INTRODUCTION
Bipolar disorder (BD) is a chronic disorder, which is characterized by recurrent episodes of mania/hypomania and depression, with intervening periods of clinical remission.[ 1 ] Traditionally, it was believed that cognitive impairment in subjects with BD is short-lasting and is seen during affective episodes.[ 2 ] However, this understanding has changed over the last 2–3 decades, and it is now well-known that cognitive impairments are seen in patients with BD, even during the euthymic phase.[ 2 ] Available data also suggests that cognitive impairments in patients with BD are associated with poor functioning,[ 3–9 ] impaired quality of life,[ 10 ] and poorer psychosocial adjustment.[ 11–13 ]
Various domains of neurocognition, which have been reported to be affected in subjects with BD include attention/processing speed, verbal fluency, working memory, verbal learning/memory, and executive functions, including cognitive flexibility and inhibitory control.[ 14 , 15 ] A meta-analysis of studies on cognitive function assessed by objective measures in BD found the following domains to be affected during the euthymic phase: verbal learning (0.81) and long-delay verbal free recall (0.78), followed by delayed non-verbal recall (0.80), semantics (0.75), verbal fluency, verbal interference (0.75) and set-switching tasks (0.73), immediate non-verbal memory (0.73), sustained visual vigilance (0.69) and speeded visual scanning (0.65), psychomotor speed (0.66), working memory (0.65), executive functions concerning problem-solving tasks (0.54), visuospatial function (0.55), and phonemic (0.51) fluency. During the acute bipolar depressive episode, the domains affected are verbal memory (1.20), phonemic fluency (0.93), attention (0.80), and executive function in speeded set-shifting (0.64). In the manic/mixed states, impairment is noted in verbal learning (1.43) and delayed free verbal recall (1.05), attention (0.79–0.90), general executive function (0.72) and speeded set-shifting (0.64), semantic fluency (0.59), and letter fluency (0.51).[ 16 ]
Several clinical variables are associated with objective cognitive impairment in patients with BD. A recent meta-analysis reported that the most critical clinical variables that influence cognitive impairment in patients with BD include the subtype of BD (i.e., type-I or type-II) and the presence or absence of psychotic symptoms in the episodes. This meta-analysis showed that compared to BD-II, those with BD-I have a higher level of global cognitive impairment and higher impairment in specific domains such as verbal memory, processing speed, executive function speed, and executive function accuracy.[ 6 ] Similarly, the presence of psychotic symptoms in BD is associated with higher cognitive impairment in verbal memory, processing speed, speed of executive functioning, accuracy of executive functioning, working memory, and social cognition.[ 6 ]
Objective neurocognitive impairment in subjects with BD is associated with insight ,[ 17 , 18 ] number of manic episodes, number of hospitalizations, and duration of illness.[ 11 , 14 , 19 ] Variables that have shown an inconsistent association with neurocognitive impairments in patients with BD include age, age of onset, gender,[ 20 ] substance use,[ 20 , 21 ] and medications.[ 20 ]
However, a majority of studies evaluating cognitive impairment in patients with BD are based on neurocognitive batteries, which are time-consuming and are not used routinely in clinical practice. Keeping this in mind, in recent years, some of the authors have designed user-friendly instruments that are time economical and measure subjective cognitive complaints. Further, there is a lack of consensus with regard to subjective and objective cognitive impairment in patients with BD. One of the studies, which evaluated both subjective and objective cognitive performance of 70 patients with BD, reported that although there is a significant correlation between the subjective and objective performance on global measures, but not at the individual cognitive domain level. This study also showed that subjective cognitive impairment was associated with self-rated psychosocial difficulties, and both these variables were predicted by depressive symptoms.[ 22 ] Another study, which included only 15 patients with BD reported a lack of correlation between subjectively reported and objectively measured cognitive impairment in patients with BD.[ 23 ] Other studies which have evaluated subjective cognitive dysfunction in patients with BD conclude that subjective cognitive dysfunction is predicted by the severity of depression, anxiety, and manic symptoms, rather than diagnosis, age, gender, and alcohol abuse. A study that assessed subjective complaints and objective impairment among[ 24 ] patients with BD, in different phases of the illness, suggested that there was a significant correlation between subjective and objective cognitive performance among the patients in the euthymic phase, but the same was not seen among patients in acute episodes and subjective complaints were associated with depressive symptoms.[ 25 ]
However, most of the studies, which have evaluated subjective neurocognitive functions in BD, have small sample sizes. They have included a heterogeneous sample (i.e., including euthymic subjects and those currently in an episode) and have not assessed the association of subjective cognitive complaints with psychosocial outcomes. This study aimed to evaluate the prevalence of subjective cognitive complaints in subjects with BD. Additionally, the study aimed to assess the association of subjective cognitive complaints with the course of illness, residual symptoms and other clinical variables, insight , and disability.
METHODOLOGY
This cross-sectional study was conducted across 14 teaching institutes in India. The study received ethical clearance from all the participating sites’ local institutional ethics committees, and all the participants provided written informed consent before enrollment. This study focused on understanding the course and outcome of BD in the form of the number of episodes, residual symptoms, disability, insight , and subjective cognitive dysfunction.[ 26–28 ] In this paper, we focus on cognitive dysfunction and its association with other variables.
All the participants fulfilled the diagnosis of BD as per the Diagnostic and Statistical Manual for Mental disorders, Fourth edition[ 29 ] (DSM-IV), and confirmed by using the Mini-International Neuropsychiatric Interview (MINI-PLUS).[ 30 ] For inclusion into the study, the participants were required to be in the age ≥ of 18 years, have an illness of at least ten years, and currently in clinical remission. Clinical remission was defined by using Hamilton Depression Rating Scale (HDRS)[ 31 ] and the Young Mania Rating Scale (YMRS),[ 32 ] with patients having a score of ≤7 on both scales. Patients were also required to be able to read Hindi/English. Those with organic brain syndrome, intellectual disability, organic BD, and medically too sick to participate were excluded.
The course of the BD was evaluated by using the National Institute of Mental Health - Retrospective Life Charts - Clinician and Self-rated versions (NIMH: LCM - P and S/R).[ 33 ] Cognitive functions were evaluated by using the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA),[ 34 ] and insight was evaluated by using the insight scale for affective disorders (ISAD).[ 35 ] Both these scales were translated into Hindi using World Health Organization methodology, recommended for translation and back-translation. Disability was evaluated by using the Indian Disability Evaluation Assessment Scale (IDEAS).[ 36 ]
ISAD: This clinician-administered scale, based on the Scale for Unawareness among Mental Disorders (SUMD), was developed to assess insight in patients with mood disorders. It consists of 17 items, rated on a 6-point scale, varying from 0 (cannot be evaluated or item not relevant) to 5 (no awareness). The scale has been found to have adequate face and content validity of its items.[ 35 ]
COBRA: The Bipolar Disorder Program was developed by the COBRA at the Hospital Clinic of Barcelona to detect the main daily cognitive complaints experienced by bipolar patients. It is a 16-item self-report instrument for subjective assessment of cognitive dysfunctions in BD patients, including executive function, processing speed, working memory, verbal learning and memory, attention/concentration, and mental tracking. The scores partially correlate with the objective assessment of memory and executive functions.[ 34 ] A higher total score suggests a higher level of subjective complaints. A score of >10 is considered to be an indicator of the presence of cognitive impairment. It has high convergent validity and high internal consistency.
IDEAS: The IDEAS evaluates disability in four domains, namely, self-care, interpersonal activities, communication and understanding, and work. Each item is scored on a 5-point scale with a range of 0–4, i.e., from no (0) to profound disability (4). In addition, the duration of illness is also given weightage while calculating the disability score. The total disability score is obtained by summing up the ratings on the four domains. The global disability score is calculated by adding the “total disability score” and duration of illness score. A global disability score of more than 7 signifies a disability of >40%.
Statistical Package for Social Sciences, the fourteenth version (SPSS-14) (SPSS for Windows, Version 14.0. Chicago, SPSS Inc.) was used to analyze the data. The mean and standard deviation were computed for the continuous variables. Categorical variables were analyzed as frequency and percentages. Comparisons were made by using the t-test, Chi-square test, and Fischer’s exact test. Correlations were assessed using Pearson correlation coefficient and Spearman rank correlation as per the requirement. Regression analysis was carried out to evaluate the predictors of subjective cognitive complaints.
RESULTS
The study sample comprised of 773 subjects, with a maximum of 107 (13.8%) patients from one of the centers in Mumbai, followed by 92 (11.9%) patients from Chandigarh center (PGIMER, Chandigarh), 63 (8.2%) patients from Bardwan center, 58 (7.5%) patients each from a center in Kalyani and another in Kolkata, 52 (6.7%) patients from Manipal center, 51 (6.6%) patients from Puducherry, 50 (6.5%) patients each from Mullana, second centers in Mumbai and New Delhi, 49 (6.3%) patients from Jodhpur center, 47 (6.1%) from Silchar center, 25 (3.2%) patients from Ahmedabad, and 21 (2.7%) patients from Murshidabad center.
The mean total COBRA score was 9.79 (SD: 6.99), with a range of 0–40. When the cut-off of >10 was used, 322 (41.7%) of the participants were found to have subjective cognitive impairment.
Comparison of socio-demographic and clinical profile of those with and without subjective cognitive complaints
The mean age of the participants was 45.66 (SD: 10.5) years and the mean duration of education in years was 10.3 (SD: 4.45) years. The majority of the participants were male (63.6%), currently married (82.7%), on paid employment (65.7%), from nuclear families (57.6%), rural locality (53%), and Hindu by religion (73.2%). The mean income of the patients was rupees 24,463 (SD: 21,665), with a range of 1,000 to 1,00,000 and a median of 18,000. When those with cognitive complaints were compared to those without cognitive complaints, those with cognitive complaints were more often married, from non-nuclear families, and Hindu by religion [Table 1 ].
Table 1: Comparison of demographic variables of patients with and without cognitive complaints
In terms of clinical profile, compared to those without cognitive complaints, those with cognitive complaints more often had depression as the first episode in the lifetime, had higher prevalence of alcohol dependence, higher number of depressive episodes in the lifetime, higher number of depressive episodes per year of illness, higher number of manic and also depressive episodes in the first 5 years of disease, more often had depressive or indeterminate predominant polarity, lower prevalence of at least 1 lifetime episode with psychotic symptoms, higher severity of residual depressive and manic symptoms, more often had depression as the most recent episode, spent more time in the episodes in the lifetime, spent more time in the manic episodes in the lifetime, had overall higher severity of the lifetime depressive episodes, higher proportion of them consulted a faith healer in the lifetime, were less often hospitalized for BD, and less often had history of being treated with electroconvulsive therapy (ECT) [Table 2 ].
Table 2: Clinical profile of the participants with and without cognitive complaints
In terms of insight and disability, compared to those without cognitive complaints, those with cognitive complaints had poorer insight and a higher level of disability in all the domains of IDEAS, and a higher proportion of them had benchmark disability [Table 2 ].
In terms of treatment received at the time of assessment, compared to those without cognitive complaints, those with cognitive complaints, were less often not on any medications, were more often on a combination of mood stabilizers, antidepressants, and antipsychotic medications (with or without benzodiazepines), less often were receiving only mood stabilizers, were more often on antidepressants, less often on lithium and more often on valproate, and were more often getting a benzodiazepine [Table 3 ].
Table 3: Comparison of the treatment profile of those with and without cognitive complaints and association of cognitive complaints
Regression analysis
We used regression analysis to assess the predictors of subjective cognitive complaints. In the regression analysis, the total COBRA score was used as the dependent variable and other variables which differed significantly between the two groups were used as independent variables. In the enter method, only 12.1% of the variance of the subjective cognitive complaints was explained by affective morbidity index, duration of current remission, the total number of manic episodes in first 5 years of illness, the severity of depressive episodes, HDRS total score, YMRS total score, number of depressive episodes per year, total time spent in the episodes in a lifetime (in months), ISAD total score, depressive affective morbidity index, manic affective morbidity index, self-care, communication and understanding, duration of manic/hypomanic episodes in months, interpersonal relationship domain of IDEAS, and the total number of depressive episodes.
In the stepwise method, the maximum variance was explained by IDEAS interpersonal relationship domain (7.4%), followed by the affective morbidity index (1.4%), HDRS total score (1%), and severity of depressive episodes (0.5%).
Additionally, we also carried out the binary logistic regression analysis to assess the factors associated with the presence of subjective cognitive impairment. The odds of having subjective cognitive complaints were higher for those who were married, from extended/joint families, having depressive-manic-interepisodic course, having alcohol dependence in the lifetime, no lifetime psychotic episodes, intermediate predominant polarity, and having benchmark disability [Table 4 ].
Table 4: Binary logistic regression depicting the variables having significant association
DISCUSSION
In the present study, when the cut-off of >10 was used, 41.7% of the participants were found to have subjective cognitive impairment with a mean COBRA score of 9.79 (SD: 6.99). Previous studies which have used COBRA in patients of BD suggest the mean scores to a range of 8.32 (SD: 6.6)[ 37 ] to 17.01 (7.69),[ 38 ] and the findings of the present study are within this reported range. Although many studies have used COBRA to assess subjective cognitive complaints in patients with BD, there is a relative dearth of data concerning the proportion of patients with BD having subjective cognitive complaints. A study from China, by using the Chinese version of COBRA, suggested that 72.14% of patients with BD have a subjective cognitive impairment, with the highest prevalence among those with bipolar depression (97.62%), followed by a 78.0% among the patients who were currently euthymic and 43.75% in patients who were presently hypomanic/manic.[ 25 ] The reason for the lower prevalence of cognitive complaints in our euthymic BD patients is not apparent. Still, factors such as the different versions of the instrument, education, and age may confound the findings. Nevertheless, the presence of cognitive complaints in two-fifths of the sample in euthymia underscores the need to regularly assess cognitive complaints among patients with BD. Also, cognitive remediation strategies should be readily available for these patients to reduce cognitive impairment in the functioning of patients with BD.
In our study, age did not have an association with the presence or absence of cognitive complaints or the severity of cognitive dysfunction. There is a lack of consensus on this association, with some of the studies suggesting that younger people have a lower level of cognitive complaints. In contrast, others suggest that older people have higher cognitive complaints.[ 39 ] However, many studies refute this association.[ 40 ] A meta-analysis concluded that age does not influence cognitive impairments.[ 4 , 20 ] In the present study, age of onset also did not emerge as a factor that was associated with subjective cognitive complaints. Some of the studies suggest that early age of onset, especially onset during the pediatric age group, is associated with higher cognitive impairment.[ 41 ] Accordingly, this lack of association in the present study could be attributed to very few patients with childhood-onset BD.
We found that those with cognitive complaints have more severe illness and a higher level of residual symptoms. The higher severity of illness as indicated by the higher number of depressive episodes in the lifetime and per year of illness, the higher number of manic and also depressive episodes in the first five years of illness, spent more time in the episodes in the lifetime, spent more time in the manic episodes in the lifetime, and had overall higher severity of the lifetime depressive episodes. It has been suggested that neurocognitive impairments in patients with BD may be due to neurodevelopmental and neurodegenerative processes.[ 42 ] Accordingly, it can be said that the association of neurocognitive complaints with higher severity of illness over the years may be due to neurodegenerative processes, arising due to the toxic effect of higher number and more severe episodes in the lifetime, consistent with neuro-progression in the long-term course of BD, at least in a proportion of patients.[ 20 ]
Findings of the present study of the association of cognitive complaints with alcohol dependence are supported by previous studies, which also suggest higher severity of cognitive impairment among those with comorbid substance use.[ 20 , 21 ] Accordingly, it can be said that it is essential to address substance use in patients with BD, to minimize its impact on neurocognitive functioning. Clinicians should psychoeducate the patients about the association of substance use with cognitive complaints and aim for complete abstinence to minimize the negative impact on cognitive functioning.
Available studies suggest that compared to those without psychotic symptoms during the episodes, the presence of psychotic symptoms in patients with BD is associated with higher cognitive impairment in the domains of verbal memory, processing speed, speed of executive functioning, the accuracy of executive functioning, working memory, and social cognition.[ 6 ] However, in the present study, those with cognitive complaints had a lower prevalence of at least one-lifetime episode with psychotic symptoms. The lack of association in the present study could be attributed to the fact that we assessed psychotic symptoms only as present or absent in the lifetime and did not evaluate the total number of psychotic episodes. Consistent with our findings, few studies suggest a lack of association of cognitive impairment with psychotic symptoms in patients with BD.[ 6 ] Furthermore, compared to BD-II patients, those with BD-I have a higher level of global cognitive impairment, specifically in verbal memory, processing speed, executive function speed, and executive function accuracy.[ 43 ] However, we did not find any such association with subtypes of BD. It is important to note that some of the previous studies which have reported this association have relied on objective assessment instruments to assess cognitive impairment, which has been shown to have only a modest correlation with subjective cognitive complaints.[ 22 ]
Further, in contrast to expected, in the present study, those with cognitive complaints less often had a history of being treated with ECT.[ 44 ] This could be attributed to the relatively higher use of ECT in patients with BD in the Indian context, and better control of symptoms with ECT, which counteract the residual symptoms of BD.
We found a lower proportion of those with cognitive complaints had prior treatment with ECT, contrary to the studies that report cognitive impairments in those receiving ECT.[ 44 , 45 ] Relatively higher use of ECT in patients with BD in the Indian context may lead to better control of symptoms, which counteract the residual symptoms of BD.
In terms of other treatment variables compared to those without cognitive complaints, those with cognitive complaints were less often not on any medications, were more often on a combination of mood stabilizers, antidepressants, and antipsychotic medications (with or without benzodiazepines), less often were receiving only mood stabilizers, were more often on antidepressants, less often on lithium and more often on valproate, and were more often getting a benzodiazepine. Existing literature suggests that both ongoing medications and long-term use of medications in patients with BD influence the level of cognitive complaints.[ 20 ] The associations found in the present study can be understood as a reflection of a higher number of medications having an adverse impact on cognitive functions. Another possible explanation could be that the use of a higher number of medications among those with cognitive complaints was indicative of more severe illness and hence, required a higher number of medications. However, the effect of drugs on cognitive complaints is far from clear, and there is a need to evaluate their impact during long-term use.
In the present study, neurocognitive complaints were associated with a higher level of residual psychopathology, poorer insight , and a higher level of disability in all the domains. These associations are supported by the existing literature.[ 17 , 18 , 46 , 47 ] The implications of these findings include adequate symptom control and proper psychoeducation of patients to improve their insight into the illness is of paramount importance for the management of BD. Some of the studies which have evaluated the association of insight and neurocognitive impairment suggest that neurocognitive impairment leads to poor insight in patients with BD.[ 48 ] The association of higher neurocognitive complaints with a higher level of disability suggests that neurocognitive complaints are an important marker of BD, which influences the psychosocial outcomes of BD. Hence, all efforts must be made to minimize the neurocognitive complaints in patients with BD to improve psychosocial outcomes.
However, in the regression analysis, only 12.1% of the variance of the subjective cognitive impairment was explained by all the variables studied. Among the various variables, the maximum variance was explained by IDEAS interpersonal relationship domain (7.4%), followed by the affective morbidity index (1.4%), HDRS total score (1%), and severity of depressive episodes (0.5%). However, it is important to note that the association of subjective cognitive compliants and interpersonal relationship domain of disability may be more of an impact of cognitive impairment rather than a cause of the same. In the binary logistic regression analysis, the odds of having subjective cognitive complaints were higher for those who were married, from extended/joint families, having depressive-manic-interepisodic course, having alcohol dependence in the lifetime, no lifetime psychotic episodes, intermediate predominant polarity, and having benchmark disability. These findings suggest clinical variables, i.e., the variables describing the life course of BD influence the subjective cognitive complaints than other variables.
The limitations include a lack of objective measures for the assessment of cognitive functions. Although we evaluated the relationship of subjective cognitive complaints with current prescriptions, this study was not designed to assess the impact of long-term treatment on cognitive functions. The assessment of cognitive complaints was cross-sectional. Hence, the present study’s findings do not provide any information about the longitudinal course of cognitive complaints in patients with BD.
To conclude, the present study suggests that about two-fifths of patients with BD have subjective cognitive complaints. Cognitive complaints are associated with more severe illness, higher levels of residual symptoms, use of a higher number of medications, poor insight , and higher disability. Accordingly, any rehabilitation effort for patients with BD should focus on cognitive remediation, which should start as early as possible during the longitudinal course of illness. Further, efforts must be made to minimize residual psychopathology, which is also considered to have a negative impact on cognitive functioning.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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