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.

The Effect of Cumulative Lifetime Estrogen Exposure on Cognition in Depressed Versus Non-Depressed Older Women.

OBJECTIVES: Two-thirds of individuals living with Alzheimer's disease are women. Declining estrogen levels influence mood and cognition. Cumulative lifetime estrogen exposure (CLEE) correlates with cognition later in life. We examined the relationship of CLEE to depression and cognition in older women with major depression compared to non-depressed women. DESIGN: Older women (age ≥60 years) with depression were compared to non-depressed women using a lifetime estrogen exposure questionnaire. CLEE was defined as combined durations of reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Higher vs lower CLEE groups were based on a median of 474 months of estrogen exposure. SETTING: University hospital outpatient research program. PARTICIPANTS: 135 women ≥60 years; 64 depressed and 71 non-depressed. MEASURMENTS: Participants completed a comprehensive cognitive test battery. General linear models were used to examine the association between cognitive domain scores and CLEE in depressed and non-depressed women, controlling for age, education, and ethnicity. RESULTS: Depressed and non-depressed groups had significantly different levels of CLEE, measured in months: mean 495.7 (SD 108.6) vs 456.4 (SD 66.0) months, F(1,130) = 5.01, p = .03. Within the non-depressed participants, higher CLEE was associated with improved delayed recall (F(1,59) = 5.94, p = .02, effect size = .61), while no such relationship was observed in the depressed group. CONCLUSION: Higher CLEE was associated with improvement in delayed recall among non-depressed, but not among depressed participants. This suggests a protective role of estrogen on memory in non-depressed older postmenopausal women. Further research should examine the role of the CLEE in antidepressant response and cognitive decline.

Complementary and Integrative Medicine for Neurocognitive Disorders and Caregiver Health.

PURPOSE OF REVIEW: Integrative medicine is the practice of combining conventional medical treatments with "alternative" or "complementary" therapies. Integrative psychiatry is a holistic, person-centered approach to neuropsychiatric disorders that emphasizes a person's physical, emotional, interpersonal, behavioral, nutritional, environmental, and spiritual dimensions to achieve well-being. Older adults are more prone to physical injury, interpersonal loss, chronic illnesses, and physical and cognitive decline that can manifest as anxiety, depression, with functional decline and inability to care for self. Additionally, stress of caring for older adults with dementia can adversely affect caregivers' health. Although integrative approaches are perceived as safer and less stigmatizing, it is important to understand the risks and benefits of such therapies for older adults with neurocognitive disorders and their caregivers. RECENT FINDINGS: Here, we summarize the results of the recent clinical trials and meta-analyses that provide evidence for integrative approaches to treating older adults with cognitive disorders and their caregivers which include the use of diet and supplements, and mind-body therapies. Dietary and mind-body therapies have become increasingly popular and show the strongest evidence of effectiveness for cognitive disorders and caregiver stress. Vitamins and supplements are the most popular integrative intervention, but there is mixed evidence supporting their use and the concern for herb (supplement)-drug interactions. While there is increasing popularity of integrative treatments, information to guide clinicians providing care for older adults remains limited, with variable scientific rigor of the available RCTs for a large number of commonly used integrative interventions particularly for cognitive disorders and caregiver stress and well-being.

Cognitive Improvement in Older Adults in the Year After Hip Fracture: Implications for Brain Resilience in Advanced Aging.

OBJECTIVE: We examined cognitive function in nondemented, nondelirious older adults 1 year post hip fracture. DESIGN: Prospective observational study. SETTING AND PARTICIPANTS: Three hundred eighty-six hip fracture patients aged 60 years and older with no history of cognitive impairment, such as clinical dementia or persistent delirium, recruited from eight area hospitals 2-3 days after hip surgery (week 0), and 101 older adults with no recent acute medical events for control comparison. METHODS: Cognitive function was examined with the Repeatable Battery for the Assessment of Neuropsychological Status and the Short Blessed Test (SBT) at weeks 0 (SBT only), 4, and 52 using a repeated measures mixed model analysis. Baseline predictor variables included demographics, personality, genetic factors, and depressive symptom level. RESULTS: Hip fracture participants had lower cognitive scores than healthy comparisons. Cognitive scores improved in the hip fracture group relative to healthy comparison participants from week 4-52. The only significant predictor of cognitive improvement after hip fracture was education: individuals with college education showed cognitive improvement by week 52, while those with high school or less did not. CONCLUSION: Nondemented, nondelirious older adults suffering hip fracture have poorer cognitive function immediately after the fracture but then exhibit cognitive improvement over the ensuing year, especially among those with high education. This demonstrates brain resilience in older adults even in the context of advanced age, medical illness, and frailty.

Tobacco Cessation Treatment Pathways for Patients With Cancer: 10 Years in the Making.

Tobacco use is the most common cause of preventable morbidity and mortality in the United States; it accounts for one-third of all cancer deaths and is thought to account for half of preventable cancer deaths. This article describes the Tobacco Treatment Program at a major academic cancer center. Patients and employees may access these services in a number of ways. All current smokers and recent quitters are proactively contacted and invited to participate. Services provided are tailored to the motivational level of individual patients and their immediate medical needs. The treatment pathways we present are based on our experience from the last 10 years in treating more than 5,000 unique patients with around 60,000 patient visits. These pathways include behavioral counseling and pharmacotherapy, including first-line, second-line, and off-label medication use. This article describes the program with the goal of providing guidance and ideas to others who are developing treatment programs and providing treatment to tobacco users.

Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2.

BACKGROUND: The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis. METHODS: The effect of LXR activation on microglia and central nervous system (CNS) inflammation was studied using a synthetic LXR agonist in cultured microglia, a microglial cell line and experimental allergic encephalomyelitis (EAE), an animal model of CNS inflammation. RESULTS: LXR activation inhibited nitric oxide synthase 2, inducible (Nos2) expression and nitric oxide production in lipopolysaccharide (LPS)-stimulated microglia. Inhibition of microglial activation in response to interferon-γ was less reliable. In LPS-stimulated cells, LXR activation did not inhibit nuclear translocation of NF-kappaB1 p50. Instead, LXR-dependent Nos2 repression was associated with inhibition of histone 4 acetylation and inhibition of NF-kappaB1 p50 binding at the Nos2 promoter. Histone acetylation and NF-kappaB1 p50 binding were mechanistically linked, and histone deacetylase (HDAC) activity appeared to be important for LXR-dependent transcriptional repression of Nos2. Analysis of CNS gene expression in animals undergoing EAE showed that the expressions of Lxr and LXR-dependent genes were downregulated during CNS inflammation. Nevertheless, administration of LXR agonist GW3965 during the effector phase of EAE delayed the onset of clinical disease and reversed the diminished expression of LXR-dependent reverse cholesterol transport genes. However, the CNS expressions of Nos2 and other inflammatory genes were not significantly inhibited by LXR activation in EAE, and clinical disease severity was comparable to vehicle controls at later time points in LXR agonist treated animals. CONCLUSIONS: LXR can be targeted to modulate microglial activation. LXR-dependent repression of inflammatory genes may be stimulus-dependent and impaired by HDAC inhibition. Endogenous LXR activity does not appear to modulate CNS inflammation, but LXR activity can be partially restored in the CNS by administration of exogenous LXR agonist with an impact on clinical disease severity at early, but not late, time points in EAE.

Use of Complementary and Integrative Medicine for Alzheimer's Disease and Cognitive Decline.

Integrative medicine takes a holistic approach because it considers multiple aspects of the individual. This includes a person's physical, emotional, interpersonal, behavioral, nutritional, environmental, and spiritual dimensions of wellbeing that contribute to the Whole Person Health. There is increasing interest and popularity of integrative approaches to treating cognitive decline and dementia because of the multifactorial nature of aging and the limited pharmacological interventions available in treating cognitive decline and dementia, particularly Alzheimer's disease, the most common type of dementia. This review summarizes the existing evidence using complementary and integrative medicine therapies in cognitive decline and Alzheimer's disease. This includes the use of mind-body therapies, lifestyle interventions (nutritional, physical exercise, stress reduction), and other integrative modalities. Unfortunately, there are still limited studies available to guide clinicians despite the increasing popularity of integrative treatments.

Women who breastfeed exhibit cognitive benefits after age 50.

BACKGROUND AND OBJECTIVES: Women who breastfeed may experience long-term benefits for their health in addition to the more widely appreciated effects on the breastfed child. Breastfeeding may induce long-term effects on biopsychosocial systems implicated in brain health. Also, due to diminished breastfeeding in the postindustrial era, it is important to understand the lifespan implications of breastfeeding for surmising maternal phenotypes in our species' collective past. Here, we assess how women's breastfeeding history relates to postmenopausal cognitive performance. METHODOLOGY: A convenience sample of Southern California women age 50+ was recruited via two clinical trials, completed a comprehensive neuropsychological test battery and answered a questionnaire about reproductive life history. General linear models examined whether cognitive domain scores were associated with breastfeeding in depressed and non-depressed women, controlling for age, education and ethnicity. RESULTS: Women who breastfed exhibited superior performance in the domains of Learning, Delayed Recall, Executive Functioning and Processing Speed compared to women who did not breastfeed (P-values 0.0003-0.015). These four domains remained significant in analyses limited to non-depressed and parous subsets of the cohort. Among those depressed, only Executive Functioning and Processing Speed were positively associated with breastfeeding. CONCLUSIONS AND IMPLICATIONS: We add to the growing list of lifespan health correlates of breastfeeding for women's health, such as the lower risk of type-2 diabetes, cardiovascular disease and breast cancer. We surmise that women's postmenopausal cognitive competence may have been greater in past environments in which breastfeeding was more prevalent, bolstering the possibility that postmenopausal longevity may have been adaptive across human evolutionary history. LAY SUMMARY: Breastfeeding may affect women's cognitive performance. Breastfeeding's biological effects and psychosocial effects, such as improved stress regulation, could exert long-term benefits for the mother's brain. We found that women who breastfed performed better on a series of cognitive tests in later life compared to women who did not breastfeed.

Enhancing Cognition in Older Persons with Depression or Anxiety with a Combination of Mindfulness-Based Stress Reduction (MBSR) and Transcranial Direct Current Stimulation (tDCS): Results of a Pilot Randomized Clinical Trial.

Objectives: Individuals with subjective memory complaints and symptoms of depression and/or anxiety are at high risk for further cognitive decline, and possible progression to dementia. Low-burden interventions to help slow or prevent cognitive decline in this high-risk group are needed. The objective of this study is to assess the feasibility of combining Mindfulness-Based Stress Reduction (MBSR) with transcranial direct current stimulation (tDCS) to increase putative benefits of MBSR for cognitive function and everyday mindfulness in depressed or anxious older adults with subjective cognitive decline. Methods: We conducted a two-site pilot double-blind randomized sham-controlled trial, combining active MBSR with either active or sham tDCS. The intervention included weekly in-class group sessions at the local university hospital and daily at-home practice. Anodal tDCS was applied for 30 min during MBSR meditative practice, both in-class and at-home. Results: Twenty-six individuals with subjective cognitive complaints and symptoms of depression and/or anxiety were randomized to active (n = 12) or sham tDCS (n = 14). The combination of MBSR and tDCS was safe and well tolerated, though at-home adherence and in-class attendance were variable. While they were not statistically significant, the largest effect sizes for active vs. sham tDCS were for everyday mindfulness (d = 0.6) and social functioning (d = 0.9) (F (1,21) = 3.68, p = 0.07 and F (1,21) = 3.9, p = 0.06, respectively). Conclusions: Our findings suggest that it is feasible and safe to combine tDCS with MBSR in older depressed and anxious adults, including during remote, at-home use. Furthermore, tDCS may enhance MBSR via transferring its meditative learning and practice into increases in everyday mindfulness. Future studies need to improve adherence to MBSR with tDCS. Trial Registration: ClinicalTrials.gov (NCT03653351 and NCT03680664). Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-021-01764-9.

Predicting Remission in Late-Life Major Depression: A Clinical Algorithm Based Upon Past Treatment History.

OBJECTIVE: To determine the likelihood of antidepressant response in older adults with major depression as a function of their prior antidepressant trials. METHODS: 500 older adults with major depression as diagnosed by DSM-IV criteria for major depressive episode were treated with venlafaxine extended release for 12 weeks. Participants were recruited from July 2009 to January 2014. For each participant, we collected detailed data on prior antidepressant trials for the current episode of depression. We examined the prospective remission rates as a function of number and class of prior antidepressant trials in a post hoc analysis of pooled data from 2 prior trials. RESULTS: Remission rates with venlafaxine were inversely correlated with the number of prior adequate medication trials (66% for no prior adequate trials, 45% for 1 prior adequate trial, 23% for 2 or more prior adequate trials; P < .0001). Additionally, if prior treatment trials included a serotonin-norepinephrine reuptake inhibitor, participants were even less likely to achieve remission with venlafaxine (32% for 1 prior adequate trial, 18% for 2 or more prior adequate trials; P < .0001). Those with prior adequate trials were also more likely to require a higher dosage of venlafaxine to achieve remission. CONCLUSIONS: Information on an individual patient's number and class of prior adequate antidepressant trials can be used to predict the likelihood of a successful treatment outcome with a given antidepressant in older adults with major depression. Further work is needed to refine this approach to provide personalized antidepressant treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00892047 and NCT02263248.

Concurrent Ramsay Hunt syndrome and disseminated herpes zoster in a patient with relapsed chronic lymphocytic leukemia.

Ramsay Hunt Syndrome (RHS) is a rare complication of latent varicella-zoster virus (VZV) infection that can occur in immunocompetent host. It usually involves ipsilateral facial paralysis, ear pain and facial vesicles. Disseminated herpes zoster is another complication of VZV infection typically seen in immunocompromised hosts. We describe a patient with relapsed chronic lymphocytic leukemia (CLL) who presented simultaneously with RHS and disseminated herpes zoster. While other complications have been documented to coexist with RHS, to our knowledge, this is the first reported case in the literature of concurrent RHS with disseminated herpes zoster.