Amanda Olley, M Clin Neuropsych4
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Objective: To compare and contrast the neuropsychological profile of the 3 phases of bipolar disorder (BD) to achieve a better definition of BD and to identify potential state and trait deficits.
Method: We conducted a search for English-language papers published in journals from 1965 onward, using the following terms in Medline and Embase: neuropsychology or neuropsychological and BD, depression, mania, and euthymia. We scrutinized suitable subheadings and retrieved familiar papers and literature.
Results: We initially identified more than 100 articles and then excluded reviews and papers that did not directly administer neuropsychological tests. This left 27 papers, which we further examined and the findings of which we tabulated and discussed. Cognitive and executive functioning deficits were found, including set-shifting, verbal fluency, planning, attention, and memory.
Conclusion: The neuropsychological deficits found in bipolar depression, mania or hypomania, and euthymia provide important insights into the pathophysiology of BD and may, in future studies, form the basis of clinically meaningful subtypes.
(Can J Psychiatry 2004;49:813–819)
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Clinical Implications
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A range of subtle neuropsychological deficits that have putative clinical salience have been implicated across all phases of bipolar disorder (BD).
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In practice, euthymia is incorrectly equated to clinical recovery, the prognostic ramifications of which need to be carefully reexamined.
With a greater understanding of the neuropsychological profile of BD, it is likely that cognitive and psychotherapeutic interventions can be developed that are better tailored to patients’ needs.
Limitations
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Too few longitudinal neuropsychological studies have been conducted that examine patients with BD across specific phases of the illness.
Current neuropsychological tests may not capture the subtle “real-world” neurocognitive deficits that BD patients experience clinically.
The clinical impact of the neurocognitive profile of BD patients is unknown and difficult to measure.
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Key Words: bipolar disorder, neuropsychology, bipolar depression, mania, euthymia
Résumé : Le trouble bipolaire, imaginaire? Portrait neuropsychologique d’un trouble biologique
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. . . Whether ‘tis nobler in the mind to suffer . . . (1).
Shakespeare’s eloquent question, when considered in the context of bipolar disorder (BD), is answerable with consummate ease. Naturally, no one would want to experience or wish upon anyone else the ravages of this illness, with its extremes of melancholic lows and psychotic highs, which much like a tempest, leave behind a trail of destruction and misery. However, in practice, patients and clinicians rarely face such a pristine choice. In the 21st century, the definition of BD has broadened considerably to the extent that some argue for a bipolar spectrum (2) that approximates to the DSM-IV category of bipolar disorder not otherwise specified (BD NOS); others propose a broad bipolar spectrum incorporating bipolar I, II, III, and more (3). There is no doubt that the incidence of BD is much greater than previously suggested (4) and that this realization alone has contributed to a heightening of research interest. However, we need to proceed with caution because even the most basic distinction, namely, that between unipolar and bipolar depression, often eludes us. For instance, it is now apparent that bipolar depression is distinct from major depression (MD) phenomenologically (5) and biologically (6); yet only recently have treatment studies begun to specifically examine bipolar depression.
The diagnosis of bipolar II disorder (BD II) mandates the occurrence of at least one episode of both MD and hypomania (7) and, therefore, rests on carefully determining whether a patient has experienced an episode of hypomania. However, few groups have attempted to subtype mania or hypomania in the manner that Parker and colleagues have used to dissect unipolar (that is, major) depression (8,9). This, along with a more precise definition and better understanding of bipolar depression, is a fundamental prerequisite for future research. Thus, in this brief paper, we principally review the neuropsychological literature pertinent to BD to determine whether this will ultimately contribute to its diagnosis and subtyping.
Method
We conducted a search for English-language papers published in journals from 1965 onward, using the following terms in Medline and Embase: neuropsychology or neuropsychological and BD, depression, mania, and euthymia. We selected suitable search specifiers and subheadings, and we retrieved and scrutinized familiar papers and literature. We initially identified over 100 articles, from which we excluded reviews and papers that did not directly administer neuropsychological tests. This left a total of 27 papers, the findings of which we tabulated and discussed.
Neuropsychological Profile of BD
Like MD, BD is a recurring depressive illness that is additionally punctuated by episodes of mania and (or) hypomania (10). In most instances, depressive episodes precede the occurrence of a manic or hypomanic episode and, as such, the diagnosis of BD is often delayed by months or years (11). Therefore, the most clinically valuable distinction in terms of diagnosis is that between MD and bipolar depression (12). Additionally, the differentiation of state-specific neuropsychological deficits that successfully partition bipolar depression, euthymia, hypomania, and mania may be useful in defining BD II. However, relatively few studies have attempted to determine the neuropsychological profile of patients with BD (13–15), and few have examined BD II patients specifically (16,17). Indeed, most studies report findings from patients with bipolar I disorder (BD I), and few examine a mixture of BD I and BD II.
State-Specific Deficits
One approach that many groups have adopted when researching the neuropsychological profile of BD is to make cross-sectional, between-subject comparisons of specific mood states against healthy control subjects. These studies are useful because they delineate the overall pattern of deficits in each phase of BD. However, the inferences that can be drawn from the findings are somewhat limited, because researchers have used various tests that are often not comparable and the various patient groups differ considerably in terms of demographics and extent of morbidity.
Bipolar Depression
Unipolar and bipolar depression have long been thought to exact a similar toll on cognition and learning; however, early studies failed to distinguish between the 2 and were also unable to separate depression from other psychiatric diagnoses, such as schizophrenia. In general, BD patients are not that different from patients with unipolar depression in terms of severity and pattern of neuropsychological impairment. For instance, memory and executive functioning are similarly impaired across both disorders, affecting verbal learning (18). However, patients with bipolar depression are marginally more impaired on both verbal recall and recognition, suggesting that the depressed state may incur deficits in memory encoding. In addition, the impairment in verbal fluency may be a factor of depression severity; the BD patients with depression in this study experienced a much greater rate of hospitalization. Such subtle differences suggest that bipolar depression is likely to be associated with a greater degree of impairment than is MD (18,19). This is certainly the case with respect to immediate and delayed verbal recall (18,20), though recognition memory in BD patients with depression is largely intact (20).
Relative to control subjects, BD patients with depression have significantly impaired sustained attention, which is greater than that found in patients with MD and results in errors of omission (19). It is therefore not surprising that BD patients with depression routinely perform poorly on tests that involve attentional set-shifting, problem solving, decision making, and concept formation (21,22). However, deficits in verbal fluency are more selective, with only semantic categories being affected in BD patients with depression (23), compared with persons with MD, where both semantic and phonemic category scores are significantly reduced (24). Psychomotor slowing is observed in both BD patients with depression and persons with unipolar depression (25–27). In the latter, psychomotor slowing confers subtype specificity (8) and may do the same in BD. However, the extent to which psychomotor slowing in BD is affected by illness severity and the degree to which it normalizes with treatment are yet to be determined.
Bipolar Mania or Hypomania
Mania is a difficult condition to investigate because patients are usually unable to undergo long periods of testing. Although for decades it has been thought that cognition is impaired in mania (28), only recently have investigations begun to corroborate this suggestion. Studies that examined patients with mania have used tests that assess learning and memory, executive function, and visuospatial ability. Early studies associated mania with learning (29) and memory (28) deficits and global cognitive impairment (30). These findings were partly explained as altered patterns of verbal association and as a result of the fact that in mania, memory function is overinclusive, such that it is inefficient in screening environmental stimuli (29). More recent studies examining memory have failed to achieve consensus, with some suggesting that patients with mania have difficulties in both acquisition and retention in verbal and nonverbal domains (21,31,32). Part of the problem is that there are deficits in attention and in executive and nonverbal intellectual functioning (33). For instance, studies using continuous performance tests that assess executive control have shown that, in mania or hypomania (34,35), sustained attention is significantly impaired; manic and hypomanic patients are more impulsive and have more errors of commission.
It has also been mooted that mania is a dysexecutive syndrome because of the real-world difficulties patients face, such as poor social judgement and decision making. Patients with mania, and especially those with a history of psychosis, have been found to be impaired on tests of attentional set-shifting and concept formation (36). Further, patients perform poorly on planning, problem-solving, and decision-making tasks, with deficits becoming more marked as the severity of mania increases (22). Such impairments are partly attributable to impaired impulse control; however, the extent to which these deficits are state-specific is unclear, and in fact, some deficits (such as those in memory and attention) are found across several psychotic illnesses, regardless of diagnosis (22,37).
Euthymia
Until recently it has been widely accepted that, between episodes of depression and mania, patients with BD recover completely and that euthymia is in essence “normality.” Indeed, this is the very fulcrum upon which Kraepelin levered the separation of schizophrenia and manic-depressive illness (38). When well, patients with affective disorders were thought to have regained intact cognition. However, recent studies have cast serious doubt on this assumption and have demonstrated that euthymic patients continue to suffer psychosocial difficulties, perhaps because of ongoing cognitive compromise. One of the first studies to examine recovered subjects compared patients with BD with schizophrenia patients (39). BD patients were not as impaired as patients with schizophrenia on tests of attention and visual processing, though their performance was also not equivalent to that of healthy control subjects. More recent studies have also noted a range of cognitive impairments in euthymic BD patients (40–42), but some of these may be the consequence of residual affective symptoms (35,43). The few studies that have controlled for such symptomatology have identified various deficits. One group has noted a specific deficit in working memory and executive control and posits frontal lobe dysfunction as the cause (44). Other groups using different neuropsychological tests have found similar impairments in both verbal learning and executive function (35), suggesting that these findings are not task-related. However, the various tests employed are not truly equivalent, and the variations in assessment limit the extent to which findings can be combined or compared. Interestingly, one robust study reported executive function to be largely intact; however, visuospatial memory and response latency in their euthymic BD patients was significantly impaired (45), implicating temporal lobe and perhaps hippocampal dysfunction.
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Table 1 The neuropsychological profile of bipolar disorder
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Cognitive domain
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Bipolar depression
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Euthymia
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Mania
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Set-shifting and (or) concept formation
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¯
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¯¯
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¯¯
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Verbal fluency
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¯
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¯ ·
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¯
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Decision making
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—
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¯ ·
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¯
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Planning and (or) problem solving
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¯
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¯
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¯¯
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Nonverbal intelligence
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¯
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· · ·
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¯
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Sustained attention
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¯
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¯¯¯
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¯¯
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Verbal memory–delayed recall
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¯
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¯
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¯
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Visual memory
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¯
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¯ ·
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¯
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¯ = Reduced and (or) impaired, compared with healthy control subjects;
· = no change, compared with healthy control subjects. Each symbol denotes
the finding from one study.
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The issue of a persistent neuropsychological deficit in euthymia is of profound importance, not least because of its potential as a trait marker for BD. Such a deficit, in addition to influencing our understanding of the pathophysiology of the disorder, would also have serious prognostic ramifications for patients.
Fortunately, general intellectual functioning does not appear to be significantly impaired in euthymic BD patients, though the number of studies examining this capacity that control for confounds is relatively few (44). Thus the pattern of neuropsychological deficits in euthymic BD patients remains undecided. There is a growing consensus that some degree of residual cognitive impairment that cannot be accounted for by confounds such as medication and residual subclinical symptoms is likely.
Phenotypic Comparisons
Similar to the studies that have examined state-specific deficits, those that have chosen to compare across phenotypes have mostly used cross-sectional designs. The neuropsychological profile of mania has been compared with that of both MD and schizophrenia. Early studies assessed attention, memory, and visuospatial functions and found that patients with MD and mania were equally impaired on measures of cognition (46) and executive functioning (47). More recent comparisons using more standardized tests have also shown that patients with mania (48) are impaired on tests of delayed visual recognition and pattern and spatial recognition memory and that the pattern of impairment overlaps remarkably with that found in MD. This commonality has prompted speculation that patients with MD and mania share a mechanism of neurocognitive compromise and that this may involve functions subserved by frontal, temporal, or subcortical brain regions (49). However, a common neuropsychological framework for these deficits encompassing response style, motivation, and cognitive capacity is yet to be formulated.
Comparisons between mania and schizophrenia also point to substantial overlap. Deficits on tests of perceptual span (50), selective attention (51), and shifting attentional set (52) fail to separate the 2 groups. These and other neurocognitive deficits in patients with either BD or schizophrenia (53) appear to be present from the early stages of illness (37), affecting memory, attention, and delayed recall.
In general, this comparative approach across phenotypes has yielded few distinguishing neuropsychological markers, perhaps reflecting the heterogeneity of psychiatric disorders and the poor functional specificity of many of the tests employed.
Summary and Functional Implications
The cognitive deficits in BD principally affect executive functioning, attention, and memory.
The executive domains that are compromised in BD implicate frontal lobe structures, particularly the dorsolateral prefrontal cortex, which is involved in problem solving, planning, attentional set-shifting, working memory, and temporal sequencing of information (45,54,55). Damage to this brain region disrupts organization and the execution of plans (56,57). Similarly, poor performance on sustained attention measures, especially in mania, has been associated with compromised frontal and parietal lobe functioning. Interestingly, attention has been variously associated with several brain regions, including the anterior cingulate, prefrontal cortex, and thalamus (58)—structures that are also linked by frontostriatal loops implicated in the generation and modulation of emotion.
The memory and learning deficits noted in BD point to temporal lobe involvement, in particular, the hippocampus and functionally related structures such as the thalamus. These brain regions, along with the ventromedial prefrontal cortex, are implicated in verbal fluency, inhibition, and self- monitoring, such that cortical structures recruit subcortical assistance with increases in task demands (59). When considering the neuropsychological profile of BD, the orbitofrontal cortex is likely to feature prominently, as damage affects decision making and increases risk-taking behaviour (60,61)— both of which are key problems in mania. This is particularly noticeable when decisions have an affective component, suggesting that emotional tasks influence executive functioning, producing neural interference that manifests clinically as cognitive compromise.
Confounds and Limitations
The first and perhaps most basic problem is likely to be the most difficult to resolve. Many neuropsychological studies have not assessed subsyndromal symptoms in the patients they define as euthymic. Euthymia has been assumed to be a true baseline and has been clinically equated to recovery. Gradually, it has become apparent that euthymic patients also have neuropsychological deficits that may in fact be bipolar traits. To determine whether this is the case and to characterize these deficits accurately, it is necessary to test patients that are free from residual symptomatology. In doing so, it is important to acknowledge that in BD, subsyndromal residual symptomatology may in fact be normal.
The effects of medication further confound this fundamental problem. Patients with BD are rarely medication-free, even when asymptomatic. At the very least, most patients with BD are on mood stabilizers, and many are prescribed additional psychotropic medications. The withdrawal of these may exacerbate symptoms or precipitate relapse, precluding the assessment of medication-free patients. The only other option is to examine first-onset drug-naive patients. However, diagnosis is often difficult and may take months and years to establish. Thus, in reality, this approach is also impractical. It is of no surprise that few such studies have been attempted and that little is known about the neuropsychological profile of medication-free BD patients. Conversely, the effects of medications are also poorly understood. It has recently been suggested that lithium has neuroprotective effects in patients with BD (62), raising the possibility of treatment-related improvements in cognition. Some studies have also associated the administration of lithium with either no significant affect on attention, memory, or visuomotor functioning (63) or with significant neuropsychological impairment (64).
Another important limitation of neuropsychological studies is the small number of subjects examined. Statistically, most studies have been underpowered and are significantly compromised by small sample size (15). Future studies need to be statistically more robust.
The Functional Anatomy of BD
Brain lesion data in animals and humans, along with findings from neuroimaging studies, have made it possible to functionally localize neuropsychological deficits and provide some tentative insights into the pathophysiology of BD.
Structural neuroimaging studies of patients with BD reveal enlarged lateral and third ventricles (65), as well as increased white matter hyperintensities in periventricular white matter, frontal lobes, and basal ganglia (66) that occur more commonly than in schizophrenia (67) and MD (68). Prefrontal and subgenual cingulate volumes are also reduced in BD (69–71); however, subcortical and medial temporal structures, including the basal ganglia and amygdala, are actually enlarged, whereas in MD, these structures are reduced in size (72–74). This suggests that changes in subcortical structures are likely to be of greater assistance in defining the bipolar phenotype.
Functional neuroimaging studies of BD have generally identified the same brain regions thought to be important in the generation and modulation of mood in health and MD. Several studies have begun to identify trait- and state-specific abnormalities and to implicate greater involvement of subcortical processes (75–77) in both mania and bipolar depression (78–83). Of particular note is a functional magnetic resonance imaging study that has examined all 3 phases of BD and found state-related changes in the caudal ventral prefrontal cortex in both mania and depression, as well as trait-related abnormalities across all phases of illness in the rostral ventral prefrontal cortex (84). Further, the observed deficits in affective and attentive processing in BD could be the result of reduced frontocortical functioning, as evidenced by reduced activation of the prefrontal cortex and increased activation of the amygdala during affect discrimination in euthymic BD patients (85).
In essence, the disruption of cortical-subcortical neural circuits in BD may translate to an affective disturbance in which patients are unable to regulate emotional behaviour and identify the emotional salience of affective stimuli (48,86).
Conclusion
The deficits in executive functioning, sustained attention, and memory in patients with BD have attracted several explanations. The residual deficits in executive functioning in euthymic BD patients merit particular attention, because they raise the possibility of primary cognitive changes that are at least independent of mood state. This is important because changes in executive functioning influence social and occupational domains (87), which if remedied successfully, would have significant clinical benefits. Similarly, attention and memory deficits are likely the consequence of reduced cognitive effort or inefficient encoding and retrieval strategies, which result in poor free recall (20,88). In general, this contributes to poor cognitive functioning, and any improvement would be of great clinical salience. However, an overarching model of BD is needed. This would allow the separation of mania and depression and perhaps provide a more meaningful and consistent subtyping of BD. The evidence to date suggests that the primary abnormality in BD is likely to be a dysfunctional prefrontal cortex that manifests clinically as cognitive and social compromise and that prompts compensatory recruitment of subcortical processing. This trait abnormality may be developmentally based, with under- and overcompensation by surrounding networks, resulting in the vicissitudes of mood. Such speculation invites numerous research paradigms.
The neuropsychological profile of BD is difficult to determine definitively because of a paucity of studies and many significant confounds. It seems likely that neuropsychological deficits are not confined to periods of illness and that these deficits may eventually assist in phenotypically differentiating BD and may contribute to its subtyping. This is not yet possible, and many more neuropsychological investigations are needed to advance the field. Ideally, these should be longitudinal in design, have large sample sizes, and be coupled with functional and neuroimaging assessments.
Funding and Support
We acknowledge support from the National Health and Medical Research Council (program grant 222308) and the New South Wales Centre for Mental Health.
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Author(s)
Manuscript received October 2003, revised, and accepted November 2003.
1Consultant Psychiatrist, Mood Disorders Unit, Black Dog Institute, Prince of Wales Hospital; Senior Lecturer, School of Psychiatry, University of New South Wales; Honorary Senior Research Associate, Mayne Clinical Research Imaging Centre, Prince of Wales Medical Research Institute, Sydney, Australia.
2Research Psychologist, Mood Disorders Unit, Black Dog Institute, Prince of Wales Hospital, Sydney, Australia.
3Research Assistant, Mood Disorders Unit, Black Dog Institute, Prince of Wales Hospital, Sydney, Australia.
4Clinical Neuropsychologist, Department of Neuropsychology, Hunter Mental Health, Newcastle, England.
Address for correspondence: Dr GS Malhi, Neuroscience Research Group, Mayne Clinical Research Imaging Center, Prince of Wales Medical Research Institute, Barker Street, Randwick NSW 2031, Sydney, Australia
e-mail: g.malhi@unsw.edu.au
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