Executive dysfunction and cognitive subgroups in a large sample of euthymic patients with bipolar disorder

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Abstract

Bipolar disorder (BP), at the group level, is associated with significant but modest cognitive deficits, including executive dysfunction. Among executive functions, response inhibition deficits have been suggested to be particularly relevant to BP. However, BP is associated with significant heterogeneity in neurocognitive performance and level of functioning. Very few studies have investigated neurocognitive subgroups in BP with data-driven methods rather than arbitrarily defined criteria. Other than having relatively small sample sizes, previous studies have not taken into consideration the neurocognitive variability in healthy subjects. Five-hundred-fifty-six euthymic patients with BP and 416 healthy controls were assessed using a battery of cognitive tests and clinical measures. Neurocognitive subgroups were investigated using latent class analysis, based on executive functions. Four neurocognitive subgroups, including a good performance cluster, two moderately low-performance groups, which differ in response inhibition and reasoning abilities, and a severe impairment cluster were found. In comparison to healthy controls, BP patients were overrepresented in severe impairment cluster (27% vs 5.3%) and underrepresented in good performance cluster. BP patients with lower educational attainment and older age were significantly more likely to be members of cognitively impaired subgroups. Antipsychotic use was less common in good performance cluster. These results suggest that there is a considerable overlap of cognitive functions between BP and healthy controls. Neurocognitive differences between BP and healthy controls are driven by a subgroup of patients who have severe and global, rather than selective, cognitive deficits.

Introduction

Bipolar disorder (BP) is associated with neurocognitive deficits (Torres et al., 2007, Bora et al., 2009a, Bourne et al., 2013, Aydemir et al., 2014, Levent et al., 2014, Bora et al., 2016, Bora and Pantelis, 2015, Hıdıroğlu et al., 2015) and these deficits are already evident at the first-episode (Lee et al., 2014, Bora and Pantelis, 2015). However, cognitive impairment in BP is relatively less severe than schizophrenia (Krabbendam et al., 2005, Bora et al., 2009b). Neurocognitive functioning in BP is also more heterogeneous than schizophrenia. While, there is some heterogeneity in cognitive functioning in schizophrenia, only a minority of patients perform at the level of population average or above (Palmer et al., 1997, Kremen et al., 2000, Reichenberg et al., 2009, Bora et al., 2010, Lewandowski et al., 2014). As a result, patients with schizophrenia are much less likely to be employed and have long-term relationships (Mueser and Bellack, 1998). In contrast, bipolar disorder (BP) has been associated not only with poor functioning in many patients but also preserved functioning and success in academic, creative and professional life in others (MacCabe et al., 2010, Kyaga et al., 2011, Bora, 2015a). As a group, meta-analytical studies in euthymic BP suggested that most of the deficits have medium to large effect sizes (Cohen d=0.5–0.8) and are most pronounced in executive functions, processing speed, sustained attention and verbal memory (Torres et al., 2007, Bora et al., 2009a). These findings suggest that relatively large number of patients with BP perform at the level of population average or above. Variability of neurocognitive and social functioning in BP might likely reflect the heterogeneity of aetiology in BP including potential subtypes associated with different genetic susceptibility factors (Bora, 2015a). Current subtyping of BP in existing diagnostic criteria (BP-I vs II) is based solely on clinical symptoms (presence or absence of full manic episode) and naturally does not well reflect the variability of neurocognition in BP. Better characterisation of cognitive heterogeneity in BP can potentially facilitate genetic and biological studies to define more valid subtypes of BP and can also help clinicians and researchers to develop more effective intervention strategies (i.e. cognitive rehabilitation and cognitive enhancers) targeting cognitive deficits (Fuentes-Durá et al., 2012, Vreeker et al., 2015).

Very few studies have investigated neurocognitive subgroups in BP. Several studies have categorised BP patients into cognitively impaired and unimpaired groups based on arbitrary cut-off scores (Thompson et al., 2005, Martino et al., 2008). These studies have relatively small number of BP patients included (n=50–110) and used variable cut-off scores such as scoring 1–2 SD below controls or scoring at or below the 5th percentile (Thompson et al., 2005, Martino et al., 2008, Sánchez-Morla et al., 2009, Iverson et al., 2011, Martino et al., 2013, Volkert et al., 2015). Findings of these studies suggest that around 40% of patients with BP have no neurocognitive deficits at all (Martino et al., 2008, Volkert et al., 2015) and other patients have variable levels of cognitive deficits. Studies using strict cut-off scores (such as 2 SD below) found that 25–30% patients with BP have severe cognitive deficits (Gualtieri and Morgan, 2008, Iverson et al., 2011). At the other hand, two other studies have attempted to identify cognitive subgroups of BP with a data-driven approach (rather than arbitrary cut-off scores) using cluster analysis (i.e. K-means and hierarchical). Burdick et al. (2014) have investigated 136 BP patients and found 3 clusters according to neurocognitive performance. These clusters included a neuropsychologically intact (30%), selectively impaired (30%) and globally impaired (40%) groups. In another cluster analysis study, Lewandowski et al. (2014) found that 40% of 73 BP were neuropsychologically normal, 15% had a global cognitive impairment. In this study, other patients were members of two different selective cognitive impairment clusters (total number of clusters 4). Both of these studies have included BP patients who were not strictly euthymic and latter study included acutely symptomatic patients. Also, these cluster analytical studies have not investigated variability in cognitive functioning in healthy controls and cannot tell whether any of the subgroups are more specifically related to BP than controls.

Potential cognitive subgroups in BP might be the product of differences in developmental and post-illness onset trajectories of global or selective cognitive factors in distinct neurobiological subtypes (Bora, 2015a). There might be a subgroup of BP patients with very severe and global cognitive deficits (Bora, 2015a). Other subgroups of patients with BP might have more selective deficits. As premorbid IQ differences between BP and healthy controls are marginal (Torres et al., 2007, Bora et al., 2009a), global cognitive impairment in most patients with BP should reflect deficits in fluid intelligence (but not crystallised intelligence), which is robustly correlated with executive functions and complex aspect of other cognitive functions including processing speed, attention and working memory, in most patients (Redick et al., 2012, Roca et al., 2014). However, the concept of executive functions refers to a heterogeneous group of cognitive functions. In factor analytical studies reviewed by Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative (Nuechterlein et al., 2004), tasks that were loaded to executive function factor were tests measuring strategy and reasoning such as Mazes, Wisconsin card sorting test (WCST) and tower of London test (“Reasoning” domain of EF for the purpose of this article). At the other hand, Stroop and Trail making B tests, which are also conceptualised as executive function tests (response inhibition and set-shifting/executive control), were loaded to processing speed factor and were not shortlisted as candidate tasks for reasoning and problem-solving domain of MATRICS Consensus Cognitive Battery (MCCB). However, measures such as Stroop interference and Trail making B score might be important to characterise EF impairment in BP (Yatham et al., 2010). Response inhibition (or inhibitory control) has been advocated as particularly relevant aspect of EF for BP (Frangou et al., 2005). Motor and cognitive aspects of response inhibition/interference control as assessed with tasks such as Go–NoGo, Stroop interference and Hayling sentence completion test are impaired in BP. Set-shifting/executive control abilities in BP is also significantly impaired (Bora et al., 2009a). It was also hypothesised that abnormalities in these tasks and other cognitive abilities (i.e. decision making) can reflect underlying ventrolateral prefrontal cortex (VPFC) dysfunction in BP. While both reasoning and response inhibition aspects of EF are impaired in BP, it was hypothesised that latter might be a more core feature of BP (Frangou et al., 2005, Larson et al., 2005, Bora et al., 2009a, Hıdıroğlu et al., 2015). For example, Frangou et al. (2005) suggested that deficits in response inhibition but not reasoning are evident in family members in BP. Response inhibition deficits might be relevant for behavioural manifestations of BP including impulsivity and poor decision making (Christodoulou et al., 2006).

The current study investigates cognitive subgroups, based on reasoning and response inhibition, in BP in a large sample of euthymic patients with BP and healthy controls. We hypothesised that: (1) there will be specific subgroups including with severe global impairment and preserved cognition, and the severe global impairment would be overrepresented in BP sample; (2) there would be subgroups which are impaired only in one domain of executive functions and the subgroup with impaired response inhibition (and executive control) would be more specifically related to BP than controls. We also aimed to explore cognitive, clinical and demographical profiles of each group.

Section snippets

Experimental procedures

Participants of this multi-centre study of neurocognition in euthymic bipolar disorder were recruited from outpatient clinics of seven university hospitals in Turkey (Bulent Ecevit University, Celal Bayar University, Dokuz Eylul University, Ege University, Karadeniz Technical University, Ondokuz Mayis University, and Pamukkale University). Written informed consent was sought from all participants and procedures followed in the study were approved by local research ethics committees.

The study

Results

Demographical and clinical variables including mean scores of YMRS and HDRS are reported in Table 1. Mean duration since the last episode was 26.3 (29.9) months and minimum duration since the last episode was two months. Most patients were receiving mood stabilizing medications including lithium (63.2%) and sodium valproate (47.6%) and others (carbamazepine and lamotrigine) (2.8%). Less than half of the patients were taking antipsychotic medications (47.2%), mostly atypicals (45.0%).

Discussion

In this study, we investigated cognitive subgroups in a large sample of euthymic BP and healthy controls. We identified 4 neurocognitive clusters. Our findings confirmed our first hypothesis. One of these neurocognitive clusters, severe impairment group, was made up primarily of patients with BP. In contrast, healthy controls were over-represented in good performance cluster. However, our findings were not supportive of our second hypothesis as BP and healthy controls were equally represented

Role of the funding source

Not applicable. This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Contributors

All authors contributed to design of the study. All authors contributed to data collection and/or management of the study. E.B conducted the analyses and wrote the first draft. All authors had critically reviewed and contributed to manuscript. All authors approved the final version of the paper.

Conflict of interests

None.

Acknowledgement

None.

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