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.

Relationship between Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores in older adults with major depressive disorder: An analysis of the OPTIMUM clinical trial.

BACKGROUND: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults. METHODS: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187). Equipercentile linking was performed on the training sample to produce conversion tables for PHQ-9 and MADRS. We compared the original and estimated scores in the validation sample with Bland-Altman analysis. We compared the depression severity level using the original and estimated scores with Chi-square tests. RESULTS: The Bland-Altman analysis confirmed that differences between the original and estimated scores for at least 95 % of the sample fit within 1.96 standard deviations of the mean difference. Chi-square tests showed a significant difference in the proportion of participants at each depression severity category determined using the original and estimated scores. LIMITATIONS: The conversion tables should be used with caution when comparing depression severity at the individual level. CONCLUSIONS: Our conversion tables relating PHQ-9 and MADRS scores can be used to compare treatment outcomes using aggregate data in studies that only used one of these scales.

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.

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.).

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.

Proof of Concept of the Contribution of the Interaction between Trait-like and State-like Effects in Identifying Individual-Specific Mechanisms of Action in Biological Psychiatry.

Background: Identifying individual-specific mechanisms of action may facilitate progress toward precision medicine. Most studies seeking to identify mechanisms of action collapse together two distinct components: pre-treatment trait-like characteristics differentiating between individuals and state-like characteristics changing within each individual over the course of treatment. We suggest a conceptual framework highlighting the importance of studying interactions between trait-like and state-like components in the development of moderated mediation models that can guide personalized targeted interventions. Methods: To facilitate implementation of this framework, two empirical demonstrations are presented from a recent clinical trial and neuroimaging study. The first examines limbic reactivity during an emotional face task; the second concerns striatal activation in a monetary reward task. Results: In both tasks, considering the interaction between trait-like and state-like components predicted treatment outcome more robustly than did the trait-like or state-like components examined individually. Conclusions: These findings suggest that the extent to which state-like modulation of neural activations can serve as a potential treatment target depends on the pre-treatment, trait-like levels of activation in these regions. Thus, the interaction between trait-like and state-like components can serve as a promising path to the development of personalized interventions within a precision medicine framework in which mechanisms of action are individual-specific.

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.

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.

Frailty and Depression in Late Life: A High-Risk Comorbidity With Distinctive Clinical Presentation and Poor Antidepressant Response.

BACKGROUND: To investigate the longitudinal relationship between physical frailty, the clinical representation of accelerated biological aging, and antidepressant medication response in older adults with depressive illness. METHODS: An 8-week randomized placebo-controlled trial (escitalopram or duloxetine) followed by 10 months of open antidepressant medication treatment (augmentation, switch strategies) was conducted in an outpatient research clinic. 121 adults aged 60 years or older with major depressive disorder (MDD) or persistent depressive disorder and a 24-item Hamilton Rating Scale for Depression (HRSD) ≥16 were enrolled. Primary measures assessed serially over 12 months include response (50% reduction from baseline HRSD score), remission (HRSD score <10), and frailty (non/intermediate frail [0-2 deficits] vs frail [≥3 deficits]); latent class analysis was used to classify longitudinal frailty trajectories. RESULTS: A 2-class model best fit the data, identifying a consistently low frailty risk (63% of the sample) and consistently high frailty risk (37% of the sample) trajectory. Response and remission rates (ps ≤ .002) for adults in the high-risk frailty class were at least 21 percentage points worse than those in the low-risk class over 12 months. Furthermore, subsequent frailty was associated with previous frailty (ps ≤ .01) but not previous response or remission (ps ≥ .10). CONCLUSIONS: Antidepressant medication is poorly effective for MDD occurring in the context of frailty in older adults. Furthermore, even when an antidepressant response is achieved, this response does little to improve their frailty. These data suggest that standard psychiatric assessment of depressed older adults should include frailty measures and that novel therapeutic strategies to address comorbid frailty and depression are needed.

"What else can we do?"-Provider perspectives on treatment-resistant depression in late life.

BACKGROUND: Treatment-resistant depression in late-life (TRLLD) is common. Perspectives of primary care providers (PCPs) and psychiatrists treating TRLLD could give insights into the challenges and potential solutions for managing this condition. METHODS: To identify perspectives of providers who treat TRLLD, we conducted a qualitative descriptive study using semi-structured interviews with providers treating older adults with TRLLD in five locations across North America (i.e., Los Angeles, New York City, Pittsburgh, St. Louis, and Toronto). We conducted semi-structured interviews with 50 care providers (24 primary care providers [PCPs], 22 psychiatrists, and 4 depression care managers). Interviews elicited providers' perspectives on treatment options for TRLLD, including treatment within the primary care setting and referral to psychiatry, and sought suggestions for improvement. RESULTS: We identified four themes. (1) Treating TRLLD takes an emotional toll on providers; (2) existing psychiatric services are inadequate to meet the needs of patients with TRLLD, mainly because of lack of access; (3) PCPs often attempt to treat TRLLD, even when they are not comfortable doing so; and (4) to better meet the needs of patients with TRLLD, providers recommend integrated care models involving PCPs, psychiatrists, and psychotherapists, potentially made more feasible by the growth of telehealth. CONCLUSIONS: Findings from these qualitative interviews show the challenges in providing care for TRLLD. These findings can guide knowledge dissemination to psychiatrists, PCPs, policy-makers, and other stakeholders involved in the mental health system. They can also inform structural changes to clinical practice that may increase the implementation of the best treatment strategies across settings to improve long-term outcomes for TRLLD.

Who benefits most from expectancy effects? A combined neuroimaging and antidepressant trial in depressed older adults.

Depressed patients' expectations of improvement drive placebo effects in antidepressant clinical trials, yet there is considerable heterogeneity in the magnitude of expectancy effects. The present study seeks to identify those individuals who benefit most from expectancy effects using baseline neuroimaging and cognitive measures. Older adult outpatients diagnosed with major depressive disorder (MDD) participated in a prospective, 8-week clinical trial in which expectancy was experimentally manipulated and its effects on depression outcome measured. Based on the literature, we selected a priori 12 cognitive and brain-based variables linked to depression and expectancy, together with demographic variables, and incorporated them into a combined moderator. The combined moderator was developed as a weighted combination of the individual moderators, and was used to identify individuals who benefited most from expectancy effects. The combined moderator was found to predict differential change in depression severity scores between the high- vs. low-expectancy groups with a medium-size effect (Spearman effect size: 0.28). While at the sample level no expectancy effect was found, the combined moderator divided older adults with MDD into those who did and those who did not improve as the result of expectancy manipulation, with those benefiting from the manipulation showing greater processing speed, executive function, and frontostriatal white matter tract integrity. The findings suggest that it is possible to identify a subgroup of older adult individuals with MDD for whom expectancy manipulation results in greater antidepressant treatment response, supporting a precision medicine approach. This subgroup is characterized by distinct cognitive dysfunction and neuroimaging impairments profiles.