Treatment of Functional Impairment in Patients with Bipolar Disorder

Traditionally, functional impairment has received little attention in bipolar disorder, despite the fact that many patients experience significant impairments in daily life. In the last decade, research has changed its focus from clinical remission to functional recovery in bipolar patients as a priority. A literature review of this topic will allow us provide an overview of the relevance of functional impairment as well as the potential factors that can predict or contribute to low functioning in bipolar disorder (BD). Treatment approaches should consider not only euthymia as a goal but also cognitive and functional improvement of patients with such a complex disorder. Functional remediation and psychoeducation among psychological interventions may help to enhance functioning. The combination of cognitive enhancers and cognitive/functional remediation programs may help in improving cognitive and functional impairments. Early interventions are essential to prevent cognitive deficits and disability.     

Functional Impairment,Stress, and Psychosocial Intervention in Bipolar Disorder

The longitudinal course of bipolar disorder (BD) is highly impairing. This article reviews recent research on functional impairment in the course of BD, the roles of social and intrafamilial stress in relapse and recovery, and the role of adjunctive psychosocial interventions in reducing risk and enhancing functioning. Comparative findings in adult and childhood BD are highlighted. Life events and family-expressed emotion have emerged as significant predictors of the course of BD. Studies of social information processing suggest that impairments in the recognition of facial emotions may characterize both adult- and early-onset bipolar patients. Newly developed psychosocial interventions, particularly those that focus on family and social relationships, are associated with more rapid recovery from episodes and better psychosocial functioning. Family-based psychoeducational approaches are promising as early interventions for children with BD or children at risk of developing the disorder. For adults, interpersonal therapy, mindfulness-based strategies, and cognitive remediation may offer promise in enhancing functioning.     

Resting-State fMRI Connectivity Impairment in Schizophrenia and Bipolar Disorder

Background: Schizophrenia and bipolar disorder share aspects of phenomenology and neurobiology and thus may represent a continuum of disease. Few studies have compared connectivity across the brain in these disorders or investigated their functional correlates. Methods: We used resting-state functional magnetic resonance imaging to evaluate global and regional connectivity in 32 healthy controls, 19 patients with bipolar disorder, and 18 schizophrenia patients. Patients also received comprehensive neuropsychological and clinical assessments. We computed correlation matrices among 266 regions of interest within the brain, with the primary dependent measure being overall global connectivity strength of each region with every other region. Results: Patients with schizophrenia had significantly lower global connectivity compared with healthy controls, whereas patients with bipolar disorder had global connectivity intermediate to and significantly different from those of patients with schizophrenia and healthy controls. Post hoc analyses revealed that compared with healthy controls, both patient groups had significantly lower connectivity in the paracingulate gyrus and right thalamus. Patients with schizophrenia also had significantly lower connectivity in the temporal occipital fusiform cortex, left caudate nucleus, and left thalamus compared with healthy controls. There were no significant differences among the patient groups in any of these regions. Lower global connectivity among all patients was associated with worse neuropsychological and clinical functioning, but these effects were not specific to any patient group. Conclusions: These findings are consistent with the hypothesis that schizophrenia and bipolar disorder may represent a continuum of global disconnectivity in the brain but that regional functional specificity may not be evident.Key words: resting-state fMRI, schizophrenia, bipolar disorder, connectivity     

Functional Impairment in Patients with Panic Disorder

Objective Anxiety and depression and sociodemographic factors such as age, gender, education level, income, and marital status among people with panic disorder (PD) are associated with functional impairment in the areas of work, social, and family. Although both PD-specific scales such as the Panic Disorder Severity Scale (PDSS) and Anxiety Sensitivity Inventory-Revised (ASI-R) and early trauma have been investigated, their relationship with functional impairment in PD patients has not been clarified. Methods This study included 267 PD patients. The PDSS, Beck Depression Inventory (BDI), ASI-R, and Early Trauma Inventory were used. Pearson’s correlation and multiple linear regression analyses were performed. The Sheehan Disability Scale (SDS) was administered to assess the functional impairment level in PD patients. Results Our findings showed that high levels of PDSS, BDI, and ASI-R were significantly correlated with the functional impairment among PD patients. Multiple regression analyses showed that PDSS, BDI, and ASI-R can predict the functional impairment levels, and PDSS and ASI-R were significantly associated with lost and underproductive days in PD patients. Conclusion Panic-specific symptoms, depression, and AS are associated with functional impairment level in PD patients. Elevated symptom severity can play a role by affecting productivity and daily responsibilities in PD patients.     

SHORT COMMUNICATION: Apolipoprotein E genotype and Cognition in Bipolar Disorder

Apolipoprotein E (APOE) has been extensively studied as a risk factor for sporadic and late onset Alzheimer's Disease (AD). APOE allele*3, the most frequent variant, is not associated to cognitive dysfunction (CD) or to increased AD risk. Differently, the *4 allele is a well‐established risk factor for CD, while the *2 allele is associated with survival and longevity. CD is an important feature of Bipolar Disorder (BD) and recent data suggest that CD may be one of its endophenotypes, although controversial results exist. The aim of this research is to study the association of APOE genotype (APOE) and neurocognitive function in a sample of drug free young BD‐type I patients. Sample consisted of 25 symptomatic BD (type I) patients (age 18–35 years old). They were submitted to an extensive neuropsychological evaluation and genotyped for APOE. Subjects with allele*2 presented better cognitive performance. The presence of allele*4 was associated with worse performance in a few executive tasks. APOE*3*3 was associated with overall severe dysfunction on cognitive performance. In young individuals with nontreated BD‐type I, APOE may predict cognitive performance. Further and larger studies on APOE and cognition in BD are required to clarify whether APOE is a BD cognitive endophenotype.     

Differentiating Patterns of Amygdala-Frontal Functional Connectivity in Schizophrenia and Bipolar Disorder

Background:

Insight into the neural mechanisms underlying the shared and disparate features of schizophrenia (SZ) and bipolar disorder (BD) is limited. The amygdala and prefrontal cortex (PFC) appear to have crucial roles in SZ and BD, yet abnormalities appear to manifest differently in the 2 disorders.

Methods:

Eighteen participants with SZ, 18 participants with BD, and 18 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Resting-state functional connectivity (rsFC) between the PFC and the amygdala divided into 3 subregions (the laterobasal, centromedial, and superficial amygdala) was examined using probabilistic anatomic maps. For each participant, rsFC maps of the 3 amygdala subregions were computed and compared across the 3 groups.

Results:

Compared with the HC group, we found significant differences in rsFC between the amygdala and PFC in the SZ and BD groups. In direct comparison between the SZ and BD groups, distinct patterns of rsFC between the amygdala and PFC were observed, particularly in the superficial amygdala. RsFC between the amygdala and the dorsal lateral PFC was significantly decreased in the SZ group, whereas rsFC between the amygdyala and the ventral PFC was significantly decreased in the BD group.

Conclusions:

These results strongly suggest dorsal vs ventral PFC differentiation in amygdala-PFC neural system abnormalities between SZ and BD. These regional differences in SZ and BD may give rise to the differences in clinical characteristics observed in SZ and BD, and may implicate potential avenues for differentiating the 2 disorders during early stages of illness.Key words: schizophrenia, bipolar disorder, resting state, functional connectivity, amygdala, prefrontal cortexSchizophrenia (SZ) and bipolar disorder (BD) have long been viewed as separate neuropsychiatric disorders; however, the distinctiveness of these 2 disorders from each other has also long been questioned. SZ and BD have shared symptomatology, and neurocognitive deficits persist in affected individuals in both disorders.¹ Additionally, SZ and BD share similar susceptibility genes² and frequently co-occur within families.³ While the debate regarding the distinctions between SZ and BD continues, understanding of the neural basis for the shared and disparate features of the 2 disorders remains limited. Recently, convergent evidence suggests disruptions within the frontotemporal neural systems that subserve emotional and cognitive processing in both SZ and BD, including abnormalities in 2 regions with critical roles in this system, the amygdala and prefrontal cortex (PFC).^4,5While it appears that the amygdala and PFC are shared regions for abnormalities in SZ and BD, the manifestation of abnormalities within these regions may differ between the 2 disorders. Postmortem histological studies provide preliminary evidence of reduced amygdala volumes and alterations in gene expression in the amygdala in SZ.^6,7 Reduced amygdala volumes in SZ have been confirmed by several magnetic resonance image (MRI) studies and recent meta-analysis studies.^8,9 Postmortem histological studies have also demonstrated abnormalities in the amygdala in BD. These studies have shown decreased glial density and neuron somal size in the amygdala in BD.^7,10 However, while decreased amygdala volume is one of the most consistent neuroimaging findings in pediatric BD,¹¹ findings of abnormalities in amygdala volume in adult BD, although frequently reported, are inconsistent.¹²With respect to the PFC, previous studies have found differences in frontal activation between SZ and BD using task-related functional MRI.^13,14 Moreover, other studies have found decreased activation in the dorsal PFC in SZ,^15,16 whereas studies using similar methods have found altered activation in the ventral PFC (VPFC) in BD.^17,18 In this article, the dorsal PFC is defined as including the dorsal lateral PFC (DLPFC) and dorsal anterior cingulate cortex (ACC), and the VPFC is defined as including the orbitofrontal cortex (OFC), the inferior and rostral frontal cortices, ventral and rostral components of the ACC. These contrasting PFC described above are of considerable interest as the dorsal PFC has been associated with working memory impairment, a core cognitive process abnormality in SZ.¹⁹ Whereas the VPFC has been associated with hedonic processes²⁰ linked to the core psychopathology of BD.The regional differences between SZ and BD observed in the PFC (dorsal vs ventral) suggest that differences between the 2 disorders may also exist in the connectivity between the PFC and regions such as the amygdala. The amygdala has multiple reciprocal channels of communication with the dorsal PFC through the hippocampus,²¹ and it is highly interconnected with the VPFC.²² The cingulum and uncinate fasciculus provide substantial connections between the amygdala and the dorsal and ventral PFC.^23–25 Additionally, the amygdala is a complex structure comprised of multiple nuclei with varied function and roles. Differences in human resting-state FC (rsFC) patterns of the laterobasal (LB), centromedial (CM), and superficial (SF) amygdala have been previously reported in a recent resting-state fMRI study in healthy control (HC) individuals.²⁶ Moreover, the SF amygdala has been particularly implicated in emotional processing, for which differences between SZ and BD have been demonstrated.^27,28In recent years, rsFC has been successfully applied for mapping complex neural circuits. Coherent spontaneous blood oxygen level-dependent (BOLD) activity during rest among specific subsets of brain regions is thought to reflect the natural organization of brain networks and may have significant implications regarding the pathophysiology of psychiatric disorders. We are not aware of any studies directly comparing SZ and BD with regards to rsFC between the amygdala and PFC.In this study, we utilized a region-of-interest (ROI)–based approach to examine rsFC in individuals with SZ and BD, and HC participants. We selected the amygdala as the ROI and focused on its rsFC with the PFC. Given the differences in function and rsFC within the amygdala, we examined the amygdala as 3 subregions, the LB, CM, and SF amygdala, to explore rsFC differences between these subregions and the PFC in the 3 groups (SZ, BC, and HC). Subdivision of the amygdala in this study was based on known differences in functional roles and connections with other brain regions and a recently developed stereotaxic, cytoarchitectonic maps.²⁹ We hypothesized that both the SZ and BD groups would show altered rsFC between the amygdala and PFC when compared with the HC group; furthermore, we hypothesized that, in direct comparison between the SZ and BD groups, altered rsFC between the amygdala and dorsal PFC would be more prominent in SZ, whereas it would be more prominent with the VPFC in BD.     

Bipolar Disorder

Manic–depressive (bipolar) disorder is a severe, relapsing mental illness that shares characterstics both with major depressive disorder and with serious mental illnesses such as schizophrenia. Like schizophrenia, it is a chronic disorder, and is treated primarily in the specialty mental health sector. Rates of appropriate treatment are low. Functional outcome is compromised for the majority of individuals who have this disorder. Societal costs are exceeded only by those for schizophrenia. Existing cost calculations likely underestimate societal costs because of underestimating functional impact and neglecting to account for the substantial proportion of individuals who are institutionalized outside of the health care system (e.g., in prison). Little is known as yet regarding manic–depressive disorder in historically underserved groups and in vulnerable groups such as the elderly. There are major lacunae with regard to this disorder in the grant portfolios of all federal agencies mandated to address the needs of Americans with serious mental illnesses. The authors in the context of the Wider NIMH Affective Disorders Workgroup propose several specific recommendations to address the needs of this costly and underresearched disorder.     

Insight in Bipolar Disorder

Although there has been interest in insight in bipolar disorder, research has not been as developed as in schizophrenia. The Medline, Embase, and PsychInfo data bases were searched. The key words used in the search were "bipolar", "mania", "manic", "awareness", and "insight". Books, editorials, letters, and reports on pediatric subjects were excluded. Abstracts or full texts were screened for relevance. Better insight is associated with better adherence to treatment and better outcomes. Impairments of executive functions and memory, as well as higher severity of psychotic symptoms, are associated with impairments of insight. Insight is more impaired during an illness episode than during remission, in mixed than in pure manic episodes, in bipolar II than in bipolar I patients, in pure mania than in bipolar or unipolar depression. Psychosocial treatments improve insight and outcomes. There is a need for integration of quantitative assessment methods and their introduction into research and clinical practice.     

Bipolar Disorder and Violence

Violent behavior presents many social, legal, and clinical problems. A number of models have been developed to explain violence, representing a variety academic disciplines and theoretical orientations. Unfortunately none of these approaches have led to a comprehensive understanding of violence and aggression. The issue of violence is particularly perplexing in connection with the role of psychiatric disorders as contributing factors. Several psychiatric conditions, including bipolar disorder, have been implicated with increased rates of violent behavior. This paper examines various models of violence, influences on violent behavior, and violence associated with psychiatric disorders. Particular attention is devoted to the connection between bipolar disorder and violence.     

Meta-analysis of Cognitive Impairment in First-Episode Bipolar Disorder: Comparison With First-Episode Schizophrenia and Healthy Controls

Neurocognitive deficits are evident both in established schizophrenia and bipolar disorder (BP). However, it has been suggested that schizophrenia, but not BP, is characterized by neurodevelopmental abnormalities that can lead to cognitive deficits at the earliest stages of the illness. The aim of this meta-analytic review was to compare neurocognitive deficits in first-episode BP (FEBP) with healthy controls and first-episode schizophrenia (FES) patients. The current meta-analysis included a total of 22 adult studies and involved comparisons of 533 FEBP patients with 1417 healthy controls and 605 FEBP and 822 FES patients. FEBP patients were significantly impaired in all cognitive domains (d = 0.26–0.80) and individual tasks (d = 0.22–0.66) investigated. FES patients significantly underperformed FEBP patients in most cognitive domains (d = 0.05–0.63) and on individual tasks (d = 0.13–0.77). Neuropsychological impairment, which is comparable to chronic BP, was evident in FEBP. Similar to chronic patients, cognitive functions in FEBP lie intermediate between FES and healthy controls. Neurodevelopmental factors are likely to play a significant role not only in schizophrenia but also in BP.Key words: bipolar disorder, cognition/mania, psychosis, schizophrenia     

Staging Bipolar Disorder

The purpose of this study was to analyze the evidence supporting a staging model for bipolar disorder. The authors conducted an extensive Medline and Pubmed search of the published literature using a variety of search terms (staging, bipolar disorder, early intervention) to find relevant articles, which were reviewed in detail. Only recently specific proposals have been made to apply clinical staging to bipolar disorder. The staging model in bipolar disorder suggests a progression from prodromal (at-risk) to more severe and refractory presentations (Stage IV). A staging model implies a longitudinal appraisal of different aspects: clinical variables, such as number of episodes and subsyndromal symptoms, functional and cognitive impairment, comorbidity, biomarkers, and neuroanatomical changes. Staging models are based on the fact that response to treatment is generally better when it is introduced early in the course of the illness. It assumes that earlier stages have better prognosis and require simpler therapeutic regimens. Staging may assist in bipolar disorder treatment planning and prognosis, and emphasize the importance of early intervention. Further research is required in this exciting and novel area.