Cognitive impairment in bipolar disorder in comparison to mild cognitive impairment and dementia: a systematic review

Abstract Objective To conduct a systematic review to describe cognitive abilities in bipolar disorder (BD) in comparison to cognitive abilities in mild cognitive impairment (MCI) and dementia. Methods A literature search was performed with no year or language restrictions. The search yielded 1,461 articles, with 1,261 remaining after removal of duplicates, five of which were suitable for the systematic review: two for the comparison between BD and MCI and three comparing BD and dementia. Results Analyses from our systematic review showed that euthymic individuals with BD present impairments in cognitive domains such as attention and executive functioning, motor skills, conceptual thinking, and visuo-spatial abilities that are equally severe as or more severe than the impairments observed in individuals with MCI. In contrast, studies comparing BD and dementia indicated that Alzheimer’s disease (AD) dementia and behavioral variant frontotemporal dementia (bvFTD) both showed greater cognitive deficits than BD during euthymia, whereas BD during a mood episode demonstrated higher cognitive impairments than bvFTD. Conclusion Findings from our systematic review suggest that cognitive impairments in euthymic BD fall into a range between the impairments seen in MCI and those seen in dementia. More studies are needed to analyze these comparisons, while also focusing on comparing different clinical stages of BD with MCI and dementia to analyze the progression of the clinical course and cognitive dysfunction in BD.PROSPERO registration ID: CRD42020150412


Introduction
Bipolar disorder (BD) is a chronic and recurrent disorder characterized by episodes of mood oscillation. 1 The lifetime prevalence ranges from 0.4 to 2.4% worldwide, varying according to the subtype of the disorder. 2 BD is known to affect individuals' overall functioning and quality of life. [3][4][5][6] Additionally, a subset of patients with BD experience neurocognitive impairment. 3,6 Many features, such as the number and length of mood episodes, childhood trauma, and severity of manic and depressive symptoms can influence the cognitive abilities of individuals with BD. 6 These deficits are present in several cognitive domains, such as attention, verbal learning, mental flexibility, and memory. 7,8 Cognitive dysfunction has become a recognized feature of BD, evident across all mood states of the disorder. 9,10 Although it is hard to estimate the prevalence of cognitive impairments in individuals with BD, a study by Douglas et al. 11 suggested that 64.4% of patients with BD during a depressive episode, and 57.1% of euthymic individuals with BD demonstrate impairments across one or more cognitive domains. Differences in cognitive abilities between BD and healthy individuals are noticeable and widely reported, [12][13][14]  to other cognitive disorders. The association between BD and dementia due to the development of cognitive symptoms in BD has raised significant concerns. 17 One of the largest studies of BD and dementia found that the rate of admission for dementia among individuals with BD increased by 6% with each additional mood episode that they experienced in their lifetime. 18 There are also reports implying that a previous diagnosis of BD increases the risk of a dementia diagnosis by 2.36 times, 17,19 and a more recent meta-analysis reported individuals with BD to be 2.96 times more likely to develop dementia in comparison to controls. 20 These findings suggest that a diagnosis of BD is a serious risk factor for dementia.
Furthermore, an intriguing comparison that has not been extensively studied is cognitive performance in BD relative to mild cognitive impairment (MCI). MCI is another cognitive disorder that has a wide range of types and severity of cognitive impairments, but MCI is typically regarded as a less severe cognitive disorder than dementia. 21 Similar to BD, individuals with MCI are at risk of potentially developing dementia as their cognitive symptoms worsen over time. 22,23 There have been some further similarities reported between cognitive impairments in BD and MCI, 24   We used the following inclusion criteria to determine whether an article was relevant to our study: the study should 1) present original data, 2) include patients with BD, 3) and compare them to subjects with MCI or dementia, 4) with regards to cognitive complaints/ cognitive performance. The exclusion criteria were 1) reviews, 2) meta-analyses, and 3) case-reports.
The studies were selected by two blinded reviewers (MS and AM) who determined if studies met the inclusion criteria. Articles were assessed independently by both raters and disagreements were resolved by consensus in a meeting with a third researcher (TAC).
First the raters screened articles based on their titles and abstracts and then they screened articles selected as relevant by reading the full text. Duplicates, review articles, and articles that did not fulfill the inclusion criteria were excluded.

Data extraction
Two researchers (MS and AM) conducted the data extraction process. The following data were extracted: authorship, year of publication, journal, country, aim Full-text articles excluded (n = 5) 3 studies were poster presentations (not full studies), 1 study contained the same sample of patients as another study, and 1 study did not have data on a specific BD group (generalized as affective disorders) Records after duplicates removed (n = 1,261) Records identified through Embase (n = 391) of the study, population included in the study, study design, assessments, and main results of the study.
All cognitive domains were included in extraction and analysis, provided they were assessed using valid cognitive tests.

Quality assessment
Each manuscript included in the review was independently assessed by two blinded researchers (MS and AM) using the Newcastle-Ottawa Quality Assessment Scale (NOQAS). 25 Disagreements were resolved by consensus in a meeting with a third researcher (TAC).

Results
The literature search yielded 1,461 articles. Once duplicates had been removed, 1,261 papers remained.
We excluded 1,251 studies based on the titles and abstracts and another five articles based on fulltext screening. Additionally, we hand-searched the references of the studies included from the database searches and found one additional study that fit the inclusion criteria. This resulted in a final total of five studies to be included in the systematic review. Figure  Characteristics of studies included

Quality assessments of the included studies
Each study included in this review was examined and critically appraised using the adapted NOQAS for cross-sectional studies. 25 Results are shown in Table 2.
The maximum score on the scale for cross-sectional studies is 10 and the scores of the studies included ranged from 9 to 10, with a mean score of 9.4. All five of the studies included were rated as high quality.

Cognitive performance between bipolar disorder and mild cognitive impairment
Two studies assessed cognitive performance between BD and MCI 24,28 and the main results showed that BD subjects demonstrated greater cognitive impairment than MCI subjects, especially in the following specific areas: attention, 24,28 motor initiative, 24,28 conceptual thinking, 24 calculation, 24 and visual-spatial abilities. 28 On the other hand, MCI subjects were significantly more impaired in tests of immediate and delayed recall (logical memory) 17 than individuals with BD.
Silva et al. 24   in BD was also assessed. There were no differences in neurocognitive performance between patients with BD on mood stabilizer monotherapy, neuroleptic monotherapy, or polypharmacy.

Cognitive performance between bipolar disorder and dementia
We included three studies assessing cognitive performance between BD and dementia. 26,27,29 Two out of the three studies included compared BD to bvFTD, 26,27 while one study compared euthymic BD to AD. 29   The BD-CIND group performed significantly better than the AD group on all the assessments in this comparison, with the exception of the CDT, for which we did not find any differences between the groups.
In addition, patients with BD were taking lithium

Discussion
Findings from our systematic review indicate more severe cognitive deficits in euthymic BD relative to MCI, but less severe than deficits observed in dementia. to MCI. 24 The second study, conducted by Osher et al., 28 suggested more severe deficits in visuo-spatial processing in euthymic BD relative to MCI. These are very intriguing findings, considering these domains may not be closely investigated in common diagnostic assessments. In contrast, the study conducted by Silva et al. 24 suggested more severe deficits in logical memory (immediate and delayed recall) in MCI in comparison to BD, which is one of the hallmark symptoms of dementia.
Regarding other cognitive domains examined in these studies, there were no differences between BD and MCI in language or verbal functioning, indicating similar abilities between these two diagnostic groups.

Comparison between bipolar disorder and dementia
As expected, we also found that older adults with dementia demonstrated significantly greater cognitive deficits than in BD subjects in euthymia in general cognitive assessments, such as the CAMCOG and MMSE, as well as in specific assessments of verbal fluency, executive function, attention, working memory, and theory of mind. 26,29 Findings from these examinations imply that major cognitive domains are not affected in euthymic BD to the extent seen in different types of dementia (bvFTD and AD). However, an intriguing observation from the Aprahamian et al. 29 study is the similarity in scores on the CDT between the cognitively impaired BD group and the AD subjects.
The CDT is a widely used screening tool for dementia and for detection of cognitive decline. 34,35 The similarity of scores in this comparison could hint at progressive cognitive decline in BD towards the levels of impairment seen in AD.
In contrast, in the study by Vijverberg et al.,27 subjects with BD who were currently experiencing either a manic or depressive episode demonstrated greater impairments in attention, memory, verbal learning, and executive function, compared to the group of people with bvFTD. 27 It is interesting to note the difference in cognitive performances in BD during a mood episode and euthymia, relative to cognition in bvFTD. Frontotemporal dementia is far less common than AD, with more than half of affected individuals experiencing behavioral changes such as interpersonal skills, executive dysfunction, and emotional dysregulation. 36 Findings from this systematic review suggest that the severity of cognitive impairments in bvFTD ranges between those seen in euthymic BD and in BD during a mood episode.
Further investigations should be conducted analyzing the similarities and differences in this fairly new cognitive comparison between BD and bvFTD.
The differences in cognitive performance in BD during euthymia and an acute mood episode have previously been observed in several studies. 12

Limitations and strengths
The findings reported in this review should be