|Year : 2015 | Volume
| Issue : 1 | Page : 1-8
Sex differences in cognitive dysfunction among bipolar disorder patients
Heba Aly1, Hoda Salama2, Soha Ibrahim2, Hesham El-Shestawy2
1 El Maamoura Mental Hospital, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Neuropsychiatry Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Web Publication||23-Mar-2015|
Neuropsychiatry Department, El Hadra University Hospital, El Hadra, Alexandria 26122
Source of Support: None, Conflict of Interest: None
Studies have proposed that cognitive deficits are present in a variety of mood states in bipolar disorder (BD). In addition, a few studies have pointed to the presence of sex-related differences in cognitive dysfunction in BD.
Aim of the work
This comparative study aimed to study the cognitive functioning of BD patients in different episodes, and detect any sex-related differences in cognitive functioning in the studied sample.
Patients and methods
The recruited sample consisted of 150 patients selected at random from El Maamoura Mental Hospital over 6 months. Four groups were formed: group I, comprising 38 (19 male and 19 female) BD patients having manic episodes; group II, comprising 26 (12 male and 14 female) BD patients having depressive episodes; group III, comprising 36 (20 male and 16 female) patients in remission (euthymic); and group IV, comprising 50 controls matched for age, sex, and education. Clinical and psychiatric evaluations were carried out and psychometric assessment was performed using the 17-item Hamilton Depressive Scale and the Young Mania Rating Scale, as well as cognitive assessments using three tests: Wisconsin's Card Sorting Test (WCST), the digit span subtest of the WAIS-R and DSST (the digit symbol subtest of the WAIS-R).
The BD patients in the three groups having BD showed significant cognitive deficits compared with controls. Manic and depressive patients showed impairment in attention, working memory, and executive functions. Euthymic patients showed significant impairment in working memory and executive functions. Only euthymic patients revealed a statistically significant sex-related difference in terms of short-term memory, attention, and working memory, with women being worse than men. Interestingly, in the control group a difference in executive functions was reported wherein healthy control women performed significantly better than control men on the WCST-128 (completed significantly more number of categories and committed significantly fewer perseverative errors).
Cognitive dysfunction should be regarded as a core feature of BD as it was present across all mood states in our sample. In addition, discrepancy has been found between male and female euthymic patients regarding cognitive functions, suggesting a sex-related difference in the clinical expression of BD.
Keywords: 17-item Hamilton Depressive Scale, bipolar disorder, cognitive assessments, cognitive dysfunction, digit span subtest of the WAIS-R and DSST (the digit symbol subtest of the WAIS-R), sex difference, Wisconsin′s Card Sorting Test, Young Mania Rating Scale
|How to cite this article:|
Aly H, Salama H, Ibrahim S, El-Shestawy H. Sex differences in cognitive dysfunction among bipolar disorder patients. Egypt J Psychiatr 2015;36:1-8
|How to cite this URL:|
Aly H, Salama H, Ibrahim S, El-Shestawy H. Sex differences in cognitive dysfunction among bipolar disorder patients. Egypt J Psychiatr [serial online] 2015 [cited 2017 Dec 12];36:1-8. Available from: http://new.ejpsy.eg.net/text.asp?2015/36/1/1/153766
| Introduction|| |
Cognitive dysfunction is a significant phenomenological dimension of many psychiatric illnesses, including bipolar disorder (BD). Impairments in psychomotor speed, attention, executive function, memory, and fine motor skills have been extensively reported in BD, even in the euthymic state (Murray and Lopez, 1996; Balanza et al., 2010; Bonnin et al., 2010). Recent studies have found evidence for persistent cognitive impairment in BD in the absence of clinical symptoms and therefore cast doubt on the full remission between episodes. Studies with euthymic patients emphasize the fact that some cognitive impairments still remain after remission. Recent findings have revealed impairment in executive function, attention, and verbal memory in euthymic patients with BD (Martinez-Aran et al., 2004). The study of persistent cognitive deficits in euthymic states in bipolar patients is very important because of the possibility of such deficits being a trait rather than a state marker for BD (Bora et al., 2009; Ferrier and Thompson, 2002; Martinez-Aran et al., 2004). Persistent cognitive disability, especially in the domains of verbal/learning and memory and executive function, has been associated with poor functional outcome and psychosocial adjustment in BD patients as measured by both subjective reports and objective performance-based indexes such as vocational, education, and marital status (Seema and Sophia, 2002; Wingo et al., 2009). Only a few studies have specifically assessed BD and its impact on cognitive performance, and fewer studies have examined sex-related differences in neurocognitive functioning in BD, despite evidence of sexual dimorphism in normal brain structures, as well as sex-related differences in neurocognition in healthy participants and in schizophrenic patients (Barrett et al., 2008). Research data on this field would be useful to determinate whether sex is important in influencing illness variables such as course, symptoms expression, and comorbidity, with important clinical implication in diagnosis and treatment (Colom et al., 2006; Alessandra and Nivolia, 2011).
| Aim of the work|| |
The aim of this investigation was to study the cognitive functioning of BD patients in different episodes, as well as detect any sex-related difference in cognitive functioning in the studied sample.
| Patients and methods|| |
This study was carried out on 150 patients who were recruited by random sampling from among inpatients and outpatients at El Maamoura Mental Hospital over a period of 6 months. Four groups were formed: group I, comprising 38 (19 male and 19 female) BD patients having manic episodes; group II, comprising 28 (12 male and 14 female) BD patients having depressive episodes; group III, comprising 32 (20 male and 16 female) patients in remission (euthymic); and group IV, comprising 50 controls matched for age, sex, and education. The inclusion criteria for participants were BD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders-IV-TR (DSM-IV-TR) diagnostic criteria (American Psychiatric Association, 2000), age range from 18 to 50 years, and written informed consent. Individuals of either sex could participate. Exclusion criteria focused on the exclusion of any physical, neurological, or other psychiatric disorders producing cognitive dysfunction. The sample also excluded BD patients with a history of substance dependence or abuse and electroconvulsive therapy in the last year.
The recruited sample was subjected to the following:
Hamilton depression rating scale
- Complete history taking and clinical, physical, and neurological examination.
- Psychiatric examination by two expert psychiatrists using the DSM-IV-TR criteria.
- Psychometric assessment.
Psychometric evaluation was carried out using 17 items of the Hamilton Depression Scale. It is a clinician-administered scale that assesses the severity of depression. A score of 8 or lower is considered to reflect an asymptomatic state, with an increasing continuum of symptom severity as scores increase (Hamilton, 1967; Lotfy, 1994).
The young mania rating scale
The Young Mania Rating Scale is an 11-item clinician-administered scale used to measure the severity of mania. Each item is rated on the basis of the individual's subjective report over the previous 48 h, as well as on the behavioral observations of the clinician. The rating of each item is on a scale of 0-4 (absent to overtly present), except for four items, which receive double the weighting and are rated on a scale of 0-8 (Young et al., 1978).
Cognitive function assessment
The Wisconsin Card Sorting Test (WCST-128 manual version): The WCST was originally developed in 1948 by Grant and Berg as a measure of abstract reasoning ability, mental flexibility, and ability to shift cognitive set. As such, the WCST can be considered a measure of 'executive functions', involving the ability to develop and maintain an appropriate problem-solving strategy across changing stimulus conditions to achieve a future goal. It also requires strategic planning, organized searching, and modulating impulsive responding. Perseverative errors on the WCST are indicators of deficits in cognitive set shifting (which is hypothesized to implement features of a replanning strategy, such as task-set activation and inhibition) and mental flexibility (ability to reconfigure the cognitive system to meet shifting task demands), whereas nonperseverative errors are indicators of deficits in generalized reasoning. Abilities like concept formation (the requirement to identify the abstract or conceptual relationships shared by stimuli) are measured by the number of categories achieved on the WCST. Data suggest that abnormalities in those frontal systems that are likely to mediate abstract concept formation may be related to the degree of familial loading for psychotic disorders (Berg, 1948; Heaton et al., 1993; Sullivan et al., 1993; Kongs et al., 2000; Kohli and Kaur, 2006).
Digit span test (Arabic version)
The forward and backward digit span tests from the Wechsler Adult Intelligence Scale - Revised (WAIS-R) were administrated. Increasingly long series of digits have to be repeated verbally in the same order up to nine digits (forward digit span) or in reverse order up to eight digits (backward digit span). Testing ended when a participant was incorrect on two trials of the same length. The total number of correct trials for each span was scored. The forward digit span was used as a measure of short-term memory requiring simple retention and recall of information from working memory, general attention, and span of apprehension, whereas the backward digit span was used as a measure of verbal working memory requiring additional manipulation or rearrangement of information within working memory (Meleika, 1996; Koenigs et al., 2009).
Digit symbol substitution test (the Arabic version)
The digit symbol substitution test from the WAIS-R was administered. Patients were presented with rows of empty boxes labeled with a digit. They were required to fill out these boxes as quickly as they could with a corresponding symbol, according to a digit symbol code that was permanently displayed. The total number of boxes accurately filled in within 90 s was scored. Thus, the test involved two components: a cognitive component (matching digits with symbols) and a motor component (writing up the symbols). This test measures processing speed. Processing speed simply refers to the speed at which different cognitive operations can be executed. Thus, the test reflects accelerated performance of a number of straightforward scanning, matching, switching, and writing operations. It is believed that this performance dimension represents a very general constraint on cognitive processing (Meleika, 1996; Rosano et al., 2008).
Data were fed to the computer and analyzed using IBM SPSS (Wadsworth, Cangage Learning, Belmont, California, USA) software package version 20.0. Qualitative data were described using number and percentage. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Comparison between different groups regarding categorical variables was tested using the χ2 -test. When more than 20% of the cells have an expected count less than 5, correction for χ2 was conducted using Fisher's exact test or Monte Carlo correction. The distributions of quantitative variables were tested for normality using the Kolmogorov-Smirnov test, the Shapiro-Wilk test, and the D'Agostino test. Histograms and QQ plots were used for vision test. In the case of normal data distribution, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used. For normally distributed data, comparison between the three studied groups was made using the F-test (ANOVA) and post-hoc test (Scheffe). For abnormally distributed data, comparison between two independent populations was made using the Mann-Whitney U-test, whereas the Kruskal-Wallis test was used to compare between different groups and pairwise comparison was made using the Mann-Whitney U-test. Significance of the obtained results was judged at the 5% level (Kotz et al., 2006; Kirkpatrick and Feeney, 2013).
| Results|| |
In the present study, the four groups were matched for age (F = 0.52, P = 0.67), sex distribution (χ2 = 57, P = 0.91), and duration of education (χKW 2 = 1.8, P = 0.62). The number of smokers among BD patients was found to be significantly higher than that among controls (χ2 = 21.04, P < 0.001), whereas the number of employed patients was significantly higher among controls (χ2 = 49.96, P < 0.001) ([Table 1]).
Clinical variables and medications
Family history of psychiatric illness was found in all patient groups but showed no statistically significant difference among the three groups (χ2 = 0.73, P = 0.74). The lowest mean age of illness onset was in manic patients (25.79 ± 7.30 years) who also had the longest duration of illness (9.61 ± 6.85 years), but none of these findings reached statistically significant difference (χKW 2 = 3.78, P = 0.15, and χKW 2 = 1.071, P = 0.59, respectively) ([Table 2]).
As regards the number of previous episodes and hospitalizations, again manic patients showed the highest mean number of previous episodes (10.58 ± 7.41 episodes) and highest frequency of hospitalization (9.29 ± 7.89), with a statistically significant difference (χKW 2 = 7.05, P = 0.03, and χKW 2 = 8.05, P = 0.02, respectively) ([Table 2]).
In terms of severity, psychotic features had the highest frequency among manic patients (78.9%) with a statistically significant difference among the three groups (χ2 = 37.34, P < 0.001). Moreover, a significant high score for Hamilton Depression Rating Scale was seen among depressed patients (χKW 2 = 58.26, P < 0.001) and a significant high score was seen among manic patients (χKW 2 = 71.32, P < 0.001) ([Table 2]). With regard to compliance to treatment and medications used, as listed in [Table 2], the highest rate of compliance was seen in euthymic patients [23 (63.9%)] with a statistically significant difference (χKW 2 = 7.05, P = 0.03).
All patient groups showed impairment on executive functions, which were assessed using the WCST-128. A statistically significant difference was found only in the number of completed categories and perseverative errors. Manic, depressed, and euthymic patients completed significantly fewer categories and committed more perseverative errors compared with controls (χKW 2 = 66.62, P < 0.001, and χKW 2 = 62.2, P < 0.001, respectively).Only the acutely ill, manic, and depressed patients showed significantly poorer performance on short-term memory and attention. Both showed lower scores on the forward digit span subtest of the WAIS-R compared with controls and this finding reached a statistically significant difference (χKW 2 , P = 0.006 and 0.004, respectively). As for working memory, the backward digit span scores were significantly lower than those of controls with a statistically significant difference (χKW 2 = 29.63, P < 0.001). Regarding the processing speed, all patients had lower scores on the digit symbol subtest of the WAIS-R compared with controls and again this result reached a statistically significant difference (χKW 2 = 46.53, P < 0.001) ([Table 3]).
|Table 3 Distribution of scores of the cognitive psychometric tests in the studied groups|
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Moreover, among the bipolar subgroups significant differences were present. Manic and depressed patients completed significantly fewer categories (manic patients: χKW 2 , P < 0.001; depressed patients: χKW 2 , P* = 0.001) and committed more perseverative errors (manic patients: χKW 2 , P < 0.001; depressed patients: χKW 2 , P = 0.039) on the WCST-128, and obtained significantly lower scores on the digit symbol subtest of the WAIS-R (χKW 2 , P = 0.008 and 0.040, respectively) in comparison with euthymic patients. Also both groups showed a poorer performance on the forward and backward digit span subtests of the WAIS-R compared with the euthymic group; however, there was no statistically significant difference among the three groups ([Table 3]).
In the present study, no significant sex-related difference was found with respect to cognitive dysfunction among the manic and depressed patients. However, in the euthymic patients' group results revealed a statistically significant sex-related difference between male and female euthymic patients in measures of short-term memory, attention, and working memory. Female euthymic patients performed significantly worse than male euthymic patients in the forward and backward digit span subtests of the WAIS-R (Z = 2.95, P = 0.003, and Z = 2.04, P = 0.042, respectively). Again, in the control group a difference in executive functions was reported wherein healthy control women performed significantly better than control men on the WCST-128, completed significantly more number of categories, and committed significantly fewer perseverative errors (Z = 2.89, P = 0.004, and Z = 2.76, P = 0.006, respectively) ([Table 4]).
| Discussion|| |
First, the present study assessed cognitive functions in the form of executive functions using the WCST-128, short-term memory and attention using the forward digit span subtests of the WAIS-R, working memory using the backward digit span of the WAIS-R, and processing speed using the digit symbol subtest of the WAIS-R on 100 bipolar patients across different states. Our findings indicated that all BD participants had impairment on executive functions compared with controls. Manic, depressed, and euthymic patients completed significantly fewer categories and committed more perseverative errors on the WCST-128. Furthermore, both BD groups in the active phase of the illness performed poorly on short-term memory and attention compared with euthymics. Also, the working memory and processing speed were impaired in all patient groups. Similarly, Henry et al. (2013) assessed executive functioning with the WCST and its relation to everyday functional ability using the UCSD Performance-Based Skills Assessment (UPSA-2) in manic, depressed, and euthymic adult BD patients. All patients showed executive function impairment (more perseverative errors and fewer categories completed) and exhibited functional ability deficits on the UPSA-2 independent of the phase of their illness (Henry et al., 2013).
Consistent with our results, Ryan et al. (2012) examined the influence of BD illness on executive functioning using a battery of neuropsychological tasks. All BD patients performed worse than healthy controls on tasks of Processing Speed with Interference Resolution (PSIR) measured by digit symbol and Conceptual Reasoning and Set-Shifting (CRSS) measured by the WCST. The E-BD performed similarly to the D-BD group and the HM/M-BD group on PSIR and CRSS. The study suggested that executive tasks that comprise a set-shifting or interference resolution component are weaker among BD patients, regardless of mood state, and are potentially strong intermediate phenotypes in BD (Ryan et al., 2012). Langenecker et al. (2010) studied bipolar patients across different states and assessed them with variable neuropsychological tests. Their findings agreed with ours, as there were significant difficulties with processing speed, which were assessed with the digit symbol subtest of the WAIS-R, we close the sentence and start a new one. The findings were identified as potential markers for an intermediate cognitive phenotype of BD (Langenecker et al., 2010).
Fleck et al. (2008) conducted a study to examine the influence of mood state and early illness course on WCST performance in BD. The WCST was administered to patients with bipolar I disorder diagnosed on the basis of the DSM-IV criteria and to healthy comparison individuals. Both first-episode and multiple-episode groups exhibited poor performance on the WCST as regards perseverative errors compared with the healthy control group. The study suggested that the executive dysfunction in BD is characterized by cognitive inflexibility during acute manic or mixed states with observable cognitive deficits at first episode. Our results were congruent with the findings of Fleck et al. (2008) for manic and depressed BD patients but not for euthymic patients. The difference may be explained by different durations of illness, sample size, sex, education, and medications used.
The current study findings further add to the literature that shows that executive functions, working memory, and processing speed are impaired in BD, independently of clinical state. The impairment of executive functions reflects difficulty in strategic planning, problem solving, working memory, strategy development, ability to shift cognitive strategy, inhibitory control, and cognitive flexibility (Struss and Levine, 2002; Heaton et al., 2003). BD is characterized by marked anomalies in the frontal cortex, including decreased neuronal density and reduced cerebral blood flow (Rajkowska et al., 2001; Frangou et al., 2005), which could potentially mediate effective WCST performance and also play a role in everyday functional impairment (Lovstad et al., 2012).
Second, the present study found sex-related differences in cognitive functioning among euthymic patients and controls but not among manic and depressed patients. The euthymic patient group results revealed a statistically significant sex-related difference as female euthymic patients performed significantly worse compared with male euthymic patients in the forward and backward digit span subtests of the WAIS-R. Bόcker et al. (2014) examined 60 euthymic bipolar patients (29 men and 31 women) and 90 healthy controls (42 men and 38 women) using the Cambridge Automated Neuropsychological Testing Battery (CANTAB V2 System). Results showed that euthymic bipolar I patients as a group had poorer cognitive performance compared with age-matched and sex-matched healthy controls. Sex has been an important determinant of neurocognitive function: men performed better than women on measures of sustained attention and set shifting (Bόcker et al., 2014).
In contrast with the present sex-related findings, Vaskinn et al. (2011) conducted a study on a group of 106 euthymic BD I patients (55 women and 51 men) who were assessed with an extensive neuropsychological test battery and the social functioning questionnaire and compared the results with a control group (158 women and 182 men) and schizophrenic patients (60 women and 94 men). The patient groups performed worse than healthy controls on all neuropsychological tests (except attention). The authors found greater impairment in working memory including spatial memory in male bipolar patients with a history of psychosis in comparison with the remaining female bipolar patients. Also, our results were in contrast to those of Carrus et al. (2010, who evaluated the performance of remitted patients with BD type I (36 male and 50 female) and healthy participants (21 male and 25 female) on tasks of general intellectual ability, memory encoding, recognition and retrieval, response inhibition, and executive function (abstraction and perseveration) using the Wechsler Memory Scale‐III, WAIS‐R, Hayling Sentence Completion Task, and the WCST. They found a sex-related effect on immediate memory, both auditory and visual, but not in general intellectual ability, concept formation, and perseveration or response inhibition. Male patients performed worse than female patients and healthy controls. Results revealed that immediate memory correlated with GAF scores and this association was statistically significant for male patients (Carrus et al., 2010).
Again, Barrett et al. (2008) reported opposite results to the current study. They compared the results of euthymic BD outpatients (12 male and 14 female patients) with those of healthy controls (12 male and 14 female patients) on letter fluency, spatial working memory, planning, and cognitive set shifting using the CANTAB and the Controlled Oral Word Association Task. Male patients performed worse than female patients in measures of spatial working memory, whereas male controls outperformed female controls. However, in that study, male patients had been both significantly older and more symptomatic than female patients, which may be the reason for the difference (Barrett et al., 2008). The higher preponderance of male sex for better cognitive function in our work may be explained as follows:
Interestingly, healthy female controls completed significantly more number of categories and committed significantly fewer perseverative errors. A normal variation in cognitive functioning has been mentioned in the literature in terms of executive functions with the male and female brains being compared with each other regarding the different aspects of mental functions (Colom et al., 2006; Barrett et al., 2008; Alessandra and Nivolia, 2011).
- Different methodologies and sampling techniques;
- Focus of Egyptian culture on male education rather than female education;
- Men usually work outside the home and hence make better use of the cognitive function compared with women who are usually housewives;
- Men seek treatment more often than women, as, in our culture, men are the main breadearners, and therefore their earlier treatment might have helped preserve their cognitive function.
| Conclusion|| |
Cognitive disturbances were seen in BD patients across different episodes of illness, suggesting it to be a core diagnostic and prognostic feature. Sex-related differences were noted for euthymic patients and there remains a need to evaluate its impact on the clinical expression and prognosis of BD.
| Acknowledgements|| |
Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4]