recruitment of samples. This research has been possible thanks to the support from the Generalitat de Catalunya, AGAUR SGR-1119. This research has been possible thanks to the grants obtained from CIBERSAM (Madrid, Spain) and Alicia Koplowitz Foundation (Madrid, Spain).

References Arango, C., Fraguas, D., Parellada, M., 2014. Differential neurodevelopmental trajectories in patients with early-onset bipolar and schizophrenia disorders. Schizophr. Bull. 40 (Suppl. 2), 138–146. http://dx.doi.org/10.1093/schbul/sbt198. Arts, B., Jabben, N., Krabbendam, L., van Os, J., 2008. Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives. Psychol. Med. 38, 771–785. Beck, A.T., Ward, C.H., Mendelson, M., Mock, J., Erbaugh, J., 1961. An inventory for measuring depression. Arch. Gen. Psychiatry 4, 561–571. Biederman, J., Petty, C.R., Wozniak, J., Wilens, T.E., Fried, R., Doyle, A., Henin, A., Bateman, C., Evans, M., Faraone, S.V., 2011. Impact of executive function deficits in youth with bipolar I disorder: a controlled study. Psychiatry Res. 186, 58–64. Bora, E., Yucel, M., Pantelis, C., 2009. Cognitive endophenotypes of bipolar disorder: a meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. J. Affect. Disord. 113, 1–20. Brissos, S., Dias, V.V., Soeiro-de-Souza, M.G., Balanza-Martinez, V., Kapczinski, F., 2011. The impact of a history of psychotic symptoms on cognitive function in euthymic bipolar patients: a comparison with schizophrenic patients and healthy controls. Rev. Bras. Psiquiatr. 33, 353–361. Benton, A.L., 1969. Development of a multilingual aphasia battery. Progress and problems. J. Neurol. Sci. 9, 39–48. Cahill, C.M., Walter, G., Malhi, G.S., 2009. Neurocognition in bipolar disorder and juvenile bipolar disorder. J. Can. Acad. Child Adolesc. Psychiatry 18, 221–230. Carlson, G.A., Findling, R.L., Post, R.M., Birmaher, B., Blumberg, H.P., Correll, C., DelBello, M.P., Fristad, M., Frazier, J., Hammen, C., Hinshaw, S.P., Kowatch, R., Leibenluft, E., Meyer, S.E., Pavuluri, M.N., Wagner, K.D., Tohen, M., 2009. AACAP 2006 research forum – advancing research in early-onset bipolar disorder: barriers and suggestions. J. Child Adolesc. Psychopharmacol. 19, 3–12. Colom, F., Vieta, E., Martinez-Aran, A., Garcia-Garcia, M., Reinares, M., Torrent, C., Goikolea, J.M., Banús, S., Salamero, M., 2002. Spanish version of a scale for the assessment of mania: validity and reliability of the young mania rating scale. Med. Clin. (Barc.) 119, 366–371. Doyle, A.E., Wilens, T.E., Kwon, A., Seidman, L.J., Faraone, S.V., Fried, R., Swezey, A., Snyder, L., Biederman, J., 2005. Neuropsychological functioning in youth with bipolar disorder. Biol. Psychiatry 58, 540–548. Doyle, A.E., Wozniak, J., Wilens, T.E., Henin, A., Seidman, L.J., Petty, C., Fried, R., Gross, L.M., Faraone, S.V., Biederman, J., 2009. Neurocognitive impairment in

53

unaffected siblings of youth with bipolar disorder. Psychol. Med. 39, 1253–1263. Frangou, S., Haldane, M., Roddy, D., Kumari, V., 2005. Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder. Biol. Psychiatry 58, 838–839. Glahn, D.C., Bearden, C.E., Barguil, M., Barrett, J., Reichenberg, A., Bowden, C.L., Soares, J.C., Velligan, D.I., 2007. The neurocognitive signature of psychotic bipolar disorder. Biol. Psychiatry 62, 910–916. Golden, C.J., Marsella, A.J., Golden, E.E., 1975. Personality correlates of the stroop color and word test: more negative results. Percep. Mot. Skills 41, 599–602. Golden, C.J., 2005. Test de Colores y Palabras (Stroop). TEA Ediciones, Madrid. Gualtieri, C.T., Johnson, L.G., 2006. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. Med. Gen. Med. 8, 46. Heaton, R.K., Chelune, G.J., Talley, J.L., Kay, G., Curtiss, G., 1997. Wisconsin Card Sorting Test (WCST). TEA Ediciones, Madrid. Holmes, M.K., Erickson, K., Luckenbaugh, D.A., Drevets, W.C., Bain, E.E., Cannon, D.M., Snow, J., Sahakian, B.J., Manji, H.K., Zarate, C.A., 2008. A comparison of cognitive functioning in medicated and unmedicated subjects with bipolar depression. Bipolar Disord. 10, 806–815. Heaton, R.K., 1981. Wisconsin Card Sorting Test Manual. Psychological Assessment Resource Inc., Odessa, FL. Jabben, N., Arts, B., van Os, J., Krabbendam, L., 2010. Neurocognitive functioning as intermediary phenotype and predictor of psychosocial functioning across the psychosis continuum: studies in schizophrenia and bipolar disorder. J. Clin. Psychiatry 71, 764–774. Joseph, M.F., Frazier, T.W., Youngstrom, E.A., Soares, J.C., 2008. A quantitative and qualitative review of neurocognitive performance in pediatric bipolar disorder. J. Child Adolesc. Psychopharmacol. 18, 595–605. Karakurt, M.N., Karabekiroğllu, M.Z., Yüce, M., Baykal, S., Şenses, A., 2013. Neuropsychological profiles of adolescents with bipolar disorder and adolescents with a high risk of bipolar disorder. Turk. Psikiyatri. Derg. 24, 221–230. Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., Williamson, D., Ryan, N., 1997. Schedule for affective disorders and schizophrenia for schoolage children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J. Am. Acad. Child Adolesc. Psychiatry 36, 980–988. Lazaro, L., Castro-Fornieles, J., de la Fuente, J.E., Baeza, I., Morer, A., Pamias, M., 2007. Differences between prepubertal- versus adolescent- onset bipolar disorder in a Spanish clinical sample. Eur. Child Adolesc. Psychiatry 16, 510–516. Lera-Miguel, S., Andres-Perpina, S., Calvo, R., Fatjo-Vilas, M., Fananas, L., Lazaro, L., 2011. Early-onset bipolar disorder: how about visual-spatial skills and executive functions? Eur. Arch. Psychiatry Clin. Neurosci. 261, 195–203. Lopez-Jaramillo, C., Lopera-Vasquez, J., Ospina-Duque, J., Garcia, J., Gallo, A., Cortez, V., Palacio, C., Torrent, C., Martinez-Aran, A., Vieta, E., 2010. Lithium treatment effects on the neuropsychological functioning of patients with bipolar I disorder. J. Clin. Psychiatry 71, 1055–1060. Martinez-Aran, A., Torrent, C., Tabares-Seisdedos, R., Salamero, M., Daban, C., Balanza-Martinez, V., Sanchez-Moreno, J., Goikolea, M.J., Benabarre, A., Colom, F., Vieta, E., 2008. Neurocognitive impairment in bipolar patients with and without history of psychosis. J. Clin. Psychiatry 69, 233–239. McClellan, J., Kowatch, R., Findling, R.L., 2007. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J. Am. Acad. Child Adolesc. Psychiatry 46, 107–125. Meyer, S.E., Carlson, G.A., Wiggs, E.A., Martinez, P.E., Ronsaville, D.S., KlimesDougan, B., Gold, P.W., Radke-Yarrow, M., 2004. A prospective study of the association among impaired executive functioning, childhood attentional problems, and the development of bipolar disorder. Dev. Psychopathol. 16, 461–476. Mur, M., Portella, M.J., Martinez-Aran, A., Pifarre, J., Vieta, E., 2008. Long-term stability of cognitive impairment in bipolar disorder: a 2-year follow-up study of lithium-treated euthymic bipolar patients. J. Clin. Psychiatry 69, 712–719. Nieto, R.G., Castellanos, F.X., 2011. A meta-analysis of neuropsychological functioning in patients with early onset schizophrenia and pediatric bipolar disorder. J. Clin. Child Adolesc. Psychol. 40, 266–280. Pavuluri, M.N., Passarotti, A.M., Mohammed, T., Carbray, J.A., Sweeney, J.A., 2010. Enhanced working and verbal memory after lamotrigine treatment in pediatric bipolar disorder. Bipolar Disord. 12, 213–220. Pavuluri, M.N., West, A., Hill, S.K., Jindal, K., Sweeney, J.A., 2009. Neurocognitive function in pediatric bipolar disorder: 3-year follow-up shows cognitive development lagging behind healthy youths. J. Am. Acad. Child Adolesc. Psychiatry 48, 299–307. Perlis, R.H., Dennehy, E.B., Miklowitz, D.J., Delbello, M.P., Ostacher, M., Calabrese, J.R., Ametrano, R.M., Wisniewski, S.R., Bowden, C.L., Thase, M.E., Nierenberg, A.A., Sachs, G., 2009. Retrospective age at onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study. Bipolar Disord. 11, 391–400. Post, R.M., Leverich, G.S., Kupka, R.W., Keck Jr., P.E., McElroy, S.L., Altshuler, L.L., Frye, M.A., Luckenbaugh, D.A., Rowe, M., Grunze, H., Suppes, T., Nolen, W.A., 2010. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J. Clin. Psychiatry 71, 864–872. Rey, A., 1980. Test de la Figura Compleja de Rey. TEA Ediciones, Madrid. Reynolds, C.R., Bigler, E.D., 1994. Test of Memory and Learning. Pro-Ed, Austin, TX. Reynolds, C.R., Bigler, E.D., 2001. TOMAL: Test de Memoria y Aprendizaje. TEA Ediciones, Madrid. Roalf, D.R., Gur, R.E., Ruparel, K., Calkins, M.E., Satterthwaite, T.D., Bilker, W.B., Hakonarson, H., Harris, L.J., Gur, R.C., 2014. Within-individual variability in neurocognitive performance: age- and sex-related differences in children and youths from ages 8 to 21. Neuropsychology (Epub ahead of print).

54

S. Lera-Miguel et al. / Journal of Affective Disorders 172 (2015) 48–54

Samamé, C., Martino, D.J., Strejilevich, S.A., 2014. Longitudinal course of cognitive deficits in bipolar disorder: a meta-analytic study. J. Affect. Disord. 164, 130–138. http://dx.doi.org/10.1016/j.jad.2014.04.028. Santos, J.L., Aparicio, A., Bagney, A., Sánchez-Morla, E.M., Rodríguez-Jiménez, R., Mateo, J., Jiménez-Arriero, M.A., 2014. A five-year follow-up study of neurocognitive functioning in bipolar disorder. Bipolar Disord. http://dx.doi.org/10.1111/bdi.12215 (Epub ahead of print). Schulze, K.K., Walshe, M., Stahl, D., Hall, M.H., Kravariti, E., Morris, R., Marshall, N., McDonald, C., Murray, R.M., Bramon, E., 2011. Executive functioning in familial bipolar I disorder patients and their unaffected relatives. Bipolar Disord. 13, 208–216. Selva, G., Salazar, J., Balanza-Martinez, V., Martinez-Aran, A., Rubio, C., Daban, C., Sanchez-Moreno, J., Vieta, E., Tabares-Seisdedos, R., 2007. Bipolar I patients with and without a history of psychotic symptoms: do they differ in their cognitive functioning? J. Psychiatr. Res. 41, 265–272. Torrent, C., Martinez-Aran, A., Daban, C., Amann, B., Balanza-Martinez, V., Bonnin, C., Cruz, N., Franco, C., Tabares-Seisdedos, R., Vieta, E., 2011. Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients. Compr. Psychiatry 52, 613–622. Torrent, C., Martinez-Aran, A., del Mar, B.C., Reinares, M., Daban, C., Sole, B., Rosa, A.R., Tabares-Seisdedos, R., Popovic, D., Salamero, M., Vieta, E., 2012. Long-term outcome of cognitive impairment in bipolar disorder. J. Clin. Psychiatry 73, e899–e905. http://dx.doi.org/10.4088/JCP.11m07471. Udal, A.H., Oygarden, B., Egeland, J., Malt, U.F., Groholt, B., 2012. Memory in early onset bipolar disorder and attention-deficit/hyperactivity disorder: similarities and differences. J. Abnorm. Child Psychol. 40, 1179–1192. http://dx.doi.org/ 10.1007/s10802-012-9631-x. Ulloa, R.E., Ortiz, S., Higuera, F., Nogales, I., Fresan, A., Apiquian, R., Cortés, J., Arechavaleta, B., Foulliux, C., Martínez, P., Hernández, L., Domínguez, E., de la

Peña, F., 2006. Interrater reliability of the Spanish version of schedule for affective disorders and schizophrenia for school-age children – present and lifetime version (K-SADS-PL). Actas Esp. Psiquiatr. 34, 36–40. Vázquez, C., Sanz, J., 1978. Adaptación Española del Inventario de Depresión de Beck: Propiedades Psicométricas y Clínicas en Muestras Clínicas y en Población General. Universidad Complutense, Facultad de Psicología, Madrid. Wang, L.J., Yeh, C.B., Huang, Y.S., Tang, C.S., Chou, W.J., Chou, M.C., Chen, C.K., 2012. Neurocognitive effects of aripiprazole in adolescents and young adults with bipolar disorder. Nord. J. Psychiatry 66, 276–282. Wechsler, D., 1999. Escala de Inteligencia de Wechsler para Adultos-III. TEA Ediciones, Madrid. Wechsler, D., 2006. Escala de Inteligencia de Wechsler para Niños, 4a edición. TEA Ediciones, Madrid. Wechsler, D., 2004. The Wechsler Intelligence Scale for Children, fourth ed. Pearson Assessment, London. Wechsler, D., 1997a. Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) Administration and Scoring Manual. The Psychological Corporation A Harcourt Assessment Company, San Antonio, TX. Wechsler, D., 1997b. Wechsler Memory Scale-Third Edition Administration and Scoring Manual. The Psychological Corporation, San Antonio, TX. Young, RC., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating scale for mania: reliability, validity and sensitivity. Br. J. Psychiatry 133, 429–435. Zabala, A., Rapado, M., Arango, C., Robles, O., de la Serna, E., González, C., RodríguezSánchez, J.M., Andrés, P., Mayoral, M., Bombín, I., 2010. Neuropsychological functioning in early-onset first-episode psychosis: comparison of diagnostic subgroups. Eur. Arch. Psychiatry Clin. Neurosci. 260, 225–233. http://dx.doi.org/ 10.1007/s00406-009-0046-9.