Clinical practice guidelines on cognitive impairment in bipolar disorders – Assessment and management

INTRODUCTION Bipolar disorder (BD) affects about 0.5% of the Indian population.[1] Individuals with BD experience residual symptoms between episodes and manifest significant functional and cognitive impairments, even during remission. Patients with BD show notable cognitive impairment across all clinical states, including euthymia, even when potential confounding factors like demographic variables, medication effects, and residual depressive symptoms are controlled for.[2] Neurocognitive deficits are not only a persistent aspect of the illness but also postulated to be a fundamental primary characteristic, rather than a result of the mood state or medication.[3] A significant and widespread neurocognitive deficit reportedly exists even before the first onset of mood symptoms, persists through various phases, and often deteriorates as the illness progresses.[4–6] Cognitive functioning is a key predictor of occupational functioning in BD and may exert a greater influence than other clinical factors. Considering the widespread and negative psychosocial impact of cognitive dysfunction in the illness, it is crucial to utilize appropriate cognitive measures to enhance our understanding of the nature, severity, and correlates of cognitive deficits in the illness and to develop effective therapeutic strategies to address this cognitive impairment in BD. PROCESS OF DEVELOPMENT OF GUIDELINES A thorough literature search was conducted using the key words/MeSH terms neurocognition, cognitive function, cognitive deficits OR executive functions OR working memory, cognitive domains AND bipolar disorder, mania, and bipolar depression. The 1643 articles that were returned were scrutinised for relevance. In addition, the Medline search returned about 63 systematic reviews and 46 meta-analyses on the search terms neurocognition and bipolar disorder. The articles were then screened for relevance on the title and abstract. The ones that were more recent were included in the review on the understanding that they would include the previous articles. Search for Indian literature using the same search terms returned about 30 articles, most of which have been included in this guideline. Weightage was given to meta-analysis where available. The manuscript has been organised in a manner that would provide good flow for the reader, including what is the evidence available including social cognition, what assessments are possible, time taken for each assessment, what are the treatment options investigated and which of these are feasible in clinical practice. A flow chart is incorporated to highlight the same. COGNITIVE DEFICITS IN BD – EVIDENCE SO FAR To understand cognition in BD, let us try to answer a few questions that commonly arise when we talk about cognition in this group of patients. Are cognitive deficits present in BD? Many studies have supplemented the clinical observation that not all BD patients have cognitive deficits. Three distinct cognitive subgroups have been identified in BD subjects in remission – those with intact cognition, those with selective cognitive impairment, and those with global cognitive impairment (Burdick, 2014; Lima, 2019).[7,8] These differences remained over a 5-year longitudinal course, thereby further highlighting that cognitive deficits in BD could represent a significantly heterogeneous group (Elhrich, 2022)[9] and the cognition remained intact in the high-performance group relative to healthy subjects. Cognitive heterogeneity is now being increasingly recognized, and the cognitive trajectory of BD is a subject of scholastic debate and enquiry (Van Rheenan, 2020).[10] Despite this, there is a consensus that not only the performance on neurocognitive tasks in nearly every major domain is disrupted during manic, depressed, or mixed phases of BD but also the deficits persist even in euthymia. Studies have noted that in euthymic BD, domain-specific deficits have been demonstrated in attention, verbal learning memory, and executive functions.[11] Attention is a complex neurocognitive domain with several subcomponents and is essential to all higher cognitive functions. Sustained attention is impaired in BD in all phases of the illness, and these impairments do not remit completely during euthymia. Selective attention deficits present in the acute episodes also persist during euthymia.[12] Verbal immediate and delayed recall is also impaired in remitted BD. Executive function deficits are the most consistent neurocognitive deficit reported in euthymic BD in different aspects of executive function like planning, set-shifting, cognitive control, and verbal fluency.[12–14] In summary, multiple investigations have consistently provided evidence of neurocognitive deficits in individuals with BD across all clinical stages, including euthymia. These impairments have been found to have moderate to high effect sizes. Deficits in verbal memory and certain aspects of executive functioning seem to be more pronounced compared to other cognitive domains. The findings of various studies are summarized below [Table 1].Table 1: Summary of studies on cognitive deficits in BDAt what stages are cognitive deficits noted? At what stage in the course of the illness do cognitive deficits occur, does illness progression has an impact on the progression of the cognitive deficits, and what is the potential for intervention at each stage are some questions that are of clinical relevance. Some studies (individual and reviews/meta-analyses) have evaluated cognitive deficits in the different stages of BD and the correlation between illness progression and the progression of cognitive deficits. The individual studies are mostly cross-sectional though longitudinal studies would be more informative. Most of these studies have reported that cognitive deficits are present from the very early stages, that is, even in the first-degree unaffected family members also, and these are more pronounced after the onset of the first episode. A recent study by Reddy et al., 2023 done at NIMHANS also showed similar results.[19] A study done at NIMHANS[20] that evaluated cognition across stages of BD also noted that those with a higher number of episodes, especially more than three manic episodes, show higher deficits than those with one or two episodes. Some of these studies are summarized below [Table 2].Table 2: Summary of studies on cognitive deficits across stages of BDAre there distinct cognitive subgroups of BD? Some of the studies have attempted to investigate this question. Bora (2018) examined the impact of a history of psychotic characteristics and full manic episodes on neurocognitive performance. The results showed that those with a history of psychotic symptoms and individuals with a history of full manic episodes, that is, BD-I, had slightly more severe cognitive deficits. BD-I significantly underperformed BD-II in global cognition, verbal memory, and processing speed. Psychotic BD was associated with significantly impaired cognition in global cognition verbal memory processing speed, EF speed, EF accuracy, working memory, and social cognition.[26] Studies have also attempted to see the difference between BD I and BD II, and they reported similar cognitive profiles. A recent systematic review reported similar cognitive profiles in BD I and BD II.[27] Lima et al.in 2019 did a hierarchical cluster analysis to investigate the presence of discrete neurocognitive subgroups using a neurocognitive battery as the basis for classification. The Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and Functioning Assessment Short Test (FAST) were employed to evaluate self-reported cognitive challenges and the extent of functional impairment. The study delineated three distinct subgroups: The first comprised individuals with normal cognitive function (43.5%), the second included individuals with specific cognitive impairments (33.3%), and the third encompassed individuals with overall cognitive impairments (23.3%). The intact group had significantly greater levels of schooling and higher estimated IQ compared to both the generally and selectively affected groupings. Furthermore, they received a diagnosis of BD at an earlier age and underwent their initial hospitalization at a younger age than individuals with general cognitive impairment. Evidence supports the presence of a spectrum of severity ranging from patients without any impairment to those with significant cognitive dysfunction. Patients in the intact group exhibit a greater level of cognitive reserve compared to the other two groups. Nevertheless, they also encountered cognitive grievances and a certain level of functional debilitation.[8] These findings indicate that it is crucial to utilize a combination of tools, such as objective and subjective cognitive measures along with functioning instruments, in order to fully evaluate patients with BD. The above studies suggest that we definitely need a better understanding of the determinants of cognitive deficits in BD patients. Let us discuss these determinants in further detail.DETERMINANTS OF COGNITIVE DEFICITS IN BDASSESSMENT OF COGNITIVE FUNCTIONS The assessment of cognitive deficits can be outlined in two steps: Screening for cognitive deficits Evaluation of cognitive deficits Like schizophrenia, where researchers have developed cognitive batteries like the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), researchers working on cognition in BD have developed screening tools that can identify cognitive deficits in BD. Before we screen the patient for cognitive deficits, assessment of the baseline IQ is very important. Screen patients when they are in remission (currently euthymic). Clinicians can use the Wechsler Abbreviated Scale of Intelligence® - Second Edition (WASI®-II) to assess the IQ. The WASI is intended to provide estimates of verbal and performance intelligence consistent with previous Wechsler tests in addition to measuring general, or full scale, intelligence.[36] The screening tools that have been validated for use in BD are listed below [Table 3].Table 3: Screening Tools for Cognitive Deficits in Bipolar DisorderAmong the computer-based tests, THINC-IT takes less time (15 minutes) when compared to ICAT (35 min), but THINC-IT is validated only for bipolar depression and has poor psychometric quality, so ICAT is a better screening instrument. Among the paper–pencil screening tests, COBRA takes 10 minutes and is a self-report-based test, whereas SCIP takes 15 minutes is a clinician-assessed, performance-based tool. The International Society of Bipolar Disorder (ISBD) formulated a task force to develop a consensus statement about the neurocognitive deficits in BD. This team reviewed various available cognitive batteries and the individual domain tests for their utility in BD.[41] ISBD Battery for Assessment of Neurocognition (ISBD-BANC) outlines the cognitive domains and neuropsychological tests relevant to BD. The NIMHANS neuropsychological battery which is validated for use in the Indian population has tests that can be used to assess the same cognitive domains [Table 4].Table 4: Proposed Cognitive Battery for Bipolar DisorderOut of the other cognitive batteries that could be relevant in BD but warrant further studies include: Hayling Sentence Completion Test (HSCT) for testing inhibitory control, Cambridge Neuropsychological Test Automated Battery intradimensional ⁄ extradimensional (CANTAB-IDED) set-shifting task, Tower of London (and variants) for planning, inhibition, and working memory, Balloon Analogue Risk Task (BART) for decision-making/risk-taking, and Theory of Mind Advanced Test for Theory of Mind. Keefe et al. group also working on cognition in BD adopted the Brief Assessment of Cognition in Schizophrenia (BAC-S) scale for assessing cognition in BD and called it Brief Assessment of Cognition in Affective Disorders (BAC-A). This battery has been studied extensively and validated for assessing cognition in BD patients.[42] The tests included in the BAC-A battery are as mentioned in the below table [Table 5].Table 5: BAC –A SubtestsRecommendation: If cognitive impairment is suspected during clinical evaluation, initially screen and/or monitor the patient’s cognitive performance using one of four instruments (THINC-it, ICAT, COBRA, and SCIP). If deficits are identified, then we can proceed to the next level of assessment, choosing between BAC-A and ISBD-BANC [Figure 1].Figure 1: Algorithm for the type of tests to be used for screening and assessing cognitive deficits in BDBAC-A takes 45 minutes, clinician-assessed, performance-based tests, and ISBD-BANC takes around 90 minutes, clinician-assessed, performance-based tests. Since BAC-A assesses a component of affective memory and emotional inhibition, also takes lesser time, it might be more feasible in clinical settings. SOCIAL COGNITION IN BIPOLAR DISORDER Social cognition (SC) is a discipline that seeks to understand how brain function facilitates the cognitive processes that underlie social behavior. It encompasses a range of intricate processes that enable us to engage in adaptive social interactions. These processes include representing internal bodily states, self and other knowledge, interpersonal motivations, and the ability to respond appropriately to socioemotional information.[43] The National Institute of Mental Health (NIMH) has categorized five fundamental areas within this concept: Theory of Mind (ToM), Social Perception, Social Knowledge, Attribution Bias, and Emotion Processing (EP).[44] The theory of mind pertains to the capacity to comprehend and assign mental states, including beliefs, wants, and intentions, to oneself and others. Mentalizing talents are also referred to as the capacity for understanding and attributing meaning to mental processes in oneself and others. Attributional bias refers to the inclination to attribute the reason for occurrences to oneself, others, or the situation to understand social events and interactions. Emotional processing refers to the cognitive and psychological mechanisms involved in understanding and managing emotions. Emotional intelligence is the capacity to accurately observe and interpret facial expressions that convey emotions, as well as effectively utilize and regulate one’s own emotions. Social perception refers to the process by which individuals interpret and understand the behavior, intentions, and characteristics of others in social situations. Social competence refers to the capacity to recognize, assess, and effectively utilize social cues to make accurate assessments about social roles, norms, connections, and the circumstances of others. Social knowledge, also known as social schema, is the understanding of the rules, objectives, and roles that define social circumstances and facilitate social interactions. Patients with euthymic BD experience a decline in ToM function, particularly in verbal ToM. Regarding ToM abilities in individuals with BD, there is a widespread observation of impairment during the acute periods of the illness.[45,46] However, the evidence of abnormalities in remission samples has been less compelling. The study of sociocognitive impairment in euthymic states is highly significant since these deficiencies can significantly hinder social reintegration and rehabilitation.[47] Considering the significance and influence of ToM performance on various aspects of life such as quality of life, social perception, and social behavior, it is crucial to conduct additional research on the psychological and neurobiological mechanisms behind these impairments. This research is necessary to identify specific areas to focus on in the development of personalized SC training for this particular population. A study conducted by Choudhary et al. in 2021[48] indicates that individuals with BD exhibit the lowest performance, while the HC (healthy controls) demonstrate the highest performance on the majority of SC (social cognition) tasks. Siblings, conversely, occupy an intermediate position between the patients and healthy controls for performance on all social cognition subtests, with the exception of the faux pas composite index and externalising bias, where siblings exhibited inferior performance compared to the patient group. Within the several areas of SC, the faux pas index, which reflects deficiencies in ToM, could potentially be explored as a potential endophenotype for BD. However, it is essential to replicate these findings with a larger sample size, undertake normalcy assessments for task performances, and analyze biomarkers to draw definitive conclusions from these results. In the overall population of patients with BD, there is no association between SC and demographic and clinical factors. Nevertheless, SC exhibits a notable correlation with neurocognition in both patients and siblings of patients with BD. Figure 2 presents the algorithm of approach to cognitive evaluation for BD patients.Figure 2: Algorithm of approach to cognitive evaluation in BD patientsMANAGEMENT OF COGNITIVE DEFICITS IN BD Cognitive dysfunction has been linked to psychosocial dysfunction and reduced quality of life in individuals with BD. Secondary expenses associated with BD (such as unemployment and reduced workplace efficiency) present a significantly larger economic burden. There is a pressing need for procognitive treatment to enhance the functioning and quality of life in individuals with cognitive impairment in BD.[49] Below, we present the evidence from various trials that have looked at pharmacological and nonpharmacological interventions [Tables 6 and 7, respectively].Table 6: Summary of pharmacological intervention study details and resultsTable 7: Summary Psychosocial and Other Biological Intervention Study Details and ResultsTo summarize the above findings at present, no intervention has shown strong, separate, and beneficial effects on cognitive function in adults with BD, as indicated by findings from randomized, double-blind, placebo-controlled It is to such as the study population with have cognitive impairment and include those are in remission. The also a cognitive that is with a impact from and is of as a Since we do not have any or that can or cognitive deficits in BD, it that we focus on before these deficits that is, the of cognitive impairment. This can be done first by the of the cognitive impairments and second by The of cognitive deficits of BD are and intelligence of cognitive clinical acute depressive symptoms, psychotic symptoms, bipolar or illness number of episodes, pharmacological and The potential strategies would be to multiple episodes with effective and the of that with cognitive function, depressive symptoms, and healthy and cognitive or functional procognitive and use brain early in the course of the illness, that is, after the first IN interventions in The early interventions can be one in the have developed the illness and are in the early course and second in those are at high of BD. In BD patients in the early course of illness, the ISBD task force has given certain after a systematic that the combination of psychological and interventions may provide effects, the most effective interventions or for this specific group in the early stages are also suggest the potential of in in the early stages of illness, along with the the use of both medication and it is to assess the of and in the early stages of on the available evidence the use of both medication and psychological individuals in the early stages of BD be provided with the to and effective systematic review that evaluated the of early intervention in individuals an affected that studies provide the to BD, which is the primary in early intervention studies with sample and a group of would provide the impact of a with in mood episodes, such as cognitive and moderate be for in this particular population. It is to assess the of to a group. intervention in the initial phases of a can the impact of the and significant in terms of both and economic and to the onset of AND Many individuals with BD exhibit cognitive impairment in all clinical phases, including euthymia, even after for potential confounding factors such as demographic effects, and residual This cognitive impairment affects all it is especially pronounced in verbal memory and executive studies provide evidence that treatment has a effect on cognitive performance in a certain of with BD do not respond well to the is linked to cognitive function in to other used to the effect of on cognition is research indicates in to individuals with schizophrenia, the majority of with BD exhibit cognitive abilities that are or higher than normal to the onset of the disorder. Nevertheless, a of individuals with BD has that early may to the development of BD in this specific group of patients. The available studies do not provide evidence to the of cognitive in BD after the initial episode. In certain research indicates that patients may observe in cognitive performance through treatment the initial manic episode. Cognitive functioning a crucial in how well with BD can do their and results from studies have indicated the potential effects of interventions as well as pharmacological interventions and and interventions and longitudinal studies on the neurocognitive functioning of individuals at high of BD can enhance our understanding of how neurocognitive impairment and in BD. This can then be used to develop specific early intervention strategies that to or and potentially cognitive Furthermore, it is crucial to the significant influence that cognitive abilities have on the overall functioning of individuals with BD. trials also the and negative effects of on cognitive performance and functional and of There are no of