Neuropsychological functions in patients with bipolar I and bipolar II disorder

Objectives:  The literature reports persistent cognitive impairments in patients with bipolar disorder even after prolonged remission. However, a majority of studies have focused only on bipolar I disorder (BP-I), primarily because bipolar II disorder (BP-II) is often underdiagnosed or misdiagnosed. More attention should be paid to the differences between BP-I and BP-II, especially the aspects of neuropsychological functioning. We examined the different neuropsychological functions in BP-I and BP-II patients and compared them with those of healthy controls.
Methods:  The study included 67 patients with interepisode bipolar disorder (BP-I: n = 30; BP-II: n = 37) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function.
Results:  The BP-I group performed poorly on verbal memory, psychomotor speed, and executive function compared to the BP-II and control groups. Both bipolar groups performed significantly less well than the control group on measures of working memory and psychomotor speed, while the BP-II group showed an intermediate level of performance in psychomotor speed compared to the BP-I and control groups. There was no difference between the groups on visual memory.
Conclusions:  BP-I was characterized by reduced performance in verbal memory, working memory, psychomotor speed, and executive function, while BP-II patients showed a reduction only in working memory and psychomotor speed. Cognitive impairment existed in both subtypes of bipolar disorder, and was greater in BP-I patients. Rehabilitation interventions should take into account potential cognitive differences between these bipolar subtypes.     

The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder.

BACKGROUND: Because alterations in cortisol negative feedback inhibition associated with aging are generally opposite of those observed in posttraumatic stress disorder (PTSD), we examined the cortisol and glucocorticoid receptor (GR) response to dexamethasone (DEX) in older trauma survivors.METHODS: Twenty-three Holocaust survivors (9 men, 14 women), 27 combat veterans (all male), and 10 comparison subjects (7 men, 3 women) provided samples for plasma or salivary cortisol and glucocorticoid receptor determination in mononuclear leukocytes at 8:00 AM on the day of, and following, 0.5 mg of DEX at 11:00 PM.RESULTS: Greater percent suppression of cortisol and lymphocyte GR was observed in older trauma survivors with PTSD compared to survivors without PTSD and comparison subjects. There was a significant main effect of depression in the direction of reduced suppression following DEX, consistent with the effects of DEX in major depressive disorder patients. Responses to DEX were uncorrelated with PTSD symptom severity, but cortisol suppression was associated with years elapsed since the most recent, but not focal, traumatic event.CONCLUSIONS: The response to DEX is generally similar in older and younger trauma survivors, but the findings suggest that age, symptom severity, and lifetime trauma exposure characteristics may influence this response.     

Neuropsychological deficits in adolescents with conduct disorder and comorbid bipolar disorder: a pilot study

OBJECTIVE: We report pilot data on neuropsychological deficits in aggressive juvenile offenders with and without bipolar disorder compared with each other and healthy controls. METHOD: We assessed 52 adolescents and their parent or guardians: 36 incarcerated juvenile offenders and 16 community controls using the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Life-Time Version and a neuropsychological testing battery. All incarcerated subjects (n=34) met criteria for Conduct Disorder (CD); 26 are classified as Non-BD-CD, and eight with CD and Bipolar disorder (CD-BD). These subjects were compared to community controls (n=16) matched for age, gender, SES and ethnicity. RESULTS: Relative to controls, the Non-BD-CD subjects' impairments (p<0.05) were in cognitive ability, set shifting/inhibition, planning and verbal memory-language functioning. The CD-BD group displayed impairments (p<0.05) relative to controls in cognitive ability, set shifting, verbal memory-language functioning, and visuospatial tasks. The Non-BD-CD and CD-BD groups however did not display significant differences on most neuropsychological measures compared with each other. When we controlled for Attention Deficit Hyperactivity Disorder, the Non-CD-BP subjects continued to show deficits on Verbal measures where the CD-BD subjects maintained deficits in measures of cognitive ability, verbal measures and visual spatial tests. CONCLUSIONS: Juvenile offender with CD displayed a wide range of deficits on neuropsychological testing compared with controls. Although juvenile offenders with and without BD differed on their clinical presentation, differences on neuropsychological measures are not specific and may be related to comorbid diagnoses.     

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta‐analysis

Objective

An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta‐analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view.

Method

Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task.

Results

Impairments were found for all 11 test‐measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26–0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test‐measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression.

Conclusion

This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta‐analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.     

Verbal memory impairment in new onset bipolar disorder: Relationship with frontal and medial temporal morphology

Objectives. Verbal memory (VM) impairment is a trait feature of bipolar I disorder (BDI) that is present at illness onset and associated with functional outcome. However, little is known about the morphological abnormalities underlying this deficit early in the disease course. This study examined the neurobiological correlates of VM impairment in euthymic newly diagnosed patients, with attention to frontal and medial temporal (MT) structures known to contribute to VM. Methods. Euthymic patients with BDI recently recovered from their first episode of mania (n = 42) were compared with healthy subjects (n = 37) using measures of the California Verbal Learning Test (CVLT-II) associated with frontal and MT functioning. A subset of participants had 3T MRI scan (n = 31 patient group, n = 30 healthy subject group). Hippocampal and prefrontal volumes were analyzed using FreeSurfer 5.1 and correlated with their corresponding CVLT-II subscores. Results. Patients showed decreased performance in total learning as well as short and long delay verbal recall. Consistent with MT dysfunction, they also showed deficits in recognition discriminability and learning slope. In the patient group only, left hippocampal volumes were negatively correlated with these measures. Conclusions. These results suggest that anomalous MT functioning is involved with VM impairment early in the course of BDI.     

Neurocognitive impairment in euthymic young adults with bipolar spectrum disorder and recurrent major depressive disorder

OBJECTIVE: Patients with remitted major depressive disorder (MDD) and bipolar disorder have persistent impairments in executive function and verbal memory that may represent endophenotypic abnormalities. In this study, we examine neurocognitive function in a sample of euthymic young adults with bipolar spectrum disorder (BSD) (Can J Psychiatry 2002; 47: 125-134) and compare this to well-matched samples of young adults with recurrent MDD and controls. METHOD: Twenty-one euthymic young adult patients with BSD were compared with 42 young adult patients with MDD and 33 controls on a neuropsychological battery assessing attention, executive function and verbal memory. RESULTS: Patients with BSD were significantly more impaired than MDD patients and controls on tests of executive function and verbal memory. MDD patients did not differ significantly from controls on verbal memory function but performed less well on a test of executive function. CONCLUSION: Euthymic young adults with BSD had greater impairment on neurocognitive measures associated with prefrontal and hippocampal function than MDD patients and controls. This is a reflection of a strong bipolar diathesis in the BSD group rather than being a consequence of a more severe unipolar illness.     

Neuropsychological symptom dimensions in bipolar disorder and schizophrenia

BACKGROUND: While neurocognitive (NC) impairments have been well documented in schizophrenia (SZ), there is limited data as to whether similar impairments are present in other persistent mental illnesses. Recent data indicate that NC impairments may be manifested in bipolar disorder (BPD) and that they persist across disease states, including euthymia. An important question is whether a comparable structure of NC impairments is present in the 2 diagnostic groups. OBJECTIVE: In a previous factor analytic study, we identified 6 factors to describe the basic underlying structure of neuropsychological (NP) functioning in SZ: Attention, Working Memory, Learning, Verbal Knowledge, Non-Verbal Functions, Ideational Fluency. The goal of this study was to investigate whether this factor structure is generalizable for BPD. METHODS: The BPD sample included patients (n = 155) from an ongoing longitudinal study evaluating BPD at the time of hospitalization for relapse and at multiple time points over the following 2 years. The SZ sample included patients (n = 250) from a 3-year study. For the current examination the baseline NP evaluations were selected for both samples. RESULTS: Exploratory and confirmatory factor analyses in the BPD sample yielded factors similar to those identified in the SZ sample. The coefficients of congruence ranged between 0.66-0.90 for the individual factors, indicating a good overall correspondence between the factor structures in the 2 diagnostic groups. Analysis of covariance (ANCOVA) analysis with education level, full scale-IQ, gender and ethnicity as covariates indicated that SZ patients had markedly worse performance on the Attention and Non-Verbal Functioning factors compared to the BPD patients. CONCLUSIONS: Together, these data suggest that while the same underlying factor structure describes NP functioning in both groups, the profile of impairments appears to vary with the diagnosis.     

Spatial working memory function in twins with schizophrenia and bipolar disorder.

BACKGROUND: Family studies are in conflict as to whether schizophrenia and bipolar disorder have independent genetic etiologies. Given the relatively low prevalence (approximately 1%) of these disorders, the use of quantitative endophenotypic markers of genetic liability might provide a more sensitive strategy for evaluating their genetic overlap. We have previously demonstrated that spatial working memory deficits increase in a dose-dependent fashion with increasing genetic proximity to a proband among the unaffected co-twins of schizophrenic patients. Here, we evaluated whether such deficits might also mark genetic susceptibility to bipolar disorder. METHODS: The Wechsler Memory Scale-Revised Visual Memory Span and Digit Span subtests were administered to 46 schizophrenic patients, 32 of their unaffected co-twins, 22 bipolar patients, 16 of their unaffected co-twins, and 100 control twins, representing unselectively nationwide twin samples. RESULTS: Schizophrenic patients and their unaffected co-twins performed significantly worse than control subjects on the spatial working memory task, whereas only the schizophrenic patients performed significantly below the control subjects on the verbal working memory task. Neither bipolar patients nor their unaffected co-twins differed from control subjects on these measures. CONCLUSIONS: Our findings support the hypothesis that impairment in spatial working memory might effectively reflect an expression of genetic liability to schizophrenia but less clearly to bipolar disorder.     

Neuropsychological dysfunction in bipolar affective disorder: a critical opinion

Data from the imaging literature have led to suggestions that permanent structural brain changes may be associated with bipolar disorder. Individuals diagnosed with bipolar disorder display deficits on a range of neuropsychological tasks in both the acute and euthymic phases of illness, and correlations between experienced number of affective episodes and task performance are commonly reported. These findings have renewed interest in the neuropsychological profile of individuals with bipolar disorder, with deficits of attention, learning and memory, and executive function, asserted to be present. This paper critically reviews five different potential causes of neurocognitive dysfunction in bipolar disorder: (i) iatrogenic, (ii) acute functional changes associated with depression or mania, (iii) permanent structural lesions of a neurodegenerative origin, (iv) permanent structural lesions that are neurodevelopmental in origin, and (v) permanent functional changes that are most likely genetic in origin. Although the potential cognitive effects of residual symptomatology and long-term medication use cannot be entirely excluded, we conclude that functional changes associated with genetically driven population variation in critical neural networks underpin both the neurocognitive and affective symptoms of bipolar disorder. The philosophical implications of this conclusion for neuropsychology are briefly discussed.     

Visuospatial working memory deficits in remitted patients with bipolar disorder: susceptibility to the effects of GABAergic agonists

Pan Y‐J, Hsieh MH, Liu S‐K. Visuospatial working memory deficits in remitted patients with bipolar disorder: susceptibility to the effects of GABAergic agonists.
Bipolar Disord 2011: 13: 365–376. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Visuospatial working memory (VSWM) deficit under high working memory (WM) load deserves further investigation as a potential trait marker for bipolar disorder (BPD). However, VSWM performances may depend on basic neurocognitive processes and are possibly compromised by neurocognitive effects of psychotropic medications. Methods: A total of 32 remitted BPD patients and 39 healthy controls undertook parametric VSWM tasks and assessments for selective attention, sustained attention, psychomotor speed, mental flexibility, and Wechsler Adult Intelligence Scale‐III full IQ. Using a multivariate model and trend analysis and controlling for other basic neurocognitive ability, the effects of mood stabilizers, antipsychotics, GABAergic agonists, and anticholinergics on VSWM performances were explored by post‐hoc analysis comparing performances across WM loads between healthy controls and patients treated and not treated with a specific medication. Results: Remitted BPD patients showed more pronounced performance declines in VSWM performances as WM loads increased, indicating inefficient VSWM processing. The VSWM deficits of remitted patients were independent of their impairments in attentional processes or psychomotor speed. Among the medications, only GABAergic agonists were associated with impaired VSWM performances. Conclusions: Remitted BPD patients had WM‐load‐dependent VSWM processing deficits after controlling for neurocognitive performances. As these deficits were associated with the use of GABAergic agonists, altered GABAergic neurotransmission might be involved with the underlying mechanisms of the impaired VSWM processing of BPD. Since GABAergic agonist use is often continued from the acute to the remitted phase in BPD and might potentially affect the functional recovery, clinicians should be aware of these neurocognitive side effects, even at low dosages. Close monitoring and timely discontinuation of GABAergic agonists is of utmost importance for clinical practice.     

Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report

OBJECTIVE: Patients with remitted bipolar disorder (BD) have persistent impairments in neuropsychological function, particularly in the domains of executive control and declarative memory [Br J Psychiatry 180 (2002) 293]. If these were the phenotypic expression of genetic vulnerability to BD, then healthy subjects with a genetic predisposition to BD would be expected to display the same deficits. This study, therefore, examined neuropsychological function in healthy first-degree relatives of patients with BD. METHOD: A cross-sectional design was employed to compare the performance of 17 unaffected first-degree relatives of BD patients and 17 demographically matched controls on a range of neuropsychological tests. RESULTS: Relatives were significantly impaired on Backward Digit Span, Spatial Span and on tasks of visuospatial declarative memory in comparison with controls. Psychomotor performance and verbal declarative memory were intact, as were non-working memory aspects of executive performance. CONCLUSION: The selective deficits in executive control and declarative memory exhibited by relatives in this study have previously been reported in euthymic BD patients suggesting they may be useful endophenotypic markers of genetic vulnerability to BD.     

Neuropsychological functioning in youth with bipolar disorder.

BACKGROUND: Little is known about the neuropsychological status of youth with bipolar disorder (BPD) or whether cognitive deficits in this population are accounted for by comorbidity with attention deficit/hyperactivity disorder (ADHD). We compared neuropsychological and academic functioning of youth with and without DSM-IV BPD, controlling for effects of comorbid ADHD. METHODS: Fifty-seven youth with BPD and 46 healthy control subjects were assessed on a battery of clinical neuropsychological measures including subtests from the Wechsler Intelligence Scales for Children and Adults (Third Editions), the Stroop, the Wisconsin Card Sorting Test, the Rey-Osterreith Complex Figure, an auditory working memory Continuous Performance Test, a measure of verbal learning, and the Wide Range Achievement Test-Third Edition. RESULTS: Bipolar disorder was associated with impairments on subtests reflecting sustained attention, working memory, and processing speed after controlling for ADHD. Additionally, decrements of moderate effect sizes were found for measures of interference control, abstract problem solving, and verbal learning but did not meet criteria for statistical significance. CONCLUSIONS: After controlling for ADHD, youth with BPD show neuropsychological deficits similar to impairments found in adults with the disorder. Further studies are needed to understand the clinical implications of these impairments as well as their role in the underlying risk for pediatric BPD.     

Neuropsychological profile in bipolar disorder: a preliminary study of monotherapy lithium-treated euthymic bipolar patients evaluated at a 2-year interval

Objective: To investigate the cognitive impairment of a sample of euthymic bipolar patients treated with lithium monotherapy at baseline in a 2‐year longitudinal study. Method: Fifteen DSM‐IV‐TR bipolar out‐patients and 15 healthy‐matched controls were cognitively assessed twice over a 2‐year follow‐up. All patients underwent lithium monotherapy on the first evaluation, and they were euthymic in both evaluations. Cognitive assessment was performed by means of a neuropsychological test battery tapping into the main cognitive domains (executive function, attention, processing speed, verbal memory and visual memory). Results: Repeated measures multivariate analysis of variance showed that the bipolar disorder group was cognitively impaired in the executive domain, attention and processing speed, and such deficits were maintained over time. Conclusion: Our results showed that executive dysfunction is the main long‐term neuropsychological deficit of bipolar disorder. Also, the persistence of these deficits did not seem to be influenced by any clinical or pharmacological variables.     

Declarative memory impairment in pediatric bipolar disorder

OBJECTIVES: Impaired verbal declarative memory has been proposed as a trait marker for adult bipolar disorder. However, similar impairments in juvenile-onset bipolar disorder have not been yet documented. Here, we assessed declarative memory in a large sample of clinically well-characterized children with bipolar disorder. METHODS: Forty-one children and adolescents with bipolar disorder [21 bipolar I disorder (BP-I), 10 bipolar II disorder (BP-II), and 10 bipolar disorder, not otherwise specified (BP-NOS)] and 17 demographically matched healthy participants completed a standardized learning and memory test. RESULTS: BP-I children recalled and recognized significantly fewer words than healthy subjects, whereas children with BP-II and BP-NOS did not differ from controls. However, individuals with BP-NOS made more perseverative errors and intrusions than the other groups. Severity of mood symptomatology was not associated with memory performance in any bipolar subtype. CONCLUSIONS: Findings suggest that declarative memory impairments in juvenile BP-I are similar to those seen in the adult form of the illness. These impairments do not appear to be secondary to clinical state; rather, they may reflect trait-related impairments. Distinct performance patterns in BP-I, BP-II, and BP-NOS suggest that the broadly defined phenotype is significantly heterogeneous, and may not be informative for pathogenetic investigations of bipolar disorder.     

Genetic dissection of glucocorticoid receptor function in the mouse brain

In the brain, glucocorticoids exert functions in neurogenesis, synaptic plasticity and behavioural responses, as well as in the control of hypothalamic-pituitary-adrenal axis activity. The generation of mice harbouring germline mutations that result either in loss or in gain of glucocorticoid receptor function provided a useful tool for understanding the role of glucocorticoids in the brain in vivo . The improvement of genomic technologies additionally allowed the establishment of mouse models with function-selective point mutations of the receptor as well as the generation of mice harbouring spatially and/or temporally restricted loss of glucocorticoid receptor, specifically within the brain. These models will provide the opportunity to better understand the mechanisms involved in glucocorticoid signalling within the nervous system.     

Dexamethasone suppression test in borderline personality disorder: impact of PTSD symptoms

The purpose of the present study was to investigate the impact of post-traumatic stress disorder (PTSD) symptoms on hypothalamic-pituitary-adrenal axis feedback regulation in 18 female patients with borderline personality disorder (BPD) and 21 healthy controls. Reduced feedback sensitivity was found in BPD patients with a low number of PTSD symptoms, while findings in the BPD group with a high number of PTSD symptoms did not differ from those in controls. The results suggest a hypo-suppression in the dexamethasone suppression test in BPD with few PTSD symptoms.     

Differential working memory impairment in bipolar disorder and schizophrenia: effects of lifetime history of psychosis

BACKGROUND: Although bipolar disorder and schizophrenia have long been viewed as distinct illnesses, there is growing evidence that these two complex diseases share some common genes, which may manifest as overlapping neuropsychological impairments. Although working memory dysfunction has been proposed to be central to the pathophysiology of schizophrenia, it has received less attention in studies of bipolar disorder. METHOD: We applied measures of working memory to patients with schizophrenia (n = 15), patients with schizoaffective disorder (n = 15), patients with psychotic (n = 11) and non-psychotic (n = 15) bipolar disorder, and demographically matched healthy subjects (n = 32), in order to determine the extent to which these groups show common or unique impairments. RESULTS: While patients with bipolar disorder (with and without psychotic features) and those with schizophrenia/schizoaffective disorder were impaired on backward digit span, only patients with a lifetime history of psychotic features, regardless of diagnosis, were impaired on spatial delayed response task. CONCLUSIONS: Backward digit span performance is comparable in bipolar disorder and schizophrenia, and may be an appropriate endophenotypic marker that cuts across diagnostic categories. In contrast, spatial working memory performance clearly distinguishes non-psychotic bipolar disorder patients from patients with functional psychosis.