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ScienceDirect Comprehensive Psychiatry xx (2015) xxx – xxx www.elsevier.com/locate/comppsych
Executive function in parents of patients with familial versus sporadic bipolar disorder Ferdi Kosger⁎, Altan Essizoglu, Mehmet Baltacioglu, Nuriye Ulkgun, Cinar Yenilmez Eskisehir Osmangazi University, Faculty of Medicine, Department of Psychiatry, Eskisehir, Turkey
Abstract Objective: Studies investigating the cognitive function of healthy relatives of patients with bipolar disorder are conflicting, and the neurocognitive profile of relatives of bipolar disorder probands is still unclear. We aimed to evaluate executive function in unaffected parents of familial and sporadic patients with bipolar disorder. Methods: The study included 24 unaffected familial parents (FP) of patients with bipolar disorder, 26 unaffected sporadic parents (SP) of patients with bipolar disorder and 26 controls matched with the parents for gender, age and duration of education (76 subjects in total). All of the subjects were interviewed with the Structured Clinical Interview for DSM-IV-Axis I. Executive function was assessed using the California Verbal Learning Test (CVLT), the Trail Making Test (TMT), the Wisconsin Card Sorting Test (WCST) and the Stroop test. Results: In comparison to their respective matched controls, FP performed significantly worse on the CVLT, TMT, WCST and Stroop test, whereas SP performed significantly worse only on WCST perseverative errors and Stroop color test. FP performed significantly worse than SP on the CVLT, TMT, and WCST. Conclusion: The present study investigated relatives with and without a family history of bipolar disorder separately and found that executive function was impaired in parents with a positive family history of bipolar disorder. These findings bring more evidence suggesting that deficits in prefrontal executive function and verbal memory are associated with familial vulnerability to bipolar disorder and that executive function and verbal memory impairments may represent a potential endophenotype of bipolar disorder. © 2015 Elsevier Inc. All rights reserved.
1. Introduction The family studies about bipolar disorder suggest that there is a genetic basis of the disease [1–3]. Endophenotypes are observable characteristics that can be robustly and reliably measured and are thought to be strongly genetic in origin. To be considered an endophenotype, a marker must be associated with illness in the population, be heritable, and be state independent, and both the marker and the illness must co-segregate within the family [4]. It is important to identify an endophenotype in bipolar disorder for predicting which individuals are at increased risk for developing bipolar disorder [5]. Impairments in cognitive function such as executive functioning, processing speed, attention and verbal memory have been reported in euthymic bipolar patients [6–9]. Cognitive functions have been considered potential endophe-
⁎ Corresponding author. Tel.: +90 222 2392979. E-mail address: [email protected] (F. Kosger). http://dx.doi.org/10.1016/j.comppsych.2015.05.013 0010-440X/© 2015 Elsevier Inc. All rights reserved.
notypic markers of bipolar disorder, and cognitive functions of relatives of patients with bipolar disorder have been investigated in recent years. Nevertheless, studies investigating cognitive function in healthy relatives of patients with bipolar disorder are conflicting, and the neurocognitive profile of relatives of bipolar disorder probands is still unclear [10]. Some studies have reported impaired response inhibition in healthy relatives of patients with bipolar disorder [11–14], whereas other studies reported intact response inhibition [15–18]. Moreover, most of the studies reported intact set shifting and cognitive flexibility [11,14,15,19–22], and some studies reported impairments in those abilities [23,24]. Studies conducted on cognitive test performance of patients' relatives show that these studies have some limitations. The healthy relatives were mostly selected from mixed relative groups (include not only unaffected parents but also patients' offspring and siblings) [11,13–18,22,23,25,26], and the majority of the studies involved siblings [12,18–20,24,27] or even offspring [21]. Studying parents rather than siblings decreases common environmental factors, which are more present among siblings and may be confused with heredity.
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Additionally, compared to siblings, parent groups have a lower risk of conversion to bipolar disorder because of their advanced age. Previous studies have always investigated relatives with and without genetic loading as a mixed group without distinguishing them from each other. In this study, we tested whether executive function deficits were potential markers of genetic vulnerability to bipolar disorder using a more careful design. First, we separated parents of patients with bipolar disorder into two groups, familial and sporadic. A patient's parent who had a family history of bipolar disorder (except for his/her children) in first-degree relatives was selected for the familial parent (FP) group. A patient's parent who had no family history of bipolar disorder was selected for the sporadic parent (SP) group. The purpose of the FP-SP division was to produce populations with presumed high and low genetic liability to bipolar disorder. Measuring cognitive function in healthy relatives of patients who have genetic vulnerability could help to determine which cognitive impairments may be endophenotypes of bipolar disorder. We investigated the cognitive function of the FP, SP and healthy control groups (matched for gender, age and duration of education). We hypothesized that if executive function deficits are endophenotypes of bipolar disorder, unaffected FP should have more deficits than unaffected SP. The goal of our study is to evaluate executive function in unaffected FP and SP. 2. Materials and methods 2.1. Setting and sample Our study involved 24 FP of patients with familial bipolar I disorder and 26 SP of patients with sporadic bipolar I disorder. The study also included 26 healthy controls who matched the parents with respect to age, gender and duration of education, resulting in a total population of 76 subjects. Parents of patients were recruited from the Affective Disorders Unit of Eskisehir Osmangazi University Medical School and participated in the study between June 2013 and January 2015. Patients were diagnosed using the Structured Clinical Interview for DSM-IV (SCID-I) [28,29]. Only patients with a history of psychotic features (delusions or hallucinations) during their mood episodes were included in the study. Parents and their controls were screened with the SCID-I, and those who met criteria for any psychiatric disorder were excluded. Exclusion criteria for all subjects included mental retardation, identifiable neurological disorder or significant medical illness, substance use in the past 6 months, visual impairment, color blindness, younger than 18 years and older than 65 years. In the FP group we included only parents with who had bipolar disorder in his/her first degree relatives (mother, father, brother, or sister). The SP group did not have family histories of bipolar disorder by definition. Healthy controls were recruited from the hospital cleaning staff, and they were excluded if they had positive family histories of bipolar
disorder or psychosis. Neither parents nor controls used any psychotropic medications. After description of the study, written informed consent was obtained from all participants. All participants were administered the California Verbal Learning Test (CVLT) [30], Trail Making Test (TMT) [31], Stroop test [32,33], and Wisconsin Card Sorting Test (WCST) [34] in the same order by an investigator (N.U.). The interviewing and screening process with the SCID-I was conducted by another investigator (M.B.). All raters were blind. 2.2. Instruments The CVLT is a widely used clinical test of verbal declarative memory and of executive function [30]. The administration procedure involves the oral presentation and recall of a 16-item word list over five learning trials, a single presentation of a second list, short and long delay recall trials of the first list, and a recognition trial of the first list. We used learning trials 1–5 (total), free short recall, free delayed recall, and recognition parameters of the test. The TMT was developed by Reitan [31]. It is a test of complex visual scanning with a motor component, which can evaluate the flexibility in shifting the course of an ongoing activity. It consists of two sections: Section A and Section B. Section B is an indicator of executive function as well. Our study used the test durations and the number of errors. The Stroop test is a test of selective attention [32]. The scores were the number of items completed in 45 seconds during three trials. The first trial consists of reading the names of colors. The second trial is color naming. The third trial tests the interference with the color–word score as suggested by Golden [33]. The WCST was developed by Heaton [34]. It is a measure of executive function and abstract thinking in which participants are required to shift a mental set as they match 128 stimulus cards on the basis of color, shape or number with minimal instruction or feedback from the examiner. It is considered particularly sensitive for dorsolateral prefrontal cortex function. Our study used the number of categories achieved and the number of perseverative errors. Complex attention, response inhibition, working memory and cognitive flexibility are the important parts of executive function that enable us to create a plan, initiate its execution and persevere on the task at hand until its completion [35]. Therefore, executive tests are likely to reflect various cognitive processes. The CVLT measures verbal memory and learning. The TMT part A measures processing speed, and part B measures processing speed together with set shifting and selective attention. The Stroop test measures response inhibition. The WCST measures the acquisition of new rules and the initiation of appropriate actions [35]. These tests share an underlying commonality. For instance, both the WCST and the TMT-B measure set shifting [35]. Furthermore, the same test may measure two different components of executive functioning, such that WCST may assess attention control as well as cognitive flexibility [35].
F. Kosger et al. / Comprehensive Psychiatry xx (2015) xxx–xxx
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Table 1 Demographic characteristics of parent and control groups.
Male/female (n) Age, mean ± SD (years) Education, mean ± SD, (years) Employee/unemployed/retired (n)
FP (n = 24)
SP (n = 26)
Control (n = 26)
Statistical test
13/11 57.54 ± 7.58 7.71 ± 3.22 6/11/7
12/14 56.08 ± 5.77 9.50 ± 4.18 8/10/8
13/13 54.15 ± 3.27 9.81 ± 3.44 13/6/7
χ 2 = 0.312,p = 0.852 H = 2.310, p = 0.315 H = 4.553, p = 0.103 χ 2 = 4.429, p = 0.351
FP: familial parent, SP: sporadic parent, SD: standard deviation.
Therefore, it is difficult to measure executive function selectively, and executive tests should be used together for precise results [36,37]. 2.3. Statistical analysis The data analysis was performed using the SPSS (Statistical Package for Social Sciences) program, Version 21.0 for Windows. The gender distribution was compared using the chi-square test. Kolmogorov–Smirnov test was performed for normality. Age, duration of education and test scores were compared using the Kruskal–Wallis test, as the data distribution was not normal. Pairwise comparison was applied for multiple comparisons of the groups. In all analyses, p levels (two tailed) less than 0.05 were considered statistically significant. 2.4. Ethics The study protocol was approved by the Regional Ethics Committee of Eskisehir Osmangazi University, Faculty of Medicine.
3. Results The FP and SP groups and their respective matched control groups did not differ significantly in gender distribution, age, duration of education, and employment (Table 1). Compared to their respective matched controls, the FP group performed significantly worse on the verbal memory, learning, processing speed, set shifting, selective attention, cognitive flexibility, and response inhibition, whereas the SP group performed significantly worse only on the cognitive flexibility and response inhibition. Additionally, the FP group performed significantly worse than the SP group on the verbal memory, learning, processing speed, set shifting, selective attention, and cognitive flexibility (Table 2). However, a significant difference was observed between FP and control group for education (z = 2.156, p b 0.05). Hence, non-parametric or rank analysis of covariance test (Quade's test) [38] was performed for correction of the effect of education on the verbal memory and executive function in which education was modeled as covariate. Consequently, the results which founded by pairwise comparison did not vary.
4. Discussion The current study provides evidence for impairments of verbal memory and executive function in the patients' parents who had a family history of bipolar disorder compared to parents of sporadic bipolar patients and controls. Impairments in verbal memory, learning, processing speed, set shifting, selective attention, and response inhibition have been widely reported in relatives of bipolar disorder patients [12,13,19,20,22,25,26]. Deficits in cognitive flexibility have been reported previously [13,23]. However, previous research has presented evidence that unaffected relatives of patients with bipolar disorder are not impaired in cognitive flexibility [11,20–22,27]. Additionally, a meta-analysis emphasized impairments in set shifting and selective attention but not in cognitive flexibility, in relatives of bipolar disorder patients [6]. Erol et al. also reported impairments in processing speed, selective attention, and response inhibition but not in cognitive flexibility in their parent-only study and indicated that deficits in tasks of ventral, but not dorsal prefrontal, executive function may reflect familial predisposition to bipolar disorder. That study included 50 unaffected parents of patients with bipolar disorder, so the sample size was large [39]. However, parents were not evaluated for family history of bipolar disorder in that study. Bora et al. discussed that these seemingly inconsistent findings could be related to the effect of proneness to psychotic features in mood episodes and reported that deficits in cognitive flexibility were found only in relatives of probands with a history of psychotic mood episodes. They indicated that a cognitive flexibility deficit may be an endophenotype of psychosis in general [13]. However, the relatives of probands with a history of psychotic mood episodes were composed of only 10 volunteers, and mixed relatives were included in that study. We found that the FP group performed significantly worse than the SP group in verbal memory, learning, processing speed, set shifting, selective attention, and cognitive flexibility. Both groups had probands with a history of psychotic features during their mood episodes in our study. This finding may be incompatible with the argument that the cognitive flexibility deficit may be an endophenotype of psychosis in general. However, we should state that a cognitive flexibility deficit is widely reported in schizophrenia [36]. The argument that a cognitive flexibility deficit may be an endophenotype of psychosis should be studied with larger sample sizes. We should indicate that attention, response inhibition, working memory and cognitive flexibility are important
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Table 2 Comparison of test scores between the FP, SP and control groups. Test
FP (mean ± SD)
SP (mean ± SD)
Control (mean ± SD)
Kruskal–Wallis test
Pairwise comparison (Dunn test)
39.50 ± 10.68
49.46 ± 6.54
48.62 ± 8.47
H = 13.205 p b 0.01
8.21 ± 2.75
11.42 ± 1.90
10.54 ± 2.40
H = 17.287 p b 0.001
8.88 ± 3.19
12.27 ± 1.97
11.35 ± 2.51
H = 16.014 p b 0.001
86.25 ± 8.43
95.88 ± 3.68
89.54 ± 19.42
H = 18.556 p b 0.001
WCST categories achieved
1.13 ± 1.30
3.23 ± 1.63
4.50 ± 1.63
H = 36.305 p b 0.001
WCST perseverative errors
52.96 ± 26.52
40.85 ± 22.89
23.46 ± 13.51
H = 18.995 p b 0.001
TMT part A seconds
82.25 ± 34.45
67.08 ± 20.98
53.77 ± 19.02
H = 13.675 p b 0.01
0.42 ± 0.50
0.12 ± 0.43
0.12 ± 0.33
H = 10.034 p b 0.01
197.50 ± 95.71
105.88 ± 42.49
98.62 ± 29.87
H = 19.210 p b 0.001
TMT part B errors
2.38 ± 1.91
0.42 ± 0.76
0.35 ± 0.56
H = 25.738 p b 0.001
Stroop color score
20.88 ± 6.46
18.00 ± 6.96
13.81 ± 2.73
H = 21.025 p b 0.001
Stroop word score
29.83 ± 8.70
24.42 ± 7.41
20.15 ± 4.12
H = 17.177 p b 0.001
Stroop color word score
39.42 ± 12.67
34.50 ± 9.99
28.88 ± 5.98
H = 13.194 p b 0.01
FP-control p b 0.01 FP-SP p b 0.01 SP-control p = 1.00 FP-control p b 0.05 FP-SP p b 0.001 SP-control p = 0.773 FP-control p b 0.05 FP-SP p b 0.001 SP-control p = 0.641 FP-control p b 0.05 FP-SP p b 0.001 SP-control p = 0.366 FP-control p b 0.001 FP-SP p b 0.001 SP-control p = 0.084 FP-control p b 0.001 FP-SP p = 0.537 SP-control p b 0.01 FP-control p b 0.01 FP-SP p = 0.429 SP-control p = 0.075 FP-control pp b 0.05 FP-SP p b 0.05 SP-control p = 1.00 FP-control p b 0.001 FP-SP p b 0.01 SP-control p = 1.00 FP-control p b 0.001 FP-SP p b 0.001 SP-control p = 1.00 FP-control p b 0.001 FP-SP p = 0.120 SP-control p b 0.05 FP-control p b 0.001 FP-SP p = 0.068 SP-control p = 0.172 FP-control p b 0.01 FP-SP p = 0.425 SP-control p = 0.089
CVLT Free short recall
CVLT Free delayed recall
CVLT Learning trials 1–5 (total)
CVLT Recognition
TMT part A errors
TMT part B seconds
FP: familial parent, SP: sporadic parent, SD: standard deviation, CVLT: California Verbal Learning Test, TMT: Trail Making Test, WCST: Wisconsin Card Sorting Test.
components of executive function and that tests of executive function should be used together for precise results. There are mixed results in the neuroimaging studies that have been conducted with unaffected relatives of patients with bipolar disorder. Van der Schot et al. found that genetic liability for bipolar disorder is associated with decreased gray matter in the right medial frontal gyrus and the right insula and increased gray matter in the right orbitofrontal gyrus [40]. In contrast, McDonald et al. found that gray matter deficits of the right anterior cingulate gyrus and ventral striatum were associated with genetic risk for bipolar disorder [41]. Kempton et al. reported that the genetic predisposition to bipolar disorder was associated with increased left insula volume [42], whereas Matsuo et al. indicated an association with the right insula [43]. In addition to these reports, a recent, more carefully designed study conducted with unaffected healthy siblings of patients with
bipolar disorder suggested that a reduction in the volume of the orbitofrontal cortex is associated with the heritability of bipolar disorder [44]. This suggestion is partially consistent with our findings. Our study has various advantages. First, executive function was evaluated with multiple tests that measure various aspects of executive function. Second, our study involved only parents and has the advantages of a parent-only study. To our knowledge, this is the first parent-only study on executive function in relatives of bipolar disorder patients, differentiated with respect to genetic loading. A limitation of this study is the lack of IQ and premorbid IQ measures of the groups. Another limitation of our study is the relatively small sample size. Our findings need to be replicated in future studies which should consider the dose effect of genetics with larger sample sizes.
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In conclusion, our results support that deficits in prefrontal executive function are associated with familial vulnerability to bipolar disorder and that executive function and verbal memory impairments may represent a potential endophenotype of bipolar disorder.
Competing interest statement The authors have no competing interests to report. Acknowledgment The authors would like to thank Ertugrul Colak, Associate Professor of Biostatistic. References [1] McInnis MG. Recent advances in the genetics of bipolar disorder. Psychiatr Ann 1997;27:482-8. [2] Blackwood DH, Visscher PM, Muir WJ. Genetic studies of bipolar affective disorder in large families. Br J Psychiatry Suppl 2001;178:134-6. [3] Sourney D, Mussat I, Mendlewicz J. Genetics of BPD. J Affect Disord 2000;18:278-86. [4] Gottesman II, Gould TJ. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003;160:636-45. [5] Frantom LV, Allen DN, Cross CL. Neurocognitive endophenotypes for bipolar disorder. Bipolar Disord 2008;10:387-99. [6] Arts B, Jabben N, Krabbendam L, van Os J. Meta-analyses of cognitive functioning in euthymic bipolar patients and their first degree relatives. Psychol Med 2008;38:771-85. [7] Torres IJ, Boudreau VG, Yatham LN. Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr Scand 2007;434:17-26. [8] Robinson LJ, Thompson JM, Gallagher P, Goswami U, Young AH, Ferrier IN, et al. A metaanalysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 2006;93:105-15. [9] Bora E, Yucel M, Pantelis C. Cognitive endophenotypes of bipolar disorder: a meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. J Affect Disord 2009;113:1-20. [10] Balanza-Martinez V, Rubio C, Selva-Vera G, Martinez-Aran A, Sanchez-Moreno J, Salazar-Fraile J, et al. Neurocognitive endophenotypes (endophenocognitypes) from studies of relatives of bipolar disorder subjects: a systematic review. Neurosci Biobehav Rev 2008;32:1426-38. [11] Zalla T, Joyce C, Szoke A, Schurhoff F, Pillon B, Komano O, et al. Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res 2004;121:207-17. [12] Christensen MV, Kyvik KO, Kessing LV. Cognitive function in unaffected twins discordant for affective disorder. Psychol Med 2006;36:1119-29. [13] Bora E, Vahip S, Akdeniz F, Ilerisoy H, Aldemir E, Alkan M. Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder. Psychiatry Res 2008;161:318-24. [14] Schulze KK, Walshe M, Stahl D, Hall MH, Kravariti E, Morris R, et al. Executive functioning in familial bipolar I disorder patients and their unaffected relatives. Bipolar Disord 2011;13:208-16. [15] Kremen WS, Faraone SV, Seidman LJ, Pepple JR, Tsuang MT. Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands. Psychiatry Res 1998;79:227-40.
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Executive function in parents of patients with familial versus sporadic bipolar disorder Ferdi Kosger⁎, Altan Essizoglu, Mehmet Baltacioglu, Nuriye Ulkgun, Cinar Yenilmez Eskisehir Osmangazi University, Faculty of Medicine, Department of Psychiatry, Eskisehir, Turkey
Abstract Objective: Studies investigating the cognitive function of healthy relatives of patients with bipolar disorder are conflicting, and the neurocognitive profile of relatives of bipolar disorder probands is still unclear. We aimed to evaluate executive function in unaffected parents of familial and sporadic patients with bipolar disorder. Methods: The study included 24 unaffected familial parents (FP) of patients with bipolar disorder, 26 unaffected sporadic parents (SP) of patients with bipolar disorder and 26 controls matched with the parents for gender, age and duration of education (76 subjects in total). All of the subjects were interviewed with the Structured Clinical Interview for DSM-IV-Axis I. Executive function was assessed using the California Verbal Learning Test (CVLT), the Trail Making Test (TMT), the Wisconsin Card Sorting Test (WCST) and the Stroop test. Results: In comparison to their respective matched controls, FP performed significantly worse on the CVLT, TMT, WCST and Stroop test, whereas SP performed significantly worse only on WCST perseverative errors and Stroop color test. FP performed significantly worse than SP on the CVLT, TMT, and WCST. Conclusion: The present study investigated relatives with and without a family history of bipolar disorder separately and found that executive function was impaired in parents with a positive family history of bipolar disorder. These findings bring more evidence suggesting that deficits in prefrontal executive function and verbal memory are associated with familial vulnerability to bipolar disorder and that executive function and verbal memory impairments may represent a potential endophenotype of bipolar disorder. © 2015 Elsevier Inc. All rights reserved.
1. Introduction The family studies about bipolar disorder suggest that there is a genetic basis of the disease [1–3]. Endophenotypes are observable characteristics that can be robustly and reliably measured and are thought to be strongly genetic in origin. To be considered an endophenotype, a marker must be associated with illness in the population, be heritable, and be state independent, and both the marker and the illness must co-segregate within the family [4]. It is important to identify an endophenotype in bipolar disorder for predicting which individuals are at increased risk for developing bipolar disorder [5]. Impairments in cognitive function such as executive functioning, processing speed, attention and verbal memory have been reported in euthymic bipolar patients [6–9]. Cognitive functions have been considered potential endophe-
⁎ Corresponding author. Tel.: +90 222 2392979. E-mail address: [email protected] (F. Kosger). http://dx.doi.org/10.1016/j.comppsych.2015.05.013 0010-440X/© 2015 Elsevier Inc. All rights reserved.
notypic markers of bipolar disorder, and cognitive functions of relatives of patients with bipolar disorder have been investigated in recent years. Nevertheless, studies investigating cognitive function in healthy relatives of patients with bipolar disorder are conflicting, and the neurocognitive profile of relatives of bipolar disorder probands is still unclear [10]. Some studies have reported impaired response inhibition in healthy relatives of patients with bipolar disorder [11–14], whereas other studies reported intact response inhibition [15–18]. Moreover, most of the studies reported intact set shifting and cognitive flexibility [11,14,15,19–22], and some studies reported impairments in those abilities [23,24]. Studies conducted on cognitive test performance of patients' relatives show that these studies have some limitations. The healthy relatives were mostly selected from mixed relative groups (include not only unaffected parents but also patients' offspring and siblings) [11,13–18,22,23,25,26], and the majority of the studies involved siblings [12,18–20,24,27] or even offspring [21]. Studying parents rather than siblings decreases common environmental factors, which are more present among siblings and may be confused with heredity.
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Additionally, compared to siblings, parent groups have a lower risk of conversion to bipolar disorder because of their advanced age. Previous studies have always investigated relatives with and without genetic loading as a mixed group without distinguishing them from each other. In this study, we tested whether executive function deficits were potential markers of genetic vulnerability to bipolar disorder using a more careful design. First, we separated parents of patients with bipolar disorder into two groups, familial and sporadic. A patient's parent who had a family history of bipolar disorder (except for his/her children) in first-degree relatives was selected for the familial parent (FP) group. A patient's parent who had no family history of bipolar disorder was selected for the sporadic parent (SP) group. The purpose of the FP-SP division was to produce populations with presumed high and low genetic liability to bipolar disorder. Measuring cognitive function in healthy relatives of patients who have genetic vulnerability could help to determine which cognitive impairments may be endophenotypes of bipolar disorder. We investigated the cognitive function of the FP, SP and healthy control groups (matched for gender, age and duration of education). We hypothesized that if executive function deficits are endophenotypes of bipolar disorder, unaffected FP should have more deficits than unaffected SP. The goal of our study is to evaluate executive function in unaffected FP and SP. 2. Materials and methods 2.1. Setting and sample Our study involved 24 FP of patients with familial bipolar I disorder and 26 SP of patients with sporadic bipolar I disorder. The study also included 26 healthy controls who matched the parents with respect to age, gender and duration of education, resulting in a total population of 76 subjects. Parents of patients were recruited from the Affective Disorders Unit of Eskisehir Osmangazi University Medical School and participated in the study between June 2013 and January 2015. Patients were diagnosed using the Structured Clinical Interview for DSM-IV (SCID-I) [28,29]. Only patients with a history of psychotic features (delusions or hallucinations) during their mood episodes were included in the study. Parents and their controls were screened with the SCID-I, and those who met criteria for any psychiatric disorder were excluded. Exclusion criteria for all subjects included mental retardation, identifiable neurological disorder or significant medical illness, substance use in the past 6 months, visual impairment, color blindness, younger than 18 years and older than 65 years. In the FP group we included only parents with who had bipolar disorder in his/her first degree relatives (mother, father, brother, or sister). The SP group did not have family histories of bipolar disorder by definition. Healthy controls were recruited from the hospital cleaning staff, and they were excluded if they had positive family histories of bipolar
disorder or psychosis. Neither parents nor controls used any psychotropic medications. After description of the study, written informed consent was obtained from all participants. All participants were administered the California Verbal Learning Test (CVLT) [30], Trail Making Test (TMT) [31], Stroop test [32,33], and Wisconsin Card Sorting Test (WCST) [34] in the same order by an investigator (N.U.). The interviewing and screening process with the SCID-I was conducted by another investigator (M.B.). All raters were blind. 2.2. Instruments The CVLT is a widely used clinical test of verbal declarative memory and of executive function [30]. The administration procedure involves the oral presentation and recall of a 16-item word list over five learning trials, a single presentation of a second list, short and long delay recall trials of the first list, and a recognition trial of the first list. We used learning trials 1–5 (total), free short recall, free delayed recall, and recognition parameters of the test. The TMT was developed by Reitan [31]. It is a test of complex visual scanning with a motor component, which can evaluate the flexibility in shifting the course of an ongoing activity. It consists of two sections: Section A and Section B. Section B is an indicator of executive function as well. Our study used the test durations and the number of errors. The Stroop test is a test of selective attention [32]. The scores were the number of items completed in 45 seconds during three trials. The first trial consists of reading the names of colors. The second trial is color naming. The third trial tests the interference with the color–word score as suggested by Golden [33]. The WCST was developed by Heaton [34]. It is a measure of executive function and abstract thinking in which participants are required to shift a mental set as they match 128 stimulus cards on the basis of color, shape or number with minimal instruction or feedback from the examiner. It is considered particularly sensitive for dorsolateral prefrontal cortex function. Our study used the number of categories achieved and the number of perseverative errors. Complex attention, response inhibition, working memory and cognitive flexibility are the important parts of executive function that enable us to create a plan, initiate its execution and persevere on the task at hand until its completion [35]. Therefore, executive tests are likely to reflect various cognitive processes. The CVLT measures verbal memory and learning. The TMT part A measures processing speed, and part B measures processing speed together with set shifting and selective attention. The Stroop test measures response inhibition. The WCST measures the acquisition of new rules and the initiation of appropriate actions [35]. These tests share an underlying commonality. For instance, both the WCST and the TMT-B measure set shifting [35]. Furthermore, the same test may measure two different components of executive functioning, such that WCST may assess attention control as well as cognitive flexibility [35].
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Table 1 Demographic characteristics of parent and control groups.
Male/female (n) Age, mean ± SD (years) Education, mean ± SD, (years) Employee/unemployed/retired (n)
FP (n = 24)
SP (n = 26)
Control (n = 26)
Statistical test
13/11 57.54 ± 7.58 7.71 ± 3.22 6/11/7
12/14 56.08 ± 5.77 9.50 ± 4.18 8/10/8
13/13 54.15 ± 3.27 9.81 ± 3.44 13/6/7
χ 2 = 0.312,p = 0.852 H = 2.310, p = 0.315 H = 4.553, p = 0.103 χ 2 = 4.429, p = 0.351
FP: familial parent, SP: sporadic parent, SD: standard deviation.
Therefore, it is difficult to measure executive function selectively, and executive tests should be used together for precise results [36,37]. 2.3. Statistical analysis The data analysis was performed using the SPSS (Statistical Package for Social Sciences) program, Version 21.0 for Windows. The gender distribution was compared using the chi-square test. Kolmogorov–Smirnov test was performed for normality. Age, duration of education and test scores were compared using the Kruskal–Wallis test, as the data distribution was not normal. Pairwise comparison was applied for multiple comparisons of the groups. In all analyses, p levels (two tailed) less than 0.05 were considered statistically significant. 2.4. Ethics The study protocol was approved by the Regional Ethics Committee of Eskisehir Osmangazi University, Faculty of Medicine.
3. Results The FP and SP groups and their respective matched control groups did not differ significantly in gender distribution, age, duration of education, and employment (Table 1). Compared to their respective matched controls, the FP group performed significantly worse on the verbal memory, learning, processing speed, set shifting, selective attention, cognitive flexibility, and response inhibition, whereas the SP group performed significantly worse only on the cognitive flexibility and response inhibition. Additionally, the FP group performed significantly worse than the SP group on the verbal memory, learning, processing speed, set shifting, selective attention, and cognitive flexibility (Table 2). However, a significant difference was observed between FP and control group for education (z = 2.156, p b 0.05). Hence, non-parametric or rank analysis of covariance test (Quade's test) [38] was performed for correction of the effect of education on the verbal memory and executive function in which education was modeled as covariate. Consequently, the results which founded by pairwise comparison did not vary.
4. Discussion The current study provides evidence for impairments of verbal memory and executive function in the patients' parents who had a family history of bipolar disorder compared to parents of sporadic bipolar patients and controls. Impairments in verbal memory, learning, processing speed, set shifting, selective attention, and response inhibition have been widely reported in relatives of bipolar disorder patients [12,13,19,20,22,25,26]. Deficits in cognitive flexibility have been reported previously [13,23]. However, previous research has presented evidence that unaffected relatives of patients with bipolar disorder are not impaired in cognitive flexibility [11,20–22,27]. Additionally, a meta-analysis emphasized impairments in set shifting and selective attention but not in cognitive flexibility, in relatives of bipolar disorder patients [6]. Erol et al. also reported impairments in processing speed, selective attention, and response inhibition but not in cognitive flexibility in their parent-only study and indicated that deficits in tasks of ventral, but not dorsal prefrontal, executive function may reflect familial predisposition to bipolar disorder. That study included 50 unaffected parents of patients with bipolar disorder, so the sample size was large [39]. However, parents were not evaluated for family history of bipolar disorder in that study. Bora et al. discussed that these seemingly inconsistent findings could be related to the effect of proneness to psychotic features in mood episodes and reported that deficits in cognitive flexibility were found only in relatives of probands with a history of psychotic mood episodes. They indicated that a cognitive flexibility deficit may be an endophenotype of psychosis in general [13]. However, the relatives of probands with a history of psychotic mood episodes were composed of only 10 volunteers, and mixed relatives were included in that study. We found that the FP group performed significantly worse than the SP group in verbal memory, learning, processing speed, set shifting, selective attention, and cognitive flexibility. Both groups had probands with a history of psychotic features during their mood episodes in our study. This finding may be incompatible with the argument that the cognitive flexibility deficit may be an endophenotype of psychosis in general. However, we should state that a cognitive flexibility deficit is widely reported in schizophrenia [36]. The argument that a cognitive flexibility deficit may be an endophenotype of psychosis should be studied with larger sample sizes. We should indicate that attention, response inhibition, working memory and cognitive flexibility are important
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Table 2 Comparison of test scores between the FP, SP and control groups. Test
FP (mean ± SD)
SP (mean ± SD)
Control (mean ± SD)
Kruskal–Wallis test
Pairwise comparison (Dunn test)
39.50 ± 10.68
49.46 ± 6.54
48.62 ± 8.47
H = 13.205 p b 0.01
8.21 ± 2.75
11.42 ± 1.90
10.54 ± 2.40
H = 17.287 p b 0.001
8.88 ± 3.19
12.27 ± 1.97
11.35 ± 2.51
H = 16.014 p b 0.001
86.25 ± 8.43
95.88 ± 3.68
89.54 ± 19.42
H = 18.556 p b 0.001
WCST categories achieved
1.13 ± 1.30
3.23 ± 1.63
4.50 ± 1.63
H = 36.305 p b 0.001
WCST perseverative errors
52.96 ± 26.52
40.85 ± 22.89
23.46 ± 13.51
H = 18.995 p b 0.001
TMT part A seconds
82.25 ± 34.45
67.08 ± 20.98
53.77 ± 19.02
H = 13.675 p b 0.01
0.42 ± 0.50
0.12 ± 0.43
0.12 ± 0.33
H = 10.034 p b 0.01
197.50 ± 95.71
105.88 ± 42.49
98.62 ± 29.87
H = 19.210 p b 0.001
TMT part B errors
2.38 ± 1.91
0.42 ± 0.76
0.35 ± 0.56
H = 25.738 p b 0.001
Stroop color score
20.88 ± 6.46
18.00 ± 6.96
13.81 ± 2.73
H = 21.025 p b 0.001
Stroop word score
29.83 ± 8.70
24.42 ± 7.41
20.15 ± 4.12
H = 17.177 p b 0.001
Stroop color word score
39.42 ± 12.67
34.50 ± 9.99
28.88 ± 5.98
H = 13.194 p b 0.01
FP-control p b 0.01 FP-SP p b 0.01 SP-control p = 1.00 FP-control p b 0.05 FP-SP p b 0.001 SP-control p = 0.773 FP-control p b 0.05 FP-SP p b 0.001 SP-control p = 0.641 FP-control p b 0.05 FP-SP p b 0.001 SP-control p = 0.366 FP-control p b 0.001 FP-SP p b 0.001 SP-control p = 0.084 FP-control p b 0.001 FP-SP p = 0.537 SP-control p b 0.01 FP-control p b 0.01 FP-SP p = 0.429 SP-control p = 0.075 FP-control pp b 0.05 FP-SP p b 0.05 SP-control p = 1.00 FP-control p b 0.001 FP-SP p b 0.01 SP-control p = 1.00 FP-control p b 0.001 FP-SP p b 0.001 SP-control p = 1.00 FP-control p b 0.001 FP-SP p = 0.120 SP-control p b 0.05 FP-control p b 0.001 FP-SP p = 0.068 SP-control p = 0.172 FP-control p b 0.01 FP-SP p = 0.425 SP-control p = 0.089
CVLT Free short recall
CVLT Free delayed recall
CVLT Learning trials 1–5 (total)
CVLT Recognition
TMT part A errors
TMT part B seconds
FP: familial parent, SP: sporadic parent, SD: standard deviation, CVLT: California Verbal Learning Test, TMT: Trail Making Test, WCST: Wisconsin Card Sorting Test.
components of executive function and that tests of executive function should be used together for precise results. There are mixed results in the neuroimaging studies that have been conducted with unaffected relatives of patients with bipolar disorder. Van der Schot et al. found that genetic liability for bipolar disorder is associated with decreased gray matter in the right medial frontal gyrus and the right insula and increased gray matter in the right orbitofrontal gyrus [40]. In contrast, McDonald et al. found that gray matter deficits of the right anterior cingulate gyrus and ventral striatum were associated with genetic risk for bipolar disorder [41]. Kempton et al. reported that the genetic predisposition to bipolar disorder was associated with increased left insula volume [42], whereas Matsuo et al. indicated an association with the right insula [43]. In addition to these reports, a recent, more carefully designed study conducted with unaffected healthy siblings of patients with
bipolar disorder suggested that a reduction in the volume of the orbitofrontal cortex is associated with the heritability of bipolar disorder [44]. This suggestion is partially consistent with our findings. Our study has various advantages. First, executive function was evaluated with multiple tests that measure various aspects of executive function. Second, our study involved only parents and has the advantages of a parent-only study. To our knowledge, this is the first parent-only study on executive function in relatives of bipolar disorder patients, differentiated with respect to genetic loading. A limitation of this study is the lack of IQ and premorbid IQ measures of the groups. Another limitation of our study is the relatively small sample size. Our findings need to be replicated in future studies which should consider the dose effect of genetics with larger sample sizes.
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In conclusion, our results support that deficits in prefrontal executive function are associated with familial vulnerability to bipolar disorder and that executive function and verbal memory impairments may represent a potential endophenotype of bipolar disorder.
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