MEDLINE Abstracts: Bipolar Disorder and Cognitive Functioning

February 23, 2004

What's new concerning bipolar disorder and cognitive functioning? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Psychiatry & Mental Health.

Martinez-Aran A, Vieta E, Reinares M, et al
Am J Psychiatry. 2004;161:262-270

Objective: The study aims were to address neuropsychological functioning across different states of bipolar illness and to determine relationships among clinical features, neuropsychological performance, and psychosocial functioning.
Method: Several domains of cognitive function were examined in 30 depressed bipolar patients (DSM-IV criteria for major depression, Hamilton Depression Rating Scale score ≥17), 34 manic or hypomanic bipolar patients (DSM-IV criteria for manic or hypomanic episode, Young Mania Rating Scale score ≥12), and 44 euthymic bipolar patients (6 months of remission, Hamilton depression scale score ≤8, and Young Mania Rating Scale score ≤6). The comparison group consisted of 30 healthy subjects without history of neurological or psychiatric disorders. A neuropsychological battery assessed executive function, attention, and verbal and visual memory.
Results: The three groups showed cognitive dysfunction in verbal memory and frontal executive tasks in relation to the comparison group. Low neuropsychological performance was associated with poor functional outcome. Impairment of verbal memory was related to the duration of illness and the numbers of previous manic episodes, hospitalizations, and suicide attempts.
Conclusions: A poorer performance was observed in all bipolar groups regarding executive function and verbal memory in relation to the healthy comparison subjects. These cognitive difficulties, especially related to verbal memory, may help explain the impairment regarding daily functioning, even during remission. Further studies should focus on testing, whether optimizing prophylactic pharmacological treatment and psychoeducation might reduce cognitive impairment, and whether bipolar patients would benefit from neuropsychological rehabilitation in order to reduce the impact of cognitive impairment in their overall functioning.

Macqueen G, Young T
Bipolar Disord. 2003;5(suppl 2):53-61

Studies examining cognitive dysfunction in bipolar disorder have documented neuropsychologic impairment in some patients. Recollection memory, attention, and visual information processing may be particularly impaired in patients with bipolar illness. Cognitive impairment appears to worsen with illness progression, and may have a significant impact on function. Pharmacotherapy to treat bipolar disorder including lithium, anticonvulsants, antidepressants, and atypical antipsychotics may have varying effects on cognitive functioning. Treatment with atypical antipsychotics has been associated with improvement in various cognitive measures in patients with schizophrenia, and the little data available in patients with bipolar disorder suggest the potential for similar benefits. Studies to determine if current treatments for bipolar disorder can prevent, delay, or even improve cognitive dysfunction are needed.

Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Cole S, Yolken RH
Psychiatr Serv. 2004;55:54-58

Objective: The purpose of this study was to identify variables associated with employment status among persons with bipolar disorder, including cognitive functioning, severity of symptoms, demographic variables, and variables related to course of illness.
Methods: The authors assessed the current employment status of 117 persons with bipolar disorder. Study participants' cognitive functioning was evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status, the information and letter-number sequencing subtests of the Wechsler Adult Intelligence Scale III, and part A of the Trail Making Test. Symptoms were rated by using the Brief Psychiatric Rating Scale, the Hamilton Depression Scale, and the Young Mania Rating Scale. A stepwise multivariate logistic regression analysis was used to predict employment status.
Results: Fifty-one percent of the study participants had no current work activity, 21 percent worked part-time or as volunteers, and 27 percent had full-time competitive employment. 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 at onset of illness.
Conclusions: Vocational programs for persons with bipolar disorder would benefit from inclusion of a formal cognitive assessment to better assess work potential and to study the predictors of work-related outcomes.

Robertson HA, Kutcher SP, Lagace DC
Bipolar Disord. 2003;5:330-339

Objective: The purpose of this study was to determine the presence or absence of attentional problems and prior diagnosis of ADHD in a cohort of stabilized bipolar I relative to unipolar and normal control.
Method: Indices of attention were obtained from bipolar (n = 44), unipolar (n = 30), and normal controls (n = 45). Measures included: Freedom from Distractibility (FD) Composite Index of the WISC III, Conners' Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), and a checklist measure of subjective cognitive/attentional problems (SIP-AV).
Results: Bipolar (6.8%), unipolar (10%), and no control youth report a prior diagnosis of ADHD. No significant group or sex differences were observed on FD Composite Index, various CPT indices, or the WCST. Despite normative attentional function by objective testing, subjectively experienced cognitive problems in the clinical probands were reported.
Conclusions: This cohort of well-functioning bipolar youth diagnosed on average 3-4 years prior to assessment do not possess attentional deficits based on a variety of objective tests compared to unipolar or control youth, but self report subjective difficulties in attentional/problem solving ability. In contrast to other authors, we do not find that bipolar youth have high rates of comorbid ADHD.

Carey KB, Carey MP, Simons JS
J Nerv Ment Dis. 2003;191:300-308

This study compared psychiatric outpatients who were never, former, and current substance abusers on psychiatric, social, and cognitive functioning. Fifty-six outpatients with schizophrenia spectrum and bipolar disorders volunteered to complete diagnostic and social role function interviews, self-report inventories, and neuropsychological tests. Multinomial logit regression analyses indicated that current and former abusers reported greater subjective feelings of distress than those who never abused. Contrary to expectations, however, both groups of substance abusers performed better on nonverbal cognitive tests compared with those who never abused. Differences in social functioning were also observed: former abusers demonstrated better instrumental role functioning than those who never abused. This pattern of findings challenges assumptions about additive effects of comorbid disorders on cognitive and social functioning.

Shear PK, DelBello MP, Lee Rosenberg H, Strakowski SM
Neuropsychol Dev Cogn Sect C Child Neuropsychol. 2002;8:285-295

Bipolar disorder (BPD) is a serious mental illness that affects children and adolescents at a rate similar to that seen in adults. Extremely little is known, however, about cognitive functioning in childhood and adolescent BPD. The present study represents an initial effort to examine executive functioning in adolescents with BPD who are in a manic or mixed mood state, by collecting data from caregivers about the participants' performance on everyday tasks thought to be mediated by executive functioning abilities, using the Behavior Rating Inventory of Executive Function. In comparison to healthy volunteers, adolescents with BPD exhibited significant elevations across all of the measured functional domains. These elevations were evident even in adolescents with BPD who did not have comorbid ADHD, although they were most prominent in those with comorbidity. The findings suggest that adolescents with BPD have functional deficits on tasks requiring executive functioning skills that are not explicable solely on the basis of comorbid ADHD.

Sobczak S, Honig A, Schmitt JA, Riedel WJ
Neuropsychopharmacology. 2003;28:711-719

Cognitive impairment has repeatedly been described in bipolar disorders (BD). Serotonin (5-hydroxytryptophan; 5-HT) is possibly involved in these cognitive processes, more particularly in executive functions, learning, memory, and attention. The aim of this study was to investigate serotonergic vulnerability and its relation to cognitive functioning in healthy first-degree relatives of BD patients. We investigated the effects of an intravenous (i.v.) tryptophan (Trp) challenge and placebo on cognitive performance in 30 healthy first-degree relatives of bipolar patients (FH) and 15 matched controls in a double-blind crossover design. A distinction was made between relatives of type I BD patients (FH I) and type II BD patients (FH II). Performances on planning, memory, attention, and psychomotor tasks were assessed 3 h after Trp infusion. After Trp, planning and attention were impaired in FH subjects but not in controls. Independent of Trp, FH subjects showed cognitive deficits on memory, focused and divided attention, and psychomotor performance. FH I subjects showed more pronounced cognitive impairments then FH II and controls. In all groups, Trp impaired memory and psychomotor performance significantly. In conclusions, cognitive deficits in FH following Trp may reflect a central 5-HT vulnerability in frontal brain areas. Independent of Trp, cognitive deficits in FH provide evidence for a trait marker for BD.

Miklowitz DJ, Richards JA, George EL, et al
J Clin Psychiatry. 2003;64:182-191

Background: Several studies have established the efficacy of psychosocial interventions as adjuncts to pharmacotherapy in the symptom maintenance of bipolar disorder. This study concerned a new psychosocial approach - integrated family and individual therapy (IFIT) - that synthesizes family psychoeducational sessions with individual sessions of interpersonal and social rhythm therapy.
Method: Shortly after an acute illness episode, 30 bipolar patients (DSM-IV criteria) were assigned to open treatment with IFIT (up to 50 weekly sessions of family and individual therapy) and mood-stabilizing medications in the context of a treatment development study. Their outcomes over 1 year were compared with the outcomes of 70 patients from a previous trial who received standard community care, consisting of 2 family educational sessions, mood-stabilizing medications, and crisis management (CM). Patients in both samples were evaluated as to symptomatic functioning at entry into the project and then every 3 months for 1 year.
Results: Patients in IFIT had longer survival intervals (time without relapsing) than patients in CM. They also showed greater reductions in depressive symptoms over 1 year of treatment relative to their baseline levels. The results could not be explained by group differences in baseline symptoms or pharmacologic treatment regimens.
Conclusion: Combining family and individual therapy with medication may protect episodic bipolar patients from early relapse and ongoing depressive symptoms. Further examination of this integrative model within randomized controlled trials is warranted.

Lam DH, Watkins ER, Hayward P, et al
Arch Gen Psychiatry. 2003;60:145-152

Background: Despite the use of mood stabilizers, a significant proportion of patients with bipolar affective disorder experience frequent relapses. A pilot study of cognitive therapy (CT) specifically designed to prevent relapses for bipolar affective disorder showed encouraging results when used in conjunction with mood stabilizers. This article reports the outcome of a randomized controlled study of CT to help prevent relapses and promote social functioning.
Methods: We randomized 103 patients with bipolar 1 disorder according to the DSM-IV, who experienced frequent relapses despite the prescription of commonly used mood stabilizers, into a CT group or control group. Both the control and CT groups received mood stabilizers and regular psychiatric follow-up. In addition, the CT group received an average of 14 sessions of CT during the first 6 months and 2 booster sessions in the second 6 months.
Results: During the 12-month period, the CT group had significantly fewer bipolar episodes, days in a bipolar episode, and number of admissions for this type of episode. The CT group also had significantly higher social functioning. During these 12 months, the CT group showed less mood symptoms on the monthly mood questionnaires. Furthermore, there was significantly less fluctuation in manic symptoms in the CT group. The CT group also coped better with manic prodromes at 12 months.
Conclusion: Our findings support the conclusion that CT specifically designed for relapse prevention in bipolar affective disorder is a useful tool in conjunction with mood stabilizers.

Martinez-Aran A, Vieta E, Colom F, et al
Neuropsychobiology. 2002;46(suppl 1):16-21

Introduction: Recent studies have suggested that the presence of persistent cognitive dysfunctions in bipolar patients is not restricted to acute episodes, but they persist even during remission states. Nevertheless, there are several methodological pitfalls in most studies, such as unclear remission criteria, diagnostic heterogeneity or small sample sizes.
Patients and Methods: Several domains of cognitive function were examined in 30 depressed bipolar patients [DSM-IV criteria for major depression, Hamilton Depression Scale (HDRS) > or =17] and 30 euthymic bipolar patients (at least 6 months of remission, HDRS < or =8 and Young Mania Rating Scale, YMRS < or =6). Psychosocial functioning was assessed through General Assessment of Functioning.
Results: The two groups showed a similar pattern of neuropsychological performance. However, the depressed group was significantly impaired on the Controlled Oral Word Association Test, FAS (COWAT), a measure of verbal fluency, compared with the euthymic group. On the other hand, functional outcome in euthymic patients was related to verbal fluency, even after controlling for residual depressive symptoms.
Conclusions: Neuropsychological performance was similar in both groups, except for verbal fluency, which was lower in the depressed group. Poor verbal fluency was related to a poor social outcome in euthymic patients. Further research including longitudinal designs aimed at evaluating changes in cognition in these patients is warranted.

Ball J, Mitchell P, Malhi G, Skillecorn A, Smith M
Aust N Z J Psychiatry. 2003;37:41-48

Objective: Acceptance of, and adaptability to illness, are major determinants of adherence to treatment and functional recovery. This paper addresses the major psychosocial factors associated with bipolar disorder and the role of psychological interventions in symptom management and adaptability to the illness experience. A new model is presented highlighting the role of developmental experiences and temperament in determining reactions to bipolar disorder. The authors propose that by addressing reactions to the illness experiences and effects on self-concept through schema-focused cognitive therapy, functional recovery is more likely to occur among those patients functioning below expectation.
Method: A systematic review of the current literature including an Index Medicus/MEDLINE search was conducted, focusing on risk factors, cognitive vulnerabilities and triggers associated with bipolar disorder. Psychological treatments available for the treatment of bipolar disorder are reviewed and details of a novel schema-focused cognitive model for this condition are presented. Traditional models of adaptation to chronic illness are outlined and incorporated into the proposed model. Schema-focused cognitive therapy is proposed as an approach to help patients reduce cognitive vulnerability to relapse in addition to adopting effective mood management strategies.
Results and Conclusions: There is a need for psychological treatments which reduce the risks associated with poor functionality in patients with bipolar disorder. Schema-focused cognitive therapy specifically targets the temperament, developmental experiences and cognitive vulnerabilities that determine adjustment to illness. This proposed treatment, combined with pharmacotherapy, may offer new psychotherapeutic options for the future.

Lagace DC, Kutcher SP, Robertson HA
Am J Psychiatry. 2003;160:100-104

Objective: This study examined mathematical ability in adolescents with bipolar I disorder, compared to adolescents with major depressive disorder and psychiatrically healthy comparison subjects.
Method: Participants (N=119) included adolescents in remission from bipolar disorder (N=44) or major depressive disorder (N=30), as well as comparison subjects (N=45) with no psychiatric history. Participants were assessed with the following measures: the Wide-Range Achievement Test, Revised 2 (WRAT-R2), Peabody Individual Achievement Test, Bay Area Functional Performance Evaluation Task-Oriented Assessment (functional mathematics subtest), Test of Nonverbal Intellegence-2, and a self-report of mathematics performance.
Results: WRAT-R2 and Peabody Individual Achievement Test scores for spelling, mathematics, and reading revealed that adolescents with bipolar disorder had significantly lower achievement in mathematics, compared to subjects with major depressive disorder and comparison subjects. Results for the Test of Nonverbal Intellegence-2 were not significantly different between groups. Adolescents with bipolar disorder took significantly longer to complete the Bay Area Functional Performance Evaluation mathematics task. Significantly fewer adolescents with bipolar disorder (9%) reported above-average mathematics performance, compared with the other groups.
Conclusions: Adolescents with remitted bipolar disorder have a specific profile of mathematics difficulties that differentiates them from both adolescents with unipolar depression and psychiatrically healthy comparison subjects. These mathematics deficits may not derive simply from more global deficits in nonverbal intelligence or executive functioning, but may be associated with neuroanatomical abnormalities that result in cognitive deficits, including a slowed response time. These deficits suggest the need for specialized assessment of mathematics as part of a comprehensive clinical follow-up treatment plan.

McDonough-Ryan P, DelBello M, Shear PK, Ris DM, Soutullo C, Strakowski SM
J Clin Exp Neuropsychol. 2002;24:280-285

It has been hypothesized that children who are at genetic risk to develop bipolar disorder demonstrate deficiencies consistent with the syndrome of nonverbal learning disabilities (NLD); however, this hypothesis has never been tested directly. In the present study, a group of at-risk children (AR group; N = 28) was compared to a demographically matched control group of children of healthy parents (HC group; N = 24) for evidence of a constellation of features associated with NLD. Some characteristic features of NLD were evident, including significant Verbal IQ (VIQ) > Performance IQ (PIQ) discrepancies and psychomotor deficits. However, academic deficiencies in mechanical arithmetic relative to reading and spelling abilities were not demonstrated. These findings replicate and extend the current literature on the cognitive functioning of children of parents with Bipolar disorder (BPD). The results, however, do not support the presence of NLD in these children.

Harmer CJ, Grayson L, Goodwin GM
Biol Psychiatry. 2002;51:298-304

Background: Bipolar disorder is associated with functional and structural abnormalities in the brain circuits involved in processing emotional stimuli. Although impairments of cognitive function have been found to persist in bipolar patients during periods of euthymic mood, it is not known whether abnormalities in emotional processing also occur during these periods of recovery.
Methods: The present investigation assessed the ability of euthymic patients with bipolar disorder to recognize different facial expressions of emotion, compared with matched controls. A nonemotional facial categorization task was used to control for possible nonspecific differences in perception or attention.
Results: In contrast to the small impairments seen in the nonemotional categorization task, patients with bipolar disorder showed a robust facilitation in the discrimination of disgusted facial expressions. The recognition of other basic negative and positive emotions was unchanged.
Conclusions: The present results suggest a selective facilitation of the processes involved in recognizing facial expressions of disgust in patients with bipolar disorder. This difference in perception may be relevant to the decreased self-esteem and social functioning that have been associated with the euthymic phase of this disorder.

Martinez-Aran A, Penades R, Vieta E, et al
Psychother Psychosom. 2002;71:39-46

Background: Recent studies have reported that differences in cognitive performance between schizophrenic and bipolar patients seem to be smaller than expected. Patients with schizophrenia have consistently shown frontal executive dysfunctions, but studies regarding executive abilities in bipolar patients are scarce and discrepant. As executive function has been associated with psychosocial functioning in schizophrenia, we wanted to investigate if such a relationship is also present in bipolar disorder and the differences between the two groups.
Methods: Executive function was assessed in 49 euthymic (at least 6 months in remission, Hamilton Depression Rating Scale < or = 8 and Young Mania Rating Scale < or = 6) bipolar and in 49 schizophrenic, residual-type (with at least 1 year without acute exacerbation and predominant negative symptomatology) patients, by the Wisconsin Card Sorting Test (WCST), FAS Test (COWAT) and Trail Making Test. Baseline clinical and psychosocial variables were controlled and psychopathology evaluated by means of the Positive and Negative Syndrome Scale (PANSS).
Results: The two groups showed a similar pattern of cognitive deficits in tests of executive function, except for the number of categories achieved in the WCST, which was significantly lower in the schizophrenic group (F = 7.26; p = 0.009). Functional outcome was predicted by the negative syndrome (PANSSN) and perseverative errors (WCST) in schizophrenic patients, and general psychopathology (PANSSG) was the best predictor of functional outcome in the bipolar group.
Conclusion: Executive function was a good predictor of functional outcome in the schizophrenic group, whereas clinical variables were more predictive of the bipolar one. Patterns of cognitive disturbances in tasks of executive function are similar in both groups but quantitatively more marked in schizophrenia. Copyright 2001 S. Karger AG, Basel

Bhana N, Perry CM
CNS Drugs. 2001;15:871-904

Olanzapine, a thienobenzodiazepine derivative, is a psychotropic agent that has shown efficacy in the treatment of patients with bipolar I disorder. Olanzapine has a multireceptorial binding profile including a greater affinity for serotonin 5-HT(2A) than for dopamine D(2) receptors. Olanzapine 5 to 20 mg/day demonstrated significantly greater antimanic efficacy than placebo in two double-blind, randomised 3- or 4-week trials of patients with bipolar I disorder of either manic or mixed episodes, with or without psychotic features. Additionally, in one of these trials, improvements in cognitive function and hostility were superior with olanzapine. In cohorts of severely depressed and rapid cycling patients, improvements in manic and depressive symptoms and in manic symptoms only, were superior with olanzapine compared with placebo. Significant improvements from baseline in symptoms of mania, depression, cognitive functioning and hostility were seen with olanzapine in a 49-week extension phase study. In double-blind trials, olanzapine 10 mg/day appeared to have similar antimanic efficacy to oral lithium 400mg twice daily in the treatment of patients with pure mania (4-week small study). In patients with acute manic or mixed episodes olanzapine 5 to 20 mg/day appeared to be more effective than oral valproate semisodium (divalproex sodium) 500 to 2500 mg/day (3-week study) and at least as effective as oral haloperidol 3 to 15 mg/day (12-week study). Preliminary results from a large 6-week placebo-controlled study suggest that olanzapine 5 to 20 mg/day in combination with mood stabilisers (lithium or valproate semisodium) provides effective augmentation of antimanic treatment of patients with bipolar I disorder, with benefits seen in the first week. Adverse events reported significantly more often with olanzapine than with placebo were somnolence, dry mouth, dizziness and bodyweight gain, and in comparison with valproate semisodium were somnolence, dry mouth, increased appetite and bodyweight gain. Olanzapine was generally well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results.
Conclusion: Olanzapine demonstrated superior efficacy compared with placebo in the short-term treatment of patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features, and was generally well tolerated. According to preliminary data the antimanic efficacy of olanzapine appears similar to that of haloperidol and better than that of valproate semisodium in patients with bipolar I disorder experiencing a manic or mixed episode; among nonpsychotic patients with manic or mixed episodes olanzapine appears to be superior to haloperidol. Available data support the choice of olanzapine as an option in the short-term management of mania in patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features.

Bearden CE, Hoffman KM, Cannon TD
Bipolar Disord. 2001;3:106-150; discussion 151-153

Objectives: To present a comprehensive review of the existing neuropsychological and neuroimaging literature on bipolar affective disorder. This review critically evaluates two common conceptions regarding the neuropsychology of bipolar disorder: 1) that, in contrast to schizophrenia, bipolar affective disorder is not associated with general cognitive impairment independent of illness episodes, and 2) relative right hemisphere (RH) dysfunction is implicated in bipolar illness patients, supported by reports of relatively greater impairment in visuospatial functioning, lateralization abnormalities, and mania secondary to RH lesions.
Methods: The major computerized databases (Medline and PSYCInfo) were consulted in order to conduct a comprehensive, integrated review of the literature on the neuropsychology and neuroanatomy of bipolar disorder. Articles meeting specified criteria were included in this review.
Results: In a critical evaluation of the above notions, this paper determines that: 1) while there is little evidence for selective RH dysfunction, significant cognitive impairment may be present in bipolar illness, particularly in a subgroup of chronic, elderly or multiple-episode patients, suggesting a possible toxic disease process, and 2) the underlying functional correlate of these cognitive deficits may be white matter lesions ('signal hyperintensities') in the frontal lobes and basal ganglia, regions critical for executive function, attention, speeded information processing, learning and memory, and affect regulation. While this hypothesized neural correlate of cognitive impairment in bipolar disorder is speculative, preliminary functional neuroimaging evidence supports the notion of frontal and subcortical hypometabolism in bipolar illness.
Conclusions: The etiology of the structural brain abnormalities commonly seen in bipolar illness, and their corresponding functional deficits, remains unknown. It is possible that neurodevelopmental anomalies may play a role, and it remains to be determined whether there is also some pathophysiological progression that occurs with repeated illness episodes. More research is needed on first-episode patients, relatives of bipolar probands, and within prospective longitudinal paradigms in order to isolate disease-specific impairments and genetic markers of neurocognitive function in bipolar disorder.


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