Stephen F. Smagula

Risk factors for sleep disturbances in older adults: Evidence from prospective studies

No systematic review of epidemiological evidence has examined risk factors for sleep disturbances among older adults. We searched the PubMed database combining search terms targeting the following domains 1) prospective, 2) sleep, and 3) aging, and identified 21 relevant population-based studies with prospective sleep outcome data. Only two studies utilized objective measures of sleep disturbance, while six used the Pittsburgh sleep quality index (PSQI) and thirteen used insomnia symptoms or other sleep complaints as the outcome measure. Female gender, depressed mood, and physical illness were most consistently identified as risks for future sleep disturbances. Less robust evidence implicated the following as potentially relevant predictors: lower physical activity levels, African-American race, lower economic status, previous manual occupation, widowhood, marital quality, loneliness and perceived stress, preclinical dementia, long-term benzodiazepine and sedative use, low testosterone levels, and inflammatory markers. Chronological age was not identified as a consistent, independent predictor of future sleep disturbances. In conclusion, prospective studies have identified female gender, depressed mood, and physical illness as general risk factors for future sleep disturbances in later life, although specific physiological pathways have not yet been established. Research is needed to determine the precise mechanisms through which these factors influence sleep over time.

Association between sleep duration and mortality is mediated by markers of inflammation and health in older adults: the Health, Aging and Body Composition Study.

STUDY OBJECTIVES Inflammation may represent a common physiological pathway linking both short and long sleep duration to mortality. We evaluated inflammatory markers as mediators of the relationship between sleep duration and mortality in community-dwelling older adults. DESIGN Prospective cohort with longitudinal follow-up for mortality outcomes. SETTING Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS Participants in the Health, Aging and Body Composition (Health ABC) Study (mean age 73.6 ± 2.9 years at baseline) were sampled and recruited from Medicare listings. MEASUREMENTS AND RESULTS Baseline measures of subjective sleep duration, markers of inflammation (serum interleukin-6, tumor necrosis factor-α, and C-reactive protein) and health status were evaluated as predictors of all-cause mortality (average follow-up = 8.2 ± 2.3 years). Sleep duration was related to mortality, and age-, sex-, and race-adjusted hazard ratios (HR) were highest for those with the shortest (< 6 h HR: 1.30, CI: 1.05-1.61) and longest (> 8 h HR: 1.49, CI: 1.15-1.93) sleep durations. Adjustment for inflammatory markers and health status attenuated the HR for short (< 6 h) sleepers (HR = 1.06, 95% CI = 0.83-1.34). Age-, sex-, and race-adjusted HRs for the > 8-h sleeper group were less strongly attenuated by adjustment for inflammatory markers than by other health factors associated with poor sleep with adjusted HR = 1.23, 95% CI = 0.93-1.63. Inflammatory markers remained significantly associated with mortality. CONCLUSION Inflammatory markers, lifestyle, and health status explained mortality risk associated with short sleep, while the mortality risk associated with long sleep was explained predominantly by lifestyle and health status.

Intrinsic functional connectivity in late-life depression: trajectories over the course of pharmacotherapy in remitters and non-remitters

Previous studies in late-life depression (LLD) have found that patients have altered intrinsic functional connectivity in the dorsal default mode network (DMN) and executive control network (ECN). We aimed to detect connectivity differences across a treatment trial among LLD patients as a function of remission status. LLD patients (N=37) were enrolled into a 12-week trial of venlafaxine and underwent five functional magnetic resonance imaging resting state scans during treatment. Patients had no history of drug abuse, psychosis, dementia/neurodegenerative diseases or medical conditions with known effects on mood. We investigated whether there were differences in three networks: DMN, ECN and anterior salience network connectivity, as well as a whole brain centrality measure (eigenvector centrality). We found that remitters showed increases in ECN connectivity in the right precentral gyrus and decreases in DMN connectivity in the right inferior frontal gyrus and supramarginal gyrus. The ECN and DMN had regions (middle temporal gyrus and bilateral middle/inferior temporal/fusiform gyrus, respectively) that showed reversed effects (decreased ECN and increased DMN, respectively). Early changes in functional connectivity can occur after initial medication exposure. This study offers new data, indicating that functional connectivity changes differ depending on treatment response and can occur shortly after exposure to antidepressant medication.

Sleep Architecture and Mental Health Among Community-Dwelling Older Men

OBJECTIVES To investigate the association of mood and anxiety symptoms with sleep architecture (the distribution of sleep stages) in community-dwelling older men. METHOD We used in-home unattended polysomnography to measure sleep architecture in older men. Men were categorized into 4 mental health categories: (a) significant depressive symptoms only (DEP+ only, Geriatric Depression Scale ≥ 6), (b) significant anxiety symptoms only (ANX+ only, Goldberg Anxiety Scale ≥ 5), (c) significant depressive and anxiety symptoms (DEP+/ANX+), or (d) no significant depressive or anxiety symptoms (DEP-/ANX-). RESULTS Compared with men without clinically significant symptomology, men with depressive symptoms spent a higher percentage of time in Stage 2 sleep (65.42% DEP+ only vs 62.47% DEP-/ANX-, p = .003) and a lower percentage of time in rapid eye movement sleep (17.05% DEP+ only vs 19.44% DEP-/ANX-, p = .0005). These differences persisted after adjustment for demographic/lifestyle characteristics, medical conditions, medications, and sleep disturbances, and after excluding participants using psychotropic medications. The sleep architecture of ANX+ or DEP+/ANX+ men did not differ from asymptomatic men. DISCUSSION Depressed mood in older adults may be associated with accelerated age-related changes in sleep architecture. Longitudinal community-based studies using diagnostic measures are needed to further clarify relationships among common mental disorders, aging, and sleep.

Antidepressant Response Trajectories and Associated Clinical Prognostic Factors Among Older Adults.

IMPORTANCE More than 50% of older adults with late-life major depressive disorder fail to respond to initial treatment with first-line pharmacological therapy. OBJECTIVES To assess typical patterns of response to an open-label trial of extended-release venlafaxine hydrochloride (venlafaxine XR) for late-life depression and to evaluate which clinical factors are associated with the identified longitudinal response patterns. DESIGN, SETTING, AND PARTICIPANTS Group-based trajectory modeling was applied to data from a 12-week open-label pharmacological trial conducted in specialty care as part of the Incomplete Response in Late Life: Getting to Remission Study. Clinical prognostic factors, including domain-specific cognitive performance and individual depression symptoms, were examined in relation to response trajectories. Participants included 453 adults aged 60 years or older with current major depressive disorder. The study was conducted between August 2009 and August 2014. INTERVENTION Open-label venlafaxine XR (titrated up to 300 mg/d) for 12 weeks. MAIN OUTCOMES AND MEASURES Subgroups exhibiting similar response patterns were derived from repeated measures of overall depression severity obtained using the Montgomery-Asberg Depression Rating Scale. RESULTS Among the 453 study participants, 3 subgroups with differing baseline depression severity clearly responded to treatment: one group with the lowest baseline severity had a rapid response (n = 69 [15.23%]), and distinct responses were also apparent among groups starting at moderate (n = 108 [23.84%]) and higher (n = 25 [5.52%]) baseline symptom levels. Three subgroups had nonresponding trajectories: 2 with high baseline symptom levels (totaling 35.98%: high, nonresponse 1, n = 110 [24.28%]; high, nonresponse 2, n = 53 [11.70%]) and 1 with moderate baseline symptom levels (n = 88 [19.43%]). Several factors were independently associated with having a nonresponsive trajectory, including greater baseline depression severity, longer episode duration, less subjective sleep loss, more guilt, and more work/activity impairment (P < .05). Higher delayed memory (list recognition) performance was independently associated with having a rapid response (adjusted odds ratio = 2.22; 95% CI, 1.18-4.20). CONCLUSIONS AND RELEVANCE Based on the observed trajectory patterns, patients who have late-life depression with high baseline depression severity are unlikely to respond after 12 weeks of treatment with venlafaxine XR. However, high baseline depression severity alone may be neither a necessary nor sufficient predictor of treatment nonresponse. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00892047.

Predictors and Moderators of Remission With Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression: An Analysis of the IRL-GRey Randomized Clinical Trial

IMPORTANCE Safe, efficacious, second-line pharmacological treatment options exist for the large portion of older adults with major depressive disorder who do not respond to first-line pharmacotherapy. However, limited evidence exists to aid clinical decision making regarding which patients will benefit from which second-line treatments. OBJECTIVE To test the moderating role of pretreatment executive function, severity of anxiety, and severity of medical comorbidity in remission of treatment-resistant late-life depression after aripiprazole augmentation. DESIGN, SETTING, AND PARTICIPANTS As follow-up to a 12-week randomized clinical trial of aripiprazole augmentation for first-line treatment-resistant late-life depression (Incomplete Response in Late-Life Depression: Getting to Remission [IRL-GRey]), we evaluated the effects of the following potential moderators and their interactions with treatment: baseline assessments of executive function (set shifting measured by the Trail Making Test) and response inhibition control (measured by a Color-Word Interference task), anxiety symptoms, and medical comorbidity. Analyses were conducted in May and June 2015. INTERVENTIONS Aripiprazole or placebo tablets were started at 2 mg daily and titrated as tolerated, to a maximal dose of 15 mg daily. MAIN OUTCOMES AND MEASURES Remission of treatment-resistant late-life depression (defined as a Montgomery-Åsberg Depression Rating Scale score of ≤10 at both of the last 2 consecutive visits). RESULTS Of 181 trial participants (103 female [56.9%]) who were 60 years of age or older and whose major depression had failed to remit with venlafaxine hydrochloride monotherapy, 91 received aripiprazole and 90 received placebo. Remission occurred in 40 (43%) who received aripiprazole and 26 (29%) who received placebo. Baseline set shifting moderated the efficacy of aripiprazole augmentation (odds ratio [OR], 1.66 [95% CI, 1.05-2.62]; P = .03 for interaction with treatment). Among participants with a Trail Making Test scaled score of 7 or higher, the odds of remission were significantly higher with aripiprazole than with placebo (53% vs 28%; number needed to treat, 4; OR, 4.11 [95% CI, 1.83-9.20]). Among participants with a Trail Making Test scaled score of less than 7, aripiprazole and placebo were equally efficacious (OR, 0.64 [95% CI, 0.15-2.80]). Greater severity of anxiety at baseline predicted a lower remission rate but did not moderate aripiprazole efficacy; each standard deviation greater anxiety severity was associated with 50% reduced odds of remission in both aripiprazole and placebo arms. Medical comorbidity and Color-Word Interference test performance were neither general predictors nor treatment-moderating factors. CONCLUSIONS AND RELEVANCE Set-shifting performance indicates which older adults with treatment-resistant depression may respond favorably to augmentation with aripiprazole and thus may help to personalize treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00892047.

Circadian Rest–Activity Rhythms Predict Future Increases in Depressive Symptoms Among Community-Dwelling Older Men

OBJECTIVE Circadian rest-activity rhythms (CARs) have been cross-sectionally associated with depressive symptoms, although no longitudinal research has examined whether CARs are a risk factor for developing depressive symptoms. METHODS We examined associations of CARs (measured with actigraphy over a mean of 4.8 days) with depressive symptoms (measured with the Geriatric Depression Scale) among 2,892 community-dwelling older men (mean age: 76.2 ± 5.5 years) from the MrOS Sleep Study who were without cognitive impairment. Among 2,124 men with minimal (0-2) symptoms at baseline, we assessed associations between CAR parameters and increases to mild (3-5) or clinically significant (≥6) symptoms after an average of 1.2 (±0.32) years. RESULTS Cross-sectional associations between rhythm height parameters were independent of chronic diseases, lifestyle, sleep, and self-reported physical activity covariates. For example, men in the lowest mesor quartile had twice the adjusted odds (adjusted odds ratio [AOR]: 2.04, 95% confidence interval [CI]: 1.36-3.04, p = 0.0005) of having prevalent clinically significant symptoms (compared to minimal). Longitudinally, low CAR robustness (being in the lowest quartile of the pseudo-F statistic) was independently associated with increasing odds of developing symptoms (i.e., AOR for having clinically significant depressive symptoms at follow-up = 2.58, 95% CI: 1.11-5.99, p = 0.03). CONCLUSION CAR disturbances are indicative of depressive symptomology. Low CAR robustness may independently contribute to the risk of worsening depression symptomology.

Immunological biomarkers associated with brain structure and executive function in late-life depression: exploratory pilot study

Several immunological biomarkers are altered in late‐life major depressive disorder (LLD). Immunological alterations could contribute to LLDs consequences, but little is known about the relations between specific immunological biomarkers and brain health in LLD. We performed an exploratory pilot study to identify, from several candidates, the specific immunological biomarkers related to important aspects of brain health that are altered in LLD (brain structure and executive function).

Inflammation, sleep disturbances, and depressed mood among community-dwelling older men

OBJECTIVE High rates of sleep disturbances occur in depression. Sleep disturbances are linked to heightened inflammation. We sought to determine if sleep disturbances explain a portion of the putative inflammation - depression association among older adults. In late life, age-related immunoregulation changes may modify the inflammation-depression relationship. METHODS Cross-sectional associations of a panel of serum inflammatory markers with probable depression (measured with the Geriatric Depression Scale) were assessed among 2560 community-dwelling older men. We tested whether inflammatory marker - probable depression associations were independent of chronic diseases, as well as objective and subjectively measured sleep disturbances. We also tested whether inflammation-probable depression associations were moderated by age. RESULTS Inflammatory markers were not independently associated with higher odds of probable depression. A significant age by C-reactive protein (CRP) interaction (p=0.01) was detected such that the strength of the CRP-probable depression association decreased with age. When stratifying by the median age of 76, elevated odds of probable depression were found for men with CRP levels above the median only among the younger group (OR=2.08, 95% CI 1.18-3.69). In the final adjusted model, independent effects of chronic diseases and subjective sleep disturbances contributed to a total of 37% attenuation of the original OR (adjusted OR=1.68, 95% CI 0.911-3.10, p=.09). CONCLUSIONS In late-life, associations between inflammatory markers and mood may be explained by both chronic diseases and subjectively reported sleep disturbances. Our findings indicate that the association of CRP with probable depression diminishes in strength with age.

Actigraphy- and polysomnography-measured sleep disturbances, inflammation, and mortality among older men

Objectives To evaluate whether objectively measured sleep characteristics are associated with mortality risk independent of inflammatory burden and comorbidity. Methods The Osteoporotic Fractures in Men Sleep Study (conducted in 2003–2005) included community-dwelling older men (n = 2531; average [standard deviation {SD}] age = 76.3 (5.5) years). Sleep measures from in-home polysomnography and wrist actigraphy and assessments of serum inflammatory markers levels (C-reactive protein, interleukin-6, tumor necrosis factor &agr;, tumor necrosis factor &agr; soluble receptor II, and interferon-&ggr;) were obtained. Vital status was ascertained over an average (SD) follow-up of 7.4 (1.9 SD) years. Results Three of the seven main sleep measures examined were independently associated with greater inflammatory burden. Mortality risk associated with prolonged (≥10% total sleep time) blood oxygen desaturation and short (<5 hours) sleep duration was attenuated to nonsignificance after adjusting for inflammatory burden or medical burden/lifestyle factors. Severe blood oxygen desaturation (adjusted hazard ratio [aHR] = 1.57, 95% confidence interval [CI] = 1.11–2.22), sleep fragmentation (aHR = 1.32, 95% CI = 1.12–1.57), and a lower percentage of sleep in rapid eye movement (aHR per SD = 0.90, 95% CI = 0.93–0.97) were independently associated with mortality. Conclusions Short sleep duration and prolonged blood oxygen desaturation were independently associated with inflammatory burden, which attenuated associations between these sleep characteristics and mortality. Medical and life-style factors also substantially attenuated most sleep-mortality associations, suggesting complex relations between sleep, inflammation, and disease. Sleep fragmentation, severe blood oxygen desaturation, and the percentage of sleep time in rapid eye movement were independently related to mortality risk. Future studies with repeated measures of mediators/confounds will be necessary to achieve a mechanistic understanding of sleep-related mortality risk.