An increasing number of studies have detected cognitive impairments in patients with bipolar disorders not only during acute phase but also during euthymic periods.¹ Broad cognitive impairments were present even in early phase of illness² and in unaffected relatives³ as well, suggesting that certain domains of cognitive deficits may be a potential endophenotype. According to a recent meta-analysis,¹ the largest effect sizes were noted for executive functions and verbal memory. However, it is still unclear whether these impairments reflect multiple independent cognitive deficits or a single fundamental cognitive deficit.

Performances on formal memory tests can be affected by executive functions. Ability to cluster semantically related words into a category or to organize visual information into a meaningful perceptual unit during learning enhances its subsequent recall from memory. For example, patients with fronto-striatal pathology, such as Huntington's disease and Parkinson's disease, are characterized by deficits in free recall that are not related to deficits in storing information but associated to deficits in the organization of information to be remembered.⁴ Likewise, psychiatric patients with obsessive-compulsive disorder (OCD)^5-8 or schizophrenia,⁹ that are known to be related to fronto-striatal dysfunction as well, have shown deficits in organizational strategies causing impaired memory performances. In bipolar disorders, there is inconsistent evidence for fronto-striatal dysfunction. These circuits seem to be spared in volumetric studies.¹⁰ However, contrarily to volumetric findings, the ventrolateral prefrontal and striatal regions showed abnormal activation in functional studies.¹¹ Therefore, investigating the effect of organizational strategy on recall could provide important insights into the pathophysiology of bipolar disorders.

In previous studies, deficits in verbal memory in bipolar disorder were not associated to semantic clustering¹² and were mediated to a lesser extent by organizational strategies compared to OCD,⁷ suggesting a primary deficit in encoding of verbal information. On the other hand, deficits in visual memory in patients with BD I were mediated by poor use of organizational strategies.¹³ A paucity of research on these relationships limits generalization of findings. Furthermore, these studies investigated patients with BD I^7,13 or a mixed sample of patients with BD I or bipolar II disorder (BD II).¹² To our knowledge, there has been no study to investigate the mediating effect of strategies on memory performances in BD II.

The clinical course of BD II is distinct from that of BD I.^14-16 Genetic and neuroimaging findings also suggest differences between BD I and BD II.^17-20 Regarding cognitive functions of patients with BD II, there is inconsistent evidence for verbal memory and executive functions.^21-24 In our previous volumetric and diffusion tensor imaging studies,^19,20 structural brain abnormalities in anterior limbic circuits were common in both subtypes of bipolar disorder, while BD I was characterized by further involvement of the frontal and temporal regions. Therefore, cognitive deficits in BD I would be greater or broader than those in BD II. In accordance with this hypothesis, we found that semantic organization in BD I was poorer than that in BD II.²⁵

The purpose of the current study was to compare verbal and visual memory performances between BD I and BD II and to determine whether, if present, memory deficits in BD I and BD II were mediated by organizational strategies. Based on our previous findings, we hypothesized that memory deficits would be greater in BD I than in BD II and that the mediating effect of strategies on memory deficits would be evident in BD I.

The main finding of this study is that verbal and visual memory was impaired in both BD I and BD II groups and that deficits in organizational strategies had only a partial mediating effect on memory deficits in BD I and BD II. The deficit in verbal memory was partly mediated by difficulties in Semantic Clustering in both subtypes, whereas the mediating effect of difficulties in Organization on the visual memory deficit was present only in BD I. To our knowledge, this is the first study to explore the relationships between memory performances and strategies during encoding in BD II.

The profile of performances in BD I in this study was consistent with previous reports.¹ Regardless of the information modality, the effect sizes of impairments in delayed recall were large in BD I. However, the effect sizes of Semantic Clustering and Organization were medium. Although the mediating effects of deficits in these strategies were significant, differences in verbal and visual recall between the BD I and control groups remained still significant. These findings are consistent with a previous study⁷ that has reported a weaker mediating effect of difficulties in Semantic Clustering between BD I patients and controls than that between OCD patients and controls. This suggests that patients with BD I have verbal memory problems that are not fully attributable to a failure in organizational strategies. Regarding visual memory impairment, our results showed similar findings to verbal memory impairment. Deckersbach et al.¹³ however, has reported that differences in ROCF Delayed Free Recall between BD I patients and controls did not remain significant when effects of lower organization were partialled out, which is inconsistent with our findings on visual memory impairment. One possible reason for these different findings may be explained by the sample characteristics. The patients in their study, compared to our sample, had an older age (39.9 vs. 32.1 years), earlier age at onset (16.9 vs. 22.1 years) and longer duration of illness (22.6 years vs. 10.1 years), and were euthymic. Progression of illness or a subtype with an earlier onset might have potentiated deficits in executive functions and caused increased mediating effects of executive dysfunctions on visual memory impairment. In their additional analyses, the number of mood episodes was found to be negatively correlated with Organization, which supports this tentative hypothesis. In our results, onset age was negatively correlated to ROCF Delayed Recall as well. Nevertheless, our data have a strength over previous ones in that measures of the K-CVLT and ROCF were obtained from the same sample and yielded results of similar pattern. Whether deficits in organization strategies for different information modalities would differently mediate memory impairment remains as an open question and needs further research.

The performances on verbal memory in patients with BD II and their medium effect sizes are quite consistent with previous reports.^21,23,24,35 Among 5 studies that investigated verbal memory functions in BD II, only one study²² has reported negative findings. Meanwhile, visual memory in BD II was explored in a previous study²¹ in which the ROCF performance was impaired as well. Taken together, memory impairments with medium effect sizes are evident in BD II. However, none of previous studies on BD II presented organizational strategies, making it difficult to compare our results to previous ones. In the current study, K-CVLT Semantic Clustering was lower in patients with BD II compared to controls, whereas ROCF Organization was not impaired in BD II. In a multiple regression analysis for verbal memory impairment in BD II, difficulties in Semantic Clustering partly mediated the impairment of free recall, and differences in Long-Delayed Free Recall between patients and controls remained still significant in a mediated model. This pattern is exactly similar to the case of BD I. Therefore, our results suggest that verbal memory impairment may be one of the fundamental cognitive deficits in bipolar disorders and that executive dysfunctions can exert an additional influence on memory impairments. The extent to which executive dysfunctions may have an additional effect on memory performances may differ across subtypes of bipolar illness, clinical characteristics and information modalities. One of such an example may be the absence of mediating effects of difficulties in ROCF Organization in patients with BD II on ROCF delayed recall impairment for visual information. To explore these subtle effects in BD II, we may need a larger or well-controlled sample.

Torres et al.² found core cognitive deficits that were present at illness onset and suggested that these deficits were not exclusively attributable to illness progression, which also supports our hypothesis that memory impairments are a fundamental deficit in bipolar disorder. In their comparison of the magnitude of cognitive impairments in first-episode patients with that of previously published multi-episode patients, deficits in executive function and verbal memory were smaller in first-episode.² Therefore, deficits in memory and executive functions may worsen further with advancing illness course, possibly due to the toxic effects of recurrent episodes or oxidative stress on brain. We suggest that those memory and executive impairments may worsen reciprocally in advances stages of illness and the role or degree of executive impairments may vary across the clinical spectrum.

Generally, effect sizes of memory impairments in BD I were larger than those in BD II, which is consistent with our prior hypotheses. Furthermore, the percent of variance for which a path analytic model accounted was larger in BD I than in BD II. Whether this different pattern is associated with the involvement of distinct neural networks remains elusive. In future research, we need to investigate whether the differences in cognitive and neurobiological measures between BD I and BD II are quantitative or qualitative and how they relate to each others to deepen understanding the pathophysiology of bipolar disorders.

This study has some limitations. First, the three groups were not completely matched for demographic and clinical variables. Particularly, the estimated IQ was different among the groups, which might have exerted a potential confounding effect on group differences in memory measures. However, in additional analyses, the IQ was not correlated with any of memory performances in each of the three groups, and thus could not mediate the group differences in memory measures. And we found very similar group differences in memory performances when introducing the IQ as a covariate. Because we estimated IQ by a short-version of the WAIS-R, the group differences in IQ might have been inaccurately exaggerated. Second, all subjects except two were taking medications and patients with BD I were taking lithium or antipsychotics more frequently than patients BD II. Although the daily doses of each medication were not different between two patients groups, potential medication effects on cognitive functions could not be excluded. Third, the sample consisted of heterogeneous patients with regard to clinical features. Approximately one third of patients were in a depressive episode and two thirds were euthymic. However, the ratio of depressives was not different between the two patients groups, and host-hoc comparisons did not reveal any differences in memory measures between patients in a depressive episode and euthymic patients in each group. Furthermore, group comparisons of only euthymic patients revealed the same profile of cognitive impairments and the same relationship of memory and organization strategies. Therefore, different mood states of our sample could not weaken our findings. Patients with psychiatric comorbid conditions were not excluded. Again, these comorbidity did not have an effect on memory measures in each group and on group differences in post-hoc analyses. Regarding chronicity and comorbidity, we need further investigation using a more homogeneous sample. Third, clinical symptoms and their severities that had been measured using ratings scales were not available in a significant proportion of subjects, and we stratified mood states according to clinical interview and CGI-BP score. Despite these limitations, the present study, using a decent number of subjects, showed memory impairments in bipolar disorders that were not fully attributable to poor organizational strategies. Strengths of this study include concurrent investigation of verbal and visual memory performances from the same sample and a high generalizability due to the broad inclusion criteria.

In conclusion, verbal and visual memory impairments were evident not only in BD I but also in BD II. Impaired recall of verbal materials in bipolar disorders was influenced by but not fully mediated by organizational strategies.