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.[4,5,6] 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.[12,13,14] 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 BD

Study	Groups Compared and Markers Studied	Number of Subjects	Results of Group Comparisons	Correlation with Illness-Related Variables
Robinson et al., 2006[15]	• Metaanalysis – 26 studies • BD Vs HC   ✓ Executive measures   ✓ Verbal learning and memory   ✓ Attention and psychomotorspeed	BD euthymic=689 HC=721	• BD poor performance on all measures	---------------------------
Torres et al., 2007[16]	• Metaanalysis – 39 studies • BD Vs HC   ✓ Premorbid intellect   ✓ Attention/processingspeed   ✓ MemoryLearning ✓ Executive/workingmemory	BD euthymic=948 HC=1128	• BD group performed poorly on all measures	---------------------------
Kurtz et al., 2009[6]	• Metaanalysis – 60 studies • BD euthymia • BD Mania/Mixed • BD Depression • HC   ✓ Attention   ✓ WorkingMemory   ✓ Verbal Memory   ✓ Nonverbal Memory   ✓ Visuospatial   ✓ Function   ✓ Language   ✓ Psychomotar Speed   ✓ Executive Function	BD eythymia=42 studies, 1197 patients BD Mania/Mixed=13 studies, 314 patients BD Depression=5 studies, 96 patients	Euthymia Vs HC 1.Attention 2.Working memory 3.Verbal memory 4.Non-verbal memory 5.Visuospatial- block design 6.Language 7.Psychomotar speed 8. Executive function Mania/Mixed Vs HC 1.Attention 2.Verbal memory 3. Language 4. Executive functions Depression Vs HC 1. Attention 2.Verbal memory 3. Language 4. Executive functions	--------------------------
Bourne et al., 2013[17]	• Metaanalysis • BD Vs HC • Re-analysis of 31 primary data sets as asingle large sample (n=2876) • 11 measures from 4 common tests: CVLT, TMT, DigitSpan and WCST	BD euthymic=1276 HC=1609	• BD group performed poorly on all measures	• Neither lithium or antidepressants affected performance on any of the measures • Antipsychotics and no. of manic episodes showed decreased performance on verbal learning • No of depressive hospitalizations affected TMTA • Total no of hospitalisations affected TMTA, TMTB WSCT.
Daglas et al., 2015[18]	• Systematic review (7 studies) • FEM acute and remission phases • Intelligence, Processing speed, Attention, Memory, executive functions, Verbal fluency, visuaospatial orientation	3 studies with FEM 4 studies of FEM in remission BD FEM=230 HC=345	• FEM acute Vs HC Executive functions: differences • FEM remission Vs HC Attention, Memory, Response inhibition, Spatial planning, verbal working memory and Spatial working memory was poorer for the remission group	• Patients on lithium treatment performed poorer on memory tasks • Patients in remission receiving lithium had markedly superior performance in spatial reasoning/orientation and executive functioning measures compared to those on divalproex. • One study reported that increased daily dosage of antipsychotic medication correlated with a slower performance

At 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 BD

Study	Groups Compared and Markers Studied	Number of Subjects	Results of Group Comparisons	Correlation with Illness-Related Variables
Manteiga et al., 2018[21]	• Cross-sectional study • Four stages of BD • Evaluated staging, neurocognition and social functioning	• Euthymic type I BD patients in the early (n=25) • Late (n=23) stages • Healthy siblings (latent stage; n=23) • HC (n=21)	• Early-Stage Patients vs. Controls: early-stage patients showed a deficits • Early-Stage Patients vs. Siblings: early-stage patients had significantly worse performance • Late-Stage Patients vs. Controls: late-stage patients had a deficit • Late-Stage Patients vs. Siblings: late-stage patients had significantly worse performance • Patients in Early-Stage vs. Late-Stage No substantial changes were seen between the two patient groups in any of the neurocognitive measures.	• • Social functioning: Late-stage patients had inferior performance compared to early-stage patients, although both clinical groups performed worse than healthy siblings and controls. The functioning of siblings was analogous to that of the control group.
Torres et al., 2020[22]	• Longitudinal study • 3 time points (Baseline, one year, 3 years) • Newely diagnosed BD Vs HC	• BD=91 • HC=61	• At baseline, patients showed significantly lower performance across all domain scores and effect sizes • moderate to large range. • Only significant trajectory difference between groups • was observed for processing speed significant difference between • patients and controls at baseline but not at 1 year or 3 years	• Lower executive functioning in patients with substance abuse relative to those without substance abuse at 1 year but not at baseline or 3 years • Illness duration by time interaction was not noted for any of the cognitive domain scores • Change in cognition was not • significantly associated with the number of manic, depressive, or total mood episode recurrences nor • with change in mood symptom ratings • Patients who discontinued antipsychotics from baseline to 3 years showed more improvement in verbal memory than those who had no change in antipsychotics or those who had an antipsychotic added
Achalia et al., 2020[23]	• Cross-sectional study • BD FEM • BD Multiepisode • HC (a) Continuous Performance Test - Identical Pairs (CPT) for assessing sustained attention, (b) Stroop Test for evaluating response inhibition, and (c) Wisconsin Card Sorting Test (WCST) for measuring set shifting.	• BD FEM=13 • BD multiepisode=17 • HC=30	• The BD group exhibited substantial impairment across all three cognitive assessments in comparison to HC. • No significant differences were observed between first episode mania and BD with several episodes on any cognitive measure.	• Positive correlation between YMRS score and WCST-nonperseverative error • No significant correlation between other clinical variables, namely HDRS score, Simpson Angus scale score, age at onset of illness, duration of illness or antipsychotic dose measured using chlorpromazine equivalent
Chandrashekaran et al., 2020[24]	• Cross-sectional study • Unaffected siblings of BD patients • HC • Addenbrooke’s Cognitive Examination III Revised (ACE-III R) • Trail Making Test (TMT) A & B • SOFAS	• Unaffected siblings=60 • HC=60	• The siblings had underperformed significantly low scores in memory tasks of ACE-III R Cognitive domains of memory and the total score in ACE-III R were positively correlated with better functioning • TMT-A correlating negatively with psychosocial functioning	• Psychosocial functioning as dependent variables was significant for predicting attention score on ACEIIIR
Miskowiak et al., 2022[25]	• Systematic review • BD euthymic • HR	• Total number of studies=19 • BD euthymic=36–76, studies 12 • HR=84–234, studies 7	• (Hypo) manic episodes relapse were predicted • by general cognitive impairments and by verbal learning and • memory impairments • Depression relapse results are conflicting • HR group showed mixed results, fMRI based studies differential neural response in the insula, ACC and thalamus during executive functions and emotional • processing in the high-risk individuals with subsequent onset of illness • compared to the groups that remained well.	• • ---------------------------
Reddy et al., 2023[19]	• Cross-sectional study • FEM, HR and HC	• Each group n=25	• Compared to the HC group, the FEM group performed poorly on multiple cognitive domains • The performance of the HR group was comparable to the FEM group, but they showed significantly poorer performance compared to HC on verbal fluency and visual learning, and memory	• • ------------------------------
Reddy et al. (Unpublished data)	• Crosscetional Study • Multiple Episode BD, FEM, HR and HC	• Each group n=42	• The ME group with higher number of manic episodes higher cognitive deficits compared to FEM in processing speed, set shifting, verbal and visual memory • In terms of the cognitive test raw scores, the processing speed domain showed a pattern of deficits (ME>FEM>HR>HC • The FEM group lies in between the ME and HR groups in verbal learning memory and visual memory HR were similar to controls. • The HR group was comparable with the FEM and they lie between the ME and control group in set-shifting and visual memory	• Total duration of illness correlated: processing speed, set shifting, response inhibition, verbal and visual memory • Total no. of Manic episodes correlated: processing speed, set shifting scores, verbal memory • Total no of depressive episodes correlated: response inhibition, visual memory

Are 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 BD

Determinants	Evidence
Single vs multiple episodes	As mentioned earlier in this chapter, early stage BD and late stage BD performed equally and both had deficits compared to healthy subjects. In one longitudinal study with 3 years follow-up, only the processing speed domain showed a trajectory of decline over the years.[28] The rest of the deficits remained stable with the progressive course. Similarly, a PhD study done in NIMHANS[20] also noted a difference between first-episode mania and multiple-episode BD in the processing speed domain, especially after the third manic episode.
Manic vs depressive episodes	Individuals in the early stages of BD reportedly experience deficits in all cognitive domains; depressive episodes do not impose any additional burden on cognitive performance, unlike mania.[29] Nevertheless, those with lower verbal memory indicate a higher likelihood of experiencing a depressive relapse in the early stages of the illness. The residual depressive symptoms and number of manic episodes seem to have a negative impact on cognition especially in the attention and verbal learning and memory domains.[17]
Predominant polarity	As discussed above, the existing literature highlights that cognitive deficits are probably mania-driven. This finding is of utmost importance to the Indian subcontinent because most of our studies have reported a mania-predominant course in our population compared to the depression-predominant course in the West.[30]
Medications – valproate, lithium, second-generation antipsychotics	Lithium: Early in the course of BD, treatment with valproate, rather than lithium, may lead to working memory problems.[31] A comprehensive meta-analysis of cognitive research in BD indicated that patients receiving lithium treatment are more prone to exhibit learning and encoding difficulties, as well as diminished cognitive flexibility, in comparison to unmedicated patients. Subsequent investigations did not identify any significant deficiencies associated with lithium medication over a duration of 4 or 6 years. Valproate and anticonvulsants: Anticonvulsants typically result in psychomotor slowness as well as deterioration in memory and attention. Valproate, as opposed to lithium, may result in impairments in working memory. A 6-month follow-up study revealed that patients with BD treated with lamotrigine achieved superior scores in phonemic verbal fluency and, to a lesser degree, in verbal memory tasks. Antipsychotics: The inclusion of risperidone alongside a mood stabilizer adversely affects executive functions and verbal learning, a finding that is not observed with quetiapine.[32] Olanzapine and quetiapine-treated patients perform better than risperidone-treated patients.
Obesity	Early in the course of BD, overweight–obesity does not have a detrimental impact on cognitive performance. Considering the available research that suggests obesity can have a detrimental effect on the progression of illness, it is possible to intervene and address obesity at an early stage of BD.[33]
Psychotic symptoms	Executive functioning and cognitive flexibility in particular appeared to be a deficit area in BD with psychotic symptoms. Studies suggest that there may be slight cognitive variations between BD patients with or without psychotic symptoms as well as between patients with mood-incongruent and mood-congruent psychotic symptoms, immediately after the onset. Therefore, it may be worthwhile to investigate early intensive techniques to maintain cognitive functions in these specific groups of patients.[34]
Gender differences	Studies investigating sex differences have revealed significant effects on tasks related to spatial working memory and sustained attention, with males exhibiting superior performance compared to females in healthy subjects. Patients with early BD, who have recuperated from an initial manic episode, persist in demonstrating normative cognitive sex differences.[24]
Childhood Trauma	A study by Hsueh et al., 2024 explored the impact of childhood trauma on cognition in BD patients using cluster analysis. The cluster characterized by neglect had significant instances of both physical and emotional neglect, accounting for 41.8% of the cases. Patients with BD in this particular group had poorer performance in the Brief Assessment of Cognition in Affective Disorders (BAC-A) when compared to patients in the cluster with multiple trauma. This difference was particularly evident in tasks related to working memory and processing speed. The group that was focused on neglect had a noteworthy adverse impact on the composite score as well as working memory.[35]
Thyroid functions	Assess for thyroid function
Vitamin deficiencies	assess

ASSESSMENT OF COGNITIVE FUNCTIONS

The assessment of cognitive deficits can be outlined in two steps:

1. Screening for cognitive deficits

2. 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 Disorder

Name of the screening tool (author & year)	Brief description
Cognitive Complaints in Bipolar Disorder Rating Scale - COBRA (Jensen et al. 2015)[37]	A 16-item self-report instrument, validated for application in India, assesses subjective cognitive challenges, including executive function, processing speed, working memory, verbal learning and memory, attention and focus, and mental tracking. Time 10 mins
Screen for Cognitive Impairment in Psychiatry - SCIP (Schmid et al. 2021)[38]	The paper-and-pencil screening instrument detects cognitive impairments in psychiatric populations through assessments of immediate and delayed verbal learning, working memory, verbal fluency, and processing speed. Time 15 mins
THINC- Integrated Tool- THINC-IT (McIntyre et al. 2017)[39]	web-based, patient-administered cognitive screening tool Uses gamified cognitive tasks to engage patients in completing the tests. The assessment evaluates both subjective and objective cognition through four objective tests (attention and executive functions, working memory, and processing speed) and one self-report questionnaire (PDQ-5-D) that measures attention and concentration, prospective memory, retrospective memory, planning, and organisation. 15 min
Internet Based Cognitive Assessment –ICAT (Hafiz et al. 2019)[40]	The revised web-based iteration of the SCIP comprises five subtests that evaluate four cognitive domains: verbal learning, working memory, delayed verbal learning, and psychomotor speed. (35 min)

Among 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 Disorder

Cognitive Domain	Neuropsychological test (Tests from MATRICS Consensus Cognitive Battery MCCB subtests)	Indian Adaptation (Tests from NIMHANS Neuropsychological Battery) Permissions/Purchase
Speed of processing Attention/Vigilance	Brief Assessment of Cognition in Schizophrenia (BACS): Symbol Coding	Digit symbol substitution test (DSST)
	Category Fluency: Animal Naming	Controlled oral word association test (COWA)
	Trail Making Test–part A Continuous Performance Test–Identical Pairs (CPT-IP)	Color trails test (CT) 1 Digit Vigilance test
Working Memory	Wechsler Memory Scale–3 Letter-Number Sequencing	N- Back-test
	Wechsler Memory Scale–3 Spatial Span	Spatial Span
Verbal learning/memory	Hopkins Verbal Learning Test-Revised	Rey’s auditory verbal learning test (AVLT)
	California Verbal Learning Test
Visual learning	Brief Visuospatial Memory Test-Revised	Complex figure test (CFT)
Executive functions Response Inhibition	Trail Making Test–part B	Color trails (CT) 2
Set Shifting	Stroop test	Stroop test

Adapted from The International Society for Bipolar Disorders–Battery for Assessment of Neurocognition (ISBD-BANC), Yatham, et al.; 2010[41]

Out of the other cognitive batteries that could be relevant in BD but warrant further studies include:

1. Hayling Sentence Completion Test (HSCT) for testing inhibitory control,

2. Cambridge Neuropsychological Test Automated Battery intradimensional ⁄ extradimensional (CANTAB-IDED) set-shifting task,

3. Tower of London (and variants) for planning, inhibition, and working memory,

4. Balloon Analogue Risk Task (BART) for decision-making/risk-taking, and

5. 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 Subtests

Cognitive Domain	Neuropsychological tests
Affective Learning and Memory	Affective Interference test (Affective Auditory Verbal learning test)
Emotional Inhibition	Emotional Stroop
Verbal Learning/Memory	Rey’s auditory verbal learning test (AVLT)
Working memory	Digit sequencing task
Motor Speed	Token Motor Task
Verbal Fluency/Category Fluency	Controlled oral word association test (COWA)/Animal Naming
Executive functions (Planning)	Tower of London test
Attention and Motor Speed	Digit Symbol Substitution test

Recommendation: 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 BD

BAC-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 patients

MANAGEMENT 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 results

Study and year	Pharmacological Intervention and the Doses	Design	Treatment Groups	Significant Results
Toniolo et al. 2017[50]	Creatine Monohydrate 6 g/day	Sub-analysis of a randomized, double-blind, placebo-controlled trial; 6 w treatment, no follow-up	Creatine monohydrate (9) vs placebo (9)	Significant improvement in verbal fluency
Miskowiak et al. 2014[51]	Erythropoietin 40,000 IU Infusions weekly	Double-blind, randomized, placebo-controlled trial; 8 w treatment, 14 w follow-up	EPO (23) vs Placebo (20)	Significant improvement in tests for verbal memory, sustained attention, attention, executive function, and social cognition
Ghaemi et al. 2009[52]	Galantamine 8-24 mg/day	Double-blind, randomized, placebo-controlled trial; 12 w treatment, no follow-up	Galantamine (6) vs Placebo (10)	Placebo was superior to treatment in a single measure of verbal fluency
McIntyre et al. 2012[53]	Intranasal insulin 40 IU q.i.d.	Double-blind, randomized, placebo-controlled trial; 8 w treatment, no follow-up	Insulin (34) vs Placebo (28)	Significant improvement in one test of executive function (trail making B)
Yatham et al. 2017[54]	Lurasidone 20–80 mg/day	Open-label randomized controlled pilot trial; 6 w treatment, no follow-up	Lurasidone (17) vs TAU (17)	Improvement in global cognitive function and one measure of working memory (letter number sequencing)
Alda et al. 2017[55]	Methylene blue 195 mg	Double-blind crossover study; 3 months treatment, 1 week washout	n=37 Therapeutic dose methylene blue vs subtherapeutic dose methylene blue crossover	No significant changes in cognitive function
Young et al. 2004[56]	Mifepristone 600 mg/day	Double-blind crossover trial 1 w treatment 2 w washout	n=20 Mifepristone vs Placebo crossover	Significant Improvement in visuo-spatial learning, spatial working memory, and executive function.
Watson et al. 2012[57]		Double-blind, randomized, placebo-controlled trial; 1 w treatment, 7 w follow-up	Mifepristone (30) vs Placebo (30)	Significant improvement in spatial working memory
Dean et al. 2011[58]	N-acetyl cysteine 2000 mg/day	Sub-analysis of a double-blind, randomized, placebo-controlled trial; 6 m treatment, no follow-up	NAC (16) vs placebo (13)	No significant changes in cognitive function
Burdick et al. 2004[59]	Pramipexole	Double-blind, placebo-controlled trial; 8 w treatment, no follow-up	Pramipexole (24) vs placebo (26)	No significant between-group differences in cognition were reported
KauerSant’Anna et al. 2019[60]	Tianeptine 12.5–37.5 mg/day	Double-blind placebo-controlled maintenance trial; 8 w open-label phase, 24 w RCT	Tianeptine (36) vs placebo (33)	Significant improvement in one test of working memory (letter number sequencing)
Chengappa et al. 2013[61]	Withania Somnifera 500 mg/day	Double-blind, randomized, placebo-controlled trial; 8 w treatment, no follow-up	WSE (30) vs Placebo (30)	Significant improvement in social cognition and two tests of attention.

Table 7.

Summary Psychosocial and Other Biological Intervention Study Details and Results

Study and Year	Intervention	Design	Treatment groups	Significant Results
Torrent et al. 2013[62]	Functional remediation and psychoeducation	Randomized, rater blind, controlled trial 21 w treatment No follow-up	Functional remediation (77) vs psychoeducation (82) vs TAU (80)	No significant changes in cognitive function in both the functional remediation and psychoeducation groups
Demant et al. 2015[63]	Cognitive remediation	Randomized, rater blind, controlled trial 12 w treatment 26 w follow-up	CR (23) vs TAU (23)	Significant improvement in subjective cognitive abilities, but in no objective cognitive assessments.
Lewandowski et al. 2017[64]		Randomized, rater blind, controlled trial; 24 w treatment, 6 m follow-up	CR (39) vs active control (36)	Improvement in verbal learning and a composite cognitive score
Gomes et al. 2019[65]	Cognitive behavioural rehabilitation	Randomized, rater blind, placebo controlled trial 12 w treatment 24 w follow-up	CBR (31) vs TAU (29)	Significant improvement in reaction time and emotion recognition.
Myczkowski et al. 2018[66]	rTMS	Randomized, double-blind, sham controlled trial; 4 w treatment, 4 w follow-up	Active rTMS (20) vs sham (23)	Significant improvement in the language domain
Lin-Lin et al. 2019[67]		Single-blinded randomized sham controlled trial; 10 d treatment, 2 w follow-up	Active rTMS (25) vs sham (27)	Significant improvement in visual learning and processing speed.
Bersani et al. 2017[68]	tDCS	Double blind controlled trial; 3 w treatment, no follow-up	tCDS (21) vs sham tDCS (21)	Significant improvement in executive function and visuospatial memory.

To 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 investigations. It is recommended to consider methodological concerns such as enriching the study population with persons who have pretreatment cognitive impairment and include those who are in remission. The field must also determine a cognitive measure that is thorough, with a little impact from repeated practice, and is capable of detecting changes as a dependent measure. Since we do not have any agent or therapy that can improve or reverse cognitive deficits in BD, it becomes important that we focus on intervening before these deficits set in, that is, the prevention of cognitive impairment. This can be done first by identifying the mediators of the cognitive impairments and second by intervening early.

The mediators of cognitive deficits of BD are educational attainment and premorbid intelligence quotient (proxy variables of cognitive reserve), clinical symptomatology (remission vs acute episode), subclinical depressive symptoms, psychotic symptoms, bipolar diagnostic subtype, psychiatric or medical comorbidity, illness duration (chronicity), number of episodes, pharmacological treatment, and childhood adversity. The potential prevention strategies would be to prevent multiple episodes with effective pharmacotherapy and the implementation of psychoeducation programs, avoid concomitant medications that interfere with cognitive function, treat subclinical depressive symptoms, control comorbidity (mental and psychiatric), promote healthy habits and aerobic physical exercise, implement cognitive or functional remediation, prescribe adjunctive procognitive treatment, and use noninvasive brain stimulation techniques (TMS, tDCS) wherever indicated, early in the course of the illness, that is, after the first episode.[69]

APPLICATION IN CLINICAL PRACTICE

Early interventions in bd

The early interventions can again be divided into two, one in the people who have developed the illness and are in the early course and second in those who are at high risk of developing BD. In BD patients in the early course of illness, the ISBD task force has given certain recommendations after a detailed systematic review. They recommend that the combination of psychological and pharmaceutical interventions may provide synergistic effects, although the most effective interventions or combinations for this specific group in the early stages are yet uncertain. They also suggest considering the potential benefits of lithium in reducing relapses in the early stages of illness, along with the data supporting the use of both medication and psychoeducation; it is important to assess the effectiveness of combining lithium and psychoeducation therapies in the early stages of illness. Based on the available evidence supporting the use of both medication and psychological treatments, individuals in the early stages of BD should be provided with the opportunity to receive safe and effective interventions.[70]

Another systematic review that evaluated the efficacy of early intervention in high-risk individuals (with an affected FDR) concluded that existing studies provide limited data regarding the conversion to BD, which is the primary outcome measure in early intervention research. Conducting multicenter, prospective randomized studies with large sample numbers, confirmed familial risk, and a homogeneous group of participants would provide valuable insights into the impact of a single intervention. Several therapies with documented efficacy in treating mood episodes, such as cognitive behavioral therapy, atypical antipsychotics, and moderate physical exercise, should be considered for implementation in this particular population. It is important to carefully assess the ethical implications of providing antipsychotics to a high-risk group. Early intervention in the initial phases of a problem can help avoid the long-term impact of the disease and yield significant advantages in terms of both human wellbeing and economic considerations and will greatly contribute to the prevention onset of BD.[71]

SUMMARY AND CONCLUSION

Many individuals with BD exhibit measurable cognitive impairment in all clinical phases, including euthymia, even after accounting for potential confounding factors such as demographic characteristics, drug effects, and residual depressed symptoms. This cognitive impairment affects all domains, although it is especially pronounced in verbal memory and executive functioning. Several studies provide evidence suggesting that lithium treatment has a slight detrimental effect on cognitive performance in a certain subset of people with BD who do not respond well to the medication. Valproate is linked to poorer cognitive function in comparison to other drugs used to stabilize mood, although the effect of second-generation antipsychotics on cognition is still uncertain. Existing research indicates that, in contrast to individuals with schizophrenia, the majority of people with BD exhibit cognitive abilities that are average or higher than normal prior to the onset of the disorder. Nevertheless, a portion of individuals with BD has below-average premorbid intellectual ability, suggesting that early neurodevelopmental issues may contribute to the development of BD in this specific group of patients. The available prospective studies do not provide evidence to support the notion of gradual cognitive loss in BD after the initial episode. In contrast, certain research indicates that patients may observe enhancements in cognitive performance through suitable treatment following the initial manic episode. Cognitive functioning plays a crucial role in predicting how well people with BD can do their everyday activities and work. Initial results from limited studies have indicated the potential cognitive-enhancing effects of behavioral interventions (cognitive remediation) as well as pharmacological interventions (erythropoietin, intranasal insulin, lurasidone, and mifepristone) and neurostimulation interventions (rTMS and tDCS).

Conducting longitudinal studies on the neurocognitive functioning of individuals at high risk of BD can enhance our understanding of how neurocognitive impairment develops and progresses in BD. This knowledge can then be used to develop specific early intervention strategies that aim to prevent or slow down and potentially reverse cognitive decline. Furthermore, it is crucial to acknowledge the significant influence that cognitive abilities have on the overall functioning of individuals with BD. Therefore, future efficacy trials should also prioritize investigating the possible positive and negative effects of therapies on cognitive performance and functional outcomes.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.