Bipolar I Affective Disorder (BPAD-I) is a chronic and episodic psychiatric illness marked by recurring episodes of mania and depression. The disorder severely impairs social, occupational, and personal functioning and carries a suicide risk exceeding 6% in the first two decades post-diagnosis. Even during remission, cognitive deficits persist in domains such as attention, memory, and executive function [1,2].

BPAD-I is associated with poor functioning in work, social and family situations even during remission. It affects about 1% of the population with similar incidence in both sexes and commonly begins in the second decade of life, though it can manifest at any age. The high heritability of BPAD-I has been established through twin and adoption studies [3]. First-degree relatives of BPAD-I patients are ten times more likely to develop bipolar mood disorder compared to the general population.

Cognition refers to the higher-level processing of specific information, involving brain pathways that can be altered by disease processes. Domains such as attention, executive functioning, processing speed, and both working and declarative memory are notably influenced by genetic factors [4,5].

Despite progress in psychiatric genetics, no single gene has been definitively associated with any specific psychiatric disorder. Endophenotypic markers—heritable, trait-like vulnerabilities present even in asymptomatic individuals—are a promising area of focus. Neurocognitive impairments serve as potential endophenotypic markers in BPAD-I since they appear in both euthymic patients and their unaffected first-degree relatives [6–8].

These neurocognitive deficits, especially in sustained attention, verbal memory, and executive functioning, persist even during the remission phase. They correlate with disease progression and can be used to differentiate patients and their relatives from the general population [9,10]. This study aims to assess these impairments and compare performance between BPAD-I euthymic patients, their first-degree relatives, and healthy controls.

 OBJECTIVE

To assess & compare neurocognition in BPAD-1 euthymic patients, their unaffected first degree relatives and normal controls.

Study Population

The study included a total of 90 participants, divided into three groups: 30 BPAD-I euthymic patients attending the Psychiatry Outpatient Department (OPD), 30 unaffected first-degree relatives of these patients, and 30 normal controls from the general population.

Design of Study

This was a cross-sectional study conducted over a period of six months.

Sampling Method

A convenience sampling method was employed. BPAD-I euthymic patients and their first-degree relatives attending the Psychiatry OPD were selected for participation.

Inclusion Criteria

Participants were included if they were BPAD-I euthymic patients or unaffected first-degree relatives (parents, siblings, or children) of BPAD-I patients. Additional inclusion criteria included being aged between 15 and 45 years, having a minimum formal education up to the 8th standard, and providing informed consent.

Exclusion Criteria

BPAD-I patients were excluded if they had experienced manic or depressive episodes within the last six months.

For unaffected first-degree relatives and normal controls, exclusion criteria included the presence of mental retardation, a history of psychiatric illness, any neurological or systemic illness impairing cognition, a history of head injury, substance dependence, or use of cognition-impairing medications (such as benzodiazepines) within the last month.

Statistical Design

The statistical analysis was based on the data collected from neuropsychological tests, scales, and sociodemographic profiles. Statistical analysis was performed using SPSS version 14.0. Central values and dispersion were calculated. For categorical variables, the chi-square test was employed, while the student’s t-test was used for numerical values. ANOVA and Tukey’s test were used for multiple comparisons among numerical variables. Correlations among variables were assessed using Pearson’s correlation coefficient.

Tools Used

Ethical approval for the study was obtained from the Institutional Ethical Committee (IEC). Written informed consent was obtained in Tamil. A semi-structured pro forma was used to collect sociodemographic information from participants.

Neuropsychiatric evaluation was conducted using the Mini International Neuropsychiatry Interview Plus - Version 5.0. Mood assessment included the Young Mania Rating Scale and the Hamilton Depression Rating Scale.

A comprehensive neuropsychological battery was used for cognitive assessment. This included the Digit Symbol Substitution Test (DSST), Digit Vigilance Test (DVT), Rey’s Auditory Verbal Learning Test (RAVLT), Rey’s Complex Figure Test (RCFT), Controlled Oral Word Association Test (COWA), Animal Naming Test (ANT), Letter Number Sequencing Test (LNST), Spatial Span Test (SST), Stroop Test (ST), Trail Making Test Parts A and B (TMT), and the Porteus Maze Test (PMT).

results

This cross - sectional study was conducted in the psychiatry out patient department in order to assess the neurocognition in 30 BPAD-1 euthymic patients (cases), 30 their unaffected first-degree relatives (1st degree relatives) and compare with the normal controls (controls).

The results from Table 1 reveal that BPAD-I euthymic patients exhibit significant impairments in processing speed and sustained attention compared to both first-degree relatives and normal controls. These deficits are evidenced by poorer performance in the Trail Making Test-A and Digit Symbol Substitution Test, with highly significant p-values. First-degree relatives also showed statistically significant but less severe deficits in these areas when compared to normal controls, suggesting that subtle cognitive impairments are present even in individuals at genetic risk. Interestingly, there was no significant difference among the groups regarding omission errors on the Digit Vigilance Test, indicating that while attention duration is affected, attention accuracy may be preserved. These findings support the notion that processing speed and sustained attention are sensitive neurocognitive domains affected in BPAD-I and may serve as early indicators in at-risk individuals

Table 1: Processing Speed and Sustained Attention

These patients also showed marked impairment in the Letter Number Sequencing Test (LNST) and Spatial Span Test (SST), indicating compromised verbal and visual working memory. First-degree relatives of BPAD-I patients demonstrated moderate impairments, especially in RAVLT and LNST, and to a lesser extent in the Rey Complex Figure Test (RCFT) delayed recall, though the severity was consistently lower than in patients. Normal controls performed significantly better across all tasks. These findings suggest that verbal and visuospatial memory deficits are not only prominent in BPAD-I patients but also detectable in their first-degree relatives, reinforcing their value as potential endophenotypic markers for the disorder. (Table 2)

Table 2: Verbal and Visuospatial Working Memory

As presented in Table 3, BPAD-I euthymic patients showed considerable deficits in verbal fluency and executive function, performing significantly worse in the Controlled Oral Word Association Test (COWA), Animal Naming Test (ANT), and across all components of the Stroop Test (Color Naming, Word Naming, and Color-Word Naming), as well as in Trail Making Test-B (TMT-B) and the Porteus Maze Test (PMT). These impairments reflect challenges in attention control, cognitive flexibility, and problem-solving. First-degree relatives also displayed notable deficits in executive functions, particularly in the Stroop Test, TMT-B, and PMT, although the impairments were milder than those of the BPAD-I group. Normal controls consistently outperformed both other groups. These findings underscore that executive dysfunction is a core cognitive deficit in BPAD-I and may also be evident in high-risk relatives, further supporting its role as an endophenotype.

Table 3: Verbal Fluency and Executive Function

Impairments in neurocognitive abilities among BPAD-I patients are well documented [11,12]. Recent studies have increasingly focused on their unaffected first-degree relatives to evaluate endophenotypic traits [13,14]. These traits, thought to arise from shared genetic vulnerabilities, provide deeper insights into the neurodevelopmental aspects of bipolar disorder [15,16].

This study was aimed at assessing the neurocognition in BPAD-I euthymic patients, their unaffected first-degree relatives, and normal controls. This design offers valuable insight into the presence of endophenotypes—intermediate phenotypes arising due to genetic vulnerability associated with bipolar disorder [14,17]. Identifying neurocognitive endophenotypes enhances our understanding of BPAD-I.

Our findings revealed that BPAD-I euthymic patients had neurocognitive impairments across multiple domains compared to first-degree relatives and controls. Deficits were most pronounced in sustained attention, processing speed, verbal and visuospatial working memory, verbal fluency, and executive function. These impairments persisted despite clinical remission, supporting previous reports [18,19,20].

First-degree relatives exhibited milder but statistically significant impairments in similar domains, including processing speed (DSST), sustained attention (DVT), verbal working memory (RAVLT, LNST), visuospatial memory (RCFT), and executive function (Stroop, TMT-B, PMT). These findings are consistent with prior meta-analyses and cohort studies by Bora et al. [14], Chandrasekaran V et al., and Nehra R et al. [21,22], suggesting that these deficits may serve as endophenotypic markers.

Meta-analyses have shown that first-degree relatives of BPAD patients display deficits particularly in verbal working memory, sustained attention, and executive function—domains also impaired in BPAD-I patients [14,21,23]. This supports our findings and highlights the heritable nature of these impairments. Studies by Mur et al., Miskowiak et al., and Martino et al. have emphasized persistent executive dysfunction as a central feature of BPAD-I and its genetic liability [19,20,25].

Moreover, interventions such as cognitive remediation and functional rehabilitation have shown promise in addressing cognitive dysfunction in BPAD-I, as demonstrated in randomized controlled trials and longitudinal studies [20,23,24,26]. Incorporating these strategies into routine clinical practice may aid in improving long-term outcomes.

Overall, our study reinforces the evidence that cognitive deficits are a core component of BPAD-I and that similar, albeit milder, impairments in first-degree relatives may serve as reliable endophenotypic indicators [14,20,21,23,27,28].

Limitations

This study had several limitations that should be considered when interpreting the results. Firstly, the sample size was relatively small, which may limit the generalizability of the findings; larger sample sizes are necessary to replicate and validate these results. Secondly, the cross-sectional nature of the study precludes the ability to observe changes in neurocognitive functioning over time. Longitudinal studies are essential for understanding the progression and persistence of cognitive deficits in BPAD-I. Additionally, the intelligence quotient (IQ) of the participants was not assessed, which could have influenced the neurocognitive test outcomes. The use of psychotropic medications among BPAD-I euthymic patients may also have contributed to the observed cognitive impairments, representing a potential confounding factor. Lastly, tobacco use was not an exclusion criterion, and its known effects on cognition could have impacted the study's findings.

This study demonstrated that neurocognitive impairment is prevalent across all cognitive domains in BPAD-I euthymic patients. These deficits persist even during remission, highlighting the chronic nature of cognitive dysfunction in bipolar disorder. Moreover, unaffected first-degree relatives also exhibited impairments, particularly in sustained attention, verbal and visuospatial working memory, and executive functions. These cognitive deficits in high-risk relatives suggest the presence of endophenotypic markers that may be genetically linked to the disorder.

 Future Directions

Future research should focus on conducting longitudinal studies with regular follow-ups to monitor neurocognitive function over time in BPAD-I patients and their relatives. Implementing cognitive remediation exercises and evaluating their effectiveness in improving neurocognitive deficits can offer practical clinical benefits. Studies involving larger and more diverse samples using standardized and robust methodologies will provide stronger evidence and improve the reliability of findings. Furthermore, incorporating routine neurocognitive assessments into clinical practice for BPAD-I patients can help in early detection and timely intervention to mitigate cognitive dysfunction and enhance overall functioning.

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