Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.

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.).

Poor Sleep is Common in Treatment-Resistant Late-life Depression and Associated With Poorer Antidepressant Response: Findings From the OPTIMUM Clinical Trial.

BACKGROUND: Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems; however, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD. This analysis examined: (1) the occurrence of insufficient sleep among adults with TRLLD; (2) how sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep. METHODS: Secondary analysis of data from 634 participants age 60+ years in the OPTIMUM clinical trial for TRLLD. Sleep was assessed using the sleep item from the Montgomery-Asberg Depression Rating Scale at the beginning (week-0) and end (week-10) of treatment. The analyses examined whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep during depression treatment. RESULTS: About half (51%, n = 323) of participants reported insufficient sleep at baseline. Both persistent insufficient sleep (25%, n = 158) and worsened sleep (10%, n = 62) during treatment were associated with antidepressant nonresponse. Participants who maintained sufficient sleep (26%, n = 164) or who improved their sleep (n = 25%, n = 158) were three times more likely to experience a depression response than those with persistent insufficient sleep or worsened sleep. CONCLUSION: Insufficient sleep is common in TRLLD and it is associated with poorer treatment response to antidepressants.

Alcohol and substance use in older adults with treatment-resistant depression.

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.

Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Pilot Study of Tolerability, Safety, Clinical Benefits, and Effect on Cognition.

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 (Cohen's 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.

Change in patient-centered outcomes of psychological well-being, sleep, and suicidality following treatment with intravenous ketamine for late-life treatment-resistant depression.

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.

Hearing Rehabilitative Treatment for Older Adults With Comorbid Hearing Loss and Depression: Effects on Depressive Symptoms and Executive Function.

OBJECTIVES: Recent research has revealed important neural and psychiatric consequences of hearing loss (HL) in older adults. This pilot study examined the neural effects of HL and the impact of hearing aids on neuropsychiatric outcomes in major depressive disorder (MDD). DESIGN: Twelve-week, double-blind, randomized controlled trial. PARTICIPANTS/INTERVENTION: N = 25 (≥60 years) with MDD and moderate-profound HL were randomized to receive hearing aids (100% gain targets) or sham hearing aids (flat 30 dB HL) in addition to psychiatric treatment-as-usual. MEASUREMENTS: Depressive symptoms (Hamilton Rating Scale for Depression [HRSD]), executive functioning (NIH Toolbox Flanker), integrity of auditory brain areas (structural MRI, diffusion tensor imaging). RESULTS: At baseline, worse speech discrimination was associated with auditory cortical thinning (Left anterior transverse temporal gyrus: r = 0.755, p = 0.012) and lower integrity of the superior longitudinal fasciculus (FA: Left r = 0.772, p = 0.025, Right r = 0.782, p = 0.022). After 12-weeks, hearing aids were effective at improving hearing functioning (Hearing Handicap for the Elderly: active -12.47 versus sham -4.19, t = -2.64, df = 18, p = 0.016) and immediate memory (active +14.9 versus sham +5.7, t = 2.28, df = 16, p = 0.037). Moderate improvement was observed for hearing aids on executive functioning but did not reach statistical significance (Flanker: active +4.8 versus sham -2.4, t = 1.95, df = 15, p = 0.071). No significant effect on depression was found (HRSD: active -5.50 versus sham -7.32, t = 0.75, df = 19, p = 0.46). CONCLUSIONS: HL can affect brain regions important for auditory and cognitive processing, and hearing remediation may have beneficial effects on executive functioning in MDD. Future studies may evaluate whether impairment in cognitive control consequent to HL may be an important risk mechanism for MDD.

A precision medicine tool to understand who responds best to hearing aids in late-life depression.

OBJECTIVES: Accumulating evidence suggests that hearing loss (HL) treatment may benefit depressive symptoms among older adults with Major Depressive Disorder (MDD), but the specific individual characteristics of those who stand to improve most are unknown. METHODS: N = 37 patients ≥60 years with HL and MDD received either active or sham hearing aids in this 12-week double-blind randomized controlled trial. A combined moderator approach was utilized in the analysis in order to examine multiple different pretreatment individual characteristics to determine the specific qualities that predicted the best depressive symptom response to hearing aids. Pretreatment characteristics included: Hearing Handicap Inventory for the Elderly (HHIE-S), pure tone average (PTA), speech reception threshold (SRT), Short Physical Performance Battery (SPPB), cognition (Repeatable Battery for the Assessment of Neuropsychological Status). RESULTS: The analysis revealed a combined moderator, predicting greater improvement with active versus sham hearing aids, that had a larger effect size than any individual moderator (combined effect size [ES] = 0.49 [95% CI: 0.36, 0.76]). Individuals with worse hearing-related disability (HHIE-S: individual ES = -0.16), speech recognition (SRT: individual ES = -0.14), physical performance (SPPB: individual ES = 0.41), and language functioning (individual ES = 0.19) but with relatively less severe audiometric thresholds (PTA: individual ES = 0.17) experienced greater depressive symptom improvement with active hearing aids. CONCLUSIONS: Older adults with relatively worse HL-related, physical, and cognitive functioning may stand to benefit most from hearing aids. Given the large number of older adults experiencing HL and MDD, a non-invasive and scalable means of targeting those most likely to respond to interventions would be valuable.

Frailty Worsens Antidepressant Treatment Outcomes in Late Life Depression.

OBJECTIVE: To investigate the relationship between frailty and treatment response to antidepressant medications in adults with late life depression (LLD). METHODS: Data were evaluated from 100 individuals over age 60 years (34 men, 66 women) with a depressive diagnosis, who were assessed for frailty at baseline (characteristics include gait speed, grip strength, activity levels, fatigue, and weight loss) and enrolled in an 8-week trial of antidepressant medication followed by 10 months of open-treatment. RESULTS: Frail individuals (n = 49 with ≥3 deficits in frailty characteristics) did not differ at baseline from the non/intermediate frail (n = 51 with 0-2 deficits) on demographic, medical comorbidity, cognitive, or depression variables. On average, frail individuals experienced 2.82 fewer Hamilton Rating Scale for Depression (HRSD) points of improvement (t = 2.12, df 89, p = 0.037) than the non/intermediate frail over acute treatment, with this difference persisting over 10 months of open-treatment. Weak grip strength and low physical activity levels were each associated with decreased HRSD improvement, and lower response and remission rates over the course of the study. Despite their poorer outcomes, frail individuals received more antidepressant medication trials than the non/intermediate frail. CONCLUSION: Adults with LLD and frailty have an attenuated response to antidepressant medication and a greater degree of disability compared to non/intermediate frail individuals. This disability and attenuated response remain even after receiving a greater number of antidepressant medication trials. Future research must focus on understanding the specific pathophysiology associated with the frail-depressed phenotype to permit the design and implementation of precision medicine interventions for this high-risk population.

Slowed Processing Speed Disrupts Patient Expectancy in Late Life Depression.

OBJECTIVE: Slowed processing speed and executive dysfunction are associated with poor outcomes in Late Life Depression (LLD), though it is unclear why. We investigated whether these variables interfere with the development of positive treatment expectancies in an antidepressant trial. METHODS: Depressed older subjects were randomized to Open (intended to increase patient expectancy) or Placebo-controlled (termed 'Hidden,' intended to decrease expectancy) administration of antidepressant medication for 8 weeks. Analysis of covariance analyzed the between-group difference on expectancy (Credibility and Expectancy Scale [CES]) and depression (Hamilton Rating Scale for Depression [HRSD], Clinical Global Impressions [CGI] Severity). Moderator analyses examined whether these Open versus Hidden differences varied based on higher versus lower processing speed and executive function. RESULTS: Among the 108 participants, a significant between-group difference was observed on expectancy (effect size [ES, Cohen's d] = 0.51 on CES Item 2; ES = 0.64 on Item 4), indicating the manipulation was effective. Processing speed as measured by the Stroop Color-Word Test (number color-words named in congruent condition) was a significant moderator of the Open versus Hidden effect on expectancy. Depressive symptom improvement was greater on average for Open versus Hidden participants who received active drug (CGI-severity ES = 1.25, HRSD ES = 0.41), but no neurocognitive moderators of the between-group difference reached statistical significance. CONCLUSIONS: Slowed processing speed impairs the development of expectancies in antidepressant trials for LLD, which may help explain lower antidepressant response among older adults. Future studies may address whether interventions to optimize treatment expectancies are capable of improving treatment outcomes.

The COVID-19 Pandemic as a Traumatic Stressor: Mental Health Responses of Older Adults With Chronic PTSD.

OBJECTIVE: Individuals with post-traumatic stress disorder (PTSD) who experience additional traumas or stressful life events may undergo symptomatic worsening, but no data exist on whether exposure to the COVID-19 pandemic in a high infection area worsens mental health among older adults with chronic PTSD. METHODS: Seventy-six older adults (N = 46 with PTSD and N = 30 trauma-exposed comparison subjects [TE]) for whom prepandemic data were available were interviewed between April 1 and May 8, 2020 to quantify depressive (Hamilton Rating Scale for Depression [HRSD]) and PTSD symptom (Post-traumatic Stress Disorder Checklist [PCL-5]) levels. Group differences in baseline characteristics as well as pre-post pandemic symptom levels were examined, and participant characteristics were assessed as moderators of symptom change. RESULTS: Compared to TEs, individuals with PTSD more often reported living alone and experiencing a physical illness (χ2 = 5.1, df = 1, p = 0.02). PCL-5 scores among individuals with PTSD decreased during the COVID-19 pandemic by 7.1 points (t(69) = -3.5, p = 0.0008), whereas the TE group did not change significantly. Overall no significant differences in HRSD were found between groups, but a race or ethnicity variable was found to moderate HRSD symptom change. Non-black or Hispanic individuals with PTSD experienced significantly increased HRSD scores during the pandemic compared to black or Hispanic PTSD participants. CONCLUSION: The findings are indicative of complexity in the responses of older individuals with PTSD to further stressful life events as well as possibly unique aspects to the COVID-19 pandemic as a stressor. Sources of resilience may exist based on experience with prior traumas as well as increasing age promoting more adaptive coping styles.

Association of White Matter Integrity With Executive Function and Antidepressant Treatment Outcome in Patients With Late-Life Depression.

OBJECTIVE: While patients with late-life depression (LLD) often exhibit microstructural white matter alterations that can be identified with diffusion tensor imaging (DTI), there is a dearth of information concerning the links between DTI findings and specific cognitive performance, as well as between DTI measures and antidepressant treatment outcomes. DESIGN: Neuroimaging and cognitive tests were conducted at baseline in 71 older adults participating in a larger, 8-week duration antidepressant randomized controlled trial. Correlations between DTI measures of white matter integrity evaluated with tract-based spatial statistics, baseline neurocognitive performance, and prospective antidepressant treatment outcome were evaluated. RESULTS: Fractional anisotropy (FA), an index of white matter integrity, was significantly positively associated with better cognitive function as measured by the Initiation/Perseveration subscale of the Dementia Rating Scale in the bilateral superior longitudinal fasciculus (SLF), bilateral SLF-temporal, and right corticospinal tract (CST). An exploratory analysis limited to these tracts revealed that increased FA in the right CST, right SLF, and right SLF-temporal tracts was correlated with a greater decrease in depressive symptoms. Increased FA in the right CST predicted a greater chance of remission, while increased FA in the right CST and the right SLF predicted a greater chance of treatment response. CONCLUSION: In late-life depression LLD subjects, white matter integrity was positively associated with executive function in white matter tracts which act as key connecting structures underlying the cognitive control network. These tracts may play a role as a positive prognostic factor in antidepressant treatment outcome.

Symptom profiles and treatment status of older adults with chronic post-traumatic stress disorder.

OBJECTIVE: Failure to diagnose and treat post-traumatic stress disorder (PTSD) may help explain the substantial disability, increased cognitive decline, and adverse health outcomes suffered by older adults with this disorder. To evaluate this possibility, we examined symptom differences among older and younger individuals with PTSD and measured the frequency with which older adults receive standard of care treatment. METHODS: Clinician-Administered PTSD Scale for DSM (CAPS) scores were compared between younger and older adults with PTSD. Profiles were calculated for the most dominant CAPS symptom cluster reported by each participant, and the age cutoff best differentiating symptom clusters between individuals was determined. Clinical interview data (older adult sample only) were evaluated by trained raters to determine rates at which PTSD participants accessed treatment. RESULTS: Among 108 individuals with PTSD, 69% of participants <67 years old had Criterion C (avoidance) symptoms as the most dominant cluster compared to 39% of participants ≥67 (p = 0.016). Eight percent of participants <67 years had Criterion E (hyperarousal) symptoms as the most dominant cluster compared to 30% of participants ≥67 (p = 0.016). Less than 25% of the older adults (N = 53 subsample) were receiving a first-line pharmacotherapy option for PTSD, and 0% of participants were currently participating in an evidence-based psychotherapy for PTSD. CONCLUSIONS: Clinicians evaluating patients should be aware that different symptom profiles may be present between younger and older adults with PTSD. Despite their high risk for adverse neuropsychiatric and other health consequences, older adults with PTSD appear to infrequently receive first-line clinical treatment.

Frailty and Its Correlates in Adults With Late Life Depression.

OBJECTIVE: To investigate the rates of frailty and frailty characteristics and examine the clinical and neuropsychological correlates of frailty in adults with late life depression (LLD). METHODS: Data were used from the evaluation of 134 individuals over the age of 60 years (45 men, 89 women) with a depressive diagnosis who enrolled in studies for the treatment of their depression. Depression, neuropsychological functioning, white matter hyperintensity (WMH) burden via magnetic resonance imaging, and characteristics of frailty were assessed. RESULTS: Fried frailty burden (≥3 characteristics) was present in 25% of the sample, with this rate increasing to 45.5% when using clinically meaningful cut-scores for gait speed (<1 m/s) and physical activity levels (<1000 kcal/week). Moreover, 62% of the sample exhibited gait slowing (<1 m/s) or weakness (grip strength), with 29% demonstrating both. Greater frailty burden was associated with greater Hamilton Depression Rating Scale severity in covariate adjusted linear regression models (t127 = 2.41, p = 0.02). Greater frailty burden was not associated with neuropsychological dysfunction, nor was it associated with greater WMH burden. CONCLUSION: Findings from this study show that frailty, specifically physical frailty deficits in mobility and strength, is highly comorbid in adults with LLD, associated with greater depressive symptom severity, and does not appear to be associated with the vascular depression subtype of LLD. Future research should investigate the relationship between frailty and antidepressant treatment response as well as test whether there are age-related biological processes that result in the manifestation of the frail-depressed subtype of LLD.

Experiences of American Older Adults with Pre-existing Depression During the Beginnings of the COVID-19 Pandemic: A Multicity, Mixed-Methods Study.

OBJECTIVE: To determine the effect of the COVID-19 pandemic on the mental health of older adults with pre-existing major depressive disorder (MDD). PARTICIPANTS: Participants 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 MEASUREMENTS: During 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. RESULTS: Five 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. CONCLUSION: Most 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.

A pilot randomized controlled trial of hearing aids to improve mood and cognition in older adults.

OBJECTIVES: Age-related hearing loss (ARHL) is a prevalent condition associated with increased risk for depression and cognitive decline. This 12-week prospective, double-blind pilot randomized controlled trial (RCT) of hearing aids (HAs) for depressed older adults with ARHL evaluated the feasibility of a novel research design. METHODS/DESIGN: N = 13 individuals aged ≥60 years with Major Depressive Disorder or Persistent Depressive Disorder and at least mild hearing loss (pure tone average ≥ 30 dB) were randomized to receive full- (active) vs low-amplification (sham) HAs added to psychiatric treatment as usual. Duration of HA use in hours/day, adverse events frequency, attrition rate, and maintenance of the study blinding were the primary outcome measures. RESULTS: Compliance with HAs was excellent (>9 hours/day for both groups) and rates of adverse events and drop-outs did not differ between groups. Preliminary data demonstrated differential improvement for active vs sham HAs on hearing functioning (Hearing Handicap Inventory for the Elderly [nonparametric effect size (np-ES) = 0.62]), depressive symptoms (Inventory for Depressive Symptomatology [np-ES = 0.31]), cognition (Repeatable Battery for the Assessment of Neuropsychological Status Immediate Memory [np-ES = 0.25]), and general functioning (World Health Organization Disability Assessment Schedule [np-ES = 0.53]). Significantly greater than 50% of both groups correctly guessed their treatment assignment, indicating incomplete concealment of treatment allocation. CONCLUSIONS: This pilot RCT for ARHL and late-life depression was feasible to execute and showed clinical promise, but improved methods of blinding the experimental treatments are needed. Larger studies should investigate whether hearing remediation may be an effective preventative and/or therapeutic strategy for late-life depression and cognitive decline.

Optimizing patient expectancy in the pharmacologic treatment of major depressive disorder.

BACKGROUND: Patient expectancy is an important source of placebo effects in antidepressant clinical trials, but all prior studies measured expectancy prior to the initiation of medication treatment. Little is known about how expectancy changes during the course of treatment and how such changes influence clinical outcome. Consequently, we undertook the first analysis to date of in-treatment expectancy during antidepressant treatment to identify its clinical and demographic correlates, typical trajectories, and associations with treatment outcome. METHODS: Data were combined from two randomized controlled trials of antidepressant medication for major depressive disorder in which baseline and in-treatment expectancy assessments were available. Machine learning methods were used to identify pre-treatment clinical and demographic predictors of expectancy. Multilevel models were implemented to test the effects of expectancy on subsequent treatment outcome, disentangling within- and between-patient effects. RESULTS: Random forest analyses demonstrated that whereas more severe depressive symptoms predicted lower pre-treatment expectancy, in-treatment expectancy was unrelated to symptom severity. At each measurement point, increased in-treatment patient expectancy significantly predicted decreased depressive symptoms at the following measurement (B = -0.45, t = -3.04, p = 0.003). The greater the gap between expected treatment outcomes and actual depressive severity, the greater the subsequent symptom reductions were (B = 0.49, t = 2.33, p = 0.02). CONCLUSIONS: Greater in-treatment patient expectancy is associated with greater subsequent depressive symptom reduction. These findings suggest that clinicians may benefit from monitoring and optimizing patient expectancy during antidepressant treatment. Expectancy may represent another treatment parameter, similar to medication compliance and side effects, to be regularly monitored during antidepressant clinical management.

Declining Skeletal Muscle Mitochondrial Function Associated With Increased Risk of Depression in Later Life.

OBJECTIVE: Late-life depression (LLD) is a chronic and heterogeneous disorder. Recent studies have implicated non-normative age-related processes in its pathogenesis. This investigation examined both cross-sectional and longitudinal associations between skeletal muscle mitochondrial function and LLD. METHODS: Data from 603 men and women from the Baltimore Longitudinal Study on Aging were analyzed, of whom 167 provided data from a follow-up visit. Muscle bioenergetics was measured by postexercise recovery rate of phosphocreatine (PCr) using phosphorus magnetic resonance spectroscopy. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) Scale. RESULTS: There was no cross-sectional association between baseline depression status and either the PCr recovery rate constant (kPCr; t = -0.553, df = 542; p = 0.580) or mitochondrial capacity largely independent of exercise intensity (adenosine triphosphate maximum [ATPmax]; t = 0.804, df = 553; p = 0.422). Covariate-adjusted Firth logistic regression models however showed that greater decreases in skeletal muscle mitochondrial function from baseline to follow-up were associated with higher odds of clinically significant depressive symptoms (CES-D ≥16) at follow-up (ΔATPmax: odds ratio = 2.63, χ2 = 5.62, df =1; p = 0.018; ΔkPCr: odds ratio = 2.32, χ2 = 5.79, df =1; p = 0.016). CONCLUSION: Findings suggest that declining skeletal muscle mitochondrial function in older adults is associated with clinically significant depressive symptoms at follow-up, thereby providing preliminary support for the hypothesis that mitochondrial dysfunction may be a potential key pathophysiological mechanism in adults with LLD.

Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and Treatment Characteristics of the First 396 Participants Randomized.

OBJECTIVE: Evidence from clinical trials comparing effectiveness and safety of pharmacological strategies in older adults unresponsive to first-line antidepressants is limited. The study, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), tests three hypotheses concerning pharmacotherapy strategies for treatment-resistant late-life depression: 1) augmentation strategies will provide greater improvement than switching monotherapies; 2) augmentation strategies will have lower tolerability and more safety concerns than switching monotherapies; and 3) age will moderate the effectiveness and safety differences between treatment strategies. The authors describe the methodology, processes for stakeholder engagement, challenges, and lessons learned in the early phases of OPTIMUM. METHODS: This pragmatic randomized clinical trial located in five North American regions will enroll 1,500 participants aged 60 years and older unresponsive to two or more antidepressant trials. The authors evaluate two strategies (medication augmentation versus switch) using four medications (aripiprazole, bupropion, lithium, and nortriptyline) via a stepwise, prespecified protocol. Primary outcomes include: 1) symptom remission (Montgomery Asberg Depression scale ≤10); 2) psychological well-being, comprising positive affect, general life satisfaction, and purpose; and 3) safety (rates of serious adverse events and prevalence of falls and fall-related injuries). RESULTS: To date, 396 participants have been randomized. The authors report on four challenges: 1) engagement and recruitment; 2) increasing polypharmacy in older adults, resulting in potentially hazardous scenarios; 3) reporting adverse events and procedure standardization across sites; and 4) dissemination of results. CONCLUSION: Solutions to these challenges, including early inclusion of stake holders, will inform future pragmatic studies in older adults with depression.

A Machine Learning Approach to Identifying Placebo Responders in Late-Life Depression Trials.

OBJECTIVE: Despite efforts to identify characteristics associated with medication-placebo differences in antidepressant trials, few consistent findings have emerged to guide participant selection in drug development settings and differential therapeutics in clinical practice. Limitations in the methodologies used, particularly searching for a single moderator while treating all other variables as noise, may partially explain the failure to generate consistent results. The present study tested whether interactions between pretreatment patient characteristics, rather than a single-variable solution, may better predict who is most likely to benefit from placebo versus medication. METHODS: Data were analyzed from 174 patients aged 75 years and older with unipolar depression who were randomly assigned to citalopram or placebo. Model-based recursive partitioning analysis was conducted to identify the most robust significant moderators of placebo versus citalopram response. RESULTS: The greatest signal detection between medication and placebo in favor of medication was among patients with fewer years of education (≤12) who suffered from a longer duration of depression since their first episode (>3.47 years) (B = 2.53, t(32) = 3.01, p = 0.004). Compared with medication, placebo had the greatest response for those who were more educated (>12 years), to the point where placebo almost outperformed medication (B = -0.57, t(96) = -1.90, p = 0.06). CONCLUSION: Machine learning approaches capable of evaluating the contributions of multiple predictor variables may be a promising methodology for identifying placebo versus medication responders. Duration of depression and education should be considered in the efforts to modulate placebo magnitude in drug development settings and in clinical practice.