COGNITIVE IMPAIRMENT IN BIPOLAR PATIENTS – A REVIEW FOCUSED ON RECENT NEUROPSYCHOLOGICAL ASSESSMENT IN BIPOLAR DISORDER

Cognition can be defined as the mental process of knowing and includes aspects such as awareness, perception, reasoning and judgment. The terms neurocognition and cognition are used interchangeably to denote objective, performance-based operations related to the uptake and manipulation of information, as contrasted with subjective or self-reported complains related to problems with thinking (1).
Neuropsychological functioning is not a unitary process and consists of multiple, partially dissociable cognitive domains (e.g. attention, processing speed, working or declarative memory, executive processing, language and intelligence quotient-IQ) (2).
Attention is believed by many to be the most basic cognitive construct to reflect conscious processing of information. It involves alertness, mental focus, serious consideration and concentration. Attention can be broken down into three systems: arousal (vigilance), orienting and detention. Arousal is believed to be an automatic process involving the ability to achieve and maintain an alert state (sustained attention). Orienting (attentional shifting) is an automatic process involved in target detection that allows the subject to localize a target for analyses. Specific measures used in cognitive neuroscience paradigms can differentiate this type of attention from sustained attention and detection. Detection is a complex attentional construct involving multiple overlapping concepts. Generally referred to as the executive attention network, this construct is not to be confused with executive function). It involves conscious processing by cortical areas (1). Short-term or immediate memory involves what one can repeate immediately after perceiving it. Working memory is the executive and attentional aspect of short –term memory involved in the interim integration, processing, disposal and retrieval of information (3). Working memory includes any mental process that entails temporary storage and manipulation of data, implying an active process as opposed to passive maintenance of information. Executive function encompasses an array of capacities that are generally believed to engaged and control the other cognitive processes of attention, working memory, learning and memory. Although deficits in other cognitive domains can result in specific functional deficits that can be overcome using compensatory strategies, it’s more likely that executive dysfunction will result in considerable functional disability, given its importance in social interactions and activities of daily living (1). Executive function includes the ability to move freely from one situation to another and to think flexibly in order to respond appropriately (set shifting), response inhibition, concept formation, working memory, emotional control and other aspects of mental control and self-regulation (3).
Patients with severe psychiatric disorders are found to have cognitive impairments (4). Bipolar disorder remains a leading worldwide cause of disability, morbidity and mortality from suicide. Although its precise etiologies are unknown, bipolar illness is characterized by its recurrent and episodic nature involving disturbances of mood, sleep, behaviour, perception and cognition (1). Patients with bipolar disorder show broad cognitive deficits (5, 6) in sustained attention (7, 8), memory (9, 10, 11, 12) and executive functioning (1) not only during acute mood episodes but also during euthymic periods (11, 9, 13). These pathological mood states have a clear impact on cognitive function (14). The cognitive impairments persist even after controlling for residual mood symptoms and medication variables. Thus, cognitive impairment is often characterized as trait features of illness (5). Bipolar disorder also appears to be characterized by both transient (state-related) and enduring (trait-related) (14). Both transient and enduring cognitive impairments contribute to the gap between education and the significantly lower workplace accomplishment persons with bipolar disorder (1). Currently, there is very little evidence of language or IQ deficits in patients with bipolar affective disorder (2). The most impaired domains noted (6) are executive functioning (working memory, executive control, verbal fluency, mental manipulation, cognitive flexibility), verbal learning and memory, attention deficits and psychomotor speed (6, 15, 16, 17).
Intact attentional capacity is essential to all higher cognitive skills. Sustained attention or vigilance is impaired in patient with bipolar disorder regardless of whether they are studied during periods of mania or depression (not remitted completely during euthymia). In addition, selective attention deficits during acute episodes don’t normalize during euthymia.
In euthymic patients (3, 6, 14) cognitive impairment was observed in task of executive functions (10, 15, 16, 17), sustained attention (7, 15, 17, 18, 19) and verbal memory (6, 12, 16, 20, 21, 22). These cognitive deficits seem to be related to the frequency of episodes in bipolar patients, with manic episodes impacting neuropsychological impairment most extensively (21, 23, 24). Attention and executive function is deteriorated by the recurrence of bipolar episodes (14). Moreover, the risk of development of dementia increases as a function of episode number. Rapid cycling and severity of the episodes may also contribute to neurocognitive impairment (14, 24). The length of illness was negatively correlated to scores on tests of executive function (8, 18, 21), psychomotor speed (11) and verbal memory (14, 20). Verbal memory is the cognitive domain that has been most consistently associated with duration of illness. In this regard a higher number of past manic episodes were also associated with poorer performance on verbal memory. (8, 14, 18, 20, 24,
25) The number of episodes of either polarity has been associated with diminished verbal fluency in euthymic bipolar patients as compared with healthy controls (14, 27).
Rubinsztein (9) described a relationship between visual memory measures and the number of admission, whereas Martinez-Aran (24) observed that the number of hospitalizations was correlated with verbal memory performance. Thompson (8) reported relationships between the number of hospitalizations and several neuropsychological domains, including verbal fluency, spatial memory, psychomotor speed and executive function. Zubieta (27) described a specific relationship between executive functioning measures and admission for mania (14).
Clark (18), in contrast reported a relationship between cognitive performance on several tasks and admission for depressive episodes. It is likely that the number of hospital admission constitutes an indirect measure of severity of individual episodes as well as of the course of illness (14). Euthymic bipolar patients assessed after a single manic episode showed impairment in attention, executive functions and total memory score comparison to healthy control subjects. While they performed better than euthymic bipolar patients assessed after recurrent bipolar episodes as regards attention and executive function. Elshahawi (14) and Chaves (28) emphasize that individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood (28).
Females performed better on a test for verbal memory. Elshahawi (14) and Rabie (29) found that female bipolar patients performed better than male patients in the test of verbal paired associates which is a test of verbal memory. Neither Kolur (30) nor Ferrier (31) found any significant gender difference regarding cognitive function.
Another factor that seems to have a negative influence over cognitive performance of bipolar patients is a positive family history for mood disorders, thus suggesting a genetic liability (6, 32). In contrast, Elshahawi (14), Kolur (30) and Goswami (33) found no significant differences in cognitive functions based on the presence or absence of family history.
Depressed bipolar patients have presented dysfunctions in several cognitive areas, such as attention (13, 34, 35), learning, memory (36, 37) and psychomotor speed (6, 38, 39).
The severity of the disorder also seems to be associated with cognitive deficits (6, 40). According to previous studies (21, 23, 24, 36, 41), chronic patients or patients with a history of multiple episodes and hospitalizations, present stronger cognitive deficits (6). The duration of the illness appears to interfere with attentional process and consequently, in the patients capacity to concentrate (6).
Little however is known about the presence of nature of cognitive deficit at the time of illness onset, nor its evolution throughout the course of illness (4). Results indicate that core neuropsychological deficit in sustained attention, learning and recall, spatial/nonverbal reasoning and several aspects of executive function are present at illness onset. Cognitive impairment in bipolar disorder are, thus, most likely not exclusively attributable to progressive decline associated with increased illness burden, cumulative treatment effects or chronicity of illness (5). Indeed, current conceptualizations posit that bipolar disorder is most likely characterized by both early and progressive dysfunction (5, 42, 43).
Elshahawi (14) showed that the earlier age of onset is associated with more declines in executive function and attention. The age of onset did not correlate significantly with total memory score, but showed a negative correlation with verbal memory and non verbal memory. Elshahawi (14) showed that later age of onset was inversely correlated with attention and executive function and this is consistent with Martinez-Aran (11). In contrast, El-Badri (44), Zubieta (27) and Deckersbach (25) did not find a significant correlation between age of onset and cognitive performance.
Mur (45) suggest that impaired executive function and loss of inhibition might be an important feature of bipolar disorder regardless of the severity of the disease or the effects of medication. Also, these executive- type cognitive traits may constitute and endophenotype for further studies on the ethiology of bipolar disorder. Psychotic symptoms were also described as having a significant impact on cognition, even when patients were examined in a first episode (6, 46).
R e c e n t s t u d i e s h a v e r e p o r t e d g r e a t e r neurocognitive impairment in euthymic bipolar disorder patients with a history of psychosis relative to patient without such a history (47). Psychosis has come into focus, as it often constitutes an important clinical marker for a more severe course of illness in bipolar disorder. Several authors found no differences between patients with and without a history of psychotic episodes. (47, 48,
49, 50, 51, 52) In contrast, Albus (53) reported an overall more compromised performance on cognitive measures in first-break patients who presented with psychotic symptoms. Similarly, Zubieta (27) found that patients with a history of psychosis obtained lower scores on measures of attention, verbal memory and executive functioning than healthy controls. Specific to executive functioning, Bora (54) concluded that deficits in cognitive flexibility may be the trait marker of psychotic features among patients with bipolar disorder. In the nonverbal domain of cognitive functioning, Glahn (55) reported significantly weaker performance on measures of spatial working memory in patients with a history of psychosis compared with patient without such a history (47).
Besides the influence of depressive and manic symptoms over cognition, it is reported that anxiety may affect cognitive function as well (56, 57). Bipolar disorder significantly co-occurs with anxiety disorders at rates that are higher than those in the general population (58) and the presence of the anxiety disorder (6, 59). Treatment of comorbid anxiety features may also help to improve apparent cognitive problems that might otherwise be misattributed to other aspects of psychopathology (1). While cognitive deficits are typically less pronounced than those found in other neurological or psychiatric illnesses (e.g. schizophrenia, Alzheimer dementia), reduced neuropsychological ability appears to significantly affect psychosocial functioning in bipolar patients (2).
Despite periods of symptomatic recovery, individuals with bipolar disorders often continue to experience impairments in psychosocial functioning, particularly occupational functioning (60). They do not regain premorbid level of occupational functioning even after mood episodes have resolved (61). Cognitive impairment has been associated with poor social and work performance even after long remission periods and controlling for subclinical mood symptoms (10, 16, 24, 27, 58). However, there are recent results suggesting that the functional disability may be restricted to a subgroup of cognitively impaired bipolar patients (6, 62). Two determinants of psychosocial functioning of euthymic (neither fully depressed nor manic) individuals with bipolar disorder are residual depressive symptoms and cognitive impairment. (60) Rates of unemployment and disability among individuals with bipolar disorder are considerably higher in normal population (60, 63). Two- thirds of patient with bipolar disorder experience a moderate to severe impact of the illness on occupational functioning (60, 64). Following treatment for a mood episode many people remain functionally impaired during follow-up periods despite syndromal and/or symptomatic recovery (60, 65, 66, 67). In terms of work productivity, bipolar patients miss an average equivalent of 1 week of work every month due to missed days at work and impaired work performance (68). Various determinants of functioning in bipolar patients include depressive symptoms, early onset, more and longer recent hospitalizations, comorbidity, lower socio-economic status and poorer premorbid functioning (60, 69, 70). Based on a review of studies investigating functional outcomes in bipolar individuals Bauer (71) concluded that depressive symptoms appear to be the determinant most consistently related to lower overall psychosocial functioning (60, 71, 72, 73, 74, 75). Cognitive difficulties reported by individuals with bipolar disorder at work include sluggish thoughts, difficulties focusing, getting started on task, organizing complex task and managing multiple projects, difficulties remembering and becoming easily overwhelmed (60, 76, 77). Findings of Bearden (61) indicate that better neurocognitive function in multiple domains and improvement in these domains over time are strongly predictive of subsequent occupational recovery (61). Findings of Dickerson (79) indicate that current employment status was significantly associated with cognitive performance, especially immediate verbal memory, total symptom severity, history of psychiatric hospitalization and maternal education. No association was found between employment status and history of psychotic symptoms, number of years of education or age of onset of illness (79).
It is generally believed that the depressive pole of bipolar disorder is more consistently and strongly associated with functional disability (80, 81)) than is the hypomanic or manic pole (78, 82, 83). Van der Werf- Eldering (84) confirmed that cognitive dysfunction is more severe in patients with depressive symptoms, especially regarding the domains of speed and attention. Jaegger (85) sustained that the association between affective symptom and impaired functioning is overestimated by most clinicians, when cognitive deficits more likely constitute better predictors of poor outcome (14).
At long-term follow up (15 years after an index manic episode), patient with bipolar disorder show persistent deficits in attentional processing and verbal memory and are cross-sectionally characterized by m o d e r a t e l e v e l s o f a ff e c t i v e s y m p t o m a t o l o g y. Neurocognitive capacity is associated with social, work and global functioning in patients with bipolar disorder at long-term follow up. A more severe course of illness (as defined by an increased number of hospitalizations is a significant, independent predictor of occupational impairment in bipolar disorder (86).
It is still unclear how common cognitive impairment is among bipolar patients, but a significant portion of them complain of neuropsychological difficulties. Formal neuropsychological deficits have been reported in asymptomatic patients who do not complain of cognitive difficulties. So, it’s possible that neuropsychological impairments may be more widespread than clinical experience suggest (2).
Cognitive deficits in verbal learning and memory seem to limit the psychopharmacological treatment outcome, especially through low treatment compliance (6, 11). Besides, difficulty in coding and retrieving new information may limit the benefit of psychological interventions (6, 20).
Clearly, suicidality among bipolar disorder patients is a significant public health concern worthy of extensive examination (87). Recent work found that bipolar I disorder patient were more likely to attempt suicide compared to bipolar II disorder and major depressive disorder patients (87). Other research has suggested that demographic factors such as sex may be an important predictor of suicide attempt. In one study (88) women were found to be at greater risk for suicide attempts, while another similar study (89) failed to show a sex difference (87).
Circumscribed cognitive deficits may be both iatrogenic and intrinsic to bipolar disorder. Optimal management hinges on knowledge of illness-specific cognitive domains as well as of the beneficial or adverse cognitive profiles of common psychotropic medication (90). A growing body of literature has begun to document the nature and extent of cognitive deficits among inviduals with bipolar disorder across all phases of illness, including euthymia (1, 17). In contrast to patients with schizophrenia, deficits observed among individuals with bipolar disorders appear to be more circumscribed in nature (91) and coalesce primarily around attentional processing (38), executive function (92) and verbal memory (93). Similar to patients with schizophrenia, persistently impaired work and social functioning have been demonstrated among individuals with bipolar disorder (48, 94, 95, 96), although the determinants of functional outcome in bipolar disorder are less well established (86).

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