Cognitive Impairment in Patients With Bipolar Disorder: Effect on Psychosocial Functioning

At the conclusion of a session on neuropsychological processing in bipolar disorder at last summer's meeting in Edinburgh of the International Society for Bipolar Disorders, a member of the audience thanked the panel for publicizing the cognitive deficits associated with bipolar disorder. As an advocate for and an individual with bipolar affective disorder, the woman claimed that while mental health professionals are focused on treating mood symptoms, only rarely do they consider the impact of neuropsychological difficulties on patients' lives. Indeed, she firmly stated that her poor memory and difficulty in concentrating influenced her daily life more than the affective symptoms of the disorder. Although it is unclear how well this woman represented the larger community of persons with bipolar disorder, it is clear that the cognitive sequelae of bipolar disorder and their impact on psychosocial functioning are rarely considered when developing treatment plans.

There is growing evidence that individuals with bipolar affective disorder have cognitive impairments, even during periods of symptom remission. While these impairments are typically less pronounced than those found in other psychiatric (eg, schizophrenia) or neurological (eg, Alzheimer dementia) illnesses, reduced neuropsychological ability appears to significantly affect psychosocial functioning in patients with bipolar disorder. In this article, we review evidence for cognitive disruptions in bipolar disorder and examine the relationship between these impairments and clinical outcome. In addition, we discuss the appropriateness of neuropsychological treatment targets in bipolar disorder.

Cognitive impairment
Although it is unclear how common cognitive impairment is among individuals with bipolar disorder, a significant portion of patients complain of neuropsychological difficulties. Because formal neuropsychological deficits have been documented in asymptomatic patients who do not complain of cognitive difficulties, it is possible that neuropsychological impairments may be more widespread than clinical experience suggests.¹ Indeed, we recently reported that 75% of asymptomatic patients scored more than one standard deviation below healthy controls on at least 4 cognitive measures,² suggesting widespread, but relatively mild, neuropsychological dysfunction in patients with bipolar disorder.

However, neuropsychological functioning is not a unitary process and consists of multiple, partially dissociable cognitive domains (eg, attention, processing speed, working or declarative memory, executive processing, language, intelligence quotient [IQ]). Currently, there is very little evidence of language or IQ deficits in patients with bipolar disorder. Rather, those euthymic patients with bipolar disorder who have cognitive difficulties tend to have attentional, executive, and declarative or long-term memory impairments.³

Neuropsychological impairments found in euthymic patients with bipolar disorder may be confounded by clinical variables such as the manifestation of subclinical symptoms or broader epiphenomena of an individual's illness history (eg, illness duration, number of hospitalizations, or medication use). While the importance of subclinical symptoms or illness sequelae is debated in the literature, a pragmatic approach suggests that since most patients who are in remission continue to have low-level cognitive symptoms, cognitive deficits should be considered when planning treatment strategies.

Effects of psychotropic medications on cognition
Although the use of psychotropic medications may affect neuropsychological functioning, systematic investigation of the cognitive impact of these agents in patients with bipolar disorder has been limited. A qualitative review concluded that while lithium had a negative effect on memory and speed of information processing, patients were often unaware of these deficits.⁴ Engelsmann and coworkers⁵ found that mean memory test scores remained stable over a 6-year interval in patients with bipolar disorder treated with lithium. Furthermore, after controlling for age and initial memory scores, there were no significant differences between patients with short- versus long-term lithium treatment on any measure. This suggests that long-term lithium usage is unlikely to cause progressive cognitive decline.⁵ Some antidepressant medications have been shown to have adverse cognitive effects, particularly those with anticholinergic properties.⁶

While few studies have examined neurocognitive performance in patients with bipolar disorder who were not medicated, we previously found comparably impaired verbal memory in persons receiving psychotropic medication (n = 32) and those who were drug-free (n = 17).⁷ Taken together, these findings suggest that cognitive deficits and underlying abnormalities in neuronal activation in patients with bipolar disorder are not primarily attributable to the use of psychotropic medications. However, large-scale, longitudinal investigations of patients with bipolar disorder on different medication regimens are necessary to fully address this question.

Cognition and clinical outcome
As additional studies are published, it is becoming increasingly evident that some level of neuropsychological dysfunction often occurs in individuals with bipolar disorder, which raises questions about the functional consequences of these cognitive deficits. In schizophrenia, where far more is known about the nature and extent of neuropsychological dysfunction, verbal memory and vigilance appear to be necessary for adequate functional outcomes.⁸ Furthermore, cognitive impairment with schizophrenia prevents optimal psychosocial functioning and acts as a neurocognitive "rate-limiting" factor.⁸ Currently, there are not enough data to make similar claims with bipolar disorder.

Several investigators have demonstrated that verbal memory impairments or executive dysfunction are associated with reduced social and vocational functioning in patients with bipolar disorder, even in the absence of manic or depressive symptoms.^9,10 Interestingly, even though the magnitude of neuropsychological impairment in bipolar disorder is typically less than that reported in schizophrenia, the strength of the association between cognitive functioning and functional outcome measures is comparable between the groups.^8,9 This suggests that patients with bipolar disorder could potentially benefit from cognitive remediation or rehabilitation therapies.

Cognition as a treatment target
The evidence for cognitive impairment and its functional consequences in bipolar disorder raises the issue of cognition as a target for treatment for individuals with this illness. In the literature on schizophrenia, there is substantial support for pursuing cognition as a treatment target.^11,12 The first goal in targeting cognition for either illness is to select medication treatments that do not further impair cognitive functions. A number of atypical antipsychotic medications have indications for the treatment of bipolar disorder in various phases, including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. Data for schizophrenia suggest relatively minor differences in efficacy among these medications but major differences in the side-effect profiles.¹³

To maximize cognitive function with atypical antipsychotics, it is important to use doses that adequately control target symptoms without producing extrapyramidal symptoms (EPSs) or necessitating the use of concomitant anticholinergic medications. EPSs decrease speed of response and impair performance on a range of neuropsychological tests. Anticholinergic medications have been found to cause impairments in memory function. In addition, researchers are pursuing a variety of cognitive enhancing medications that could be added to atypical antipsychotic medications in an effort to improve cognitive functioning. Indeed, preliminary data suggest that moderate doses of galantamine could help minimize cognitive dysfunction in bipolar disorder.¹⁴ Although these findings are limited, they demonstrate the potential of galantamine or other similar agents to improve the cognitive deficits in bipolar disorder.

In addition to tailoring medication treatments to maximize cognitive functioning, it is important to pursue psychosocial treatments for targeting cognitive deficits in bipolar disorder. In the schizophrenia literature, some of these approaches seek to directly improve or restore cognitive abilities. Others are considered compensatory in nature and attempt to bypass impairments in cognitive functioning to improve community outcomes.¹⁵

Cognitive remediation (CR) seeks to directly improve and/or restore cognitive functions using a variety of pen and paper or computerized tests or games requiring cognitive skills such as attention, planning, problem solving, and/or memory.¹⁶ A basic notion of CR is that the brain's neuroplasticity reserve can be enriched by cognitive experiences provided through training. Reviews of the CR literature have generally been positive and have concluded that CR improves multiple domains of cognitive functioning. These improvements are not limited to cognitive progress but encompass a range of outcomes, including improved independent living skills, increased hours worked and money earned in vocational rehabilitation, and improved social adjustment.^15,17 Effect sizes for improvements in specific training exercises have generally been large, with more moderate effect sizes for other cognitive outcomes and improvements in community functioning.^16,18,19

Rather than attempting to alter neurocognitive function per se, compensatory strategies attempt to bypass cognitive deficits by establishing supports or prosthetic devices in the environment to improve functioning. One example of such a treatment is Cognitive Adaptation Training (CAT).¹⁸ CAT uses environmental supports, including alarms, signs, checklists, and the reorganization of belongings to cue and sequence adaptive behavior in the home. Treatment strategies are based on a comprehensive assessment of cognitive functioning, behavior, and environment. CAT is based on the idea that impairments in executive functioning lead to problems in initiating and/or inhibiting appropriate behaviors. Using behavioral principles such as antecedent control, environmental adaptations are set up to cue appropriate behaviors, discourage distraction, and maintain goal-directed activity.

CAT has been shown to improve adherence to medication, community functioning, and rates of relapse for individuals with schizophrenia.^16,18,19 Effect sizes for improvements in functional outcome and medication adherence have been large for CAT relative to control conditions. The literature for schizophrenia suggests that targeting cognitive deficits can significantly improve a broad range of outcomes. Pursuing cognition as a treatment target in bipolar disorder is a logical extension of this work.

Conclusions
In the next few years, we will undoubtedly learn more about the scope and consequences of cognitive impairments in bipolar disorder. Even now, it is clear that a significant portion of patients have neuropsychological deficits that influence their social and vocational functioning and potentially limit their social problem-solving abilities. Although the cognitive impairments found in persons with bipolar disorder are often subtle, improving neuropsychological processing may dramatically improve psychosocial functioning in these patients. It would seem beneficial to consider neuropsychological functioning when developing long-term care plans for individuals with bipolar disorder. However, at present there are no standards for assessing the changes in cognitive functioning caused by behavioral or pharmacological intervention specifically designed for bipolar disorder.

Recently, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)²⁰ initiative developed a battery of neuropsychological tests for schizophrenia, and a number of pharmacological agents designed to improve cognitive functioning are currently being studied. While the MATRICS battery represents a significant advance for cognitive-pharmacological research, it is necessarily specific for schizophrenia and may need to be adjusted for use in bipolar disorder. Indeed, the development of an easily administered and psychometrically valid neuropsychological battery for use in bipolar disorder is a necessary prerequisite for the widespread use of cognitive measures when treating patients with bipolar disorder.

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