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BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

OBJECTIVE: Evidence-based treatment options for late-life treatment-resistant depression (TRD) are limited. Ketamine is a promising treatment for TRD; however, there is a paucity of data on its safety and efficacy in older adults. METHODS: In this pilot clinical trial, 25 adults aged ≥60 years with TRD received IV ketamine openly twice a week for 4 weeks; partial responders at the end of this acute phase were eligible to receive weekly infusions for 4 more weeks in a continuation phase. Acceptability, tolerability, and safety, including adverse and serious adverse events (AEs and SAEs), blood pressure changes, dissociation, craving, in addition to rates of depression response and remission were evaluated. The NIH Toolbox Cognitive Battery was used to assess specific measures of executive function (EF) and overall fluid cognition. RESULTS: Completion rates were 88% for the acute phase and 100% for the continuation phase. No AEs resulted in participant discontinuation, and there were no SAEs. Treatment-emergent elevation of blood pressure, dissociation, and craving were transient and did not result in any participant discontinuation. Depressive symptoms improved significantly and 48% of participants responded. During the acute phase, the EF measures and the fluid cognition composite score improved (Cohens d = 0.61), and these improvements were sustained in the continuation phase. CONCLUSION: This pilot study suggests that repeated IV ketamine infusions are well-tolerated and are associated with improvement in depression and EF in older adults with TRD. These promising findings need to be confirmed and extended in a larger randomized controlled trial.

ObjectiveTo determine the effect of the COVID-19 pandemic on the mental health of older adults with pre-existing major depressive disorder (MDD).ParticipantsParticipants were 73 community-living older adults with pre-existing MDD (mean age 69 [SD 6]) in Los Angeles, New York, Pittsburgh, and St Louis.Design and measurementsDuring the first 2 months of the pandemic, the authors interviewed participants with a semistructured qualitative interview evaluating access to care, mental health, quality of life, and coping. The authors also assessed depression, anxiety, and suicidality with validated scales and compared scores before and during the pandemic.ResultsFive themes from the interviews highlight the experience of older adults with MDD: 1) They are more concerned about the risk of contracting the virus than the risks of isolation. 2) They exhibit resilience to the stress and isolation of physical distancing. 3) Most are not isolated socially, with virtual contact with friends and family. 4) Their quality of life is lower, and they worry their mental health will suffer with continued physical distancing. 5) They are outraged by an inadequate governmental response to the pandemic. Depression, anxiety, and suicidal ideation symptom scores did not differ from scores before the pandemic.ConclusionMost older adults with pre-existing MDD show resilience in the first 2 months of the COVID-19 pandemic but have concerns about the future. Policies and interventions to provide access to medical services and opportunities for social interaction are needed to help to maintain mental health and quality of life as the pandemic continues.

BackgroundThe pathophysiology of late-life depression (LLD) is complex and heterogeneous, with age-related processes implicated in its pathogenesis. This study examined the cross-sectional and longitudinal association between depressive symptoms and a baseline multibiomarker algorithm of biological age (BA) that aggregates indicators of inflammatory, metabolic, cardiovascular, lung, liver, and kidney functioning.MethodData were analyzed from 2,776 men and women from the prospective observational Health Aging and Body Composition Study, who had both evaluable chronological age (CA) and BA. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale.ResultsA covariate-adjusted regression model showed that BA (B = 0.03, p = .0471) but not CA (B = -0.01, p = .7185) is associated with baseline CES-D scores. The mean baseline BA for individuals with a CES-D ≥ 10 was 1.28 years greater than in those with a CES-D < 10. Comparatively, there is only a 0.05-year difference in mean CA between the two depression groups. A covariate-adjusted longitudinal model found that baseline BA predicts CES-D score at follow-up (B = 0.04, p = .0058), whereas CA does not (B = 0.03, p = .4125). Additionally, an older BA significantly predicted a CES-D ≥ 10 (B = 0.02, p = .032) over a 10-year period.ConclusionsA multibiomarker index of an older adult's BA outperformed their CA in predicting subsequent increased and clinically significant depressive symptoms. This result supports the evolving view of LLD as a brain disorder resulting from deleterious age-associated changes across numerous physiological systems.

Depression in later life is a severe public health problem, associated with higher rates of mortality, suicide, and dementia. Effectiveness of treatment is limited by the failure to deconstruct the heterogeneity of the illness and because diagnostic criteria, pathophysiological models, and treatment algorithms for depression are primarily based on studies of younger adults even though symptoms of the illness and physiology of the patient change with age. Thus, understanding how aging interacts with depressive illness may elucidate endophenotypes of late-life depression with different clinical manifestations and underlying mechanisms that can then be targeted with more personalized approaches to treatment. This paper proposes a model for the critical confluence between depression and frailty, a high-risk morbidity and mortality syndrome of later life. This model hypothesizes that characteristics of frailty in adults with late life depression represent the clinical manifestation of greater biological aging and their presence in the context of a depressive illness exposes elders to deleterious trajectories. Potential common biological substrates that may result in the manifestation of the depressed frail phenotype including mitochondrial functioning, dopaminergic neurotransmission, and inflammatory processes and implications for the assessment and treatment of adults with late-life depression are discussed. As society continues to live longer, the preservation of the quality of these added years becomes paramount, and the combined impact of depression and frailty on the preservation of this quality warrants the attention of clinical researchers and physicians.

ObjectiveTreatment history can inform clinical decisions about subsequent treatment choices. The authors examined the impact of prior antidepressant treatment on treatment outcomes with venlafaxine only and then with augmentation with aripiprazole or placebo in depressed older adults.MethodsThe authors analyzed outcome data from a randomized, placebo-controlled clinical trial of aripiprazole augmentation in depressed older adults. The study consisted of an open-label lead-in phase with venlafaxine XR, followed by a placebo-controlled phase of aripiprazole augmentation. Treatment history was assessed with the Antidepressant Treatment History Form.ResultsDocumented prior treatment failure predicted a reduced remission rate with venlafaxine. However, aripiprazole augmentation was efficacious in those with prior treatment failure (42.6% remission with aripiprazole versus 25.8% with placebo; χ(2) = 3.87 df = 1, p = 0.049).ConclusionAripiprazole augmentation is an efficacious strategy in older depressed adults who fail to remit with two or more adequate antidepressant trials, including a course of venlafaxine.

ObjectivesClinical trials can benefit from patient perspectives to inform trial design, such as choice of outcome measures. We engaged older adults in focus groups and surveys to get their perspective regarding needs in clinical research. The goal was to inform the development of a new clinical trial of medication strategies for treatment-resistant depression in older adults.MethodsOlder adults with depression participated in focus groups and a subsequent survey in St. Louis and New York. They were queried regarding research design features including outcomes, clinical management, mobile technology and iPad-administered assessments, the collection of DNA, and the receipt of their personal results.ResultsPatients told us: (1) psychological well-being and symptomatic remission are outcomes that matter to them; (2) it is important to measure not only benefits but risks (such as risk of falling) of medications; (3) for pragmatic trials in clinical settings, the research team should provide support to clinicians to ensure that medications are properly prescribed; (4) technology-based assessments are acceptable but there were concerns about data security and burden; (5) DNA testing is very important if it could improve precision care; (6) participants want to receive aggregate findings and their own personal results at the end of the study.ConclusionsPatients gave useful and wide-ranging guidance regarding clinical and comparative effectiveness research in older adults. We discuss these findings with the goal of making the next generation of geriatric studies more impactful and patient-centered.

Introduction: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment‐resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment. Methods: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment. Results: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT‐10 score ≥5) and 41% were low‐risk drinkers (score 1–4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low‐risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers. Conclusions: One‐half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks—such as falls—of using alcohol and other substances during antidepressant treatment needs further study. Key points: Approximately half of older adults with treatment‐resistant depression acknowledged drinking alcoholAmong drinkers, 24% were also using benzodiazepine and 10% were using other substances like cannabisUse of other substances (mostly cannabis) was associated with alcohol consumption [ABSTRACT FROM AUTHOR]

BackgroundInflammation, slow gait, and depression individually are associated with mortality, yet little is known about the trajectories of these measures, their interrelationships, or their collective impact on mortality.MethodsLongitudinal latent class analysis was used to evaluate trajectories of depression (Center for Epidemiologic Studies Depression ≥ 10), slow gait ( 3.2 pg/mL) using data from the Health Aging and Body Composition Study. Logistic regression was used to identify their associations with mortality.ResultsFor each outcome, low-probability (n inflammation = 1,656, n slow gait = 1,471, n depression = 1,458), increasing-probability (n inflammation = 847, n slow gait = 880, n depression = 1,062), and consistently high-probability (n inflammation = 572, n slow gait = 724, n depression = 555) trajectories were identified, with 22% of all participants classified as having increasing or consistently high-probability trajectories on inflammation, slow gait, and depression (meaning probability of impairment on each outcome increased from low to moderate/high or remained high over 10 years). Trajectories of slow gait were associated with inflammation (r = .40, p < .001) and depression (r = .49, p < .001). Although worsening trajectories of inflammation were independently associated with mortality (p < .001), the association between worsening trajectories of slow gait and mortality was only present in participants with worsening depression trajectories (p < .01). Participants with increasing/consistently high trajectories of depression and consistently high trajectories of inflammation and slow gait (n = 247) have an adjusted-morality rate of 85.2%, greater than all other classification permutations.ConclusionsComprehensive assessment of older adults is warranted for the development of treatment strategies targeting a high-mortality risk phenotype consisting of inflammation, depression, and slow gait speed.

Objective: To examine whether psychological well‐being, sleep, and suicidality improved with treatment with intravenous (IV) ketamine for late‐life treatment‐resistant depression (TRD). Methods: This is an analysis of secondary outcomes in an open‐label late‐life TRD study examining the safety, tolerability, and feasibility of IV ketamine infusions. In the acute phase, participants (N = 25) aged 60 years or older received twice‐a‐week IV ketamine for 4 weeks. Then, participants with Montgomery‐Asberg Depression Rating Scale (MADRS) total score <10 or ≥ 30% reduction from baseline proceeded to the continuation phase, an additional four weeks of once‐a‐week IV ketamine. The secondary outcomes analyzed here are based on the National Institute of Health Toolbox Psychological Well‐Being subscales for Positive Affect and General Life Satisfaction, the Pittsburgh Sleep Quality Index, and the Scale for Suicidal Ideation. Results: Psychological well‐being, sleep, and suicidality improved during the acute phase and those improvements were sustained during the continuation phase. Greater improvements in measures of psychological well‐being and sleep were seen in participants who had greater improvements in MADRS scores and moved onto the continuation phase. All but one of the few participants with high suicidality at baseline improved; there were no cases of treatment‐emergent suicidality. Conclusions: Psychological well‐being, sleep, and suicidality improved in participants with late‐life TRD who received IV ketamine for 8 weeks. A future larger and longer controlled trial is needed to confirm and extend these findings. Registration: ClinicalTrials.gov identifier: NCT04504175. Key points: Patient‐centered outcomes are important measures in late‐life depressionSerial intravenous (IV) ketamine infusions were associated with improved patient‐centered outcomes such as psychological well‐being, sleep, and suicidality [ABSTRACT FROM AUTHOR]