John L. Beyer

Cortical White Matter Microstructural Abnormalities in Bipolar Disorder

This article reports on preliminary findings describing microstructural abnormalities in the white matter of cortical areas thought to be associated with bipolar disorder. In all, 14 patients with bipolar disorder and 21 nonpsychiatrically ill control subjects underwent MR imaging including a diffusion tensor imaging (DTI) pulse sequence (six directions, b=1000 mm2/s). DTI data were analyzed on a workstation using a program that allowed calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within the following three white matter fiber tracts bilaterally: the orbital frontal cortex, and the superior and middle frontal gyri. These values were compared across patient groups. The left and right orbital frontal white matter exhibited significantly higher ADC values in bipolar subjects than control subjects on both the left (p=0.028) and right (p=0.011). Microstructural changes in the white matter of the orbital frontal areas as reflected by increased ADC values appear to be associated with bipolar disorder. Further research is needed to better understand the interaction of microstructural changes and bipolar symptoms and whether these changes are specific to bipolar disorder.

Medical comorbidity in bipolar disorder: reprioritizing unmet needs

Purpose of review The aim of this review is to synthesize results from extant investigations which report on the co-occurrence of bipolar disorder and medical comorbidity. Recent findings We conducted a MEDLINE search of all English-language articles published between January 2004 and November 2006. Most studies report on medical comorbidity in bipolar samples; relatively fewer studies report the reciprocal association. Individuals with bipolar disorder are differentially affected by several ‘stress-sensitive’ medical disorders notably circulatory disorders, obesity and diabetes mellitus. Neurological disorders (e.g. migraine), respiratory disorders and infectious diseases are also prevalent. Although relatively few studies have scrutinized the co-occurrence of bipolar disorder in medical settings, individuals with epilepsy, multiple sclerosis, migraine and circulatory disorders may have a higher prevalence of bipolar disorder. A clustering of traditional and emerging (e.g. immunoinflammatory activation) risk factors presage somatic health issues in the bipolar disorder population. Iatrogenic factors and insufficient access to primary, preventive and integrated healthcare systems are also contributory. Summary Somatic health issues in individuals with bipolar disorder are ubiquitous, under-recognized and suboptimally treated. Facile screening for risk factors and laboratory abnormalities along with behavioral modification for reducing medical comorbidity are warranted.

Medical Comorbidity in a Bipolar Outpatient Clinical Population

The presence of medical illnesses among inpatients with bipolar disorder is known to complicate treatment and lengthen hospital stay. However, except for a few specific diseases, little is known about prevalence of medical illnesses in bipolar outpatients and the effect it may have on treatment. The authors sought to assess the presence of medical illnesses in a large outpatient clinical sample of bipolar patients, and the effect that medical illnesses may have on the clinical assessment and treatment of the underlying bipolar disorder. Using the Duke University Medical Center clinical database, the authors categorized the medical diagnoses of 1379 patients who were treated with bipolar disorder from 2001 to 2002 through outpatient psychiatric clinics. The prevalence of medical comorbidities was examined, as well as the effect their presence had on the clinicians assessment of disease severity and time to improvement. As expected, medical comorbidities increased with age. The most common systemic illnesses in bipolar outpatients were Endocrine and Metabolic Diseases (13.6% of the sample), Diseases of the Circulatory System (13.0%), and Diseases of the Nervous System and Sense Organs (10.7%). Significant specific diseases included cardiovascular diseases/hypertension (10.7%), COPD/asthma (6.1%), diabetes (4.3%), HIV infection (2.8%), and hepatitis C infection (1.9%). Clinicians assessed greater severity of illness in patients with increasing numbers of comorbid conditions; however, the time to recovery was not significantly effected by the presence of medical comorbidity. In conclusion, comorbid medical illnesses are common in bipolar outpatients, increasing with age. HIV rates may be increased relative to population norms. Their presence compounds the severity of the illness at time of presentation.

Methodology and Preliminary Results From the Neurocognitive Outcomes of Depression in the Elderly Study

A methodology is presented for following a cohort of older depressed patients to examine neurocognitive outcomes of depression. A total of 265 depressed individuals and 138 healthy, nondepressed controls age 60 and older who completed at least 1 year of follow-up data underwent periodic clinical evaluation by a geriatric psychiatrist. A subset of 141 patients and 137 controls had neuropsychological testing. A consensus panel of experts reviewed 63 depressed subjects with suspected cognitive impairment. Twenty-seven individuals in the depressed group were assigned diagnoses of dementia, including 11 with Alzheimer’s disease, 8 with vascular dementia, and 8 with dementia of undetermined etiology. In addition, 25 individuals had other forms of cognitive impairment, and 11 were considered cognitively normal. Among elderly controls, 2 developed substantial cognitive impairment with clinical diagnoses of dementia. Among the depressed group, the incidence rates for dementia for this age are much higher than would be expected. These results are consistent with prior evidence linking depression and later dementia. Future studies are needed to examine neuroimaging and genetic, clinical, and social predictors of neurocognitive decline in depression.

Pharmacotherapy of Bipolar Disorder in Old Age Review and Recommendations

The authors reviewed the evidence-base for pharmacological treatment of mania and bipolar (BP) depression in late life. Treatment benefits and side effects may be modified by age-associated factors, such as neurocognitive impairments. Lithium and divalproex have most often been studied in elderly patients, and both may be efficacious in acute treatment of mania, but there are no controlled efficacy or effectiveness trials. The role of atypical antipsychotic agents remains to be clarified. Similarly, there are no systematic studies of the treatment of BP depression in elderly patients. The authors make suggestions for management and delineate priorities for research.

Hyperintense MRI lesions in bipolar disorder: A meta-analysis and review

Background: Cortical and subcortical hyperintensities in magnetic resonance imaging (MRI) scans are thought to represent areas of ischemic damage to brain tissue. Researchers have focused on the possible role these lesions may have in psychiatric disorders, including bipolar disorder. In 1997, the proposed ‘vascular mania’ diagnosis suggested utilizing not only the presence of strokes, but also confluent hyperintensities in its diagnostic criteria. This study was conducted to use meta-analytic techniques to investigate the association of hyperintensities and bipolar illness and to evaluate the current state of the literature. Methods: Using the PubMed and MEDLINE databases, we conducted a systematic literature search of studies investigating hyperintensities in subjects with bipolar disorder and controls or other psychiatric illnesses. We identified 44 publications from which 35 studies were included for review and 27 were selected for meta-analysis. Summary statistics of the prevalence were estimated through odds-ratios and confidence interval. Heterogeneity of the results across studies was tested using Q-statistics. Results: Meta-analysis identified an odds ratio of 2.5 (95% CI 1.9, 3.3) for hyperintensities in bipolar subjects compared to controls; however, there was significant heterogeneity among the studies (Q-statistics = 32; p = 0.04). This finding was most prominent for adolescents and children where the odds ratio was 5.7 (95% CI 2.3, 13.7). Deep white matter hyperintensities (odd ratio 3.2; 95% CI 2.2, 4.5) and subcortical grey matter hyperintensities (odds ratio 2.7; 95% CI 1.3, 2.9) were more strongly associated with bipolar subjects. There were no differences between bipolar subjects and controls for perivascular hyperintensities (odds ratio 1.3; 95% CI 0.8, 1.9). Though hyperintensities were numerically greater in bipolar subjects, meta-analysis did not demonstrate any significant differences between bipolar subjects and unipolar depression subjects (OR 1.6; 95% CI 0.9, 2.7) nor subjects with schizophrenia (OR 1.5; 95% CI 0.9, 2.7). Conclusions: This meta-analysis continues to support the association of bipolar disorder and hyperintensities, especially in the deep white matter and subcortical grey matter. It also highlights the increased incidence in children and adolescence with bipolar disorder. However, hyperintensities are not specific to bipolar disorder, but appear at similar rates in unipolar depression and schizophrenia. Thus, the role of hyperintensities in the pathogenesis, pathophysiology, and treatment of bipolar disorder remains unclear. Further studies are required that are large enough to decrease the heterogeneity of the samples and MRI techniques, assess size and location of hyperintensities, and the impact on treatment response. Coordination with newer imaging techniques, such as diffusion tensor imaging (DTI) may be especially helpful in understanding the pathology of these lesions.

A report on older‐age bipolar disorder from the International Society for Bipolar Disorders Task Force

In the coming generation, older adults with bipolar disorder (BD) will increase in absolute numbers as well as proportion of the general population. This is the first report of the International Society for Bipolar Disorder (ISBD) Task Force on Older‐Age Bipolar Disorder (OABD).

Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia

Background TOR1A encodes a chaperone-like AAA-ATPase whose ΔGAG (ΔE) mutation is responsible for an early onset, generalised dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalised dystonia (DYT1), a potential genetic contribution of TOR1A to the more prevalent and diverse presentations of late onset, focal dystonia has been suggested. Results A novel TOR1A missense mutation (c.613T→A, p.F205I) in a patient with late onset, focal dystonia is reported. The mutation occurs in a highly evolutionarily conserved region encoding the AAA-ATPase domain. Expression assays revealed that expression of F205I or ΔE, but not wildtype TOR1A, produced frequent intracellular inclusions. Conclusions A novel, rare TOR1A variant has been identified in an individual with late onset, focal dystonia and evidence provided that the mutation impairs TOR1A function. Together these findings raise the possibility that this novel TOR1A variant may contribute to the expression of dystonia. In light of these findings, a more comprehensive genetic effort is warranted to identify the role of this and other rare TOR1A variants in the expression of late onset, focal dystonia.

Age-dependent reduction of amygdala volume in bipolar disorder.

The amygdala is hypothesized to play a critical role in mood regulation, yet its involvement in bipolar disorder remains unclear. The aim of the present study was to compare measurements of amygdala volumes in a relatively large sample of bipolar disorder patients and healthy controls ranging in age from 18 to 49 years. Subjects comprised 54 adult patients meeting DSM-IV criteria for bipolar disorder and 41 healthy controls matched for age, sex, and education. Magnetic resonance imaging (1.5 T) was performed to obtain volumetric measurements of the amygdala using a manual region-of-interest tracing method with software that allowed simultaneous visualization of the amygdala in three orthogonal planes. The anterior head of the hippocampus was removed in the sagittal plane prior to amygdala volumetry measurement. Multiple regression analysis was computed on amygdala volume measurements as a function of diagnosis, age, sex, and cerebral volume. Bipolar patients showed an age-related reduction of amygdala volume, but controls did not. Among bipolar subjects, amygdala volume was unrelated to medication history. There were no significant hemispheric or sex interactions with the main effects. Results support a role for amygdala dysfunction in bipolar disorder which appears most robustly in older relative to younger adult patients. Differential aging effects in bipolar disorder may compromise amygdala integrity and contribute to mood dysregulation.

Managing depression in geriatric populations.

BACKGROUND Late life depression is an increasingly acute public health concern due to the quickly expanding population of elderly in the US. The last few years has witnessed an explosion in the research literature changing our understanding of this disease. METHODS Published studies over the past decade focusing on the epidemiology, phenomenology, comorbidity, and treatment of depression in the elderly were reviewed. RESULTS The prevalence and phenomenology of depression in late-life varies with age. It remains highly prevalent in the elderly population, and certain vulnerable populations of older adults are at special risk. Further, the morbidity of late-life depression on physical health, social support systems, and overall functioning is considerable, making depression a leading cause of disability in elderly adults and a risk factor for mortality and suicide as well. Findings suggest a heterogeneity in etiology and in treatment response among older adults with depression, and differences from younger adults as well. CONCLUSIONS This paper reviews our current understanding of late life depression and the implications for treatment and prevention. In addition, we review current research questions and future considerations in this field.