Late-life Bipolar Disorder Research Articles

Decreased Brain-Derived Neurotrophic Factor in Older Adults with Bipolar Disorder

Decreased levels of brain derived neurotrophic factor (BDNF) have been found in adult patients with bipolar disorder (BD) compared with a comparison group, yet there are no data specifically examining this in geriatric patients. The objective of this study was to examine whether euthymic late-life BD patients have lower BDNF levels than healthy comparators. Cross-sectional study. Clinics at the University of Pittsburgh and the Centre for Addiction and Mental Health (Toronto). Older patients with BD (age ≥50 years, N = 118) and similarly aged healthy comparators (N = 76). There were both BD type I (N = 91) and type II (N = 27) patients. Serum BDNF levels were assessed in BD patients and healthy comparators. We found lower levels of BDNF in patients with BD than in healthy comparators (9.0 ± 6.2 versus 12.3 ± 8.9 pg/µg, t(192) = -3.01, p = 0.002), which remained even after controlling for age, sex, lithium use, and site (F(1,176) = 4.32, p = 0.039). This decrease was found specifically in patients with BD type I (8.0 ± 5.5 versus 12.3 ± 8.9 pg/µg, t(165) = 3.7, Bonferroni p < 0.001), but not type II (12.0 ± 7.5 versus 12.3 ± 8.9 pg/µg, t(101) = 0.14, Bonferroni p = 1.0). Older patients with BD have lower serum levels of BDNF compared with similarly aged comparators. These effects appear to be specific to patients with BD type I. Future studies are needed to investigate the impact of reduced BDNF levels on cognition, mood, and other aspects of BD throughout the life course.

Poster Number: EI 19 - Medical Comorbidity in Late-Life Bipolar Disorder: A Comparison of Lithium, Valproate, and Other Pharmacotherapies

Poster Number: EI 19 - Medical Comorbidity in Late-Life Bipolar Disorder: A Comparison of Lithium, Valproate, and Other Pharmacotherapies

Poster Number: EI 18 - Farewell Mood Stabilizers? Current Canadian Psychotropic Medication Prescribing Patterns in Late-Life Bipolar Disorder

Poster Number: EI 18 - Farewell Mood Stabilizers? Current Canadian Psychotropic Medication Prescribing Patterns in Late-Life Bipolar Disorder

Cognitive impairment in late‐life bipolar disorder is not associated with Alzheimer's disease pathological signature in the cerebrospinal fluid

Cognitive impairment is a common feature of late-life bipolar disorder (BD). Yet, there is limited information on the biological mechanisms associated with this process. It is uncertain whether cognitively impaired patients with BD may present the Alzheimer's disease (AD) bio-signature in the cerebrospinal fluid (CSF), defined as a combination of low concentrations of the amyloid-beta peptide (Aβ1-42 ) and high concentrations of total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau). In this study, we sought to determine whether cognitive impairment in elderly patients with BD is associated with the AD CSF bio-signature. Seventy-two participants were enrolled in the study. The test group comprised older adults with BD and mild cognitive impairment (BD-MCI; n=16) and the comparison groups comprised patients with dementia due to AD (n=17), patients with amnestic MCI (aMCI; n=14), and cognitively healthy older adults (control group; n=25). CSF samples were obtained by lumbar puncture and concentrations of Aβ1-42 , T-tau and P-tau were determined. CSF concentrations of all biomarkers were significantly different in the AD group compared to all other groups, but did not differentiate BD-MCI subjects from aMCI subjects and controls. BD-MCI patients had a non-significant reduction in CSF Aβ1-42 compared to controls, but this was still higher than in the AD group. Concentrations of T-tau and P-tau in BD-MCI patients were similar to those in controls, and significantly lower than those in AD. Cognitively impaired patients with BD do not display the so-called AD bio-signature in the CSF. We therefore hypothesize that cognitive deterioration in BD is not associated with the classical pathophysiological mechanisms observed in AD, i.e., amyloid deposition and hyperphosphorylation of microtubule-associated tau protein.

Medical comorbidity, acute medical care use in late-life bipolar disorder: a comparison of lithium, valproate, and other pharmacotherapies

Bipolar disorder is associated with high rates of medical comorbidity, particularly in late life. Little is known about medical health service utilization and potential effects of bipolar pharmacotherapy. We hypothesized that lithium use would not be associated with higher rates of medical hospitalization. Population-based retrospective cohort study of 1388 bipolar disorder patients aged ≥66years discharged from a psychiatric hospitalization in Ontario, Canada, between 2006 and 2012. Patients were divided into lithium users, valproate users, and non-lithium/non-valproate users. The main outcome was acute non-psychiatric, medical/surgical hospitalization during 1-year follow-up. The rate of medical hospitalizations was 0.22 per patient-year. Time-to-medical hospitalization did not differ among lithium, valproate, and non-lithium/non-valproate users after adjusting for age, sex, past medical hospitalization, and antipsychotic use. Lithium, valproate, and non-lithium/non-valproate users did not differ markedly in terms of reason for medical hospitalization, 1-year acute medical health utilization outcomes, and medical comorbidity rates. There were high rates of health service use for medical conditions among older adults with bipolar disorder, but this did not appear to be associated with lithium use, compared to valproate and other medication use (e.g., antipsychotics). A proactive collaborative care approach may prevent medical service utilization in severe late-life bipolar disorder.

Asenapine in the treatment of older adults with bipolar disorder.

In spite of growing numbers of older people, there are few treatment studies on late-life bipolar disorder (BD). This was a 12-week prospective, open-label trial to assess efficacy and tolerability of adjunct asenapine in non-demented older adults (≥ 60 years) with sub-optimal previous response to BD treatments. Asenapine was initiated at 5 mg/day and titrated as tolerated. Effects on global psychopathology were measured with Clinical Global Impression, bipolar version (CGI-BP), and the Brief Psychiatric Rating Scale (BPRS). Mood polarity severity was measured with the Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale, and Young Mania Rating Scale. Other outcomes included the World Health Organization Disability Assessment Schedule II. Fifteen individuals were enrolled (mean age 68.6, SD 6.12; 53% female; 73% Caucasian, 13% African American, and 7% Asian). There were 4/15 (27%) individuals who prematurely terminated the study, whereas 11/15 (73%) completed the study. There were significant improvements from baseline on the BPRS (p < 0.05), on CGI-BP overall (p < 0.01), and on CGI-BP mania (p < 0.05) and depression (p < 0.01) subscales. The mean dose of asenapine was 11.2 (SD 6.2) mg/day. The most common reported side effects were gastrointestinal discomfort (n = 5, 33%), restlessness (n = 2, 13%), tremors (n = 2, 13%), cognitive difficulties (n = 2, 13%), and sluggishness (n = 2, 13%). Older people with BD had global improvements on asenapine. Most reported adverse effects were mild and transient, but adverse effects prompted drug discontinuation in just over one quarter of patients. Although risks versus benefits in older people must always be carefully considered, asenapine may be a treatment consideration for some non-demented geriatric BD patients.

Bipolar disorder in the elderly: a cohort study comparing older and younger patients

The purpose of this study was to analyze differences in clinical and socio-demographic characteristics between older and younger bipolar outpatients paying special attention to depressive symptoms in a large, naturalistic cohort. Five hundred and ninety-three DSM-IV-TR bipolar outpatients were enrolled. Clinical characteristics were assessed according to DSM-IV-TR (SCID-I). Subjects were categorized into two groups according to current age (older OBD: age>65years; younger-YBD: age<65years). About 80% of patients were younger (N=470), and a fifth were older (N=123), with a mean age of 77.30years in OBD. Older patients were more likely to be married, not qualified, bipolar II, with depressive polarity of first episode, higher age at illness onset, higher age at first hospitalization. They were more likely to present with depressive predominant polarity, with lifetime history of catatonic, psychotic and melancholic features, age at illness onset >40years, as well as suffering from more medical comorbidities when compared to younger bipolars. The clinical presentation of bipolar disorder in late life would be defined more frequently by melancholic depressive features and a predominantly depressive polarity. These results suggest that treatment strategies for elderly bipolar patients should focus in the prevention of depressive episodes.

Neuroimaging Findings in Late-Onset Schizophrenia and Bipolar Disorder

In recent years, there has been an increasing interest in late-onset mental disorders. Among them, geriatric schizophrenia and bipolar disorder are significant health care risks and major causes of disability. We discussed whether late-onset schizophrenia (LOS) and late-onset bipolar (LOB) disorder can be a separate entity from early-onset schizophrenia (EOS) and early-onset bipolar (EOB) disorder in a subset of late-life schizophrenia or late-life bipolar disorder through neuroimaging studies. A literature search for imaging studies of LOS or LOB was performed in the PubMed database. Search terms used were "(imaging OR MRI OR CT OR SPECT OR DTI OR PET OR fMRI) AND (schizophrenia or bipolar disorder) AND late onset." Articles that were published in English before October 2013 were included. There were a few neuroimaging studies assessing whether LOS and LOB had different disease-specific neural substrates compared with EOS and EOB. These researches mainly observed volumetric differences in specific brain regions, white matter hyperintensities, diffusion tensor imaging, or functional neuroimaging to explore the differences between LOS and LOB and EOS and EOB. The aim of this review was to highlight the neural substrates involved in LOS and LOB through neuroimaging studies. The exploration of neuroanatomical markers may be the key to the understanding of underlying neurobiology in LOS and LOB.

Aging changes and medical complexity in late-life bipolar disorder: emerging research findings that may help advance care.

Demographic trends globally point in the direction of increasing numbers of older people with serious and chronic mental disorders, such as bipolar disorder (BD). While there has been growing sophistication and understanding in treatments for BD generally, data specific to older people with BD are limited. Recent reviews, secondary analyses and some new research confirm complexity and aging-related issues relevant to later-life BD. Confounding variables that must be considered when studying older BD individuals include clinical heterogeneity, medical comorbidity, cognitive impairment and concomitant psychotropic medication. This article will review current and emerging data on aging- and disease-related issues that complicate assessment and treatment of older individuals with BD. We will discuss common comorbid medical conditions that affect BD elders, how aging may affect cognition and treatment, including the effects of lithium and other psychotropic drugs on the aging brain, and recent research using neuroimaging techniques that may shed light on understanding the mechanisms of illness progression and on treatment response. Finally, we will discuss implications for future work in geriatric BD.

Neuroimaging and neurocognitive abnormalities associated with bipolar disorder in old age

Cognitive dysfunction is prevalent in older adults with bipolar disorder (BD). High white matter hyperintensity (WMH) burden, a marker of white matter disease, detected on T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) has been consistently reported in BD across all age ranges, including older adults. Yet, whether high WMH burden is related to the excess cognitive impairment present in older adults with BD is unknown. Therefore, we examine whether higher WMH burden is related to worse cognitive function in older adults with BD. This is a cross-sectional study of 27 non-demented BD patients aged ≥50 years and 12 similarly aged mentally healthy comparators (controls). Subjects underwent both brain MRI and comprehensive neurocognitive assessment. We employed correlational analyses to evaluate the burden of WMH and the relationship between WMH and cognitive function. Although BD subjects had worse performance in all cognitive domains, BD subjects had less total WMH burden (t[13.4] = -3.57, p = 0.003). In control subjects, higher WMH was related to lower global cognitive function (ρ = -0.57, n = 12, p = 0.05). However, WMH did not correlate with neuropsychological performance in BD subjects. Further, BD and control subjects did not differ with respect to total gray and hippocampal volumes. Cognitive dysfunction in late-life BD does not appear to be due primarily to processes related to increased WMH or reduced gray matter volume. Future longitudinal studies should examine other potential neuroprogressive pathways such as inflammation, mitochondrial dysfunction, serum anticholinergic burden, and altered neurogenesis.

Understanding Bipolar Disorder in Late Life

The aim of this study was to examine the demographic, clinical, and treatment correlates of bipolar disorder (BD) in outpatients 65 years or older and to compare patients with BD subtype I (BD-I) versus BD subtype II (BD-II) and patients with early onset (EO; <=50 years old) versus late onset (LO; >50 years old) of the illness. Sixty-nine consecutive outpatients with BD were included. Diagnosis was delayed for a mean of 14.1 years, significantly longer in patients with EO (18.6 years) than with LO (3.3 years). Mild to moderate depressive symptoms were detected in 29% of the patients. The patients were receiving a mean of 3 different psychotropic medications. Antidepressantswere more frequently prescribed to patients with BD-II than to patients with BD-I (75.80% vs. 48.60%) and to patients with EO (71.7%) than to LO (35.3%). Geriatric BD has similar clinical characteristics with those of younger ages, and these do not seem to greatly differ with subtype or age of onset.

A quantitative review of neurocognition in euthymic late‐life bipolar disorder

A sizeable body of work has consistently documented that a number of euthymic mixed-age bipolar disorder subjects exhibit prominent impairments in a variety of cognitive domains. By contrast, knowledge about neuropsychological functioning in elderly patients is scant, despite being necessary for the adequate treatment of this population and the understanding of illness evolution. The aim of this study was to combine findings from the available literature in order to examine the pattern and extent of cognitive deficits in euthymic late-life bipolar disorder subjects. A literature search was conducted through the online databases PubMed, ScienceDirect, EBSCO, and Wiley-Blackwell, covering the period between January 1990 and April 2012. Effect sizes reflecting patient-control differences for 10 cognitive variables were extracted from selected investigations and combined by means of meta-analytical procedures. No significant patient-control differences were found for global cognitive status as assessed with the Mini-Mental State Examination and the Clock Drawing Test. Significant overall effect sizes (Hedges' g) of between 0.61 and 0.88 were noted for sustained attention, digit span (forwards and backwards), delayed recall, serial learning, cognitive flexibility, and verbal fluency (phonemic and categorical). The extent of cognitive dysfunction in euthymic late-life bipolar disorder subjects may be, on average, similar to that reported for remitted young adult patients. Larger effect sizes of impairment may be associated with late illness onset. Implications and future directions for research are proposed.

How Can We Improve the Prognosis of Bipolar Disorder in Late Life?

How Can We Improve the Prognosis of Bipolar Disorder in Late Life?

Cognitive impairment and dementia in late-life bipolar disorder

This work aims to review the most recent publications on cognitive impairment and dementia associated with bipolar disorder (BPD), especially in the elderly. In the last years, a growing number of studies aiming at better understanding of cognitive impairment in BPD were found. Impairments found in BPD were compared with other psychiatric disorders and primary cognitive diseases. The impact of cognitive impairment on functionality was also recently highlighted. With respect to neurobiology, studies that explored inflammatory, neurotrophic and pathological cascades possibly associated with BPD and cognition were published. Finally, the first study covering treatment of cognitive impairment was carried out with pramipexole, and it raised important methodological issues for future research in BPD. Cognitive impairment and dementia in BPD should be better explored with cognitive and functionality protocols along with biological and neuroimaging markers.

1992 – Late onset bipolar disorder: challenges in diagnosis and treatment

Mania has been estimated to represent the cause of 4.6% to 18.5% of all geriatric psychiatric admissions and 10% of new-onset mania cases have been found to occur in individuals over the age of 50. Age of onset can have a significant impact on the nature and course of bipolar illness. Review the current literature of pharmacologic management of late-life bipolar disorder and discuss the differential diagnosis. Brief literature review. Case report and literature review. We describe a case of a 76-years-old female with elevated mood, verbosity, distractibility, irritability, inadequate social behavior, reduced requirement of sleep, increased physical activity, impulsive business investments. Several tests were made: analytical study, CT scan and neuropsychological evaluation, none with significant alterations. She was treated with an antipsychotic drug with improvement of symptoms. There is a limited evidence base for treatment of bipolar disorder in the elderly and further controlled studies are needed. Current data suggest that valproate and lamotrigine may be better tolerated as mood stabilizers than lithium. Preliminary reports suggest a role for the use of atypical antipsychotic in older adults with bipolar disorder although potential benefit must be balanced against the potential risks of treatment. In treating elderly bipolar patients, one has to keep in mind that pharmacokinetic and pharmacodynamic changes that occur with ageing, associated with frequent concomitant medical illnesses and their treatments, are likely to increase the risk of adverse events and drug interactions.

New Onset of Bipolar Disorder in Late Life

The subset of patients with late-life onset of bipolar disorder is widely recognized to represent an etiologically diverse group with high rates of neurologic comorbidities. Efforts to characterize the unique clinical and neurobiological features of this heterogeneous population have yielded inconsistent findings. Although there is growing evidence that geriatric-onset bipolar disorder is often attributable to a variety of secondary organic etiologies, we would like to present a case of bipolar disorder emerging in late life where no clear organic cause was identified. This case highlights the importance of a broad differential diagnosis when approaching new-onset manic symptoms among geriatric patients in an inpatient setting.

Medical and Psychiatric Comorbidities Among Elderly Individuals With Bipolar Disorder

The common comorbid conditions that accompany late-life bipolar disorder (BD) have not been well studied. This is a literature review on psychiatric and medical comorbidities among elderly individuals with BD. A focused literature review searched PubMed. Inclusion criteria were original research reports, in English, until June 2009, specifically focused on medical and psychiatric comorbidities in BD individuals over the age of 50. A limited number of studies were identified. Most involved small samples (n < 100). Metabolic syndrome, respiratory and cardiovascular conditions, and endocrine abnormalities are common, with patients having an average of 3 to 4 medical comorbid conditions. Approximately 4.5% to 19% of elderly individuals with BD have dementia. Rates of psychiatric comorbidity appear lower than in younger BD populations, with the most common concurrent psychiatric illnesses being anxiety and substance use disorders. Rates of comorbid medical conditions appear similar to rates among geriatric patients without BD. Elderly individuals with BD are burdened by multiple concomitant medical disorders. In contrast to the elevated rates of medical comorbidity, rates of psychiatric comorbidity appear lower in elderly individuals with BD than in younger populations with BD. Greater awareness of concurrent medical conditions might help inform coordinated care that considers both mental and physical health among geriatric patients with BD.

Late-Life Bipolar Disorder

As our society ages, it is critical that we expand our understanding of how best to provide care and services for the growing population of elderly patients with bipolar disorder (BD). For many years, there was a dearth of publications focused on the topic of late-life BD. Indeed, the current literature base on geriatric BD is still insufficient to address critical questions regarding etiology, assessment, treatment, and prognosis. In this special issue, we focus on BD in later life and present a series of articles that we believe will be of interest to clinicians and researchers. In the first article, Al Jurdi and colleagues used data from the National Institute of Mental Health-funded Systematic Treatment Enhancement Program for BD (STEP-BD) and compared the presence and severity of acute mood elevation (mania and hypomania) and acute depression symptoms between younger (20-59 years old) and older individuals ( 60 years old). With the exception of distractibility, all acute depression symptoms presented with comparable frequency and severity between younger and older individuals. Huang and colleagues examined the rate of silent cerebral infarctions and risk factors for cerebral infarction in 43 elderly patients with BD using whole-brain magnetic resonance imaging. Their analyses focus on the relationships between cerebral vascular disease, metabolic illness, and bipolarity. Their analyses support the understanding that there are shared neuroprogressive pathways that underlie vascular medical comorbidity, cognitive dysfunction, and mood dysregulation in BD. Lala and Sajatovic summarize the literature on comorbidity in bipolar adults aged >50 years. Psychiatric comorbidity rates appear lower than in younger BD populations, with the most common concurrent illnesses being anxiety and substance use disorders. While older adults with BD have on average of 3 to 4 medical comorbid conditions, medical condition rates appear similar among geriatric patients with and without BD. Avari and Young present a case report of BD in a patient with antiphospholipid syndrome (APS). They present this case in the context of one previous case report and literature linking APS-related immune markers to various neuropsychiatric disorders. They discuss potential vascular and direct mechanisms pertinent to an association of APS with BD, if demonstrated. They encourage additional case descriptions and suggest possible systematic studies. Bhalerao and colleagues report on mortality risk with use of atypical antipsychotics in geriatric BD. US national data from the Department of Veterans Affairs included registry information on 4717 patients 65 years and identified 6-month mortality rates with a new start of an atypical antipsychotic or valproic acid and derivatives during fiscal years 2001 to 2008. The authors report differences in mortality risks among individual antipsychotic agents, a finding that clearly demonstrates the need for continued investigation on currently used psychotropic agents in bipolar elders. Gildengers and colleagues present a secondary analysis from clinical trial data on correlates of treatment response in depressed older adults with BD. They are interested in whether an agent such as lamotrigine that appears to reduce oxidative stress is particularly effective in patients with high vascular medical comorbidity in the context of depressive illness. They present an approach to target treatment to those individuals who may respond most robustly to this type of intervention. Using a novel imaging technique, phosphorus magnetic resonance spectroscopy, Forester and colleagues examine bioenergetic pathways related to bipolar depression in older adults. They look at whether the forward rate constant of creatine kinase (kfor) is altered in older adults with bipolar depression and whether CoEnzyme Q 10, known to have properties that enhance mitochondrial function, increases kfor in older bipolar individuals compared with untreated ageand sex-matched controls. Their study builds on the growing interest in dysfunctional mitochondrial energy metabolism in BD. Rej and Shulman present a systematic review of all studies pertaining to the effects of lithium on the kidney in older adults. They note that age-specific studies are few and conclude that there is no compelling evidence for general avoidance of use of lithium in elderly individuals based on concerns about renal effects. They suggest guidelines for the approach to lithium management in elderly individuals. Finally, Al Jurdi and colleagues conducted a secondary analysis based upon the baseline data from 100 bipolar elderly individuals participating in a pharmacologic treatment Journal of Geriatric Psychiatry and Neurology 25(1) 4-5 a The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0891988712439691 http://jgpn.sagepub.com

Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder

Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear. We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI). We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between-group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls. The major limitation of our study is the small number of patients with bipolar disorder. Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder.

Use of Lithium in the Treatment of Bipolar Disorder in Late-Life

Lithium is the oldest and still one of the most frequently prescribed mood stabilizers in the treatment of bipolar disorder. Nonetheless, the evidence for lithium efficacy in older patients with bipolar disorder is almost entirely extrapolated from younger adult patients. Here we review the literature on lithium in older patients with bipolar disorder, concentrating on the past 3years. A definitive study demonstrating the efficacy and safety of lithium in older patients with bipolar disorder is still missing. However, several lines of indirect evidence suggest that it is beneficial and advantageous over other mood stabilizers in the acute and maintenance treatment of late-life bipolar disorder. In addition, lithium may have unique properties as a regenerative therapeutic with specific benefits in reducing the cognitive impairment and suicide rates associated with bipolar disorder across the adult lifespan. Aging-associated pharmacokinetic and pharmacodynamic changes as well as increased rates of medical comorbidities and polypharmacy predispose older patients to a higher risk of lithium toxicity. Careful monitoring and adjustment of lithium dosage is especially important in older adults to minimize the risk of toxicity.