|Year : 2019 | Volume
| Issue : 1 | Page : 32-38
Cognitive impairment in euthymia- A comparative study of clinical and treatment variables between bipolar affective disorder patients and normal controls at a tertiary care centre in Kerala
Megha Alathukattil Pradip, K Saibunnisa Beevi, Praveenlal Kuttichira, James T Antony
Department of Psychiatry, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India
|Date of Web Publication||24-May-2019|
Dr. Megha Alathukattil Pradip
Department of Psychiatry, Jubilee Mission Medical College and Research Institute, Thrissur - 680 005, Kerala
Source of Support: None, Conflict of Interest: None
Objective: Several studies have described cognitive impairments in euthymic state of bipolar patients. However, limited studies have established clearly the correlation between clinical variables and cognitive functions, the effect of mood stabilizers on the cognitive performance of euthymic bipolar patients and there are few studies reported from South India. This study aims to assess the cognitive impairments in euthymic state of bipolar patients when compared with normal healthy comparison group and to determine the clinical factors increasing the risk of cognitive impairment in such patients. Materials and Methods: Fifty bipolar patients in the euthymic state confirmed through Young Mania Rating Scale ≤ 6 and Hamilton Depression Rating Scale ≤8 were compared with healthy comparison group on tests for assessing set shifting, verbal learning and memory, attention, short-term memory, and verbal fluency. The clinical variables – age of onset, number of episodes, and duration of illness – were assessed to determine whether it influenced the neurocognitive functions. Results: Euthymic bipolar patients performed worse than the comparison group in the areas of executive functions, verbal learning and memory, attention, short-term memory, and verbal fluency. The duration of illness and frequency of episodes significantly correlated with the neurocognitive deficits. The age of onset and mood stabilizers prescribed also influenced the cognitive functions in these patients. Conclusion: Cognitive impairments are found in bipolar affective disorder patients even in euthymic state. The duration of illness, number of episodes, age of onset, and medications affected the cognitive functions. This calls for prompt and effective management of the bipolar patients.
Keywords: Clinical factors, cognitive impairment, comparative study, euthymic bipolar, risk
|How to cite this article:|
Pradip MA, Beevi K S, Kuttichira P, Antony JT. Cognitive impairment in euthymia- A comparative study of clinical and treatment variables between bipolar affective disorder patients and normal controls at a tertiary care centre in Kerala. Ann Indian Psychiatry 2019;3:32-8
|How to cite this URL:|
Pradip MA, Beevi K S, Kuttichira P, Antony JT. Cognitive impairment in euthymia- A comparative study of clinical and treatment variables between bipolar affective disorder patients and normal controls at a tertiary care centre in Kerala. Ann Indian Psychiatry [serial online] 2019 [cited 2019 Dec 13];3:32-8. Available from: http://www.anip.co.in/text.asp?2019/3/1/32/251361
| Introduction|| |
Bipolar disorder affects approximately 2% of the adult population. Bipolar disorder patients are generally been regarded as having a better functional outcome than those with schizophrenia. However, studies have suggested low functioning in bipolar patients even when they are in a state of clinical remission. It also contributes to the long-term disability in those individuals. This can, in turn, affect the interpersonal, social, and occupational functioning as well as the medication compliance and treatment adherence.
Near complete recovery in the euthymic phase was the old school of thought. However, recent studies have observed several impairments, especially in the realm of cognitive functions. The presence of neurocognitive impairments and its relation to worse clinical outcome are reported, and it is suggested as an indicator of illness progression and severity.
Many previous research in bipolar patients has observed cognitive impairments during the acute episodes especially in the areas of attention, learning, memory, psychomotor functioning, and frontal executive functions., Several studies have described cognitive impairments in euthymic state of bipolar patients as well. Vrabie et al. and Eric et al. observed impairments in all the cognitive domains examined, but Civil Arslan et al. found impairments in executive functions but not in any other domains.
Few studies have established clearly the correlation between clinical variables and cognitive functions and the effect of mood stabilizers on the cognitive performance of euthymic bipolar patients and there are few studies reported from South India. While Zubieta et al. and Nehra et al. reported worsened cognitive functions with multiple episodes Martino et al. has contradictory finding.
The present study was undertaken to get better knowledge regarding the impairments in the cognitive domains of bipolar affective disorder patients in their euthymic state and to find out the clinical variables affecting the cognitive functions in Kerala population, a state in South India.
| Materials and Methods|| |
The study was started after getting approval from the Institutional Ethics Committee. This was a comparative study. The primary objective was to assess the cognitive impairments in euthymic state of patients with bipolar affective disorder when compared with normal healthy comparison group. The secondary objective was to determine the clinical factors increasing the risk of cognitive impairment in euthymic bipolar patients.
Fifty patients diagnosed as bipolar affective disorder according to ICD-10 in the euthymic state confirmed with Young Mania Rating Scale (YMRS) ≤6 and Hamilton Depression Rating Scale (HDRS) ≤8 and those who were on stable dose of medications and were clinically stable as recorded by the consultant psychiatrist in the case sheet during 1 month before study participation; on follow-up at the Department of Psychiatry outpatient department, Jubilee Mission Medical College and Research Institute Thrissur, Kerala, India, aged 16–65 years were enrolled for the study. The age of 16 years was taken as cutoff so that those who completed at least high school education (matriculation) were included in the study and those above 65 years were not enrolled so as to exclude the geriatric population.
The patients as well as the relatives were explained in detail about the nature and purpose of the study, the information sheet was provided, and informed consent was taken. The comparison group consisted of 50 healthy controls who volunteered for the study, matched for age, years of formal education, and socioeconomic status, and taken up after getting informed consent. Persons with organic mental disorder, learning disabilities, and mental retardation, comorbid medical conditions, and current substance abuse were excluded from the study. Normal controls with a history of psychiatric morbidity or family history of psychiatric illness were also excluded from the comparison group. The duration of the study was 18 months, from January 2016 to July 2017.
Specially designed intake pro forma was made and details collected. The sociodemographic profile included name, age, gender, education, occupation, marital status, and religion. Clinical profile for patients included age of onset of the illness, total duration of illness, number of episodes, number of hospitalizations, and mood stabilizers prescribed. YMRS and HDRS were used to confirm the euthymic state. Neuropsychological tests to assess cognitive functions included Wisconsin Card Sorting Test (WCST) to assess set-shifting ability, Controlled Oral Word Association Test (COWAT) to assess verbal fluency, digit span test (DST) to assess working memory and attention, trail making test (TMT) to assess attention, mental flexibility and processing speed, California Verbal Learning Test (CVLT) to assess verbal learning and memory.
Statistical analysis was performed using the Statistical Package for Social Sciences (IBM SPSS Version 20, Armonk, New York). Numerical variables were expressed as mean and standard deviation and categorical variables were expressed as frequency and percentages. To obtain the association/comparison of neuropsychological tests with cases and comparison groups, Chi-square test was used. To test the statistical significance of mean values in neurocognitive tests between the two groups, independent two-sample t-test was applied for parametric variables and Mann–Whitney U-test was applied for nonparametric variables. To obtain the correlation of cognitive scores between age of onset, number of episodes, total duration, and number of hospitalizations, Karl Pearson/Spearman correlation coefficient was applied. For testing the mean differences among mood stabilizers with neurocognitive tests, analysis of variance test was applied. Since it was significant Bonferroni multiple comparison test was used. The statistical significance was assumed as P < 0.05.
| Results|| |
The study population consisted of 50 cases (euthymic bipolar patients) and 50 comparison group (normal healthy controls). Mean age of cases was 37.86 ± 9.72 and mean age of comparison group was 34.10 ± 9.54. The samples were matched for age (P = −0.056). The samples were matched for other sociodemographic variables such as gender, education, occupation, marital status, and religion [Table 1]. Most of the study population, as well as the healthy controls, were unskilled laborers. Among studied cases, YMRS scores ranged between 0 and 4 and HDRS scores ranged between 0 and 3. Mean YMRS Score and Standard deviation were 0.70 and 1.093, respectively. Mean HDRS Score and Standard deviation were 0.52 and 0.953, respectively. All the patients were in the euthymic state at the time of the study.
|Table 1: Distribution of cases and controls according to sociodemographic variables|
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Details about the illness variables and prescribed mood stabilizers of cases have been provided in [Table 2] and [Table 3], respectively. When the various neurocognitive tests were administered, the cases had performed worse than the comparison group on all the variables of the WCST tested-percentage correct responses, percentage perseverative errors, and percentage nonperseverative errors and there was statistically significant difference between the groups on the correct responses and nonperseverative errors (P < 0.05) [Table 4]. There was statistically significant difference between the two groups in the COWAT score, DST forward and backward scores, TMT A, B and B-A scores, CVLT immediate recall, short recall, and delayed recall scores [Table 4].
|Table 4: Distribution of comparison of the neurocognitive tests between cases and controls|
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When the effect of illness variables on cognitive functions was assessed, there was statistical correlation between age of onset and WCST % perseverative errors (Pearson rho −0.442) as well as between total duration of illness and COWAT score (rho −0.536), DST forward score (rho −0.457), TMT B score (rho 0.406), TMT B-A score (rho 0.370), and CVLT immediate recall score (rho −0.336). Furthermore, there was statistical correlation between total number of episodes and COWAT score (rho −0.401), DST forward score (rho −0.343), TMT B score (rho 0.284), TMT B-A score (rho 0.281), and CVLT immediate recall score (rho −0.384). When the number of manic episodes was assessed for correlation there was statistically significant correlation between the total number of manic episodes and COWAT score (rho −.300), DST forward score (rho −0.395), TMT B score (rho 0.319), B-A score (0.363), CVLT immediate recall score (rho −0.284), and CVLT short recall score (rho −0.318) and with the depressive episodes there was statistically significant correlation only between COWAT score (rho −0.421) and CVLT immediate recall score (rho −0.328). There was no statistically significant correlation found between the total number of hospitalizations and the various test scores [Table 5].
|Table 5: Distribution of the correlation between illness variables and cognitive functions|
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When the mood stabilizers prescribed were compared, statistical significance was found only in the TMT B and TMT B-A score with those prescribed lithium performing better than the other two groups [Table 6]. When the three groups were compared with the pairwise comparison, in the TMT B score statistical significance was found between lithium and lithium + divalproate (P = 0.007) and divalproate and lithium + divalproate (P = 0.036). In the B-A score also statistical significance was found between lithium and lithium + divalproate (P = 0.007) and divalproate and lithium + divalproate (P = 0.024).
| Discussion|| |
The primary objective was to assess the cognitive impairments in euthymic state of patients with bipolar affective disorder when compared with normal healthy comparison group, and the secondary objective was to determine the clinical factors increasing the risk of cognitive impairment in euthymic bipolar patients. Our study observed significant cognitive impairments in the euthymic state of bipolar affective disorder patients and that several clinical variables significantly worsened the cognitive performance.
Literature review showed that it had been two decades since the search for the neurocognitive impairment in bipolar patients in their euthymic state. However, there were only a few published studies from South India, and as such there was only one publication from Kerala.
Several studies had reported significant executive function deficits with WCST.,,, Significant perseverative errors, deficits in the categories completed and nonperseverative errors were observed compared to the normal comparison group. Patients in the current study had poor performance in the total number of correct responses, perseverative errors, and nonperseverative errors and statistically significant deficits in correct responses and nonperseverative errors compared to the controls. Poor performance in verbal fluency with COWAT was reported in several studies.,,,,, Our studies also support those findings. We observed significant deficits in both digit span forward and backward in tune with the findings of Tajand Padmavati. There are reports from elsewhere supporting, and contradicting these observations., No explanations could be offered to justify contradictory findings. Significant deficits in TMT seen in our study was in agreement with other reported studies.,,, Impairments in CVLT observed in our study were observed in other studies also.,,
The mean age of the cases in the study was 37.86 years. In other reported studies, the age ranged between 38.5 years and 45.7 years. Mean age of onset observed by Martínez-Arán et al. was 23.6 ± 7.1 years; lesser than our observation of 31.06 ± 9.12 years. Verbal memory deficits were reported to be related to the age of onset of disease,, but El-Badri et al. observed no correlation between neurocognitive performance and age of onset of illness. In our study, the age of onset is correlated with executive function deficits and showed borderline correlation with verbal learning and memory deficits.
Studies, had reported that cognitive functions worsened with the duration of illness whereas a few other studies, found no worsening of the cognitive performance as the duration of illness increased. Findings of this study support the former. However, ours was a cross-sectional study, and longitudinal studies are further required to substantiate the finding.
Verbal memory impairments correlated with the recurrent episodes, and executive function deficits correlated with the number of manic episodes., In our study, we found correlation between impairments in verbal learning and memory, verbal fluency, attention, processing speed, working memory and total number of episodes and greater correlation between all the above neurocognitive functions and total number of manic episodes. However, Nehra et al. and Martino et al. observed that experience of successive episodes was not related to a progressive neurocognitive decline.
Previous studies had shown correlation between number of hospitalizations and poorer performance on attention and memory tests; verbal learning and memory tasks, executive function, and memory deficits and verbal memory. In this study, no statistically significant correlation was found between the number of hospitalizations and the various cognitive domains. This finding may be because of the fact that there were fewer hospitalizations (mean of 1.72) in our study sample.
Effect of mood stabilizers prescribed
Pharmacological treatment makes it difficult to assess the real impact of the euthymic state on the cognitive functions. Medications by themselves can affect the cognitive performance. Gualtieri and Johnson and Senturk et al. had reported the effects of lithium and valproate on cognitive function. Studies had shown lithium causing memory deficit,, no deficit or its neuroprotective effect in bipolar affective disorder patients. In this study, patients prescribed lithium alone had performed better than the other two groups, i.e., divalproate and lithium plus divalproate group in the TMT. Significant differences between the groups were not observed on any other cognitive measures.
Patients were on multiple psychotropic medications, and that might have impacted the study results. Antipsychotics, antidepressants, and other drugs prescribed might have worsened the neurocognitive functions. Often the doses higher than what is required might be prescribed, and the course of treatment might be continued more than the actual duration of episodes.
| Conclusion|| |
Our study found that bipolar disorder patients in their euthymic state had significant cognitive impairments in the areas of set-shifting, verbal fluency, short-term memory, visual attention, and task shifting, verbal learning and memory as compared to the normal healthy comparison group; the cognitive deficits were observed in all of the tests administered. The duration of illness and frequency of episodes significantly affected the neurocognitive functions. Age of onset and mood stabilizers prescribed was also found to have correlation with the neurocognitive impairments in these patients.
The study thus establishes that illness factors significantly contributed to the neurocognitive deficits; in addition to the pharmacological agents used. It is observed that cognitive functions worsened with longer duration of illness and increasing number of episodes especially the manic episodes. Hence, there is a need for prompt and effective management of the bipolar patients to reduce the likelihood of developing cognitive impairment in euthymic state.
The future studies should investigate the cognitive impairments in the specific bipolar subtypes. Further studies need to be done to understand the effect of antipsychotics, antidepressants and other drugs on the neurocognitive functions. Furthermore, there is a need to study whether the cognitive impairments are the result of the disease process or is it really an endophenotype of bipolar affective disorder.
Limitations of the study
The study has its limitations. The patients in the present study were on multiple psychotropic medications, and their effects on the cognitive functions were not assessed in this study. The effects of these drugs on cognition could not be excluded, as it was a naturalistic study. This also was a confounding factor in the study. The sample size was small. It was a hospital based study. Educational qualification was an inclusion criterion. The smoking effects and the effects of gender were not analyzed. The study also had a wide age range. All these pose cautions against any generalization of conclusions. Euthymic state could not be confirmed for the 1 month before the inclusion in the study with a proper scale/assessment. Functional scales were also not used in the study. The study was a cross-sectional comparative study. The longitudinal course of the deficits and the factors affecting it were not considered. Finally, the neuropsychological tests administered may not have covered the entire range of cognitive functions.
I gratefully acknowledge the help of the department in helping me complete the work, with special thanks to the Institution's biostatistician, Mr. Unnikrishnan U.G.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sanchez-Moreno J, Martinez-Aran A, Tabarés-Seisdedos R, Torrent C, Vieta E, Ayuso-Mateos JL, et al.
Functioning and disability in bipolar disorder: An extensive review. Psychother Psychosom 2009;78:285-97.
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.
Zubieta JK, Huguelet P, Lajiness-O'Neill R, Giordani BJ. Cognitive function in euthymic bipolar I disorder. Psychiatry Res 2001;102:9-20.
McGrath J, Scheldt S, Welham J, Clair A. Performance on tests sensitive to impaired executive ability in schizophrenia, mania and well controls: Acute and subacute phases. Schizophr Res 1997;26:127-37.
Sweeney JA, Kmiec JA, Kupfer DJ. Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery. Biol Psychiatry 2000;48:674-84.
Vrabie M, Marinescu V, Talaşman A, Tăutu O, Drima E, Micluţia I. Cognitive impairment in manic bipolar patients: Important, understated, significant aspects. Ann Gen Psychiatry 2015;14:41.
Eric YW, Halari R, Cheng KM, Leung SK, Young AH. Cognitive performance is impaired in euthymic Chinese patients with bipolar 1 disorder. J Affect Disord 2013;151:156-63.
Civil Arslan F, Tiryaki A, Ozkorumak E. A comparison of euthymic bipolar patients with unaffected first-degree relatives and healthy controls in terms of neuropsychological functions. Int J Psychiatry Clin Pract 2014;18:208-14.
Nehra R, Chakrabarti S, Pradhan BK, Khehra N. Comparison of cognitive functions between first- and multi-episode bipolar affective disorders. J Affect Disord 2006;93:185-92.
Martino DJ, Strejilevich SA, Marengo E, Igoa A, Fassi G, Teitelbaum J, et al.
Relationship between neurocognitive functioning and episode recurrences in bipolar disorder. J Affect Disord 2013;147:345-51.
World Health Organization. The ICD-10 Classification of Mental and Behaviour Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO; 1992.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry 1978;133:429-35.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
Heaton RK, Chelune GJ, Talley JL, Kay GC, Curtiss G. Wisconsin Card Sorting Test Manual. Odessa, Florida, U.S.A: Psychological Assessment Resources INC.; 1993.
Benton AL, Hamsher KS. Multilingual Aphasia Examination. New York: Oxford University Press; 1989.
Wechsler D. Weshler Memory Scale-Revised (WSM-R). New York: The Psychological Corporation; 1987.
Tombaugh TN. Trail making test A and B: Normative data stratified by age and education. Arch Clin Neuropsychol 2004;19:203-14.
Elwood RW. The California verbal learning test: Psychometric characteristics and clinical application. Neuropsychol Rev 1995;5:173-201.
Shijin AU, Neethi V. Study on executive dysfunction in euthymic phase of patients with bipolar affective disorder. J Evid Based Med Healthc 2016;55:2840-5.
Bourne C, Aydemir Ö, Balanzá-Martínez V, Bora E, Brissos S, Cavanagh JT, et al.
Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: An individual patient data meta-analysis. Acta Psychiatr Scand 2013;128:149-62.
Palazzo MC, Arici C, Cremaschi L, Cristoffanini M, Dobrea C, Dell'Osso B, et al.
Cognitive performance in euthymic patients with bipolar disorder vs. healthy controls: A neuropsychological investigation. Clin Pract Epidemiol Ment Health 2017;13:71-81.
Torrent C, Martínez-Arán A, Daban C, Sánchez-Moreno J, Comes M, Goikolea JM, et al.
Cognitive impairment in bipolar II disorder. Br J Psychiatry 2006;189:254-9.
Jaracz M, Drozdz W, Borkowska A. Decision making, working memory and executive functions in euthymic bipolar patients. Eur Psychiatry 2009;24:S582.
Coffman JA, Bornstein RA, Olson SC, Schwarzkopf SB, Nasrallah HA. Cognitive impairment and cerebral structure by MRI in bipolar disorder. Biol Psychiatry 1990;27:1188-96.
Docherty NM, Hawkins KA, Hoffman RE, Quinlan DM, Rakfeldt J, Sledge WH, et al.
Working memory, attention, and communication disturbances in schizophrenia. J Abnorm Psychol 1996;105:212-9.
Normala I, Abdul HA, Azlin B, Nik Ruzyanei NJ, Hazli Z, Shah SA. Executive function and attention span in euthymic patients with bipolar 1 disorder. Med J Malaysia 2010;65:199-203.
Sparding T, Silander K, Pålsson E, Östlind J, Sellgren C, Ekman CJ, et al.
Cognitive functioning in clinically stable patients with bipolar disorder I and II. PLoS One 2015;10:e0115562.
Cardenas SA, Kassem L, Brotman MA, Leibenluft E, McMahon FJ. Neurocognitive functioning in euthymic patients with bipolar disorder and unaffected relatives: A review of the literature. Neurosci Biobehav Rev 2016;69:193-215.
Taj M, Padmavati R. Neuropsychological impairment in bipolar affective disorder Indian J Psychiatry 2005;47:48-50.
Thompson JM, Gallagher P, Hughes JH, Watson S, Gray JM, Ferrier IN, et al.
Neurocognitive impairment in euthymic patients with bipolar affective disorder. Br J Psychiatry 2005;186:32-40.
Trivedi JK, Tandon R, Singh AP. Neurocognitive functions in remitted patients of bipolar I disorder. Bipolar Disord 2004;6:29.
Martínez-Arán A, Vieta E, Reinares M, Colom F, Torrent C, Sánchez-Moreno J, et al.
Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry 2004;161:262-70.
Altshuler LL, Ventura J, van Gorp WG, Green MF, Theberge DC, Mintz J. Neurocognitive function in clinically stable men with bipolar I disorder or schizophrenia and normal control subjects. Biol Psychiatry 2004;56:560-9.
van der Werf-Eldering MJ, Burger H, Holthausen EA, Aleman A, Nolen WA. Cognitive functioning in patients with bipolar disorder: Association with depressive symptoms and alcohol use. PLoS One 2010;5. pii: e13032.
Bora E, Vahip S, Akdeniz F, Gonul AS, Eryavuz A, Ogut M, et al.
The effect of previous psychotic mood episodes on cognitive impairment in euthymic bipolar patients. Bipolar Disord 2007;9:468-77.
El-Badri SM, Ashton CH, Moore PB, Marsh VR, Ferrier IN. Electrophysiological and cognitive function in young euthymic patients with bipolar affective disorder. Bipolar Disord 2001;3:79-87.
Pfennig A, Alda M, Young T, MacQueen G, Rybakowski J, Suwalska A, et al.
Prophylactic lithium treatment and cognitive performance in patients with a long history of bipolar illness: No simple answers in complex disease-treatment interplay. Int J Bipolar Disord 2014;2:1.
Strejilevich SA, Martino DJ. Cognitive function in adulthood and elderly euthymic bipolar patients: A comparison to test models of cognitive evolution. J Affect Disord 2013;150:1188-91.
Martino DJ, Igoa A, Marengo E, Scápola M, Strejilevich SA. Longitudinal relationship between clinical course and neurocognitive impairments in bipolar disorder. J Affect Disord 2018;225:250-5.
Denicoff KD, Ali SO, Mirsky AF, Smith-Jackson EE, Leverich GS, Duncan CC, et al.
Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder. J Affect Disord 1999;56:67-73.
Okasha TA, El Sheikh MM, El Missiry AA, El Missiry MA, El Serafi D, El Kholy S, et al.
Cognitive functions in euthymic Egyptian patients with bipolar disorder: Are they different from healthy controls? J Affect Disord 2014;166:14-21.
Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed 2006;8:46.
Senturk V, Goker C, Bilgic A, Olmez S, Tugcu H, Oncu B, et al.
Impaired verbal memory and otherwise spared cognition in remitted bipolar patients on monotherapy with lithium or valproate. Bipolar Disord 2007;9 Suppl 1:136-44.
Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive performance: A meta-analysis. J Clin Psychiatry 2009;70:1588-97.
López-Jaramillo C, Lopera-Vásquez J, Ospina-Duque J, García J, Gallo A, Cortez V, et al.
Lithium treatment effects on the neuropsychological functioning of patients with bipolar I disorder. J Clin Psychiatry 2010;71:1055-60.
Bersani G, Quartini A, Zullo D, Iannitelli A. Potential neuroprotective effect of lithium in bipolar patients evaluated by neuropsychological assessment: Preliminary results. Hum Psychopharmacol 2016;31:19-28.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]