Sex differences in plasma proteomic markers in late-life depression.

Previous studies have shown significant sex-specific differences in major depressive disorder (MDD) in multiple biological parameters. Most studies focused on young and middle-aged adults, and there is a paucity of information about sex-specific biological differences in older adults with depression (aka, late-life depression (LLD)). To address this gap, this study aimed to evaluate sex-specific biological abnormalities in a large group of individuals with LLD using an untargeted proteomic analysis. We quantified 344 plasma proteins using a multiplex assay in 430 individuals with LLD and 140 healthy comparisons (HC) (age range between 60 and 85 years old for both groups). Sixty-six signaling proteins were differentially expressed in LLD (both sexes). Thirty-three proteins were uniquely associated with LLD in females, while six proteins were uniquely associated with LLD in males. The main biological processes affected by these proteins in females were related to immunoinflammatory control. In contrast, despite the smaller number of associated proteins, males showed dysregulations in a broader range of biological pathways, including immune regulation pathways, cell cycle control, and metabolic control. Sex has a significant impact on biomarker changes in LLD. Despite some overlap in differentially expressed biomarkers, males and females show different patterns of biomarkers changes, and males with LLD exhibit abnormalities in a larger set of biological processes compared to females. Our findings can provide novel targets for sex-specific interventions in LLD.

Apolipoprotein E and Its Association With Cognitive Change and Modification of Treatment Effects of Vitamin D3 and Omega-3s on Cognitive Change: Results From the In-Clinic Subset of a Randomized Clinical Trial.

BACKGROUND: Apolipoprotein E (APOE)-ε4 allele is associated with cognitive decline; however, its potential to modify effects of vitamin D3 and omega-3s supplementation on later-life cognition is unclear. Our objectives were to estimate among the in-clinic subset of a randomized trial: (1) associations between APOE-ε4 and global and domain-specific cognitive change, with exploration of potential sex and race differences; and (2) modification by APOE-ε4 of effects of vitamin D3 and omega-3s supplementation on cognitive change. METHODS: From an ancillary study of depression prevention within a completed 2 × 2 factorial trial testing vitamin D3 (2 000 IU per day), omega-3s (1 g per day), and/or placebos, we included 743 older adults with baseline in-person neuropsychiatric assessments and APOE genotyping data. The primary outcome was change in global cognition (averaging z-scores of 9 tests) over 2 years. Secondarily, episodic memory and executive function/attention z-scores were examined. General linear models of response profiles with multiplicative interaction terms were constructed; stratified results were reported. RESULTS: Mean age (standard deviation) was 67.1 (5.3) years; 50.6% were females; 24.9% were APOE-ε4 carriers. Compared to noncarriers, APOE-ε4 carriers had worse 2-year change in global cognition and episodic memory; differences were more apparent among females than males. There was no variation by race in APOE-ε4 associations with cognition. APOE-ε4 did not significantly modify effects of vitamin D3 or omega-3s, compared to placebo, on change in global cognition, episodic memory, or executive function/attention. CONCLUSIONS: APOE-ε4 was associated with worse cognition but did not modify overall effects of vitamin D3 or omega-3 supplementation on cognition over 2 years.

Major depression and enhanced molecular senescence abnormalities in young and middle-aged adults.

Recent evidence suggests a significant overlap in biological changes between major depression and aging across the lifespan. We aim to evaluate the impact of a major depressive episode on the Senescence-Associated Secretory Phenotype (SASP) index, a dynamic secretory molecular pattern indicative of cellular senescence. We also tested the potential moderators of the association between major depression and the SASP index. We included 1165 young and middle-aged adults (527 with a current major depressive episode (cMDE) and 638 with no lifetime history of depression) from a community-based cohort from the Netherlands. We calculated the SASP index based on a previously developed composite index involving 19 biomarkers. cMDE had higher SASP index values (t(1163) = 2.93, p = 0.003) compared to controls in the univariate analysis. After controlling for sociodemographic and somatic health covariates, there was no significant association between cMDE and SASP index (F(1,1158) = 1.09, p = 0.29). Those with the most severe depressive episodes had significantly higher SASP indices compared to those with mild-to-moderate cMDE and controls (F(2,1162) = 6.73, p = 0.001). We found a significant interaction between cMDE and overweight (F(1,1164) = 5.1, p = 0.028): those with comorbid cMDE and overweight had the highest SASP index. Our study demonstrated a complex interaction between cMDE and medical morbidity, especially overweight, on the SASP index, suggesting that their coexistence aggravate age-related biological processes. Moreover, higher SASP index can be a biomarker for more severe depressive episodes.

Depression Agency-Based Collaborative: Effect of Problem-Solving Therapy on Risk of Common Mental Disorders in Older Adults With Home Care Needs.

BACKGROUND: Interventions to prevent depression in older adults have mainly focused on young-old ambulatory adults, not on the old-old with disabilities who receive supportive services in their homes. OBJECTIVE: The Depression Agency-Based Collaborative (Dep-ABC) is a single-blind pilot randomized controlled trial assessing the effect of an intervention-development strategy using problem-solving therapy (PST) on the risk of common mental health disorders in this vulnerable population. METHODS: The intervention involved six to eight sessions of PST over 12 weeks. Participants were followed up to 12 months postintervention. RESULTS: Dep-ABC randomized 104 participants-68.4% of eligible and 17.5% of all older adults screened. The proportion of participants with incident major depressive disorder or generalized anxiety disorder was 11.4% in PST and 14.3% in the enhanced usual care control arm. A test of the interaction between time and intervention for anxiety symptoms favored the PST arm (p = 0.04). CONCLUSION: PST did not lower the risk of incident common mental illness but did lower anxiety symptom burden. Apart from low power, the effects of PST may have been blunted by referral for medical and aging services in the enhanced usual care group.

Low-dose augmentation with buprenorphine increases emotional reactivity but not reward activity in treatment resistant mid- and late-life depression.

Buprenorphine is currently being studied for treatment-resistant depression because of its rapid effect, relative safety, and unique pharmacodynamics. To understand the neural impact of buprenorphine in depression, we examined acute limbic and reward circuit changes during an intervention with low-dose buprenorphine augmentation pharmacotherapy. Mid and late-life adults with major depression (N = 31) who did not completely respond to an adequate trial of venlafaxine were randomized to augmentation with low-dose buprenorphine or matching placebo. We investigated early neural changes using functional magnetic resonance imaging (fMRI) from pre-randomization to 3 weeks using both an emotional reactivity task and a gambling task. We tested if: 1) there were significant neural changes acutely per intervention group, and 2) if acute neural changes were associated with depressive symptom change over 8 weeks using both the total score and the dysphoria subscale of the Montgomery Asberg Depression Rating Scale. Participants in both the buprenorphine and placebo groups showed similar changes in depressive symptoms. Neither the emotional reactivity nor gambling task resulted in significant neural activation changes from pre-randomization to 3-weeks. In both groups, increases in rostral anterior cingulate (rACC) and ventromedial prefrontal cortex (vmPFC) activation during the emotional reactivity task were associated with overall symptom improvement. In the buprenorphine but not the placebo group, increased activation in left anterior insula (aINS) and bilateral middle frontal gyrus (MFG) was associated with improvement on the dysphoria subscale. Activation changes in the reward task were not associated with buprenorphine. This is the first study to show an association between acute neural changes during emotion reactivity and changes in depression severity with buprenorphine treatment.

Late-life depression in the primary care setting: challenges, collaborative care, and prevention.

Late-life depression is highly prevalent worldwide. In addition to being a debilitating illness, it is a risk factor for excess morbidity and mortality. Older adults with depression are at risk for dementia, coronary heart disease, stroke, cancer and suicide. Individuals with late-life depression often have significant medical comorbidity and, poor treatment adherence. Furthermore, psychosocial considerations such as gender, ethnicity, stigma and bereavement are necessary to understand the full context of late-life depression. The fact that most older adults seek treatment for depression in primary care settings led to the development of collaborative care interventions for depression. These interventions have consistently demonstrated clinically meaningful effectiveness in the treatment of late-life depression. We describe three pivotal studies detailing the management of depression in primary care settings in both high and low-income countries. Beyond effectively treating depression, collaborative care models address additional challenges associated with late-life depression. Although depression treatment interventions are effective compared to usual care, they exhibit relatively low remission rates and small to medium effect sizes. Several studies have demonstrated that depression prevention is possible and most effective in at-risk older adults. Given the relatively modest effects of treatment in averting years lived with disability, preventing late-life depression at the primary care level should be highly prioritized as a matter of health policy.

Association of small vessel ischemic white matter changes with BOLD fMRI imaging in the elderly.

White matter hyperintensities (WMHs) are often identified on T2-weighted magnetic resonance (MR) images in the elderly. The WMHs are generally associated with small vessel ischemic or pre-ischemic changes. However, the association of WMHs with blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal is understudied. In this study, we evaluate how the BOLD signal change is related to the presence of WMHs in the elderly. Data were acquired as part of a study of late-life depression and included elderly individuals with and without major depression. The subjects were pooled because the presence of depression was not significantly associated with task-related BOLD changes, task performance, and WMH distribution. A whole brain voxel-wise regression analysis revealed a significant negative correlation between WMH burden and BOLD signal change during finger-tapping in the parietal white matter. Our observation that WMHs are associated with a significant diminution of the BOLD signal change underscores the importance of considering cerebrovascular burden when interpreting fMRI studies in the elderly. The mechanism underlying the association of WMH and BOLD signal change remains unclear: the association may be mediated by changes in neural activation, changes in coupling between neuronal activity and hemodynamics, or, perhaps, secondary to the effect of the ischemic changes on the sensitivity of the T2* BOLD MR signal.

The longitudinal course of cognition in older adults with bipolar disorder.

OBJECTIVES: Epidemiological studies suggest that elders with bipolar disorder (BD) may be at increased risk for dementia compared to the general population. We sought to investigate whether older adults with BD would present with more cognitive dysfunction than expected for their age and education, and whether they would experience a more rapid cognitive decline over three-year prospective follow-up. METHODS: Thirty-three subjects age > or = 50, mean (SD) age 69.7 (7.9) years, with BD I (n = 28) and II (n = 5) had neuropsychological examination at baseline and longitudinally over three years. All subjects were administered the Dementia Rating Scale (DRS) when euthymic. Thirty-six mentally healthy comparators ('controls'), equated on age and education, were selected from ongoing studies in our research center examining the longitudinal relationship between late-life mood disorders and cognitive function. RESULTS: Compared to mentally healthy comparators, subjects with BD performed significantly worse on the DRS at baseline [mean (SD) 135.2 (4.7); n = 33 versus 139.5 (3.3); n = 36], and over follow-up [131.9 (7.7); n = 14 versus 139.1 (3.4); n = 22]. There was a group-by-time interaction between the subjects with BD and the controls [group x time: F(1,64) = 5.07, p = 0.028]. CONCLUSIONS: In our study, older adults with BD had more cognitive dysfunction and more rapid cognitive decline than expected given their age and education. Cognitive dysfunction and accelerated cognitive decline may lead to decreased independence, with increased reliance on family and community supports, and potential placement in assisted-living facilities.

Older people's experiences of patient-centered treatment for chronic pain: a qualitative study.

INTRODUCTION: Older adults with chronic pain who seek treatment often are in a health care environment that emphasizes patient-directed care, a change from the patriarchal model of care to which many older adults are accustomed. OBJECTIVE: To explore the experiences of older adults seeking treatment for chronic pain, with respect to patient-directed care and the patient-provider relationship. DESIGN: In-depth interviews with 15 Caucasian older adults with chronic pain who had been evaluated at a university-based pain clinic. All interviews were audiotaped and the transcripts were analyzed using a grounded theory based approach. RESULTS: Older adults with chronic pain vary in their willingness to be involved in their treatment decisions. Many frequently participate in decisions about their pain treatment by asking for or refusing specific treatments, demanding quality care, or operating outside of the patient-provider relationship to manage pain on their own. However, others prefer to let their provider make the decisions. In either case, having a mutually respectful patient-provider relationship is important to this population. Specifically, participants described the importance of "being heard" and "being understood" by providers. CONCLUSIONS: As some providers switch from a patriarchal model of care toward a model of care that emphasizes patient activation and patient-centeredness, the development and cultivation of valued patient-provider relationships may change. While it is important to encourage patient involvement in treatment decisions, high-quality, patient-centered care for older adults with chronic pain should include efforts to strengthen the patient-provider relationship by attending to differences in patients' willingness to engage in patient-directed care and emphasizing shared decision-making.

Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients.

OBJECTIVE: To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. METHODS: Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used. RESULTS: There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. CONCLUSION: The results demonstrate a concentration-response relation for paroxetine in late-life depression and support the hypothesis for both a direct main effect and a moderating influence of 5-HTTLPR alleles on this concentration-response relation.

Verification of scale sub-domains in elderly patients with dementia: a confirmatory factor-analytic approach.

OBJECTIVE: Use of cognitive, psychiatric and behavioral domains to assess the effectiveness of a pharmacological or behavioral intervention in the treatment of neurodegenerative disorders (e.g., Alzheimer disease) aids the identification of specific types of impairment or distress in behavioral status and quality-of-life issues in this population. With confirmatory approaches to subscale development readily available, we can obtain a more precise understanding of the sub-components of a scale, potentially providing the basis for selecting behavioral and/or quality-of-life outcome measures that may be more sensitive to the effects of pharmacological or behavioral interventions. METHODS: The authors illustrate the use of a confirmatory factor-analytic approach to verify scale sub-domains of the Neurobehavioral Rating Scale (NBRS) in elderly patients with dementia. With data collected from two groups of patients being treated for significant psychiatric and behavioral symptoms, authors investigated the relationships among scale items in order to test several competing models, including a general one-factor model, a first-order multifactor model, and a second-order factor model. RESULTS: The first-order model, with seven factors, provided the best fit to the correlations among items in the NBRS, indicating the multidimensionality of problematic behaviors and symptoms exhibited by dementia patients. CONCLUSION: Authors advocate the use of a confirmatory factor-analytic approach to verify scale sub-domains in other, more widely used rating scales for patients with dementia.

Anxiety symptoms in elderly patients with depression: what is the best approach to treatment?

Depressed elderly persons frequently have concurrent symptoms of anxiety or comorbid anxiety disorders. Such comorbidity is associated with a more severe presentation of depressive illness, including greater suicidality. Additionally, most antidepressant treatment studies in the elderly have found poorer treatment outcomes in those with comorbid anxiety (including delayed or diminished response and increased likelihood of dropout from treatment). While antidepressants such as selective serotonin reuptake inhibitors and tricyclic agents are efficacious for late-life depression, there is no evidence that either class is superior, in terms of efficacy or tolerability, in the treatment of anxious depression. Rather, the amount and quality of clinical management, and not the particular medication chosen, appears to influence the likelihood of remission or treatment withdrawal in anxious depressed elderly patients. Co-prescription of benzodiazepines, typically lorazepam, is also warranted in some cases for severe anxiety or insomnia, but carries the risk of cognitive or motor impairment. It is our experience that close clinical monitoring, together with maximization of antidepressant treatment (by maximising dosage, augmenting or switching agents in cases of partial or no response, and/or adding psychotherapy) will almost always result in remission of depressive symptoms, together with improvement of anxiety, in these individuals. Therefore, optimism should be maintained when treating the depressed elderly individual, even when comorbid anxiety is present.

Effects of nortriptyline and paroxetine on postural sway in depressed elderly patients.

Tricyclic antidepressants (TCAs) have previously been found to be related to an increased incidence of falls in elderly persons. Recent pharmacoepidemiologic and nursing home studies have suggested that the risk of falls and fractures in elderly patients receiving selective serotonin reuptake inhibitors (SSRIs) is not different from that of patients receiving TCAs. The authors therefore evaluated postural sway in an older population of depressed patients randomly assigned to treatment with either nortriptyline or paroxetine and did not find any change in postural sway after 6 weeks' treatment with either antidepressant. Further studies with other SSRIs are needed.