|Year : 2019 | Volume
| Issue : 1 | Page : 115-122
Effect of psychotic symptoms on cognitive impairment in patients with bipolar disorder
Rashmin Mansukh Achalia1, Bhargavi Nagendra2, Garimaa Achalia3, Mahesh Chopade4, Abhijit Sable4, Ganesan Venkatasubramanian2, Naren P Rao2
1 Department of Psychiatry, Government Medical College; Achalia Neuropsychiatry Clinic, Aurangabad, Maharashtra, India
2 Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
3 Achalia Neuropsychiatry Clinic, Aurangabad, Maharashtra, India
4 Department of Psychiatry, Government Medical College, Aurangabad, Maharashtra, India
|Date of Submission||01-Jan-2019|
|Date of Acceptance||12-Aug-2019|
|Date of Web Publication||11-Dec-2019|
Dr. Naren P Rao
Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: A considerable proportion of patients with bipolar disorder (BD) have psychotic symptoms during the illness. This subset of BD due to its genetic susceptibility and family segregation has considerable overlap with schizophrenia. However, the extent to which BD patients with psychotic symptoms and without psychotic symptoms differ on neurocognitive functions is still not completely clear. Aim: The aim of this study was to examine the neurocognitive functions in BD patients with psychotic symptoms and BD without psychotic symptoms in comparison with healthy volunteers (HVs). Materials and Methods: Thirty patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition BD (16 with psychotic symptoms) and thirty age- and sex-matched HVs were recruited in the study. Clinical severity was assessed using structured rating scales. The presence of psychotic symptoms was assessed using the Lifetime Dimensions of Psychosis Scale (LDPS). All patients underwent tests, namely continuous performance test, Stroop Word-Color interference test, and Wisconsin Card Sorting Test, to measure executive functions. Differences between groups were examined using analysis of covariance with age and sex as covariates. Results: There was a significant difference between groups on the performance of all the three tests, with patients performing poorer than HVs. While the HVs differed from both BD with psychotic symptoms and without psychotic symptoms, there was no difference between BD patients with and without psychotic symptoms. There was no significant correlation between LDPS score and scores on neurocognitive tests. Conclusion: The study findings, at least with respect to cognitive function, suggest that BD with psychotic symptoms may not be a categorically distinct subtype of BD. Cognitive functions need to be assessed in all patients with BD, regardless of psychotic symptoms, and remediation interventions need to be provided.
Keywords: Bipolar disorder, cognitive functions, executive functions, genetic overlap, psychotic symptoms
|How to cite this article:|
Achalia RM, Nagendra B, Achalia G, Chopade M, Sable A, Venkatasubramanian G, Rao NP. Effect of psychotic symptoms on cognitive impairment in patients with bipolar disorder. Ind Psychiatry J 2019;28:115-22
|How to cite this URL:|
Achalia RM, Nagendra B, Achalia G, Chopade M, Sable A, Venkatasubramanian G, Rao NP. Effect of psychotic symptoms on cognitive impairment in patients with bipolar disorder. Ind Psychiatry J [serial online] 2019 [cited 2020 Jul 6];28:115-22. Available from: http://www.industrialpsychiatry.org/text.asp?2019/28/1/115/272680
Bipolar disorder (BD) is a chronic episodic illness, with lifetime estimates of 1.0% for BD-I and 1.1% for BD-II. Several studies have reported neurocognitive impairments in patients with BD in the areas of executive function, verbal memory, psychomotor speed, and sustained attention.,, These neurocognitive impairments are seen not only during acute mood episodes, but are also present in varying intensity during euthymic periods. A recent meta-analysis reported executive function, verbal memory, psychomotor speed, and sustained attention to be the most affected cognitive domains.
A subset of patients with BD has psychotic symptoms in addition to mood symptoms during the course of illness. This subset of BD due to its genetic susceptibility and family segregation has considerable overlap with schizophrenia. Neuroimaging studies have delineated differences between BD patients with psychotic symptoms and without psychotic symptoms. However, the extent to which BD patients with psychotic symptoms and without psychotic symptoms differ on neuropsychological functions is still controversial as studies have reported conflicting results; while some authors have reported poorer cognitive performance in BD patients with psychotic symptoms than in those without psychotic symptoms,,, others have reported absence of such difference,,,, or a modest difference. It is important to note that BD patients with psychotic symptoms at any time during illness are reported to have effect on the neurocognitive functioning in BD-I; that is, regardless of the cross-sectional status of the psychotic symptoms, the history of psychotic symptoms at any moment during the illness (present or past episodes) is considered in previous studies,, and is shown to have differences in neurocognitive functions compared to those without psychotic symptoms at any time during the illness.,
However, till date, no study has examined differences in neurocognitive functions between BD patients with and without psychotic symptoms from India. Considering the regional differences in BD prevalence and course, it is important to examine the nature of cognitive deficits from diverse cultural backgrounds.,, Moreover, as the presence of psychotic symptoms can influence the outcome of BD, it is critical to examine the differences between BD patients with psychotic symptoms and without psychotic symptoms. Hence, in this study, we aimed to examine the effect of the presence of psychotic symptoms on cognitive deficits in BD.
| Materials and Methods|| |
Thirty patients with BD were recruited from the psychiatry department of a hospital. Thirty age- and sex-matched healthy volunteers (HVs) were recruited from the same area by word of mouth and flyers. Written informed consent was obtained from the participants before they were enrolled in the study. All patients were examined using the Mini-International Neuropsychiatric Interview (MINI), and those satisfying the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition Text Revision (DSM-IV TR) criteria for BD were included in the study. We used the DSM-IV TR as the study was conceptualized and started in the year 2013. Patients with concurrent comorbid DSM-IV TR axis-I disorder, head injury, and neurological disorders were excluded from the study. All HVs were also examined using the MINI-Plus, and those with current or past DSM-IV TR axis-I psychiatric disorders were excluded from the study. Those HVs with a history of axis-I disorder in first-degree relatives were also excluded from the study. None of the participants had substance dependence or harmful use. Handedness was assessed using the Edinburgh handedness inventory, and we recruited only right-handed individuals. The study was approved by the institute's ethics committee. The patients continued to take their prescribed medications while participating in the study.
Relevant clinical information pertinent to illness, including age at illness onset, clinical details of previous bipolar episodes, family history, and treatment details, was collected from patient, informant, and case records by an experienced psychiatrist. The clinical severity of current mood symptoms was assessed using the Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS). We assessed the presence of psychotic symptoms, namely hallucinations and/or delusions within a mood episode, using the Lifetime Dimensions of Psychosis Scale (LDPS). The LDPS allows to characterize the positive, negative, bizarre, and disorganized symptom factors in the lifetime of an individual in addition to mood-related symptoms. This instrument was used earlier while examining differences between psychotic and nonpsychotic BD. Based on the LDPS, 16 patients were classified as having BD with psychotic symptoms and 14 as BD without psychotic symptoms. Out of the 30 patients, 17 had a prior history of depressive or manic episodes and 13 patients had one episode of mania. Twenty-two of them were treated with lithium, twenty with valproate, two with carbamazepine, and five with lamotrigine, and all participants had received atypical antipsychotics during the course of the illness.
The following neuropsychological tests, measuring different domains of executive functions, were administered: (a) Continuous Performance Test-Identical pairs (CPT) to measure sustained attention, (b) Stroop test to measure response inhibition, and (c) Wisconsin card sorting test (WCST) to measure set shifting. An experienced clinical psychologist (GA) administered the neuropsychological tests with a uniform environment and standard procedure to all participants. These tests are validated in the Indian population and have been used for both clinical and research purposes. For the Stroop effect score, the reading time and naming time were converted into seconds. The reading time was subtracted from the naming time to get the Stroop effect score.
Statistical analysis was done using the Statistical Package for Social Sciences software version 24 (IBM Corp., Armonk, NY, USA). Group differences between BD patients and HVs in age and sex were compared using independent t-test and Chi-square test, respectively. To examine the difference between BD patients and HVs in cognitive functions, Mann–Whitney U-test was conducted. To examine the effect of psychotic symptoms, analysis of covariance was conducted with age and sex as covariates between the following three groups: BD patients with psychotic symptoms, BD patients without psychotic symptoms, and HVs. Further, post hoc Bonferroni tests were conducted to examine the differences between pairs. To examine the relation between clinical variables and cognitive functions, Pearson's correlation test was conducted between scores on the LDPS, YMRS, HDRS, Simpson Angus scale, and age at onset of illness. Considering the multiple correlation analysis conducted, a conservative P < 0.01 was considered statistically significant.
| Results|| |
There was no statistically significant difference between BD patients (M: F – 18:12) and HVs (M: F – 18:12) in sex ratio (P = 0.604) or age (BD patients – 24.73 ± 6.76 years; HVs – 24.53 ± 7.00 years; t = 0.113; P = 0.911). Among patients with BD, the average duration of illness was 3.43 ± 3.67 years, the average age at the onset of illness was 21.3 ± 5.05 years, and the average number of episodes was 2.4 ± 1.71. BD patients with psychotic symptoms, BD patients without psychotic symptoms, and HVs did not differ on age and sex distribution. There was no significant difference between BD patients with psychotic symptoms and BD patients without psychotic symptoms in age at onset, average number of episodes, YMRS score, or HDRS score. However, there was a significant difference between the two in duration of illness; BD patients with psychotic symptoms had longer illness duration than those without psychotic symptoms [Table 1].
|Table 1: Demographic and clinical characteristics of bipolar disorder patients with psychotic symptoms, bipolar disorder patients without psychotic symptoms, and healthy volunteers|
Click here to view
Difference between bipolar disorder patients and healthy volunteers on cognitive functions
Patients with BD had significant cognitive impairment in comparison to HV: (a) in the CPT, BD patients had significantly higher number of wrong responses, missed responses, and lower number of correct responses; (b) in the Stroop test, BD patients had significantly higher Stroop effect time; (c) in the WCST, BD patients had higher number of errors, perseverative responses, perseverative errors, nonperseverative errors, and lower number of categories completed. However, there was no difference in CPT – response time, WCST – trials to complete first category, and WCST – failure to maintain set [Table 2].
|Table 2: Group differences between bipolar disorder patients and healthy volunteers on cognitive functions|
Click here to view
Difference among psychotic patients versus nonpsychotic patients versus healthy volunteers on cognitive function
There was a significant difference between the three groups on cognitive tests; on CPT, a significant group effect was seen in the number of correct responses, wrong responses, and missed responses but not in response time. Similarly, significant difference was seen in Stroop effect time as well as Stroop-performance percentile. In the WCST, significant difference was seen in total errors, perseverative responses, perseverative errors, and categories completed. There was no significant difference between the three groups in nonperseverative errors, trials to complete the first category, and failure to maintain set [Table 3]. On post hoc analysis, there were significant differences between HVs and both BD patients with psychotic symptoms and BD patients without psychotic symptoms. However, there was no significant difference between BD patients with and without psychotic symptoms [Table 4].
|Table 3: Group difference between bipolar disorder patients with psychotic symptoms, bipolar disorder patients without psychotic symptoms, and healthy volunteers on cognitive functions|
Click here to view
|Table 4: Mean differences between the three groups, namely bipolar disorder patients with psychotic symptoms, bipolar disorder patients without psychotic symptoms, and healthy volunteers on cognitive measures|
Click here to view
Relation between clinical variables and cognitive functions
There was a significant positive correlation between YMRS score and WCST – nonperseverative errors and trials to complete the first category, indicating that those with higher severity of mania had higher errors on the WCST. There was no significant relation between performance on cognitive functions and other clinical variables, namely LDPS score, HDRS score, Simpson Angus scale score, and age at onset of illness [Table 5].
|Table 5: Correlation between clinical variables and performance on cognitive functions|
Click here to view
| Discussion|| |
The study findings report that BD-I patients have significant cognitive impairment in executive functions in comparison to age- and sex-matched healthy controls. This impairment in executive function is consistent with prior reports and suggests neural disruption in prefrontal network. The study findings also suggest that there was no significant effect of psychotic symptoms on the cognitive functions as BD patients with psychotic symptoms and without psychotic symptoms were not significantly different. Our findings suggest that BD patients with psychotic symptoms may not be a categorically distinct subtype compared to BD patients without psychotic symptoms. Several studies have reported significant overlap between BD patients with psychotic symptoms and schizophrenia using genetic, neuroimaging, and electrophysiological assessment. However, whether the neurobiology of BD patients with psychotic symptoms and without psychotic symptoms is different is not conclusive and yet to be explored in detail.
Our findings of absence of difference between patients with and without psychotic symptoms are similar to those of earlier studies,,,, but differ from those of others.,,, Several differences may explain this discrepancy in findings. First, a few previous studies included both Type I and Type II BD,,, but we included only BD Type I to decrease the heterogeneity. Second, all participants in our study were on treatment with antipsychotics in comparison with earlier studies, considering that atypical antipsychotics are now a first-line agent for the treatment of both phases of BD, mania, and depression. As antipsychotics and anticholinergics are known to cause cognitive deficits, one cannot rule out the possibility of the confounding effect of antipsychotics. Third, the participants in this study were enrolled from a peripheral center, with a considerable proportion of patients being the first contact. As majority of the previous studies recruited patients from university hospitals, it is possible that the BD patients with psychosis recruited in earlier studies were more severely ill than those of the present study. Fourth, a considerable number of patients were in the first episode of mania in the present study. One cannot rule out the possibility that the cognitive deficits may worsen with longer duration of illness as the number of manic episodes had significant influence on the cognitive deficits in a previous meta-analysis. Fifth, the two subgroups were matched on several illness variables such as age at onset of illness and number of episodes, which may influence the cognitive performance. Finally, we examined selected cognitive domains, and it is possible that the BD patients with psychosis may differ in other cognitive domains such as verbal memory.
The study findings need to be considered in the background of the following limitations. First, the sample size was small. While the sample size was adequate to compare BD versus HV, the sample size was small to compare the subgroups. Hence, one cannot rule out type II statistical error for the absence of difference between BD patients with and without psychotic symptoms and our findings need to be considered preliminary, awaiting replication in a larger sample. Second, all patients were on treatment with antipsychotics at some point of time during illness. Although the effect of antipsychotics on cognitive performance in BD is controversial, it is important to examine those patients who have not received treatment with antipsychotics. While such a study is ideal and required for definitive answers, inclusion of patients on antipsychotics increased the generalizability of our findings as atypical antipsychotics are considered first-line treatment for both depressive and manic phases. Third, in view of the smaller number of participants, we were not able to do further analysis between those with mood-incongruent and mood-congruent psychotic symptoms. Future studies with a larger sample will be able to address this question. While these limitations need to be considered before the interpretation of results, it is important to also note the strengths of the study. BD patients and HVs were individually matched on age, sex, and education, controlling for potential confounding effects. The study participants were recruited from a hospital which caters to both first-contact and referred patients. Recruitment of patients from a nontertiary care hospital increased the generalizability significantly compared to earlier studies.
| Conclusion|| |
To summarize the study findings suggest that (a) BD patients have significant cognitive deficits compared to HVs, (b) there was no significant difference between BD patients with psychotic symptoms and BD patients without psychotic symptoms, and (c) both subgroups have significant deficits compared to HVs. The study findings provide further support to the existing literature that BD patients with psychotic symptoms may not be a distinct subtype. Regardless of the presence or absence of psychotic symptoms, cognitive functions need to be assessed in all patients with BD and intensive remediation interventions need to be provided. There is an acute need for novel pharmacological interventions for the treatment of cognitive deficits in patients with BD. The study findings also warrant future studies to include patients from the community and not from tertiary centers alone to increase generalizability.
Financial support and sponsorship
This study was supported by grant from the Medical Research Council of Maharashtra under “STAR Research Project” by the Government of Maharashtra, India.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al.
Lifetime and 12-month prevalence of bipolar spectrum disorder in the national comorbidity survey replication. Arch Gen Psychiatry 2007;64:543-52.
Bora E, Yücel M, Pantelis C. Neurocognitive markers of psychosis in bipolar disorder: A meta-analytic study. J Affect Disord 2010;127:1-9.
Bora E, Pantelis C. Meta-analysis of cognitive impairment in first-episode bipolar disorder: Comparison with first-episode schizophrenia and healthy controls. Schizophr Bull 2015;41:1095-104.
Quraishi S, Frangou S. Neuropsychology of bipolar disorder: A review. J Affect Disord 2002;72:209-26.
Martínez-Arán A, Vieta E, Reinares M, Colom F, Torrent C, Sánchez-Moreno J. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry 2004;161:262-70.
Clark L, Iversen SD, Goodwin GM. A neuropsychological investigation of prefrontal cortex involvement in acute mania. Am J Psychiatry 2001;158:1605-11.
Glahn DC, Bearden CE, Barguil M, Barrett J, Reichenberg A, Bowden CL, et al.
The neurocognitive signature of psychotic bipolar disorder. Biol Psychiatry 2007;62:910-6.
Shepherd AM, Quidé Y, Laurens KR, O'Reilly N, Rowland JE, Mitchell PB, et al.
Shared intermediate phenotypes for schizophrenia and bipolar disorder: Neuroanatomical features of subtypes distinguished by executive dysfunction. J Psychiatry Neurosci 2015;40:58-68.
Strasser HC, Lilyestrom J, Ashby ER, Honeycutt NA, Schretlen DJ, Pulver AE, et al.
Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: A pilot study. Biol Psychiatry 2005;57:633-9.
Martínez-Arán A, Vieta E, Colom F, Torrent C, Sánchez-Moreno J, Reinares M, et al.
Cognitive impairment in euthymic bipolar patients: Implications for clinical and functional outcome. Bipolar Disord 2004;6:224-32.
Reichenberg A, Harvey PD, Bowie CR, Mojtabai R, Rabinowitz J, Heaton RK, et al.
Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders. Schizophr Bull 2009;35:1022-9.
Savitz J, van der Merwe L, Stein DJ, Solms M, Ramesar R. Neuropsychological status of bipolar I disorder: Impact of psychosis. Br J Psychiatry 2009;194:243-51.
Selva G, Salazar J, Balanzá-Martínez V, Martínez-Arán A, Rubio C, Daban C. Bipolar I patients with and without a history of psychotic symptoms: Do they differ in their cognitive functioning? J Psychiatr Res 2007;41:265-72.
Noaghiul S, Hibbeln JR. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry 2003;160:2222-7.
Post RM, Altshuler LL, Leverich GS, Frye MA, Suppes T, McElroy SL, et al.
More medical comorbidities in patients with bipolar disorder from the United States than from the Netherlands and Germany. J Nerv Ment Dis 2014;202:265-70.
Sanches M, Jorge MR. Transcultural aspects of bipolar disorder. Braz J Psychiatry 2004;26 Suppl 3:54-6.
Soni A, Singh P, Shah R, Bagotia S. Impact of cognition and clinical factors on functional outcome in patients with bipolar disorder. East Asian Arch Psychiatry 2017;27:26-34.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al.
The mini-international neuropsychiatric interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59 Suppl 20:22-33.
First MB, Spitzer RL, Gibbon M, Williams JB. Structured Clinical Interview for DSM-IV-TR Axis I Disorders Research Version, Patient Edition with Psychotic Screen (SCID-I/P). New York: Biometrics Research; 2002.
Oldfield RC. The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia 1971;9:97-113.
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6:278-96.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry 1978;133:429-35.
Levinson DF, Mowry BJ, Escamilla MA, Faraone SV. The Lifetime Dimensions of Psychosis Scale (LDPS): Description and interrater reliability. Schizophr Bull 2002;28:683-95.
Anticevic A, Brumbaugh MS, Winkler AM, Lombardo LE, Barrett J, Corlett PR, et al.
Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history. Biol Psychiatry 2013;73:565-73.
Cornblatt BA, Risch NJ, Faris G, Friedman D, Erlenmeyer-Kimling L. The continuous performance test, identical pairs version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Res 1988;26:223-38.
Comalli PE Jr., Wapner S, Werner H. Interference effects of Stroop color-word test in childhood, adulthood, and aging. J Genet Psychol 1962;100:47-53.
Heaton R, Chelune G, Talley J, Kay G. Wisconsin Card Sorting Test (WCST): Manual: Revised and Expanded. Odessa, FL: Psychological Assessment Resources; 1993.
Martinez-Aran A, Vieta E, Torrent C, Sanchez-Moreno J, Goikolea JM, Salamero M, et al.
Functional outcome in bipolar disorder: The role of clinical and cognitive factors. Bipolar Disord 2007;9:103-13.
Roux P, Raust A, Cannavo AS, Aubin V, Aouizerate B, Azorin JM, et al.
Cognitive profiles in euthymic patients with bipolar disorders: Results from the FACE-BD cohort. Bipolar Disord 2017;19:146-53.
Sánchez-Morla EM, Barabash A, Martínez-Vizcaíno V, Tabarés-Seisdedos R, Balanzá-Martínez V, Cabranes-Díaz JA. Comparative study of neurocognitive function in euthymic bipolar patients and stabilized schizophrenic patients. Psychiatry Res 2009;169:220-8.
Selva G, Salazar J, Balanzá-Martínez V, Martínez-Arán A, Rubio C, Daban C, et al.
Bipolar I patients with and without a history of psychotic symptoms: Do they differ in their cognitive functioning? J Psychiatr Res 2007;41:265-72.
Simonsen C, Sundet K, Vaskinn A, Birkenaes AB, Engh JA, Faerden A, et al.
Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophr Bull 2011;37:73-83.
Martinez-Aran A, Torrent C, Tabares-Seisdedos R, Salamero M, Daban C, Balanza-Martinez V, et al.
Neurocognitive impairment in bipolar patients with and without history of psychosis. J Clin Psychiatry 2008;69:233-9.
Simonsen C, Sundet K, Vaskinn A, Ueland T, Romm KL, Hellvin T, et al.
Psychosocial function in schizophrenia and bipolar disorder: Relationship to neurocognition and clinical symptoms. J Int Neuropsychol Soc 2010;16:771-83.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al.
Canadian Network for Mood and Anxiety Treatments (CANMAT) and international society for bipolar disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord 2018;20:97-170.
Arts B, Simons CJ, Drukker M, van Os J. Antipsychotic medications and cognitive functioning in bipolar disorder: Moderating effects of COMT val108/158 met genotype. BMC Psychiatry 2013;13:63.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]