Enhancing Brain Health and Well-Being in Older Adults: Innovations in Lifestyle Interventions.

PURPOSE OF REVIEW: This article will provide clinicians with guidance on helping older adult patients make lifestyle changes to enhance brain health and well-being. RECENT FINDINGS: Evidence suggests that physical activity might be helpful in improving cognitive functioning. The data on the benefits of cognitive activity is inconsistent and not as robust. The MediDiet, DASH, and MIND diets have been associated with better cognitive health. Sleep hygiene and cognitive behavioral therapies are considered first line evidence-based treatments for insomnia and the maintenance of healthy sleep patterns. Mindfulness based interventions have been shown to reduce anxiety, depression, and stress, and can help some older adults manage pain more constructively. Evidence-based information regarding the four topics of exercise, nutrition, sleep, and mindfulness is reviewed, so that clinicians may be better able to optimize care for their older adult patients.

The Use of Antidepressants in Bipolar Depression.

Depression remains a significant debilitating and frequent phase of illness for patients with bipolar disorder. There are few FDA-approved medications for its treatment, only one of which includes a traditional antidepressant (olanzapine-fluoxetine combination), despite studies that demonstrate traditional antidepressants are one of the most commonly prescribed class of medications for bipolar patients in a depressive episode. While traditional antidepressants remain the primary option for treatment of unipolar depression, their use in bipolar depression has been controversial due to a limited efficacy evidence and the concern for potential harm. This chapter reviews the current data concerning the use of traditional antidepressants in bipolar disorder, and the current expert treatment guideline recommendations for their use.

Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

OBJECTIVE: Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire). RESULTS: Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo. CONCLUSION: The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses.

Predictors of recurrence in remitted late-life depression.

BACKGROUND: Late-life depression (LLD) is associated with a fragile antidepressant response and high recurrence risk. This study examined what measures predict recurrence in remitted LLD. METHODS: Individuals of age 60 years or older with a Diagnostic and Statistical Manual - IV (DSM-IV) diagnosis of major depressive disorder were enrolled in the neurocognitive outcomes of depression in the elderly study. Participants received manualized antidepressant treatment and were followed longitudinally for an average of 5 years. Study analyses included participants who remitted. Measures included demographic and clinical measures, medical comorbidity, disability, life stress, social support, and neuropsychological testing. A subset underwent structural magnetic resonance imaging (MRI). RESULTS: Of 241 remitted elders, approximately over 4 years, 137 (56.8%) experienced recurrence and 104 (43.2%) maintained remission. In the final model, greater recurrence risk was associated with female sex (hazard ratio [HR] = 1.536; confidence interval [CI] = 1.027-2.297), younger age of onset (HR = 0.990; CI = 0.981-0.999), higher perceived stress (HR = 1.121; CI = 1.022-1.229), disability (HR = 1.060; CI = 1.005-1.119), and less support with activities (HR = 0.885; CI = 0.812-0.963). Recurrence risk was also associated with higher Montgomery-Asberg Depression Rating Scale (MADRS) scores prior to censoring (HR = 1.081; CI = 1.033-1.131) and baseline symptoms of suicidal thoughts by MADRS (HR = 1.175; CI = 1.002-1.377) and sadness by Center for Epidemiologic Studies-Depression (HR = 1.302; CI, 1.080-1.569). Sex, age of onset, and suicidal thoughts were no longer associated with recurrence in a model incorporating report of multiple prior episodes (HR = 2.107; CI = 1.252-3.548). Neither neuropsychological test performance nor MRI measures of aging pathology were associated with recurrence. CONCLUSIONS: Over half of the depressed elders who remitted experienced recurrence, mostly within 2 years. Multiple clinical and environmental measures predict recurrence risk. Work is needed to develop instruments that stratify risk.

Advances in Pharmacotherapy of Late-Life Depression.

This paper reviews recent research on late-life depression (LLD) pharmacotherapy, focusing on updated information for monotherapy and augmentation treatments. We then review new research on moderators of clinical response and how to use the information for improved efficacy. RECENT FINDINGS: A recent review shows that sertraline, paroxetine, and duloxetine were superior to placebo for the treatment of LLD. There is concern that paroxetine could have adverse outcomes in the geriatric population due to anticholinergic properties; however, studies show no increases in mortality, dementia risk, or cognitive measures. Among newer antidepressants, vortioxetine has demonstrated efficacy in LLD, quetiapine has demonstrated efficacy especially for patients with sleep disturbances, and aripiprazole augmentation for treatment resistance in LLD was found to be safe and effective. Researchers have also been identifying moderators of LLD that can guide treatment. Researchers are learning how to associate moderators, neuroanatomical models, and antidepressant response. SSRI/SNRIs remain first-line treatment for LLD. Aripiprazole is an effective and safe augmentation for treatment resistance. Studies are identifying actionable moderators that can increase treatment response.

Longitudinal Cognitive Outcomes of Clinical Phenotypes of Late-Life Depression.

OBJECTIVE: Late-life depression is associated with cognitive deficits and increased risk for cognitive decline. The purpose of the study was to determine whether clinical characteristics could serve as phenotypes informative of subsequent cognitive decline. Age at depression onset and antidepressant remission at 3 months (acute response) and 12 months (chronic response) were examined. METHODS: In a longitudinal study of late-life depression in an academic center, 273 depressed and 164 never-depressed community-dwelling elders aged 60 years or older were followed on average for over 5 years. Participants completed annual neuropsychological testing. Neuropsychological measures were converted to z-scores derived from the baseline performance of all participants. Cognitive domain scores at each time were then created by averaging z-scores across tests, grouped into domains of episodic memory, attention-working memory, verbal fluency, and executive function. RESULTS: Depressed participants exhibited poorer performance at baseline and greater subsequent decline in all domains. Early-onset depressed individuals exhibited a greater decline in all domains than late-onset or nondepressed groups. For remission, remitters and nonremitters at both 3 and 12 month exhibited greater decline in episodic memory and attention-working memory than nondepressed subjects. Three-month remitters also exhibited a greater decline in verbal fluency and executive function, whereas 12-month nonremitters exhibited greater decline in executive function than other groups. CONCLUSION: Consistent with past studies, depressed elders exhibit greater cognitive decline than nondepressed subjects, particularly individuals with early depression onset, supporting the theory that repeated depressive episodes may contribute to decline. Clinical remission is not associated with less cognitive decline.

Effects of stressful life events on cerebral white matter hyperintensity progression.

OBJECTIVE: Exposure to stressful events is associated with both occurrence of depression and also vascular disease. The objective of this study was to determine whether higher levels of stress exposure was related to measures of pathological brain aging, specifically white matter hyperintensity volumes, in older adults with and without depression. METHODS: The sample included 130 depressed and 110 never-depressed older adults aged 60 years or older enrolled in a longitudinal study at an academic medical center. Participants completed clinical assessments, assessment of stressful event exposure and perceived stress, and magnetic resonance imaging at baseline and after 2 years. Analyses examined both cross-sectional and longitudinal relationships between stress measures and white matter hyperintensity volumes. RESULTS: There were no statistically significant relationships observed between cross-sectional baseline stress measures and either baseline hyperintensity volume or 2-year change in hyperintensity volume. However, after controlling for demographic variables and baseline measures, change in stressor exposure was associated with change in hyperintensity volumes. In this analysis, increased stressor exposure was associated with greater increases in white matter hyperintensity volume, while reductions in stressor exposure were associated with less increase in hyperintensity volume. This relationship did not significantly differ based on the presence of either depression or medical comorbidities. CONCLUSIONS: This work adds to a growing literature associating exposure to stressful events in later life with more rapid pathological brain aging. Work is needed to understand the physiological mechanisms by which stress exposure has this effect and examine whether stress reduction techniques may modify these observed outcomes. Copyright © 2016 John Wiley & Sons, Ltd.

Adjunctive brexpiprazole for the treatment of major depressive disorder.

INTRODUCTION: The lifetime prevalence of major depressive episodes in the United States is nearly 17%. Clinical trials and clinical effectiveness studies have demonstrated that many patients will fail to achieve remission using traditional monotherapy, contributing to significant morbidity and suffering. Because of this, augmentation strategies have been proposed to improve both treatment response and remission. Areas covered: Brexpiprazole is a second generation antipsychotic (SGA) approved by the US FDA in 2015 as an add-on treatment to an antidepressant medication for the treatment of adults with MDD, based on the results of two large-scale, randomized, placebo-controlled trials. It is thought to exert its antidepressant effect by a partial agonism of both the dopamine D2 and serotonin 5HT1A receptors. In addition, it also has potent antagonistic activity at 5HT2A, α1B and α2 C receptors, which may also contribute to monoamine transmission regulation. Expert Opinion: Overall, the tolerability of brexpiprazole is promising with relatively low rates of side effects and discontinuation rates, thus establishing it as a new option for the treatment of depression.

Nutrition and Bipolar Depression.

As with physical conditions, bipolar disorder is likely to be impacted by diet and nutrition. Patients with bipolar disorder have been noted to have relatively unhealthy diets, which may in part be the reason they also have an elevated risk of metabolic syndrome and obesity. An improvement in the quality of the diet should improve a bipolar patient's overall health risk profile, but it may also improve their psychiatric outcomes. New insights into biological dysfunctions that may be present in bipolar disorder have presented new theoretic frameworks for understanding the relationship between diet and bipolar disorder.

Suicide Behaviors in Bipolar Disorder: A Review and Update for the Clinician.

Suicide behaviors (ideation, attempts, and completions) are unfortunately common in patients with bipolar disorder. It is estimated that 25 to 50% attempt suicide at least once during their lifetime, and 6% to 19% complete suicide. Risk factors include a family history of suicide, previous suicide attempts, younger age of onset, comorbid psychiatric illnesses, and psychological constructs like hopelessness. Pharmacologic treatment may impact suicidal behaviors, either increasing vulnerability or resilience. Clinicians need to be particularly sensitive to their patient's thoughts and beliefs about death, particularly during stressful times of life or when in a depressive/mixed episode of bipolar disorder.

Social support in late life mania: GERI-BD.

OBJECTIVE: Using the database of the National Institute of Mental Health-sponsored acute treatment of late life mania study (GERI-BD), we assessed the role of social support in the presentation of late life bipolar mania. METHODS: In the first 100 subjects randomized in geriatric BD, we explored the demographic, clinical, and social support characteristics (assessed using the Duke Social Support Index) and aspects of manic presentation. We selected two dependent variables: symptom severity, as determined by the Young Mania Rating Scale (YMRS) at baseline, and duration of episode. We selected nine potential independent variables on the basis of Pearson correlation coefficients. We derived two final models using multiple regression analysis employing an iterative process. RESULTS: In our severity model, being married was associated with a higher YMRS score (p = 0.05), whereas higher social interaction scores with non-family members were associated with a lower YMRS score (p = 0.011). In the episode duration model, longer duration was associated with a higher Hamilton Depression Rating Scale score (p = 0.03) and higher social interaction scores with non-family members (p = 0.0003), younger age (p = 0.04), higher number of persons in one's family social network (p = 0.017), and higher instrumental support scores (p = 0.0062). CONCLUSIONS: In late life mania, more social interaction with one's community appears to be associated with less severe symptoms at presentation for treatment, however, it can also be associated with slightly longer the duration of episode. Two aspects of the Duke Social Support Index are associated with a shorter episode duration prior to seeking treatment: being part of a larger family network and a having a higher level of instrumental support prior to treatment. The Instrumental Support Subscale measures the degree of assistance that is available for the respondent in performing daily tasks. These findings suggest that in older adults with BD, close social interactions and support are important in limiting the length of the illness episode prior to treatment. Social interactions involving non-family members may be less important in moderating the intensity of the symptoms at presentation.

The relationship of bipolar disorder lifetime duration and vascular burden to cognition in older adults.

OBJECTIVES: We describe the cognitive function of older adults presenting with bipolar disorder (BD) and mania and examine whether longer lifetime duration of BD is associated with greater cognitive dysfunction. We also examine whether there are negative, synergistic effects between lifetime duration of BD and vascular disease burden on cognition. METHODS: A total of 87 nondemented individuals with bipolar I disorder, age 60 years and older, experiencing manic, hypomanic, or mixed episodes, were assessed with the Dementia Rating Scale (DRS) and the Framingham Stroke Risk Profile (FSRP) as a measure of vascular disease burden. RESULTS: Subjects had a mean (SD) age of 68.7 (7.1) years and 13.6 (3.1) years of education; 50.6% (n = 44) were females, 89.7% (n = 78) were white, and 10.3% (n = 9) were black. They presented with overall and domain-specific cognitive impairment in memory, visuospatial ability, and executive function compared to age-adjusted norms. Lifetime duration of BD was not related to DRS total score, any other subscale scores, or vascular disease burden. FSRP scores were related to the DRS memory subscale scores, but not total scores or any other domain scores. A negative interactive effect between lifetime duration of BD and FSRP was only observed with the DRS construction subscale. CONCLUSIONS: In this study, lifetime duration of BD had no significant relationship with overall cognitive function in older nondemented adults. Greater vascular disease burden was associated with worse memory function. There was no synergistic relationship between lifetime duration of BD and vascular disease burden on overall cognition function. Addressing vascular disease, especially early in the course of BD, may mitigate cognitive impairment in older age.

Variability in frontotemporal brain structure: the importance of recruitment of African Americans in neuroscience research.

BACKGROUND: Variation in brain structure is both genetically and environmentally influenced. The question about potential differences in brain anatomy across populations of differing race and ethnicity remains a controversial issue. There are few studies specifically examining racial or ethnic differences and also few studies that test for race-related differences in context of other neuropsychiatric research, possibly due to the underrepresentation of ethnic minorities in clinical research. It is within this context that we conducted a secondary data analysis examining volumetric MRI data from healthy participants and compared the volumes of the amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebral volume between Caucasian and African-American participants. We discuss the importance of this finding in context of neuroimaging methodology, but also the need for improved recruitment of African Americans in clinical research and its broader implications for a better understanding of the neural basis of neuropsychiatric disorders. METHODOLOGY/PRINCIPAL FINDINGS: This was a case control study in the setting of an academic medical center outpatient service. Participants consisted of 44 Caucasians and 33 ethnic minorities. The following volumetric data were obtained: amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebrum. Each participant completed a 1.5 T magnetic resonance imaging (MRI). Our primary finding in analyses of brain subregions was that when compared to Caucasians, African Americans exhibited larger left OFC volumes (F (1,68) = 7.50, p = 0.008). CONCLUSIONS: The biological implications of our findings are unclear as we do not know what factors may be contributing to these observed differences. However, this study raises several questions that have important implications for the future of neuropsychiatric research.

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

BACKGROUND: TOR1A encodes a chaperone-like AAA-ATPase whose Delta GAG (Delta E) 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 Delta E, 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.

Gray and white matter brain volumes in older adults with bipolar disorder.

OBJECTIVES: Structural magnetic resonance imaging (MRI) studies have been inconsistent in demonstrating volumetric differences in subjects with bipolar disorder. Most studies have not found difference in total gray or white matter in bipolar patients compared with controls, but there have been several studies suggesting that regional abnormalities are present. These have predominately been located in the frontal and temporal lobes. Since age has been inversely correlated with total gray matter in patients, analyses of gray matter changes in older adults or in studies that have included older subjects have been difficult. This study assessed the presence of gray matter volume, and the potential for regional volumetric differences in older adults with bipolar disorder. METHODS: Fifty-six older adults with DSM-IV bipolar disorder (mean age 60.5) and 43 non-psychiatrically ill controls (mean age 58.1) had structured interviews and MRI scanning on a 1.5T GE Scanner. Image parcellation divided the cerebrum into 16 units. Volumetric differences were examined using the multivariate linear regression models with alpha = 0.05. RESULTS: Relative to controls, the older adults with bipolar disorder had significantly smaller gray matter volumes bilaterally in the inferior frontal areas. White matter volume was also reduced in these same areas but did not reach statistical significance when controlled for gender and age. No significant difference was noted in total gray or white matter volumes. CONCLUSIONS: Older adults with bipolar disorder showed gray matter volumetric deficits in inferior frontal lobe regions which include structures identified as contributing to the anterior limbic network.

Temporal lobe volume in bipolar disorder: relationship with diagnosis and antipsychotic medication use.

BACKGROUND: We tested for differences in temporal lobe volume in bipolar disorder and the relationship between these volumes and psychotropic medication use. METHODS: 125 subjects with bipolar disorder and 87 comparison subjects with no psychiatric illness completed clinical interviews and 1.5T MRI brain scans. Temporal lobe volumes were manually traced and segmented into gray matter and white matter volumes using an automated process. General linear models examined the relationship between these volumes and diagnosis as the primary predictor with age, sex, education, and race as copredictors. Secondary analyses incorporated the use of psychotropic medication into the linear models, and parsimonious models developed through backwards regression. RESULTS: In initial models, subjects with bipolar disorder exhibited larger temporal lobe white matter bilaterally (left: F(1,211)=2.86, p=0.0047; right: F(1,211)=3.25, p=0.0014). Current antipsychotic use was significantly associated with larger bilateral temporal lobe white matter volumes (left: F(2,211)=9.45, p=0.0001; right: F(2,211)=10.79, p<0.0001), wherein bipolar subjects taking antipsychotics had larger volumes than bipolar subjects not taking antipsychotics or healthy comparison subjects. Temporal lobe gray matter volume was not significantly associated with diagnosis or medication use. LIMITATIONS: Excluding subjects with substance use disorders may limit the study's generalizability. CONCLUSIONS: These findings indicate that differences in temporal lobe white matter are associated with bipolar disorder and use of antipsychotic medications.

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.

Stressful life events in older bipolar patients.

OBJECTIVE: Theories about the impact of stressful life events (SLE) in bipolar disorder have focused on their role early in the disease. Few studies have examined SLE in older bipolar patients. We wanted to assess the impact of SLE in late life bipolar disorder METHODS: We evaluated negative SLE experienced by older bipolar subjects compared with younger bipolar subjects and older controls for number, type, and their association with phase of illness, age of onset, and previous episodes. RESULTS: Both younger and older bipolar subjects have more SLE than similarly aged controls. There was no significant difference in the number of stressors that younger and older bipolar subjects experienced, based on mood state, previous episodes, or age-of-onset. Both older and younger depressed bipolar subjects reported more SLE in the previous 12 months compared with those in a manic state. CONCLUSIONS: Negative SLE are much more prevalent in bipolar patients compared with age-matched controls, and continue to be frequent in later life.