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Keywords:

  • bipolar disorder;
  • depression;
  • executive function;
  • neurocognition;
  • verbal memory

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Aims

Patients with bipolar disorders (BD) show a broad range of neurocognitive impairments. We compared the patterns of neuropsychological performance in depressed and euthymic patients with BD, and explored the state-dependent cognitive markers of bipolar depression.

Methods

The study participants included 32 BD patients (15 depressed and 17 euthymic) and 42 healthy controls. All of the subjects completed tests that assessed attention, psychomotor speed, verbal and visual memory, and executive functions. Between-group neuropsychological performance differences were examined. Multidimensional scaling (MDS) was used to compare the patterns of cognitive variables in euthymic and depressed BD patients.

Results

Compared to the euthymic BD patients and healthy controls, the depressed BD patients performed lower in verbal memory and executive functions. No significant differences were found between the three groups in attention, psychomotor speed, and visual memory. The depressed BD patients showed a lower level of association between psychomotor speed and the time to initial concept formation than the healthy controls and euthymic BD patients. In contrast, the correlation between word association and verbal memory was stronger in the depressed group than either the control or euthymic groups.

Conclusion

The depressed BD patients showed greater impairments in verbal memory and executive functions than the euthymic BD patients. In addition, our study identified a differential pattern of correlations between the cognitive domains of euthymic and depressed BD patients, which suggests the potential role of verbal memory and executive functions as cognitive markers of BD.

Cognitive impairment in patients with bipolar disorders (BD) has been consistently reported in previous studies, not only in acute episodes but also in euthymic state.[1, 2] Meta-analyses of cognitive functioning in euthymic patients with BD have indicated the presence of impairments over a wide range of cognitive domains. These analyses have shown large effect sizes for executive functions and verbal memory, and medium effect sizes for attention and psychomotor speed.[3-5] Because overall cognitive impairments can be regarded as a type of neurobiological scar, the complete recovery of cognitive deficits might not occur in euthymic patients.[1] In addition, recent studies of first-degree relatives of patients with BD have shown deficits in executive functions and verbal memory, which suggests that these domains are trait-like phenotypes or cognitive markers of bipolar disorder.[3, 6, 7]

The results from previous studies have suggested that the level of cognitive impairment may be more prominent in the acute state than in the euthymic state.[1] Hence, the overall cognitive functioning in euthymic patients with BD may lie between symptomatic patients and healthy controls.[8] Verbal memory and executive function are predominantly affected in patients who are suffering from manic or hypomanic symptoms, but there are additional attention and working memory deficits.[9-11] Previous studies of the neurocognitive profiles of patients with bipolar depression have generally focused on the differences between bipolar and unipolar depression, and have reported worse performances in patients with bipolar depression compared to patients with unipolar depression.[12-14]

The patterns of cognitive deficits in depressed patients with BD are inconsistent. While many authors have suggested that executive function and memory are more impaired in the depressive phase compared with the euthymic phase of BD,[1, 9, 15] some studies have reported that memory and executive function are relatively preserved even when patients with BD are depressed.[16, 17] Some authors have also suggested that reductions in attention, psychomotor speed and processing speed are present in bipolar depression,[16-18] but these suggestions are not supported by other studies.[14, 19] To understand the inconsistent findings surrounding bipolar depression, an examination of the differential pattern of cognitive deficits in relation to mood state is required.[20]

We hypothesized that depressive symptoms might have differential effects on the cognitive domains of patients with BD. Therefore, we compared the patterns of cognitive functioning in the euthymic and depressive phases of BD. In addition, we explored state-dependent cognitive markers of bipolar depression.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Subjects

The subjects included 32 patients with BD (15 in a DSM-IV-defined major depressive episode and 17 in a euthymic state) and 42 healthy controls. All of the patients were recruited from the Mood Disorders Clinic of Seoul National University Bundang Hospital, Republic of Korea. The euthymic patients had been clinically stable for a minimum of 8 weeks, and this status was prospectively confirmed by stabilized psychotropic medication regimen and a score ≤ 2 on the Clinical Global Impressions-Bipolar version-Severity scale (CGI-BP-S).[21] All of the patients were receiving psychotropic medication at the time of neurocognitive tests. Twenty-one patients were receiving treatment with lithium and 14 with valproate. Eleven patients were receiving treatment with lamotrigine and 30 with antipsychotics. Detailed information on the medication is presented in Table 1. The following exclusion criteria were applied: comorbid psychotic disorders, substance-related problems in the last 12 months, mental retardation or learning difficulties, history of significant head injury, and clinically significant physical or neurological conditions. Healthy controls with no history of psychiatric disorders were recruited from the community through advertisement. This study was conducted in accordance with the Declaration of Helsinki. The study protocol was reviewed and approved by the institutional review board. All of the subjects received a complete description of the study and provided written informed consent.

Table 1. Demographic and clinical characteristics
 Depressed (n = 15)Euthymic (n = 17)Control (n = 42)Test of significance
  1. F-statistics were obtained from a one-way anova, t-statistics from an independent t-test, and χ2-statistics from Pearson's χ2-test.

  2. ‡Based on the Vocabulary and Block Design subtests from the Wechsler Adult Intelligence Scale, Revised.

  3. HAMD, Hamilton Depression Rating Sale; YMRS, Young Mania Rating Scale.

Age, years, mean (SD)39.2 (10.5)31.6 (13.0)34.1 (7.4)F = 2.64; P = 0.08
Sex, n (%)   χ2 = 1.31; P = 0.52
Male5 (33.3)7 (41.2)11 (26.2) 
Female10 (66.7)10 (58.8)31 (73.8) 
Education, years, mean (SD)15.3 (1.8)14.7 (2.6)15.2 (1.8)F = 0.57; P = 0.57
Estimated IQ, mean (SD)113.6 (17.9)115.4 (14.3)119.6 (12.5)F = 1.20; P = 0.31
Bipolar subtype, n (%)   χ2 = 1.61; P = 0.69
Bipolar I6 (40.0)8 (47.1) 
Bipolar II9 (60.0)9 (52.9) 
Age at onset, years, mean (SD)26.0 (10.7)19.9 (4.4)t = −1.90; P = 0.07
Illness duration, years, mean (SD)13.9 (7.9)11.0 (11.4)t = −0.81; P = 0.42
Number of episodes, mean (SD)    
Depressive4.3 (2.5)3.9 (4.2)t = −0.29; P = 0.77
Manic0.6 (0.9)1.6 (2.4)t = 1.57; P = 0.14
Hypomanic5.9 (3.2)1.4 (1.8)t = −1.50; P = 0.14
Mixed00.1 (0.2)t = 0.91; P = 0.37
Total8.0 (4.4)7.1 (4.8)t = −0.49; P = 0.63
Psychiatric hospitalizations, mean (SD)1.6 (7.9)0.8 (1.2)t = −1.07; P = 0.29
HAMD total score, mean (SD)15.1 (4.5)4.7 (2.8)t = −7.95; P < 0.001
YMRS total score, mean (SD)3.6 (3.2)2.7 (2.3)t = −0.89; P = 0.38
Medication, n (%)    
Lithium11 (73.3)10 (58.8)χ2 = 0.74; P = 0.39
Valproate7 (46.7)7 (41.2)χ2 = 0.10; P = 0.76
Lamotrigine3 (20.0)8 (47.1)χ2 = 2.59; P = 0.11
Antipsychotics14 (93.3)16 (94.1)χ2 = 0.01; P = 0.93

Clinical assessment

All of the subjects were interviewed using the Korean version of the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I).[22, 23] Experienced psychiatrists made the final consensus diagnoses based on the available data and the SCID. Demographic and clinical data were obtained from the case registration forms from the Seoul National University Bundang Hospital Mood Disorder Clinic and electronic medical records. In addition, the symptom severity evaluations were performed by trained investigators (psychiatrists and clinical psychologists). The severity of mood symptoms was assessed with the Korean version of the 17-item Hamilton Depression Rating Scale (HAMD) and the Korean version of the Young Mania Rating Scale (YMRS).[24-27] In the validation studies, the Cronbach's alpha coefficients were 0.76 for the Korean version of the HAMD and 0.73 for the Korean version of the YMRS. All of the euthymic patients scored ≤9 on the HAMD and the YMRS. In contrast, all of the depressed patients scored ≤9 on the YMRS and ≥10 on the HAMD.

Neuropsychological assessment

The neuropsychological assessments were conducted by clinical psychologists who were trained in standardized neuropsychological testing. According to the Korean version of the Wechsler Adult Intelligence Scale, Revised (WAIS-R) manual,[28] we used the Vocabulary and Block Design subtests from the WAIS-R[29] to estimate general intelligence levels. The participants completed a comprehensive neuropsychological battery that focused primarily on attention, verbal and visual memory, and executive function. We selected previously used tests to assess the cognitive functions in patients with BD. The auditory controlled Continuous Performance Test (CPT)[30] was used to assess sustained attention. The Trail Making Test-B (TMT-B)[31, 32] was also utilized to assess attention, psychomotor speed, and set switching. The California Verbal Learning Test (CVLT)[33] was administered to assess verbal learning and memory. In addition, the Rey–Osterrieth Complex Figure Test (ROCFT)[34] was used to assess visual memory. The animal category and phonemic subtests of the Controlled Oral Word Association Test (COWAT)[35] were used to assess verbal fluency. The letters K, S, and O were used because of the lexical differences between English and Korean.[36] Finally, as previously validated in a Korean sample,[37] the three indices of the Wisconsin Card Sorting Test (WCST)[38] were used to assess concept formation and cognitive flexibility. The ‘categories achieved’ index indicates the number of times 10 consecutive correct responses were made, and reflects overall success. The ‘trials to complete the first category’ index indicates the number of trials to successfully complete the first category, and reflects initial conceptual ability. The ‘perseverative errors’ index indicates the number of errors that were perseverative, and reflects the reflecting tendency toward perseveration.

Statistical analysis

The demographic characteristics of the three groups were compared by an anova and Pearson's χ2-test, as appropriate. The differences in the clinical variables were tested using independent t-tests and Pearson's χ2-tests. A manova was performed for the set of 16 neuropsychological measures, controlling for the risk of inflated family-wise error rate. One-way anovas were conducted as follow-up tests to the manova to examine between-group differences. Planned comparisons and Tukey's test were used for the post-hoc comparisons. Cohen's d was calculated to quantify the magnitudes of group effects in the differences of neuropsychological performance.[39] Pearson's correlation analyses were used to investigate the correlation between neurocognition and current symptomatology. Multidimensional scaling (MDS) was conducted to visually compare the pattern of neuropsychological measures between the three groups.[40] The MDS analysis provided a spatial model that placed each neuropsychological measure in a coordinate space that used dissimilarity data as metric distances, thereby displaying the overall structure of the complex intercorrelations among the neuropsychological measures.[41, 42] To test whether a given MDS solution was precise, the S-Stress level (Stress) was used as a badness-of-fit measure, and the R-squared index (RSQ) was used as a goodness-of-fit measure; both measures range from 0 (perfect fit for Stress; worst possible fit for RSQ) to 1 (worst possible fit for Stress; perfect fit for RSQ). A relatively high lack of fit (e.g. Stress > 0.2 or RSQ < 0.6) indicates that the number of dimensions in a given MDS solution is inappropriate.[43] The interval scale and the z-transformation were applied for the MDS analysis. All analyses were performed using pasw Statistics 18.0 for Windows (spss, Chicago, IL, USA). All P-values were two-tailed, and a P-value < 0.05 was considered indicative of statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Demographic and clinical variables

The demographic and clinical characteristics of the three groups (depressed, euthymic, and controls) are presented in Table 1. Demographic details, such as age, sex, education, and estimated IQ, were not significantly different between the three groups. The clinical variables, including the types of prescribed medications, did not differ between the depressed and euthymic groups. The two clinical groups did not differ in illness duration or number of episodes. As expected, the depressed group showed the higher HAMD score than that of the euthymic group.

Comparisons of neuropsychological test scores

The neuropsychological test results are summarized in Table 2. The results of the manova revealed a significant main effect, indicating a significant overall difference in neuropsychological performance between the groups (Pillai's trace = 0.73; F = 2.04; P = 0.003). Follow-up anovas with Tukey's post-hoc tests also detected significant group differences for each individual measure after applying the Bonferroni correction for multiple comparisons (0.05/16 = 0.003). The majority of group differences occurred between the depressed and the control groups, and the depressed group scored poorer than the control group across neuropsychological measures; the largest effect size was found for the CVLT total and the smallest for the ROCFT copy. In the planned comparisons between the euthymic and the control groups, only the TMT-B reaction time and the CVLT total showed a trend toward the lower scores in the euthymic group than in the control group (P = 0.06 for both measures).

Table 2. Neuropsychological test scores across the groups
 Depressed (n = 15)Euthymic (n = 17)Control (n = 42)anova F PTukey's testCohen's d
D-ED-CE-C
  1. *Statistically significant after the Bonferroni correction for multiple comparisons.

  2. †Data are presented as the mean (SD).

  3. ‡D, depressed; E, euthymic; C, control.

  4. CPT, continuous performance test; TMT-B, trail making test-B; CVLT, California verbal learning test; ROCFT, Rey–Osterrieth Complex Figure Test; WCST, Wisconsin Card Sorting Test.

Attention/psychomotor speed         
CPT correct response56.5 (6.9)59.6 (6.1)61.0 (2.4)5.130.01 0.480.870.30
Sensitivity A0.88 (0.10)0.94 (0.09)0.96 (0.05)6.070.004 0.631.010.27
Reaction time (ms)608 (102)603 (115)580 (82)0.630.53 0.050.300.23
TMT-B reaction time (s)95.1 (54.9)79.7 (67.1)56.1 (20.5)5.160.01 0.270.940.48
Memory         
CVLT total (trials 1–5)42.2 (10.0)52.0 (11.0)57.0 (7.5)15.23<0.001*D < E, C0.931.670.53
Short delay free recall9.8 (3.7)12.0 (3.2)12.8 (2.3)6.420.003*D < C0.640.970.29
Long delay free recall10.4 (3.2)12.4 (3.3)13.6 (2.2)8.030.001*D < C0.621.170.43
Recognition13.8 (2.0)15.4 (0.9)15.1 (1.0)8.090.001*D < E, C1.030.820.32
ROCFT copy33.7 (1.6)32.5 (2.9)33.6 (2.2)1.650.20 0.510.050.43
Immediate recall17.2 (9.0)20.7 (6.0)23.0 (5.3)4.820.01 0.460.790.41
Delayed recall17.3 (8.4)20.8 (6.1)22.1 (4.9)3.470.04 0.480.700.23
Executive function         
Category fluency (animal)16.6 (5.0)19.8 (4.7)20.2 (4.0)3.720.03 0.660.800.09
Letter fluency (S, O, K)29.0 (10.2)37.1 (10.4)41.2 (9.8)8.220.001*D < C0.791.220.41
WCST         
Categories achieved4.7 (2.1)5.5 (1.3)5.9 (0.4)5.190.01 0.460.790.42
Trials to complete first category44.5 (42.0)19.7 (22.2)18.8 (15.6)6.450.003*D < C0.740.810.05
Perseverative errors17.7 (14.8)9.9 (8.9)11.9 (6.0)3.260.04 0.640.510.26

Attention and psychomotor speed

The depressed group showed significantly lower scores on attention measures compared with the control group. There was no difference between the depressed and the control group in the comparisons of the correct response and sensitivity A scores from the CPT. However, large effect sizes were observed between the two groups in CPT correct response (Cohen's d > 0.8). In comparisons between the depressed and the euthymic groups, the CPT sensitivity A showed a medium effect size (d = 0.63) but the other measures showed small effect sizes.

Memory

Significant between-group differences were observed in verbal memory measures. The depressed group showed significantly poorer performances on total, short delayed free recall, long delayed free recall, and recognition of the CVLT compared with the control group, and the effect sizes were large. Furthermore, the depressed group scored poorer in the CVLT total and the recognition measures than the euthymic group, with medium to large effect sizes. No significant group differences were detected in the verbal memory measures between the euthymic and the control groups. However, no significant between-group differences were detected in visual memory measures on the ROCFT. The depressed group showed a tendency toward lower scores in immediate recall and delayed recall compared with the control group, with medium effect sizes.

Executive function

Letter fluency was poorer in the depressed group than in the control group, and the effect size of difference was large between the two groups. Although the differences in category fluency and letter fluency between the depressed and the euthymic groups were not significant, the effect sizes were medium to large. In addition, as assessed by WCST, a significantly poorer performance on the measure of trials to complete the first category was observed in the depressed group compared with the control group, and the effect size was large.

Correlations between clinical and neuropsychological variables

The HAMD total score negatively correlated with the CVLT total (r = −0.39, P = 0.03), the recognition (r = −0.41, P = 0.02), and the WCST trials to complete the first category (r = 0.48, P = 0.01). The YMRS total score negatively correlated with the CVLT short delayed free recall (r = −0.36, P = 0.05), the long delayed free recall (r = −0.40, P = 0.02), and the WCST trials to complete the first category (r = 0.36, P = 0.05).

Comparisons of intercorrelations among neuropsychological variables

Graphical representations of 16 neuropsychological measures are depicted in Figure 1. All of the stress values were in the range of 0.15–0.19, and all of the RSQ values ranged from 0.74 to 0.85. The distance between psychomotor speed (reaction time measures) and initial conceptual ability (trials to complete the first category) was greater in the depressed group than in both the control and euthymic groups, which indicated a weak effect of psychomotor speed on the time to initial concept formation in the patients suffering from bipolar depression. However, the distance between word association (category and letter fluency) and verbal memory (CVLT indices) was shorter in the depressed group than in either the control or euthymic groups, which suggests a close correlation between word association strategies and verbal memory retrieval in the depressed group.

figure

Figure 1. Multidimensional scaling analysis of the neuropsychological variables. (a) Controls. (b) Euthymic patients with bipolar disorders (BD). (c) Depressed patients with BD. The degrees of dissimilarity are reflected by the Euclidean distance. The white dots signify attention and psychomotor speed; the grey dots signify verbal and visual memory, and the black dots, executive functions. COWAT, Controlled Oral Word Association Test; CPT, Continuous Performance Test; CVLT, California Verbal Learning Test; ROCFT, Rey–Osterrieth Complex Figure Test; TMT-B, Trail Making Test-B; WCST, Wisconsin Card Sorting Test.

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Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

In the current study, we compared the neuropsychological performances of euthymic and depressed patients with BD. The between-group comparison results support the previous findings in depressed patients with BD; these patients present with substantial impairments in verbal memory and executive functions compared with healthy controls.[1] Additionally, depressed patients with bipolar depression scored worse than patients with remitted BD on measures of these key cognitive domains. The symptom severity, as assessed by the HAMD and YMRS total scores, was negatively associated with verbal memory and executive function as suggested by a recent meta-analysis.[44] These findings are in line with previous studies showing robust deficits in verbal memory and executive functions in depressed patients with BD.[8, 15] Verbal memory, attention, and executive functions have been proposed as trait markers of BD.[45, 46] However, as shown in this sample, some subpopulations may not show greater cognitive impairments than healthy controls, at least while they are euthymic. For instance, Clark et al.[47] reported preserved verbal memory and recognition in euthymic patients with BD. Additionally, the most significant impairments in execution and attention were observed in the patients with remitted BD by Martinez-Aran and colleagues.[48] These findings are of theoretical and clinical importance in determining the cognitive markers of BD.

The results of the MDS analyses suggest changes in the intercorrelations among the neuropsychological measures in depressed patients with BD. Deficits in memory or executive functions of depressed patients with BD may interfere with the correlation between psychomotor speed and the time to concept formation. Despite improvements in attention and psychomotor speed, depressive symptoms can lead to poor performance in executive functions.[49] In addition, performance in verbal memory may need extra cognitive efforts in depressed patients with BD compared with healthy controls or euthymic patients with BD. Therefore, further studies are needed to verify these findings and to test whether the effects of mood state on neuropsychological performance might be quantitative or qualitative.[42]

Our study did not find between-group differences in the CPT and the TMT-B reaction times. While many studies have used psychomotor function or processing speed tests, we calculated the reaction times for cognitive tests (i.e. attention and executive function tests). These methodological differences may lead to inconsistent results.[1, 16] Another possibility is that processing speed per se is the domain that is least affected by mood states or symptoms in patients with BD. Two previous longitudinal studies have revealed a weak association between processing speed and mood change in patients with BD.[14, 19]

This study had several limitations. First, the small sample size may weaken the statistical power for detecting between-group differences, and thus limit the generalizability of the findings. Further studies with larger samples would be needed to confirm our findings. Second, the cross-sectional design could not exclude the effect of sample heterogeneity on neuropsychological performance. A longitudinal design would be more appropriate to determine whether the cognitive deficits in patients with BD are trait-like or state-dependent. Third, the effects of medications on neuropsychological performance were not controlled. Finally, because the MDS analysis is exploratory and non-inferential, the results of this study remain exploratory.

In summary, depressed patients with BD demonstrated greater impairments in verbal memory and executive functions compared with euthymic patients with BD. In addition, this study identified the differential patterns of correlations between psychomotor speed, verbal memory, and executive functions in euthymic and depressed patients with BD; these patterns explain the effects of bipolar depression on overall neuropsychological performance. The findings of this study also suggest the possible role of verbal memory and executive functions as cognitive markers of bipolar depression.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This study was supported by grant A101915 from the Korea Healthcare Technology R & D Project, Ministry of Health & Welfare, Republic of Korea. The authors declare no commercial associations that might pose a conflict of interest in connection with this manuscript.

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  6. Acknowledgments
  7. References
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