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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 1  |  Page : 63-69

Neurocognitive impairment in patients with bipolar disorder: Comparison between first episode and multiple episodes

1 Department of Psychiatry, Government Medical College, Aurangabad; Department of Psychiatry, Indian Institute of Medical Science and Research, Warudi, Maharashtra, India
2 Achalia Neuropsychiatry Clinic, Aurangabad, India
3 Department of Psychiatry, Government Medical College, Aurangabad, India
4 Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Submission24-Oct-2019
Date of Decision18-Nov-2019
Date of Acceptance18-Dec-2019
Date of Web Publication30-May-2020

Correspondence Address:
Dr. Rashmin Achalia
Department of Psychiatry, Indian Institute of Medical Science and Research, Warudi, Jalna, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aip.aip_73_19

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Background: Several lines of evidence in the last few years have suggested the critical role of neurocognitive deficits in functional recovery of patients with bipolar disorder (BD). However, whether these deficits are static or progressive with the course of the illness is still debated. Surprisingly, the effect of multiple episodes on neurocognitive deficits in BD is rarely examined in first-episode Indian patients. Hence, in this study, we aimed to examine the difference between first episode mania and BD patients with multiple episodes. Methodology: Thirty patients with the Diagnostic and Statistical Manual of Mental Disorders-IV BD-I (13 with first-episode mania; 17 with multiple episodes) and 30 age- and sex-matched healthy volunteers (HV) were recruited in the study. Clinical severity was assessed using structured rating scales. All patients performed tests to measure executive functions, namely continuous performance test, Stroop color word interference test, and Wisconsin Card Sorting Test. Differences between groups were examined using the analysis of covariance with age and sex as covariates with Bonferroni post hoc analysis. Results: There was a significant difference between groups on the performance of all three tests with patients performing poorer than HV. While the HV differed from both first episode mania and BD with multiple episodes, there was no difference between the two patient subgroups. There was no significant correlation between clinical variables and scores on neurocognitive tests. Conclusions: The study findings, with respect to cognitive function, supports neurodevelopmental than neurodegenerative hypothesis. Findings indicate the need to assess cognitive functions in all patients with BD including first episode BD.

Keywords: Bipolar disorder, episode, executive functions, neurodevelopment, neuropsychology, progression

How to cite this article:
Achalia R, Achalia G, Chaudhary S, Chopade M, Kaginalkar V, Sable A, Jacob A, Venkatasubramanian G, Rao NP. Neurocognitive impairment in patients with bipolar disorder: Comparison between first episode and multiple episodes. Ann Indian Psychiatry 2020;4:63-9

How to cite this URL:
Achalia R, Achalia G, Chaudhary S, Chopade M, Kaginalkar V, Sable A, Jacob A, Venkatasubramanian G, Rao NP. Neurocognitive impairment in patients with bipolar disorder: Comparison between first episode and multiple episodes. Ann Indian Psychiatry [serial online] 2020 [cited 2020 Oct 29];4:63-9. Available from: https://www.anip.co.in/text.asp?2020/4/1/63/285514

  Introduction Top

Bipolar disorder (BD) is a chronic episodic illness with a lifetime estimate of 1.0% for BD-I and 1.1% for BD-II.[1] Several lines of evidence in the last few years have suggested the critical role of neurocognitive deficits in functional recovery of patients with BD. Neurocognitive deficits are related to functioning in the community, increased number of hospitalizations, and chronicity of illness.[2],[3] Impairments in executive function, verbal memory, psychomotor speed, and sustained attention [4],[5],[6] are consistently reported in patients with BD. Neurocognitive deficits may be considered trait markers of the illness since many executive functions, namely sustained attention, response inhibition, cognitive flexibility, and working memory are impaired in patients not only during acute mood episodes but also during the euthymic phase [7],[8]

Studies also suggest a relationship between cognitive deficits and clinical features like age at onset, inter episode recovery, premorbid functioning, and the presence of psychotic symptoms.[2],[5],[9] However, it is still debated whether these deficits progressively deteriorate over the course of the illness. While some studies suggest progressive deterioration and accumulating impairments with each episode,[10],[11] others suggest presence of abnormalities at the beginning of the illness which remain stable.[12],[13],[14] Despite being an important predictor of functional recovery,[15] the relationship between neurocognitive deficits and number of episodes is still not completely known.

Several differences in presentation and risk factors of BD have been reported across countries suggesting a possible modulatory effect of culture on expression of the disorder.[16] Since available studies are predominantly from developed countries, it is not clear whether the findings are applicable to developing countries like India. Till date, only one study has examined the effect of number of episodes and reported poorer performance of first episode BD patients compared to multi episode BD patients.[17] Hence, in this study, we aimed to examine the differences in cognitive functions between patients with first episode mania and BD with multiple episodes.

  Methodology Top

Thirty patients with BD Type I were recruited from in-patient and out-patient psychiatry clinic. Thirty healthy volunteers (HV) carefully matched with patients on age, gender, and numbers of years of education were recruited from the same catchment area. None of the HV had life time Axis I psychiatric disorder including substance use. There was no family history of Axis I psychiatric disorder in first-degree relatives. Written informed consent was obtained from the patients before they were enrolled into the study. Patients aged between 18 and 45 years satisfying Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for BD were included in the study. Patients with concurrent comorbid DSM-IV Axis 1 disorder including substance dependence, head injury and neurological disorders, electroconvulsive therapy in the past 6 months were excluded from the study. Thirty HV with no life-time history of Axis I psychiatric disorders were included into the study. In addition to the above-mentioned exclusion criteria, HV with a history of Axis I disorder in first-degree relatives were also excluded from the study.

All patients were administered Mini-International Neuropsychiatric Interview-Plus [18] to confirm the diagnosis and to rule out Axis I comorbidity. The severity of symptoms were assessed using Hamilton Depression Rating Scale (HDRS)[19] and Young Mania Rating Scale (YMRS).[20] The first author interviewed all patients and a family member to collect relevant clinical information pertinent to the illness including age at the onset of illness, details of treatment, clinical details of previous episodes, and family history. Additional information was collected from medical records, when available. Thirteen patients had a single episode of mania and 17 had a history of more than one episode. This was a naturalistic study, hence it included patients in all phases of BD. Of thirty patients, 16 patients were classified as having BD with psychotic symptoms and 14 as BD without psychotic symptoms. Out of twenty actively symptomatic patients, 9 had active psychotic symptoms. Ten patients were euthymic, 13 were in mania, and only 7 patients were in phase of depression during assessment. Twenty patients were treated with lithium, twenty with valproate, 2 with carbamazepine, and 5 with lamotrigine and all thirty had received atypical antipsychotics for varying periods during the illness. Patients continued to take their prescribed medications while participating in the study.

Neuropsychological assessment

An experienced clinical psychologist administered the neuropsychological tests with a uniform environment and standard procedure to all patients. The tests measured different subdomains of executive function; (a) continuous performance test-identical pairs (CPT) to measure sustained attention,[21] (b) Stroop test measuring response inhibition,[22] and (c) Wisconsin Card Sorting Test (WCST) to measure set shifting.[23]

Statistical analysis

Data were evaluated for normative distribution. Group differences between three groups in age and sex were compared using the analysis of variance and Chi-square tests, respectively. To examine the effect of multiple episodes, we conduced analysis of covariance with age and sex as covariates between the three groups; first episode BD, BD with multiple episodes, and HV. Post hoc Bonferroni tests were conducted to examine the differences between pairs. To correct for multiple comparisons, a conservative P < 0.01 was considered statistically significant. Pearson's correlation analysis was conducted to examine the relationship between cognitive functions and clinical variables, namely YMRS, HDRS, Simpson Angus Scale (SAS) scores, age at onset of illness, duration of illness, and chlorpromazine equivalent of antipsychotic dose. Considering the multiple correlational analysis conducted, we considered a conservative P < 0.001 as statistically significant. Statistical analysis was conducted using the Statistical package for the Social sciences version 24 (IBM Corp. Armonk, NY, USA).

  Results Top

As a group, there was no significant difference between BD and HV in age (BD - 24.73 ± 6.75 years; HV - 24.53 ± 6.99 years; t = 0.113; P = 0.911) or sex (BD – 18 males; HV – 18 males). In patients, the average duration of illness was 3.43 ± 3.67 years and with the mean age at onset 21.3 ± 5.05 years. The demographic and clinical features across three groups are described in [Table 1]. Understandably, the BD multi-episode and first episode groups differed significantly in the average duration of illness and age.
Table 1: Demographic and clinical characteristics of subjects with bipolar disorder and healthy comparison subjects

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Difference between patients and controls on cognitive domains

As expected, patients with BD as a group had significant impairment in all three cognitive tests compared to HV. On CPT, patients with BD performed poorly with significantly greater number of wrong responses (BD = 40.16 ± 55.08; HV = 7.00 ± 4.20; t = 3.28; P = 0.001), greater number of missed responses (BD = 18.13 ± 10.2; HV = 8.10 ± 5.60; t = 4.68; P < 0.001), and fewer correct responses (BD = 25.97 ± 10.11; HV = 35.83 ± 5.40; t = 4.69; P < 0.001). Patients also had significantly higher Stroop color word interference effect (BD = 215.33 ± 149.73, HV = 119.7 ± 40.7; t = 3.36; P = 0.001). On WCST, patients had significantly higher number of perseverative responses (BD = 29.06 ± 23.06, HV = 11.80 ± 9.00; t = 3.82; P = 0.002), nonperseverative errors (BD = 24.56 ± 16.14; HV = 15.10 ± 13.90; t = 2.42; P = 0.019), committed more perseverative errors (BD = 24.66 ± 17.10, HV = 10.70 ± 7.90; t = 4.05; P < 0.001), and completed fewer categories (BD = 3.86 ± 1.88, HV = 5.40 ± 1.33; t = 3.79; P < 0.001) compared to HV. There was no difference in trials to complete first category (BD = 22.96 ± 15.49; HV = 15.10 ± 13.90; t = 2.42; P = 0.40) and number of correct responses (BD = 69.36 ± 13.83; HV = 70.80 ± 10.80; t = 0.46; P = 0.64) between the groups.

Difference between first episode bipolar disorder versus multi episode bipolar disorder versus healthy volunteers on cognitive functions

There was a significant difference between the three groups on cognitive tests; on CPT, a significant group effect was seen in number of correct responses, wrong responses, missed responses but not in response time. Similarly, significant difference was seen in Stroop effect time as well as Stroop-performance percentile. In WCST, significant difference was seen in trials administered, total errors, perseverative responses, perseverative errors, nonperseverative errors, and categories completed. There was no significant difference between the three groups in trials to complete first category and failure to maintain set [Table 2]. On post hoc analysis, there were significant differences between HV and both BD with multi-episode as well as first episode mania. However, there was no significant difference between first episode mania and BD with multiple episodes on any cognitive measure [Table 3] and [Figure 1].
Table 2: Difference between first episode mania versus multi episode bipolar disorder versus healthy volunteers on cognitive functions (analysis of covariance - age and sex as covariate)

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Table 3: Mean differences between the three groups, first episode mania, bipolar disorder with multiple episodes and healthy volunteers on cognitive measures

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Figure 1: Difference between the groups on cognitive functions. *Significant difference between groups

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Correlation analysis

On correlational analysis, there was a statistically significant positive correlation between YMRS score and WCST-nonperseverative error (P = 0.001; r = 0.589). There was no significant correlation between other clinical variables, namely HDRS score, SAS score, age at onset of illness, duration of illness or antipsychotic dose measured using chlorpromazine equivalent [Table 4].
Table 4: Relation between clinical variables and cognitive functions

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  Discussion Top

Findings of the study suggest that while both first episode mania and BD with multiple episodes had significant impairment compared to HV, there was no significant difference between the two patient subgroups. These findings indicate that BD patients have significant impairment in executive functions at the onset of the illness.

Our findings are in accord with several previous studies which did not find differences between first episode and multiepisode patients.[17],[24] However, several other studies have reported progressive deterioration in neurocognitive function among multiepisodes BD compared to first episode BD.[25],[26] As BD is a heterogeneous condition, differences in the study participants could be one of the reasons for the differences. The current study participants were recruited from a nontertiary care hospital and could be different compared to many other studies conducted at tertiary care hospitals. It is possible that the participants in the current study were not as severely ill as those in earlier studies. Recruitment of participants from a nontertiary care hospital increases the generalizability of findings of the current study. Another possibility is the protective effect of medications as all patients with multiple episodes were treated with mood stabilizers and antipsychotics. Since previous studies have shown the protective effect of mood stabilizers, if started early during the illness,[27] treatment may have prevented further cognitive deterioration in multiple episode patients. One of the reasons for the current findings could be most of the MEBD patients were in euthymic phase and most of the first episode patients were either symptomatic or recently recovered.

Both neurodevelopmental and neurodegenerative models have been proposed to explain the pathophysiology of BD.[28],[29] Clinical, epidemiological, neuropathological, and neuroimaging studies suggest aberrations in brain maturation in BD.[28] This process may be like that seen in schizophrenia and may explain significant overlap between these two disorders.[30] However, others suggest progression of cognitive impairment and structural-functional brain changes in BD after the onset of illness similar to physiological aging process.[29] Our findings favor the neurodevelopmental model. However, considering the limitations of the study design these findings need to be considered preliminary and further longitudinal studies controlling for medication use and inter-individual variations are required in future.

Findings of the study raise another important issue of clinical significance; impaired executive functions in patients with one episode of mania. This suggests the importance of the assessment of neurocognitive functions in all patients with BD regardless of the stage of the illness. As neurocognitive functioning is a key determinant of functional recovery, it is important to assess and treat these deficits early on in the illness. The presence of executive function impairments suggests abnormalities in frontal-subcortical circuits in BD. As executive functions heavily depend on intact function of prefrontal cortical connections with sub-cortical structures, findings add to the existing body of literature suggesting abnormalities in these circuits. Impaired cognitive functions despite being on treatment with mood stabilizers and antipsychotics also suggest the minimal therapeutic benefit of the existing medications in the treatment of neurocognitive deficits. This indicates the need for novel therapeutic agents for the treatment of cognitive deficits in BD.

Findings of the study need to be interpreted in the background of the following limitations. First, while the study sample was adequate for examining the group differences between HV and BD, the sample size was modest for examining the subgroup differences. As the current study as well as previous study from India [17] had modest sample size, further studies with a bigger sample is required. Second, the subgroups of patients were not matched on age. However, after including age as a covariate in the analysis the results remained significant. Third, all patients were on treatment with medications which could confound the performance. It is important to examine those patients who have not received treatment medications. While such a study is ideal, it may have limited generalizability as most patients with BD are on treatment with medications. Moreover, as atypical antipsychotics are the first-line treatment for both depressive and manic phases, it is imperative to expect patients to be on treatment with both mood stabilizers and antipsychotics.[31] While antipsychotics can affect the performance on neurocognitive tests, the effect of mood stabilizers is not known.[32] However, there was no relationship between chlorpromazine equivalent of antipsychotic dose or SAS score and cognitive function suggesting the absence of a significant confounding effect. While we examined the relation between antipsychotic dose and cognitive functions, it is important to remember that mood stabilizers could also have differential impact on cognitive functions. In addition, the serum levels could also influence cognition. As the current study had a small sample size, we were not able to do a subgroup analysis based on the mood stabilizer. Future studies with a bigger sample size need to examine the effect of mood stabilizers on cognitive function in BD. Fourth, in view of the smaller number of patients, we were not able to do further analysis between those with less than three or more than three mood episodes as conducted in an earlier study. This could have answered the question of dose-dependent deterioration in cognitive deficits. Future studies with a larger sample will be able to address this question. Fifth, we examined tests that focus on attention and executive functions. While these cognitive domains are consistently reported to be impaired in BD, other cognitive domains like memory are also impaired in BD. Whether the absence of difference seen between FEM and MEBD are seen with other cognitive domains as well need to be examined in future. Sixth, the study was cross-sectional in nature and hence cannot account for the between-subject variations in performance. A longitudinal study with the examination of the same subject over a period will be ideal to examine the nature of the progression of neuropsychological deficits in BD. Future studies need to consider a longitudinal study design than a cross-sectional study design. Sixth, findings of this cross-sectional study need to be considered preliminary. While these findings favor neurodevelopmental hypothesis of BD compared to neurodegenerative hypothesis, further longitudinal, cohort studies are required for definitive answers. In the absence of longitudinal cohort studies from India, the current study provides preliminary information which can pave way for further research in the area. Seventh, though several cognitive domains are impaired in BD, an earlier meta-analysis of neuropsychological functioning in first-episode BD suggested medium to large deficits in the domains of psychomotor speed, attention, and working memory, and cognitive flexibility. The other domains, namely verbal learning and memory, attentional switching, and verbal fluency had a smaller effect size.[33] Hence, we chose to examine those domains which had medium to large deficits using CPT (attention and working memory), Stroop test (cognitive flexibility) and WCST (cognitive flexibility). Finally, while we examined the patients on treatment, several patients were actively symptomatic. While neurocognitive deficits are known to be present in both the active phase and euthymic phase of the BD, one cannot rule out the possibility of active symptoms influencing the performance during neuropsychological examination. There was only one significant correlation between YMRS score and WCST – nonperseverative error. However, there was no significant correlation between performance in other tests and clinical variables. Future studies with a larger sample size can consider doing a sub-analysis in those with active symptoms and those without, which could bring further clarity.

While these limitations need to be considered before the interpretation of results, it is important to also note the strengths of the study. Strengths of this study include carefully characterized clinical samples and the use of a hypothesis-driven test battery including both clinical neuropsychological tests. These tests are validated and used in the Indian settings. Patients and HV were comparable on age and gender which negates the confounding effects of the same. While the subgroups were not matched on age, it was used as a covariate in analysis. Uniform administration of the tests by a trained psychologist Garimaa Achalia [GA]) in the same setting ensured absence of confounding effects of environment or test administration. Use of structured clinical instruments for the diagnosis and measurement of the severity of illness further added to the methodological rigor of the study.

  Conclusion Top

To summarize the study findings suggest (a) absence of significant difference between first-episode mania and BD with multiple episodes (b) significant cognitive deficits in both first-episode mania and BD with multiple-episodes compared to HV. Findings provide further support to the existing literature that cognitive deficits in BD are not progressive in nature. Regardless of the number of mood episodes, cognitive functions need to be assessed in all patients with BD. This would help in the early recognition and initiation of prompt treatment. There is an acute need of novel therapeutic strategies for the treatment of cognitive deficits in BD.

Ethical statement

This study was approved by Institutional Ethics Committee with reference number Pharma/IEC-GMCA/597/2012 obtained on 20th December 2012.

Declaration of Patient Consent

Patient consent statement was taken from each patient as per institutional ethics committee approval along with consent taken for participation in the study and publication of the scientific results / clinical information /image without revealing their identity, name or initials. The patient is aware that though confidentiality would be maintained anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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