Cognition in Bipolar Disorder: An Update for Clinicians
Abstract
Bipolar disorder is associated with cognitive deficits, which persist across mood states and affect functional outcomes. This article provides an overview of recent progress in measuring cognition in bipolar disorder and its implications for both research and clinical practice. The authors summarize work conducted over the past decade that has helped guide researchers and clinicians in the appropriate measurement of cognitive functioning in bipolar disorder, the design of research studies targeting this domain for treatment, and the implementation of screening and psychoeducational tools in the clinic. Much of this work was conducted by the International Society for Bipolar Disorders Targeting Cognition Task Force. Here, the authors also highlight the need for clinicians to be informed about this aspect of illness and to be equipped with the necessary information to assess, track, and intervene on cognitive problems when appropriate. Finally, the article identifies gaps in the literature and suggests potential future directions for research in this area.
The cognitive deficits observed in bipolar disorder, in domains such as verbal learning, attention, and executive function (1), are qualitatively similar to those reported in schizophrenia, although less severe (2–4). It is important to note that the deficits in cognitive functioning, in areas such as attention, processing speed, explicit memory, and several aspects of executive function, persist even when patients are affectively stable (5–8) and are associated with poor quality of life (QoL) (9), disability, and an incomplete functional recovery (2, 9–17). Meta-analytic evidence shows that deficits in memory and executive function affect occupational outcomes in bipolar disorder even more than residual mood symptoms do (17, 18). Research over the past decade has described substantial heterogeneity (13) in the cognitive profiles observed among individuals diagnosed as having bipolar disorder, with 12%–40% displaying global cognitive deficits across multiple domains (i.e., verbal memory, attention, executive function, and psychomotor speed), 29%–40% displaying selective impairment in attention and psychomotor speed, and 32%–48% being relatively cognitively intact compared with healthy age‐matched individuals (13, 19–22).
The early identification of subgroups of patients with bipolar disorder who experience significant cognitive impairment, or whose course may be marked by cognitive decline, is a critical first step if intervention and prevention strategies are to succeed in promoting a full recovery (17). Clinical remission is no longer a sufficient treatment goal. Understandably, patients want to achieve functional recovery and optimize QoL; as such, this should be a key goal for clinicians who treat these patients (23). Given the prevalence and adverse psychosocial impact of cognitive dysfunction in the illness, clinicians will want to be informed about this aspect of illness and be armed with the information that they need to assess, track, and intervene on cognitive problems when appropriate. In this article, we attempt to summarize the recent progress in this area, with an eye toward a clinician audience. Here, we highlight much of the excellent work carried out by the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force over the past decade, which has helped to guide researchers and clinicians alike in the appropriate measurement of cognitive functioning in bipolar disorder, the ideal design of research studies targeting this domain for treatment, and the implementation of screening and psychoeducational tools in the clinic. Next, we briefly identify gaps in the literature and discuss potential future directions.
Measurement of Cognition in Bipolar Disorder
In the Clinic
Given the strong relationship between cognitive deficits and functional outcomes in bipolar disorder, the clinical relevance is clear, yet cognition is rarely assessed in patients with bipolar disorder in regular clinical practice. A recent paper by the ISBD Targeting Cognition Task Force outlined a plan for how clinicians might integrate cognitive assessment into the mainstream (24) (Figure 1). Recommendations included the formal assessment of cognition using brief objective and subjective cognitive screenings (e.g., the Screen for Cognitive Impairment in Psychiatry [SCIP] and the Cognitive Complaints in Bipolar Disorder Rating Assessment [COBRA]) that can be administered by any clinician (e.g., a psychiatrist, psychologist, social worker, or licensed mental health counselor) as a part of the clinical management for all adult patients (24). Formal cognitive assessments allow clinicians to track patients’ cognition over time to determine whether changes are due to illness episodes, comorbid factors (e.g., sleep problems, substance use), or the initiation of new treatments, which can help patients and clinicians make informed treatment decisions.
FIGURE 1. Abbreviated version of the International Society for Bipolar Disorders Targeting Cognition Task Force’s clinical recommendations for clinicians flow chart (24)a
aCOBRA=Cognitive Complaints in Bipolar Disorder Rating Assessment; MOCA=Montreal Cognitive Assessment; SCIP=Screen for Cognitive Impairment in Psychiatry.
Ideally, assessments should take place when patients are affectively stable to allow for the detection of cognitive deficits that are persistent rather than those that are directly related to acute mood symptoms (15–17), as these are the deficits that most directly affect community function and warrant directed treatment. Although the frequency of assessments should be based on each patient’s needs and/or clinical picture, the recommendation is for assessments to be completed as early in the course of the illness as possible and at least every 5 years thereafter.
Across the Lifespan
For youths, the rates of attention-deficit hyperactivity disorder (ADHD) are higher, which has implications for interpreting the results of cognitive testing. For example, it is important to distinguish youths who have had chronic ADHD since childhood from those whose childhood ADHD has resolved. In the latter group, major affective episodes may constitute a new precipitant of neurocognitive difficulties or lead to the reemergence of ADHD symptoms. Youths often prefer options that are computer driven and, ideally, online. This is especially relevant when formal neurocognitive testing is unavailable or expensive. Managing environmental distractions is of fundamental importance when assessing youths, particularly ensuring that phones are secured or inaccessible during testing. For elderly patients, tracking cognition may also be helpful in determining whether cognitive decline may harken the onset of dementia, which may be more common among individuals with bipolar disorder than among individuals in the general population (25–30).
Importance of Brief Objective and Subjective Cognitive Screenings
Because of time and resource concerns, the use of a tool that is brief, easy to administer and interpret, and freely available online is likely the most feasible approach to integrating this into the clinic. Because empirical research has shown a surprisingly weak correlation between objective cognitive test performance and subjective cognitive self-reports in patients with bipolar disorder (12, 31–33), the reliance on simply asking patients to self-assess their cognitive skills may be misleading, which really necessitates an objective evaluation. Objective assessments are important in evaluating the extent to which cognitive deficits are affecting community functioning (e.g., interpersonal and occupational), especially in individuals with poor insight due to executive dysfunction (34). Beyond indicating impairments, objective cognitive assessments can identify patterns of both strengths and weaknesses that can guide intervention and may, in some cases, provide relief to patients concerned about “neuroprogression” or dementia, as evidence suggests that roughly 30%–50% will be cognitively intact (24, 29).
Self-report (subjective) measurements are still important, as they take into account the patient’s perspective and cognitive concerns; however, it should be noted that they often correlate with residual mood symptoms as much as they do with true cognitive dysfunction. In particular, if a patient attributes his or her cognitive complaints to medication, there is a risk for noncompliance that needs to be addressed and discussed as a point of shared decision making between the patient and clinician. Unfortunately, tools that are freely available and easy to administer are still relatively difficult to access in this space. The ISBD Targeting Cognition Task Force identified the SCIP (35) for objective assessment and the COBRA (36) for subjective report, as these were felt to be useful assessments for clinicians (24, 32, 37–40). These are now available on the ISBD website (https://www.isbd.org/Cognitive-Assessments). Of note, cutoffs that are indicated for impairment on the SCIP and the COBRA are best used as “rough guides” and should always be considered in the context of patient demographics, mood state, and premorbid functioning.
If cognitive deficits are detected on a cognitive screening assessment, a referral for a neuropsychologist should be considered for a more thorough evaluation, which can further define strengths and weaknesses in the cognitive profile and make personalized recommendations around compensatory strategies to improve QoL, interpersonal relationships, and everyday functioning. A formal assessment can provide a basis for understanding the impact of medical (e.g., cerebrovascular disease or diabetes) or psychiatric (e.g., alcohol use disorder or anxiety disorder) comorbid conditions as well as medication or treatment (e.g., antipsychotics, elevated serum levels of lithium or anticonvulsants, and benzodiazepines). As the importance of targeting cognition for treatment in bipolar disorder moves into the mainstream, it will also be helpful for clinicians to provide psychoeducation to patients and caregivers about cognitive impairment and the benefits of protective health behaviors, such as good sleep hygiene, physical activity, reducing substance use, and treatment adherence.
Research
One of the first papers written by the ISBD Targeting Cognition Task Force was published more than 10 years ago, which was at a time when the field was still in its infancy. Although several research groups were investigating cognition in bipolar disorder, there was little consensus on how and when to best measure the deficits common to bipolar disorder. The goal of this first article was to build a consensus around a research battery to be recommended for use across the globe. This would allow for the interpretation and comparison of scores across studies, as well as the ability to pool data across cohorts, increasing sample size, power, and ability to detect effects (41). A common validated battery would also aid in the examination of the association between cognition and mood symptoms, underlying brain-based mechanisms, and functional and treatment outcomes (41). The result of several consensus-based meetings and discussions was the ISBD Battery for Assessment of Neurocognition (ISBD-BANC), a cognitive battery that is psychometrically sound, able to detect the heterogeneity in cognition observed in bipolar disorder, easy to use, and culturally fair. The proposed battery is appropriate for a variety of research approaches, including in clinical trials and the assessment of treatment effects, and is applicable for international use (35–37, 41–49) (see Table 1). The tasks selected for the ISBD-BANC include a core set of measures initially designed for use in schizophrenia—the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) (42). This was felt to be prudent as regulatory agencies, including the U.S. Food and Drug Administration (FDA) had approved this battery for use in randomized controlled trials targeting cognition in schizophrenia. However, given the evidence that cognitive deficits in bipolar disorder are generally reported to be similar in pattern but less severe than in schizophrenia, early studies focused on assessing how well the MCCB tapped into the deficits noted in bipolar disorder (50). From this work came the acknowledgment of several weaknesses in the assessment of certain domains in the original MCCB, resulting in several recommended substitutions and supplementations to the MCCB when used for bipolar disorder, including replacement of the easier Hopkins Verbal Learning Test (51) from the MCCB with the more difficult California Verbal Learning Test (43). In addition, supplementing the single executive function measure from the MCCB (Mazes) with other tests, such as the Stroop Test (44), Trail Making Test Part B (45), and the Wisconsin Card Sorting Test (46), was indicated to better assay the more subtle impairment seen in bipolar disorder relative to schizophrenia. The ISBD-BANC has been adopted by many investigators around the world over the past decade and continues to be the battery of choice as the field moves toward interventional studies for cognition in bipolar disorder (discussed later). Although a strength of the battery is the relatively low burden imposed by the duration of administration (brief relative to more comprehensive clinical neuropsychological evaluations, which often take 4 or more hours to complete), the battery does not capture all of the areas of cognitive functioning that are relevant to bipolar disorder. Specifically, as discussed later, measures of affective processing, social cognition, and reward processing are absent from this original battery. The landscape of cognition in bipolar disorder is far from completely understood, allowing for many more advances in our understanding of the cognitive factors that drive bipolar disorder and poor outcomes associated with the illness.
| Measure | Time to administer |
|---|---|
| Prescreening cognitive assessment for use in clinical trials | |
| MOCA (47) | 10 min |
| SCIP (35), objective measure | 15 min |
| Brief cognitive assessments for use in clinical settings | |
| SCIP (35), objective measure | 15 min |
| COBRA (36), subjective measure | 10 min |
| ISBD-BANC cognitive domain | |
| Speed of processing | |
| BACS: Symbol coding (42) | 3 min |
| Category fluency: animal naming (42) | 2 min |
| Trail Making Test–Part A (42) | 2 min |
| Attention/vigilance | |
| Continuous Performance Test–Identical Pairs (42) | 13 min |
| Working memory | |
| Wechsler Memory Scale–III Letter–Number Sequencing (42) | 6 min |
| Wechsler Memory Scale–III Spatial Span (42) | 5 min |
| Verbal learning | |
| California Verbal Learning Test (43) | 10 min |
| Visual learning | |
| Brief Visuospatial Memory Test–Revised (42) | 5 min |
| Executive functioning | |
| Stroop Test (44) | 5 min |
| Trail Making Test–Part B (45) | 2 min |
| Wisconsin Card Sorting Testb (46) | 20 min |
| Real-world functioning measures | |
| FAST (37) | 6 min |
| UCSD UPSA-B (48) | 15 min |
| VRFCAT (49) | 30 min |
a
BACS=Brief Assessment of Cognition in Schizophrenia; COBRA=Cognitive Complaints in Bipolar Disorder Rating Assessment; FAST=Functional Assessment Short Test; ISBD-BANC=International Society for Bipolar Disorders Battery for Assessment of Neurocognition; MOCA=Montreal Cognitive Assessment; SCIP=Screen for Cognitive Impairment in Psychiatry; UCSD UPSA-B=Brief University of California, San Diego, Performance-Based Skills Assessment; VRFCAT=Virtual Reality Functional Capacity Assessment Tool.
b
Optional.
Cognition as a Treatment Target in Bipolar Disorder
Currently, there are no approved treatment options that specifically improve cognition in bipolar disorder; however, targeting cognitive impairment in bipolar disorder has emerged as a new treatment priority, with the goal of improving functioning and minimizing societal costs (52). A recent systematic review of randomized clinical trials (RCTs; published between 2015 and 2021) that examined potential procognitive psychological, pharmacological, or biological interventions across mood disorders in remitted patients revealed mixed results (53). Studies that implemented cognitive remediation (CR) provided the most consistent and robust evidence of procognitive effects; of the four studies conducted in patients with bipolar disorder, one yielded positive results on the primary outcome (i.e., global cognition), and the remaining three demonstrated promising effects on secondary or tertiary cognitive outcomes. Of seven studies that examined the procognitive effects of adjunctive pharmacological interventions in mood disorders, only one reported beneficial cognitive effects for bipolar disorder, which were noted after 6 weeks of treatment with lurasidone (54). Negative studies included RCTs of methylene blue (55), docosahexaenoic acid (56), and pramipexole (57, 58). Two studies using various brain stimulation paradigms found selective cognitive improvement (only in specific domains), but these would not have remained statistically significant after applying the Bonferroni correction (59, 60). Of note, the clinical significance of the cognitive improvement after CR interventions and lurasidone treatment is yet to be determined, given that it frequently did not result in any improvement in overall functioning (53). In general, evidence of successful procognitive interventions in bipolar disorder is limited and requires additional study.
Methodological Recommendations for Clinical Trials Targeting Cognition
Given the growing interest in this area, to facilitate the development of targeted interventions for cognitive deficits in bipolar disorder, several guidelines have been published regarding trial design (12, 52, 53). As has previously been recommended for trials focusing on cognitive impairment associated with schizophrenia, a target for indication that is recognized by the FDA, use of a global cognitive composite as the primary outcome in cognition trials for bipolar disorder is recommended, as it is most likely to correspond to improved real-world functioning (52, 53). Indeed, alongside objective cognitive measures that track cognitive improvement, the inclusion of a functional measure as secondary outcomes is important. Although empirical data are generally limited, there are some initial recommendations for functional measures to be included (48, 49). Beyond measurement-based recommendations, lessons learned from prior studies (58) and existing guidelines (12, 41) suggest focusing on patients diagnosed as having bipolar disorder with objective evidence of cognitive impairment at baseline, using a prescreening measure such as the Montreal Cognitive Assessment (47) or the SCIP (35), given the substantial cognitive heterogeneity noted in bipolar disorder (21). Likewise, the inclusion of patients who are affectively stable will mitigate concerns regarding pseudospecificity, which is the nonspecific improvement of cognition due to treatment-related mood improvements (12, 41). Finally, given mounting evidence regarding the importance of vascular risk factors to neurocognition, particularly for individuals with bipolar disorder, there is significant value in obtaining measurements of basic vascular risk factors (e.g., blood pressure, lipids). As the vascular-cognition association is evident even among individuals below clinical cutoffs for vascular risk factors, including youths without medical comorbidity, such approaches are relevant for all individuals with bipolar disorder (61, 62).
Future Directions
Measures of Affective Cognition
Individuals with bipolar disorder are defined by difficulties in emotion regulation, yet surprisingly little research has investigated the complex processes of emotional processing and social cognition in the context of bipolar disorder (63, 64), and no studies have included these as treatment targets. The limited research shows that individuals with bipolar disorder exhibit deficits in affective cognition, including reward processing and decision making (65, 66), facial expression recognition (22, 67), and emotional regulation (68, 69) across all phases of the illness (70), and these impairments are related to mood symptoms (71–74), QoL (75), and social and occupational outcomes (76–79). Although there is increasing recognition of the need to assess and address affective cognition deficits and develop effective treatments, a recent review by the ISBD Targeting Cognition Task Force was unable to provide firm conclusions or strong recommendations given the insufficient literature in this area (e.g., limited number of studies, small effect sizes, and methodological flaws not accounting for heterogeneity) (63). However, this should be seen as an important goal for future work to include the definition of the pattern and extent of impairment in bipolar disorder as well as the identification of appropriate and sensitive measures to be used for bipolar disorder in this domain. Improvement in this domain may have a direct impact on mood stability.
Neurobiologically Relevant Biomarkers
One of the significant challenges in the development of treatment strategies targeting cognitive deficits in bipolar disorder is the lack of sensitive biomarkers for detecting and refining the therapeutic effects of novel pharmacological or psychological treatments (80).
Neuroimaging.
Integrating neuroimaging assessments into cognition trials may provide valuable information on brain-based biomarkers involved in cognitive improvement, which could help to identify early changes in neuronal networks that predict subsequent cognitive improvement and inform the development of novel interventions targeting those networks (52). A recent review by the ISBD Targeting Cognition Task Force provided consensus-based methodological guidance for neuroimaging assessments in procognitive intervention trials (81).
Inflammation-based biomarkers.
Converging evidence from epidemiological, clinical, genetic, postmortem, and preclinical studies suggests a disturbance in immune functioning in bipolar disorder (82). Meta-analytic results confirm that peripheral levels of pro-inflammatory markers are elevated in patients with bipolar disorder compared with those in healthy controls during acute phases of the disease (83). Early in the illness, there is a normalization of cytokines during euthymia (84), but there is purported to be a cumulative burden whereby, after multiple episodes, patients show persistently elevated low-grade inflammation even during remission (83) that coincides with the trajectory of cognitive and functional impairment that is seen in some patients with bipolar disorder (85–90). Specifically, recent studies have linked impaired cognition in bipolar disorder with elevated levels of C-reactive protein (91, 92), interleukin-1 family molecules (88, 90), and tumor necrosis factor (TNF) molecules (87, 93). The TNF family molecules, in particular, may mediate the effect of repeated episodes on brain function in bipolar disorder (93), which points to this molecule as a potential treatment target for cognitive impairment in bipolar disorder.
The field has come a long way over the past few decades to acknowledge cognitive impairment as a core feature in bipolar disorder; establish a clear relationship between cognitive deficits and real-world functioning, making its clinical relevance clear; and embrace cognitive impairment as an independent treatment target of high priority. Additional progress is underway, and the promise of treatment to full recovery is tangible.
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Published in print: Fall 2023
Published online: 16 October 2023
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Dr. Nicoloro-SantaBarbara and Dr. Majd are co-first authors.
Competing Interests
Dr. Burdick reports receiving an honorarium from Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2) for her role as Scientific Director for the Integrated Network. Dr. Nicoloro-SantaBarbara reports receiving consulting fees from Cogent Biosciences. Dr. Miskowiak reports receiving consultancy fees for her advisory work for Gedeon Richter, Janssen, Angelini Pharma, and Lundbeck. Dr. Goldstein acknowledges his position as RBC Investments Chair in Children’s Mental Health and Developmental Psychopathology at The Centre for Addiction and Mental Health (CAMH), a joint Hospital-University Chair between the University of Toronto, CAMH, and the CAMH Foundation. The other authors report no financial relationships with commercial interests.
Funding Information
This work was supported in part by NIMH grant R01 MH124381 (to Dr. Burdick).
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