Abstracts
There is limited data regarding the cognitive profile from screening tests of older adults with bipolar disorder (BD) with dementia.
Objective
To investigate the Clock Drawing Test (CDT) among older adults with BD with and without Alzheimer’s disease (AD).
Method
209 older adults (79 with BD without dementia and 70 controls; 60 with AD, being 27 with BD) were included to evaluate the performance of three CDT scoring scales, beyond the Mini-Mental State Examination (MMSE) and verbal fluency (VFT).
Results
Patients with BD without dementia presented with lower scores in MMSE, VF and one CDT scoring scale than controls. Patients with BD and AD presented with lower scores in VF and CDT scoring scales than patients with only AD. All CDT scales presented similar sensitivity and specificity for BD and non-BD groups.
Conclusion
Elderly subjects with BD showed greater impairment in CDT in both groups of normal cognition and AD.
Clock Drawing Test; Alzheimer’s disease; bipolar disorder
Há dados limitados sobre o perfil cognitivo de idosos com transtorno bipolar (TAB) e demência. Previamente, testes de rastreio cognitivo comuns foram pouco estudados.
Objetivo
Investigar o Teste do Desenho do Relógio (CDT) entre idosos com TAB com e sem doença de Alzheimer (DA).
Método
Foram incluídos 209 idosos (79 pacientes com TAB sem demência e 70 controles; 60 indivíduos com DA leve, sendo 27 com TAB) para avaliar três escalas de pontuação do TDR, além do Mini-Mental State Examination (MMSE) e fluência verbal (FV).
Resultados
Pacientes com TAB sem demência apresentaram menores escores no MMSE, FV e uma escala de TDR que controles. Pacientes com TAB e DA apresentaram escores mais baixos na FV e em todos os TDR comparados aos apenas com DA. As escalas de CDT apresentaram sensibilidade e especificidade semelhantes para os grupos com e sem TAB.
Conclusão
Idosos com TAB apresentaram maior comprometimento no TDR em ambos grupos com cognição normal e DA.
Teste do Desenho do Relógio; doença de Alzheimer; transtorno bipolar
Cognitive deficits are a common feature of bipolar disorder (BD), particularly in older
adults11 Aprahamian I, Nunes PV, Forlenza OV. Cognitive impairment and
dementia in late-life bipolar disorder. Curr Opin Psychiatry. 2013;26(1):120-3.
http://dx.doi.org/10.1097/yco.0b013e32835ac5f6
https://doi.org/10.1097/yco.0b013e32835a...
,22 Forlenza OV, Aprahamian I. Cognitive impairment and dementia in
bipolar disorder. Front Biosci (Elite Ed). 2013;5(1):258-65.
http://dx.doi.org/10.2741/e613
https://doi.org/10.2741/e613...
. Meta-analytical data yielded executive
and verbal memory impairments as the most common cognitive deficits in BD patients
without dementia33 Robinson LJ, Ferrier IN. Evolution of cognitive impairment in
bipolar disorder: a systematic review of cross-sectional evidence. Bipolar
Disord. 2006;8(2):103-16.
http://dx.doi.org/10.1111/j.1399-5618.2006.00277.x
https://doi.org/10.1111/j.1399-5618.2006...
,44 Arts B, Jabben N, Krabbendam L, Os J. Meta-analyses of cognitive
functioning in euthymic bipolar patients and their first-degree relatives.
Psychol Med. 2008;38(6):771-85.
http://dx.doi.org/10.1017/s0033291707001675
https://doi.org/10.1017/s003329170700167...
. Cognitive functions such as attention,
visual memory, mental speed, language and, to a lesser extent, visuospatial function
were also implicated within the spectrum of cognitive dysfunction of these patients55 Martino DJ, Strejilevich SA, Scapola M, et al. Heterogeneity in
cognitive functioning among patients with bipolar disorder. J Affect Disord.
2008;109(1-2):149-56.
http://dx.doi.org/10.1016/j.jad.2007.12.232
https://doi.org/10.1016/j.jad.2007.12.23...
,66 Radanovic M, Nunes PV, Gattaz WF, Forlenza OV. Language impairment
in euthymic, elderly patients with bipolar disorder but no dementia. Int
Psychogeriatr. 2008;20(4):687-96.
http://dx.doi.org/10.1017/S1041610208007084
https://doi.org/10.1017/S104161020800708...
,77 Schouws SN, Stek ML, Comijs HC, Beekman AT. Risk factors for
cognitive impairment in elderly bipolar patients. J Affect Disord.
2010;125(1-3):330-5. 10.1016/j.jad.2009.12.004
https://doi.org/10.1016/j.jad.2009.12.00...
. Cognition seems to be similarly impaired in BD across the life
span88 Delaloye C, Moy G, Baudois S, Bilbao F, Remund CD, Hofer F et al.
Cognitive features in euthymic bipolar patients in old age. Bipolar Disord.
2009;11(7):735-43.
http://dx.doi.org/10.1111/j.1399-5618.2009.00741.x
https://doi.org/10.1111/j.1399-5618.2009...
, and geriatric BD patients
also show a similar pattern of widespread cognitive dysfunction99 Young RC, Murphy CF, Heo M, Schulberg HC, Alexopoulos GS. Cognitive
impairment in bipolar disorder in old age: literature review and findings in
manic patients. J Affect Disord. 2006;92(1):125-31.
http://dx.doi.org/10.1016/j.jad.2005.12.042
https://doi.org/10.1016/j.jad.2005.12.04...
. However, the severity of cognitive deficits was shown
to increase along with the duration of illness and a higher probability of detecting
cognitive deficits in BD is seen among patients with early-onset disease or with older
age1010 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(1):32-40.
10.1192/bjp.186.1.32
https://doi.org/10.1192/bjp.186.1.32...
.
BD in older adults is associated with increased risk of dementia in the long-term1111 Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for
Alzheimer's disease in elderly patients with bipolar disorder. Br J
Psychiatry. 2007;190(4):359-60. 10.1192/bjp.bp.106.029868
https://doi.org/10.1192/bjp.bp.106.02986...
,1212 Kessing LV, Søndergård L, Forman JL, Andersen PK. Lithium
treatment and risk of dementia. Arch Gen Psychiatry. 2008;65(11):1331-5.
http://dx.doi.org/10.1001/archpsyc.65.11.1331
https://doi.org/10.1001/archpsyc.65.11.1...
. Alzheimer’s disease (AD) seems to be the most
frequent phenotype among the demential syndromes developed by BD subjects22 Forlenza OV, Aprahamian I. Cognitive impairment and dementia in
bipolar disorder. Front Biosci (Elite Ed). 2013;5(1):258-65.
http://dx.doi.org/10.2741/e613
https://doi.org/10.2741/e613...
,1111 Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for
Alzheimer's disease in elderly patients with bipolar disorder. Br J
Psychiatry. 2007;190(4):359-60. 10.1192/bjp.bp.106.029868
https://doi.org/10.1192/bjp.bp.106.02986...
,1212 Kessing LV, Søndergård L, Forman JL, Andersen PK. Lithium
treatment and risk of dementia. Arch Gen Psychiatry. 2008;65(11):1331-5.
http://dx.doi.org/10.1001/archpsyc.65.11.1331
https://doi.org/10.1001/archpsyc.65.11.1...
. Nevertheless, there is limited data on the cognitive
profile of older adults with BD that present with dementia. Few studies compared the
cognitive performance of patients with BD to that of patients with conditions that
primarily affect cognition, such as AD1010 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(1):32-40.
10.1192/bjp.186.1.32
https://doi.org/10.1192/bjp.186.1.32...
,1313 Gildengers AG, Butters MA, Seligman K, McShea M, Miller MD, Mulsant
BH et al. Cognitive functioning in late-life bipolar disorder. Am J Psychiatry.
2004;161(4):736-8. http://dx.doi.org/10.1176/appi.ajp.161.4.736
https://doi.org/10.1176/appi.ajp.161.4.7...
,1414 O'Shea R, Poz R, Michael A, Berrios GE, Evans JJ, Rubinsztein
JS. Ecologically valid cognitive tests and everyday functioning in euthymic
bipolar disorder patients. J Affect Disord. 2010;125(1-3):336-40.
http://dx.doi.org/10.1016/j.jad.2009.12.012
https://doi.org/10.1016/j.jad.2009.12.01...
. In this matter, many questions remain along with the proper
screening, origin, evolution and impact of cognitive impairment and dementia in BD
patients11 Aprahamian I, Nunes PV, Forlenza OV. Cognitive impairment and
dementia in late-life bipolar disorder. Curr Opin Psychiatry. 2013;26(1):120-3.
http://dx.doi.org/10.1097/yco.0b013e32835ac5f6
https://doi.org/10.1097/yco.0b013e32835a...
,22 Forlenza OV, Aprahamian I. Cognitive impairment and dementia in
bipolar disorder. Front Biosci (Elite Ed). 2013;5(1):258-65.
http://dx.doi.org/10.2741/e613
https://doi.org/10.2741/e613...
.
Both neuropsychological and biological markers of cognitive impairment are required for
the early or better identification of those BD patients that will present a higher risk
for worsening or converting this cognitive dysfunction to dementia22 Forlenza OV, Aprahamian I. Cognitive impairment and dementia in
bipolar disorder. Front Biosci (Elite Ed). 2013;5(1):258-65.
http://dx.doi.org/10.2741/e613
https://doi.org/10.2741/e613...
. In the absence of these markers, the prompt
identification and follow-up knowledge of the neuropsychological deficits presented by
these patients are fundamental as long as cognitive impairment negatively affects
functional capacity and global prognosis, facilitating the evolution to dementia1515 Depp CA, Moore DJ, Sitzer D, Palmer BW, Eyler LT, Roesch S et al.
Neurocognitive impairment in middle-aged and older adults with bipolar disorder:
comparison to schizophrenia and normal comparison subjects. J Affect Disord.
2007;101(1-3):201-9.
http://dx.doi.org/10.1016/j.jad.2006.11.022
https://doi.org/10.1016/j.jad.2006.11.02...
. In the matter of the most
significant cognitive impairments presented by BD patients, the largest effect sizes
observed by two meta-analyses indicated that executive function and verbal memory are
the most relevant domains33 Robinson LJ, Ferrier IN. Evolution of cognitive impairment in
bipolar disorder: a systematic review of cross-sectional evidence. Bipolar
Disord. 2006;8(2):103-16.
http://dx.doi.org/10.1111/j.1399-5618.2006.00277.x
https://doi.org/10.1111/j.1399-5618.2006...
,44 Arts B, Jabben N, Krabbendam L, Os J. Meta-analyses of cognitive
functioning in euthymic bipolar patients and their first-degree relatives.
Psychol Med. 2008;38(6):771-85.
http://dx.doi.org/10.1017/s0033291707001675
https://doi.org/10.1017/s003329170700167...
.
Previous studies demonstrated that is possible to identify cognitive impairment in BD
patients using simple and fast cognitive tests77 Schouws SN, Stek ML, Comijs HC, Beekman AT. Risk factors for
cognitive impairment in elderly bipolar patients. J Affect Disord.
2010;125(1-3):330-5. 10.1016/j.jad.2009.12.004
https://doi.org/10.1016/j.jad.2009.12.00...
,1616 Tsai SY, Lee HC, Chen CC, Huang YL. Cognitive impairment in later
life in patients with early-onset bipolar disorder. Bipolar Disord.
2007;9(8):868-75.
http://dx.doi.org/10.1111/j.1399-5618.2007.00498.x
https://doi.org/10.1111/j.1399-5618.2007...
,1717 Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive
impairment in euthymic older adults with bipolar disorder: a controlled study
using cognitive screening tests. Am J Geriatr Psychiatry. 2014;22(4):389-97.
http://dx.doi.org/10.1016/j.jagp.2012.08.013
https://doi.org/10.1016/j.jagp.2012.08.0...
. However, executive function and verbal memory were not
thoroughly explored within these tests, specially comparing BD patients with and without
a primary neurodegenerative disease such as Alzheimer’s disease1717 Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive
impairment in euthymic older adults with bipolar disorder: a controlled study
using cognitive screening tests. Am J Geriatr Psychiatry. 2014;22(4):389-97.
http://dx.doi.org/10.1016/j.jagp.2012.08.013
https://doi.org/10.1016/j.jagp.2012.08.0...
. Additionally, recent evidence raised
questions over the presence of clinical differences in the performance of older BD
patients compared to controls in the Mini-Mental and Clock Drawing1818 Samamé C, Martino DJ, Strejilevich SA. A quantitative review of
neurocognition in euthymic late-life bipolar disorder. Bipolar Disord.
2013;15(6):633-44. http://dx.doi.org/10.1111/bdi.12077
https://doi.org/10.1111/bdi.12077...
.
The aim of this study was to better evaluate the performance of the Clock Drawing, a fast and simple test to evaluate general executive and visuospacial skills, in patients with BD in two different states of cognition, i.e. with and without probable dementia of Alzheimer’s disease.
METHOD
The present study was conducted at a university-based psychogeriatric clinic
(Institute of Psychiatry, University of Sao Paulo, Brazil), addressing a
cross-section evaluation of 209 older adults represented by middle-income,
community-dwelling individuals from the hospital catchment area. All patients
spontaneously sought our service by being a referral center for neuropsychiatric
diseases. The study group comprised 79 patients with BD and 70 controls, both
without dementia; 60 subjects with mild AD, being 27 with BD and 33 without the mood
disorder. The DSM-IV criteria were utilized for the diagnosis of BD and dementia.
The diagnosis of probable AD was made according to the NINCDS-ADRDA, and patients
with non-AD dementias were excluded from the study. Inclusion criteria for BD
patients were: (i) 60 years of age or more; and (ii) euthymic subjects for at least
one month prior to the evaluation, as assessed by clinical impression by a
psychiatrist and a maximum score of 7 in the 21-item Hamilton Rating Scale for
Depression, and of 4 in the Young Mania Rating Scale. All patients presented stable
clinical diseases. Exclusion criteria were illiteracy, mild cognitive impairment,
visual and hearing disabilities, evidence of previous traumatic brain injury, and
other relevant health conditions that could either affect cognition or limit the
administration of neuropsychological tests, including use of medications with
cognitive side effects such as benzodiazepines, opioids and anticholinergics.
Laboratory tests performed for all participants included blood count and
biochemistry, serum levels of glucose, thyroid hormones, folic acid and vitamin B12,
lipid profile and immunotests for syphilis. Neuroimaging scans (magnetic resonance)
were performed in all subjects. Detailed information about recruitment and
inclusion/exclusion criteria pertaining to this cohort can be found in previous
publications from our group1111 Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for
Alzheimer's disease in elderly patients with bipolar disorder. Br J
Psychiatry. 2007;190(4):359-60. 10.1192/bjp.bp.106.029868
https://doi.org/10.1192/bjp.bp.106.02986...
,1717 Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive
impairment in euthymic older adults with bipolar disorder: a controlled study
using cognitive screening tests. Am J Geriatr Psychiatry. 2014;22(4):389-97.
http://dx.doi.org/10.1016/j.jagp.2012.08.013
https://doi.org/10.1016/j.jagp.2012.08.0...
,1919 Aprahamian I, Diniz BS, Izbicki R, Radanovic M, Nunes PV, Forlenza
OV. Optimizing the CAMCOG test in the screening for mild cognitive impairment
and incipient dementia: saving time with relevant domains. Int J Geriatr
Psychiatry. 2011;26(4):403-8.
http://dx.doi.org/10.1002/gps.2540
https://doi.org/10.1002/gps.2540...
.
Participants were allocated in two major diagnostic groups according to their
cognitive status: mild probable dementia of AD type or without dementia. Diagnosis
of dementia was reached at multidisciplinary consensus meetings, taking into account
the available clinical, neuropsychological, laboratorial, and neuroimaging data, in
addition to information provided by a family member interview. The study protocol
comprised patient evaluation with the Brazilian version of the Cambridge Cognitive
Test (CAMCOG)1919 Aprahamian I, Diniz BS, Izbicki R, Radanovic M, Nunes PV, Forlenza
OV. Optimizing the CAMCOG test in the screening for mild cognitive impairment
and incipient dementia: saving time with relevant domains. Int J Geriatr
Psychiatry. 2011;26(4):403-8.
http://dx.doi.org/10.1002/gps.2540
https://doi.org/10.1002/gps.2540...
, which yields
scores for the Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT) and
Verbal Fluency Test (VFT) (semantic fluency with animal naming). Diagnosis was not
based on the CAMCOG score or any results from screening tests. The CDT was
additionally scored according to three well-known qualitative and quantitative
scales to evaluate executive skills (Shulman, Mendez and Sunderland scoring
systems)2020 Sunderland T, Hill JL, Mellow AM, et al. Clock Drawing in
Alzheimer’s disease. A novel measure of disease severity. J Am Geriatr
Soc. 1989;37(8):725-9.,2121 Mendez MF, Ala T, Underwood KL. Development of scoring criteria for
the clock drawing task in Alzheimer's disease. J Am Geriatr Soc.
1992;40(11):1095-9.,2222 Shulman KI, Gold DP, Cohen CA, Zucchero CA. Clock-drawing and
dementia in the community: A longitudinal study. Int J Geriatr Psychiatry.
1993;8(6):487-96. http://dx.doi.org/10.1002/gps.930080606
https://doi.org/10.1002/gps.930080606...
BD and non-BD patients were matched for age,
education level and cognition (taking into account the CAMCOG total score).
Statistical procedures were undertaken with the Statistical Package for the Social Sciences (SPSS), 18.0 version for Windows, and significance level was defined at 5% (p=0.05). Comparison groups were analyzed for age, education and CAMCOG total score. Categorical variables were analyzed with the Pearson’s Chi-squared test. Continuous variables were analyzed with the Mann-Whitney test. Receiver operating characteristic (ROC) curves area analyses were carried out to evaluate the best match between sensitivity and specificity according to the area under the curve obtained for each test, as well as derived cut-off scores, for the cognitive tests to evaluate the cognitive groups between BD and non-BD.
This study was approved by local Ethical Committee and all participants signed an informed consent.
RESULTS
Characteristics of the sample are presented in Tables 1 and 2, regarding the cognitive condition evaluated (with or without dementia).
Subjects without dementia
BD and non-BD patients did not differ regarding age and schooling; women predominated in the non-BD group. In the cognitive tests, there were not any differences between the groups in the CAMCOG, CDT by Shulman or CDT by Sunderland scores. The two groups differed in the MMSE, VF and the CDT by Mendez scores (Table 1).
Subjects with DAT
BD and non-BD patients did not differ regarding age and schooling and gender. Regarding cognitive tests, there were not any differences between the groups in the CAMCOG, and MMSE scores. The two groups differed in the VF, CDT by Shulman, CDT by Sunderland and CDT by Mendez scores (Table 2).
ROC curve analysis
Subjects without BD
The CAMCOG and the MMSE were the best tests to discriminate subjects with and without dementia. The VF, CDT by Sunderland and CDT by Mendez also showed good sensitivity and specificity in discriminating both groups (Table 3).
Pairwise comparison between ROC curves did not reveal any differences in accuracy between the CAMCOG and the MMSE (p=0.348), the VF and the CDT, regardless of the scoring method (p=0.486 for Shulman, p=0.911 for Sunderland, and p=0.806 for Mendez), and among different scoring methods for CDT (p=0.456 for Mendez vs. Shulman; p=0.466 for Mendez vs. Sunderland; p=0.172 for Shulman vs. Sunderland). The MMSE was more accurate in discriminating the groups than VF (p<0.001), CDT by Mendez (p=0.001), CDT by Shulman (p<0.001), and CDT by Sunderland (p=0.001).
Subjects with BD
The CAMCOG was the best test to discriminate subjects with and without dementia, followed by the MMSE. The VF, CDT by Shulman, CDT by Sunderland and CDT by Mendez also showed good sensitivity and specificity in discriminating both groups (Table 4).
Pairwise comparison between ROC curves did not reveal any differences in accuracy between the CAMCOG and the MMSE (p=0.320), the MMSE and VF (p=0.234), the MMSE and the CDT, regardless of the scoring method (p=0.071 for Shulman, p=0.100 for Sunderland, p=0.112 for Mendez), the VF and the CDT, regardless of the scoring method (p=0.350 for Shulman; p=0.482 for Sunderland, and p=0.444 for Mendez), and among different scoring methods for CDT (p=0.631 for Mendez vs. Shulman; p=0.601 for Mendez vs. Sunderland; p=0.253 for Shulman vs. Sunderland).
DISCUSSION
In this study, we evaluated BD versus non-BD subjects with and without probable AD.
We explored the performance of the CDT rated with three different scoring scales
commonly used for cognitive screening between these groups and we observed clinical
differences for BD subjects especially regarding their executive and visuospatial
function. We have previously observed with another sample that demented BD patients
had a significantly worse performance on the CDT as compared with patients with
dementia due to AD1717 Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive
impairment in euthymic older adults with bipolar disorder: a controlled study
using cognitive screening tests. Am J Geriatr Psychiatry. 2014;22(4):389-97.
http://dx.doi.org/10.1016/j.jagp.2012.08.013
https://doi.org/10.1016/j.jagp.2012.08.0...
. These
functions were impaired in both BD with and without dementia, being observed through
VF test and CDT. BD subjects without dementia did not performed as mild cognitive
impairment at neuropsychological evaluation, but showed lower scores in VF and CDT.
This finding is relevant to clinical practice regarding cognitive screening of BD
subjects to avoid a false positive result towards a dementia syndrome. It is worth
noting that global cognitive measures (CAMCOG and MMSE) remained without significant
difference between these two groups. In the group with BD and AD, the observed
deficits were naturally even worse especially regarding executive and visuospatial
abilities.
In a previous study of our group with a different sample, we evaluated BD subjects
without cognitive impairment (controls), with cognitive impairment no dementia
(CIND) or mild cognitive impairment (MCI) and dementia in a broader sense (including
subjects with possible AD, e.g. vascular dementia)1717 Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive
impairment in euthymic older adults with bipolar disorder: a controlled study
using cognitive screening tests. Am J Geriatr Psychiatry. 2014;22(4):389-97.
http://dx.doi.org/10.1016/j.jagp.2012.08.013
https://doi.org/10.1016/j.jagp.2012.08.0...
. In that study, we already found a
significant clinical difference in executive function among BD subjects compared to
healthy controls or those with dementia but without BD. However, subjects with very
mild cognitive decline, such as MCI or CIND, were not discriminated through
executive tasks, but presented a lower score at the MMSE. In the present study, we
used the CDT with three scoring scales to better evaluate both executive and
visuospatial tasks in another sample with and without BD in two cognitive states,
i.e. dementia of AD type and healthy cognitive controls. We excluded other possible
dementia etiologies such as vascular or even mixed vascular and AD.
In the present study, we observed that subjects with BD but without AD showed a lower
although not clinically significant MMSE score (27.1 vs. 27.9) and a worse
performance in executive and visuospatial tests such as the VF (14.9 vs. 18) and CDT
according to Mendez scoring system (17.3 vs. 18.2). These findings are consistent
with current evidence since non-demented BD subjects do not usually present a severe
cognitive impairment that could be identified by the MMSE, usually ranging between
0.2 to 1.0 standard deviations below the respective norms during neuropsychological
evaluation33 Robinson LJ, Ferrier IN. Evolution of cognitive impairment in
bipolar disorder: a systematic review of cross-sectional evidence. Bipolar
Disord. 2006;8(2):103-16.
http://dx.doi.org/10.1111/j.1399-5618.2006.00277.x
https://doi.org/10.1111/j.1399-5618.2006...
,1010 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(1):32-40.
10.1192/bjp.186.1.32
https://doi.org/10.1192/bjp.186.1.32...
. Additionally, previous published
studies conducted in samples of non-demented young adults and elderly patients with
BD showed very small differences (less than 1 point) in the MMSE score1010 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(1):32-40.
10.1192/bjp.186.1.32
https://doi.org/10.1192/bjp.186.1.32...
,1313 Gildengers AG, Butters MA, Seligman K, McShea M, Miller MD, Mulsant
BH et al. Cognitive functioning in late-life bipolar disorder. Am J Psychiatry.
2004;161(4):736-8. http://dx.doi.org/10.1176/appi.ajp.161.4.736
https://doi.org/10.1176/appi.ajp.161.4.7...
,2323 Rubinsztein JS, Michael A, Paykel E, Sahakian B. Cognitive
impairment in remission in bipolar affective disorder. Psychol Med.
2000;30(5):1025-36. http://dx.doi.org/10.1017/s0033291799002664
https://doi.org/10.1017/s003329179900266...
. Although statistically significant, the clinical
meaning of these differences remains uncertain. Furthermore, most relevant cognitive
domains affected in BD subjects are verbal memory and executive function. This
latter can be better pointed out by brief tests such as the VF and CDT than the
MMSE. CDT scales have different scoring protocols and had never been compared
between each other among BD subjects. CDT scoring scales have different levels of
complexity to evaluate the test through more qualitative (as in Shulman scale) or
quantitative (as in Mendez and Sunderland) analysis. Although these scales appear to
have similar accuracy according to the literature, more complex and detailed scales
such as Mendez are prone to detect more subtle deficits2121 Mendez MF, Ala T, Underwood KL. Development of scoring criteria for
the clock drawing task in Alzheimer's disease. J Am Geriatr Soc.
1992;40(11):1095-9..
When AD subjects with BD were compared to those without BD but with this type of
dementia, cognitive deficits observed among the group without AD were more
pronounced. Subjects with BD and AD presented a significant decline in VF (7.8 vs.
10.8) and in all three CDT scoring scales. It is worth noting that global cognitive
measures (CAMCOG and MMSE) remained without significant difference between these two
groups. Global cognitive measures do not appear to present a significant different
between euthymic BD and non-BD control groups according to a recently published
metanalysis with late-life BD patients1818 Samamé C, Martino DJ, Strejilevich SA. A quantitative review of
neurocognition in euthymic late-life bipolar disorder. Bipolar Disord.
2013;15(6):633-44. http://dx.doi.org/10.1111/bdi.12077
https://doi.org/10.1111/bdi.12077...
. Previous studies evaluating verbal fluency in adults with
BD produced inconsistent results. Four of these studies reported some degree of
impairment in euthymic BD subjects66 Radanovic M, Nunes PV, Gattaz WF, Forlenza OV. Language impairment
in euthymic, elderly patients with bipolar disorder but no dementia. Int
Psychogeriatr. 2008;20(4):687-96.
http://dx.doi.org/10.1017/S1041610208007084
https://doi.org/10.1017/S104161020800708...
,88 Delaloye C, Moy G, Baudois S, Bilbao F, Remund CD, Hofer F et al.
Cognitive features in euthymic bipolar patients in old age. Bipolar Disord.
2009;11(7):735-43.
http://dx.doi.org/10.1111/j.1399-5618.2009.00741.x
https://doi.org/10.1111/j.1399-5618.2009...
,2424 Clark L, Iversen SD, Goodwin GM. Sustained attention deficit in
bipolar disorder. Br J Psychiatry. 2002;180(4):313-9.
10.1192/bjp.180.4.313
https://doi.org/10.1192/bjp.180.4.313...
,2525 Dixon T, Kravariti E, Frith C, Murray R M, McGuire PK. Effect of
symptoms on executive function in bipolar illness. Psychol Med.
2004;34(5):811-21. http://dx.doi.org/10.1017/s0033291703001570
https://doi.org/10.1017/s003329170300157...
, whereas four other studies did not report any clinically
significant difference between BD subjects and healthy controls2626 Cavanagh JTO, Van Beck M, Muir W, Blackwood DHR. Case-control study
of neurocognitive function in euthymic patients with bipolar disorder: an
association with mania. Br J Psychiatry. 2002;180(4):320-6.
http://dx.doi.org/10.1192/bjp.180.4.320
https://doi.org/10.1192/bjp.180.4.320...
,2727 Martinez-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(2):262-70.
http://dx.doi.org/10.1176/appi.ajp.161.2.262
https://doi.org/10.1176/appi.ajp.161.2.2...
,2828 Matsuo K, Kouno T, Hatch JP, Seino K, Ohtani T, Kato N et al. A
near-infrared spectroscopy study of prefrontal cortex activation during a verbal
fluency task and carbon dioxide inhalation in individuals with bipolar disorder.
Bipolar Disord. 2007;9(8):876-83.
http://dx.doi.org/10.1111/j.1399-5618.2007.00473.x
https://doi.org/10.1111/j.1399-5618.2007...
,2929 Bora E, Vahip S, Akdeniz F. The role and importance of cognitive
symptoms in bipolar disorders. Turk Psikiyatri Derg.
2008;19(1):81-93.,3030 Gildengers AG, Mulsant BH, Begley A, Mazumdar S, Hyams AV, Reynolds
III CF et al. The longitudinal course of cognition in older adults with bipolar
disorder. Bipolar Disord. 2009;11(7):744-52.
http://dx.doi.org/10.1111/j.1399-5618.2009.00739.x
https://doi.org/10.1111/j.1399-5618.2009...
.
On the other hand, studies exploring the performance of the CDT among BD subjects are
sparse. In one study with a small sample of early and late-onset BD patients, CDT
was scored according to Shulman scale1616 Tsai SY, Lee HC, Chen CC, Huang YL. Cognitive impairment in later
life in patients with early-onset bipolar disorder. Bipolar Disord.
2007;9(8):868-75.
http://dx.doi.org/10.1111/j.1399-5618.2007.00498.x
https://doi.org/10.1111/j.1399-5618.2007...
. CDT was abnormal in 42.3% of the total sample, in which
36.5% were from the early-onset group and 50% from subjects with onset between 40
and 50 years old. However, this study lacked a comparison group. Another study
evaluated the CDT between BD subjects and healthy matched controls according to the
scale of Rouleau et al.2929 Bora E, Vahip S, Akdeniz F. The role and importance of cognitive
symptoms in bipolar disorders. Turk Psikiyatri Derg.
2008;19(1):81-93.. The
authors did not find a significant difference between these groups. Our previous
study evaluated the CDT according only to Shulman scale between BD and non-BD
patients with normal cognition, CIND/MCI and dementia (possible and probable
AD)1717 Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive
impairment in euthymic older adults with bipolar disorder: a controlled study
using cognitive screening tests. Am J Geriatr Psychiatry. 2014;22(4):389-97.
http://dx.doi.org/10.1016/j.jagp.2012.08.013
https://doi.org/10.1016/j.jagp.2012.08.0...
. We found a significant
difference only between BD and non-BD subjects with dementia, in which the CDT was
more impaired among BD group. In a broader sense, CDT may detect a more pronounced
executive dysfunction among BD subjects, only clinically detected in more
cognitively compromised patients.
In a qualitative analysis (data not shown) of the CDT from BD compared to non-BD subjects without dementia, observed errors in clock drawings involved time indication, especially positioning the right minute hand. The discrimination between these two groups required a more complex and quantitative scale (Mendez). When patients with dementia were evaluated, both conceptual (e.g. inaccurate time setting, missing numbers, number substitutions) and visuospatial errors (e.g. numbers distribution, distance between the numbers) on the CDT were observed. All three scales could discriminate between the two groups (BD vs. non-BD). However, there were not typical errors within the BD group, but instead, a global impairment especially regarding visuospatial organization, that was more severe than that observed from the non-BD group.
Global cognitive measures such as the MMSE and the CAMCOG presented a higher
sensitivity and specificity in subjects without BD. In the group of BD subjects, VF
test showed a clinically relevant increase in sensitivity (from 74.3 to 88.9%) and
specificity (from 75.3 to 82.3%), which is in agreement with the expected more
common executive dysfunction among these subjects33 Robinson LJ, Ferrier IN. Evolution of cognitive impairment in
bipolar disorder: a systematic review of cross-sectional evidence. Bipolar
Disord. 2006;8(2):103-16.
http://dx.doi.org/10.1111/j.1399-5618.2006.00277.x
https://doi.org/10.1111/j.1399-5618.2006...
,1010 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(1):32-40.
10.1192/bjp.186.1.32
https://doi.org/10.1192/bjp.186.1.32...
,1818 Samamé C, Martino DJ, Strejilevich SA. A quantitative review of
neurocognition in euthymic late-life bipolar disorder. Bipolar Disord.
2013;15(6):633-44. http://dx.doi.org/10.1111/bdi.12077
https://doi.org/10.1111/bdi.12077...
. However, CDT did not present a higher accuracy as
expected among BD subjects. All three CDT scoring systems remained with a similar
accuracy between the two groups, although two of the scoring systems (Shulman and
Sunderland) showed a higher sensitivity among BD subjects.
Potential limitations of our study must be addressed. The study had a transversal
design and the samples with and without dementia cannot be directly compared. Our
study was not controlled for the potentially deleterious effects of the short and
long-term use of psychotropic drugs on cognition. This is a frequent and special
concern among BD patients although few studies reported a correlation between
medication use and cognitive performance. Previously, a study observed a negative
influence over verbal memory by mood stabilizers and impairments in psychomotor
speed, attention, and executive function with the use of benzodiazepines55 Martino DJ, Strejilevich SA, Scapola M, et al. Heterogeneity in
cognitive functioning among patients with bipolar disorder. J Affect Disord.
2008;109(1-2):149-56.
http://dx.doi.org/10.1016/j.jad.2007.12.232
https://doi.org/10.1016/j.jad.2007.12.23...
. However, another study did not
find any correlation with a particular class of medication77 Schouws SN, Stek ML, Comijs HC, Beekman AT. Risk factors for
cognitive impairment in elderly bipolar patients. J Affect Disord.
2010;125(1-3):330-5. 10.1016/j.jad.2009.12.004
https://doi.org/10.1016/j.jad.2009.12.00...
. In a previous study of our group, we observed that
valproate was the only drug associated with a negative effect on verbal fluency
among patients with dementia1717 Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive
impairment in euthymic older adults with bipolar disorder: a controlled study
using cognitive screening tests. Am J Geriatr Psychiatry. 2014;22(4):389-97.
http://dx.doi.org/10.1016/j.jagp.2012.08.013
https://doi.org/10.1016/j.jagp.2012.08.0...
.
Cognitive impairment is a common clinical problem associated with BD patients, even
in euthymic periods. In spite of a presumed stability of the cognitive impairment
among the majority of patients through their life span, these deficits seems
clinically important interfering negatively in functional capacity and exerting a
negative effect on the global prognosis of these patients1515 Depp CA, Moore DJ, Sitzer D, Palmer BW, Eyler LT, Roesch S et al.
Neurocognitive impairment in middle-aged and older adults with bipolar disorder:
comparison to schizophrenia and normal comparison subjects. J Affect Disord.
2007;101(1-3):201-9.
http://dx.doi.org/10.1016/j.jad.2006.11.022
https://doi.org/10.1016/j.jad.2006.11.02...
. Additionally, the characterization and follow-up
of these cognitive deficits are relevant since the risk to develop dementia among BD
patients is almost three times higher especially among older patients, when compared
to non-BD age-matched population1111 Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for
Alzheimer's disease in elderly patients with bipolar disorder. Br J
Psychiatry. 2007;190(4):359-60. 10.1192/bjp.bp.106.029868
https://doi.org/10.1192/bjp.bp.106.02986...
,1212 Kessing LV, Søndergård L, Forman JL, Andersen PK. Lithium
treatment and risk of dementia. Arch Gen Psychiatry. 2008;65(11):1331-5.
http://dx.doi.org/10.1001/archpsyc.65.11.1331
https://doi.org/10.1001/archpsyc.65.11.1...
,3030 Gildengers AG, Mulsant BH, Begley A, Mazumdar S, Hyams AV, Reynolds
III CF et al. The longitudinal course of cognition in older adults with bipolar
disorder. Bipolar Disord. 2009;11(7):744-52.
http://dx.doi.org/10.1111/j.1399-5618.2009.00739.x
https://doi.org/10.1111/j.1399-5618.2009...
. In this matter, the identification of cognitive
impairments cannot only rely on neuropsychological evaluation because of cost and
time consuming, and the utilization of brief and common tests such as the CDT are of
utmost interest.
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» https://doi.org/10.1016/j.jagp.2012.08.013 -
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» https://doi.org/10.1111/bdi.12077 -
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» https://doi.org/10.1192/bjp.180.4.313 -
25Dixon T, Kravariti E, Frith C, Murray R M, McGuire PK. Effect of symptoms on executive function in bipolar illness. Psychol Med. 2004;34(5):811-21. http://dx.doi.org/10.1017/s0033291703001570
» https://doi.org/10.1017/s0033291703001570 -
26Cavanagh JTO, Van Beck M, Muir W, Blackwood DHR. Case-control study of neurocognitive function in euthymic patients with bipolar disorder: an association with mania. Br J Psychiatry. 2002;180(4):320-6. http://dx.doi.org/10.1192/bjp.180.4.320
» https://doi.org/10.1192/bjp.180.4.320 -
27Martinez-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(2):262-70. http://dx.doi.org/10.1176/appi.ajp.161.2.262
» https://doi.org/10.1176/appi.ajp.161.2.262 -
28Matsuo K, Kouno T, Hatch JP, Seino K, Ohtani T, Kato N et al. A near-infrared spectroscopy study of prefrontal cortex activation during a verbal fluency task and carbon dioxide inhalation in individuals with bipolar disorder. Bipolar Disord. 2007;9(8):876-83. http://dx.doi.org/10.1111/j.1399-5618.2007.00473.x
» https://doi.org/10.1111/j.1399-5618.2007.00473.x -
29Bora E, Vahip S, Akdeniz F. The role and importance of cognitive symptoms in bipolar disorders. Turk Psikiyatri Derg. 2008;19(1):81-93.
-
30Gildengers AG, Mulsant BH, Begley A, Mazumdar S, Hyams AV, Reynolds III CF et al. The longitudinal course of cognition in older adults with bipolar disorder. Bipolar Disord. 2009;11(7):744-52. http://dx.doi.org/10.1111/j.1399-5618.2009.00739.x
» https://doi.org/10.1111/j.1399-5618.2009.00739.x
-
Support: The Laboratory of Neuroscience (LIM-27) receives financial support from Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS) and from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
Publication Dates
-
Publication in this collection
02 Dec 2014 -
Date of issue
Dec 2014
History
-
Received
13 May 2014 -
Reviewed
01 Aug 2014 -
Accepted
20 Aug 2014