Amy Begley

Healthy older adults' sleep predicts all-cause mortality at 4 to 19 years of follow-up.

Objective Evidence concerning whether sleep disturbances in older adults predict mortality is mixed. However, data are limited to self-reported sleep problems and may be confounded with other comorbidities. We examined whether electroencephalographic (EEG) sleep parameters predicted survival time independently of known predictors of all-cause mortality. Methods A total of 185 healthy older adults, primarily in their 60s through 80s, with no history of mental illness, sleep complaints, or current cognitive impairment, were enrolled in one of eight research protocols between October 1981 and February 1997 that included EEG sleep assessments. At follow-up (mean [SD] = 12.8 [3.7] years after baseline, range = 4.1–19.5), 66 individuals were positively ascertained as deceased and 118 remained alive (total N = 184). Results Controlling for age, gender, and baseline medical burden, individuals with baseline sleep latencies greater than 30 minutes were at 2.14 times greater risk of death (p = .005, 95% CI = 1.25–3.66). Those with sleep efficiency less than 80% were at 1.93 times greater risk (p = .014, CI = 1.14–3.25). Individuals with rapid eye movement (REM) sleep percentages in the lowest 15% or highest 15% of the total sample’s distribution (percentage of REM <16.1 or >25.7) were at 1.71 times greater risk (p = .045, CI = 1.01–2.91). Percentage of slow-wave sleep was associated with time to death at the bivariate level, but not after controlling for potential confounders. Conclusions Older adults with specific EEG sleep characteristics have an excess risk of dying beyond that associated with age, gender, or medical burden. The findings suggest that interventions to optimize and protect older adults’ sleep initiation, continuity, and quality may be warranted.

Circadian rhythms in human performance and mood under constant conditions

This study explored the relationship between circadian performance rhythms and rhythms in rectal temperature, plasma cortisol, plasma melatonin, subjective alertness and well‐being. Seventeen healthy young adults were studied under 36 h of «unmasking» conditions (constant wakeful bedrest, temporal isolation, homogenized «meals») during which rectal temperatures were measured every minute, and plasma cortisol and plasma melatonin measured every 20 min. Hourly subjective ratings of global vigour (alertness) and affect (well‐being) were obtained followed by one of two performance batteries. On odd‐numbered hours performance (speed and accuracy) of serial search, verbal reasoning and manual dexterity tasks was assessed. On even‐numbered hours, performance (% hits, response speed) was measured at a 25–30 min visual vigilance task. Performance of all tasks (except search accuracy) showed a significant time of day variation usually with a nocturnal trough close to the trough in rectal temperature. Performance rhythms appeared not to reliably differ with working memory load. Within subjects, predominantly positive correlations emerged between good performance and higher temperatures and better subjective alertness; predominantly negative correlations between good performance and higher plasma levels of cortisol and melatonin. Temperature and cortisol rhythms correlated with slightly more performance measures (5/7) than did melatonin rhythms (4/7). Global vigour correlated about as well with performance (5/7) as did temperature, and considerably better than global affect (1/7). In conclusion: (1) between‐task heterogeneity in circadian performance rhythms appeared to be absent when the sleep/wake cycle was suspended; (2) temperature (positively), cortisol and melatonin (negatively) appeared equally good as circadian correlates of performance, and (3) subjective alertness correlated with performance rhythms as well as (but not better than) body temperature, suggesting that performance rhythms were not directly mediated by rhythms in subjective alertness.

Efficacy of Brief Behavioral Treatment for Chronic Insomnia in Older Adults

BACKGROUND Chronic insomnia is a common health problem with substantial consequences in older adults. Cognitive behavioral treatments are efficacious but not widely available. The aim of this study was to test the efficacy of brief behavioral treatment for insomnia (BBTI) vs an information control (IC) condition. METHODS A total of 79 older adults (mean age, 71.7 years; 54 women [70%]) with chronic insomnia and common comorbidities were recruited from the community and 1 primary care clinic. Participants were randomly assigned to either BBTI, consisting of individualized behavioral instructions delivered in 2 intervention sessions and 2 telephone calls, or IC, consisting of printed educational material. Both interventions were delivered by a nurse clinician. The primary outcome was categorically defined treatment response at 4 weeks, based on sleep questionnaires and diaries. Secondary outcomes included self-report symptom and health measures, sleep diaries, actigraphy, and polysomnography. RESULTS Categorically defined response (67% [n = 26] vs 25% [n = 10]; χ(2) = 13.8) (P < .001) and the proportion of participants without insomnia (55% [n = 21] vs 13% [n = 5]; χ(2) = 15.5) (P < .001) were significantly higher for BBTI than for IC. The number needed to treat was 2.4 for each outcome. No differential effects were found for subgroups according to hypnotic or antidepressant use, sleep apnea, or recruitment source. The BBTI produced significantly better outcomes in self-reported sleep and health (group × time interaction, F(5,73) = 5.99, P < .001), sleep diary (F(8,70) = 4.32, P < .001), and actigraphy (F(4,74) = 17.72, P < .001), but not polysomnography. Improvements were maintained at 6 months. CONCLUSION We found that BBTI is a simple, efficacious, and durable intervention for chronic insomnia in older adults that has potential for dissemination across medical settings. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00177203.

Persistence of Neuropsychologic Deficits in the Remitted State of Late-Life Depression

OBJECTIVE Cognitive impairment in late-life depression (LLD) is prevalent, disabling, and persists despite the remission of depressive symptoms. This article characterizes neuropsychologic functioning during remission in LLD. METHODS The authors examined longitudinal performance on a comprehensive neuropsychologic battery in 56 nondemented subjects age 60 or older who initially presented with an episode of nonpsychotic unipolar major depression and 40 nondemented, age- and education-equated comparison subjects with no history of depression. Subjects were assessed at baseline (in a depressed state) and one year later (when remitted). RESULTS After one year, 45% of the LLD subjects were cognitively impaired despite remission of depression. Visuospatial ability, information-processing speed, and delayed memory were most frequently impaired; 94% of the patients who were impaired at baseline remained impaired one year later. Twenty-three percent of the patients who were cognitively normal while depressed developed impairment one year later. CONCLUSIONS Most older individuals who are cognitively impaired during a depressive episode remain impaired when their depression remits. In addition, a substantial proportion of older depressed individuals who are cognitively intact when depressed are likely to be impaired one year later, although their depression has remitted.

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Age-associated alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.

Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans.

OBJECTIVE Pharmacological and cognitive-behavioral treatments targeting insomnia and nightmares have been shown to be effective in the treatment of military veterans with sleep complaints comorbid with symptoms of stress-related disorders, including Post-Traumatic Stress Disorder (PTSD), but the two approaches have not been directly compared. This randomized controlled trial compared the effects of prazosin vs. a behavioral sleep intervention (BSI), targeting nightmares and insomnia against a placebo pill control condition on sleep and daytime symptoms. METHODS Fifty United States military veterans (mean age 40.9years, SD=13.2years) with chronic sleep disturbances were randomized to prazosin (n=18), BSI (n=17), or placebo (n=15). Each intervention lasted 8weeks. Participants completed self-report measures of insomnia severity, sleep quality, and sleep disturbances. All kept a sleep diary throughout the intervention period. Polysomnographic studies were conducted pre- and post-intervention. RESULTS Both active treatment groups showed greater reductions in insomnia severity and daytime PTSD symptom severity. Sleep improvements were found in 61.9% of those who completed the active treatments and 25% of those randomized to placebo. CONCLUSION BSI and prazosin were both associated with significant sleep improvements and reductions in daytime PTSD symptoms in this sample of military veterans. Sleep-focused treatments may enhance the benefits of first-line PTSD treatments.

Pretreatment REM sleep and subjective sleep quality distinguish depressed psychotherapy remitters and nonremitters

BACKGROUND We compared pretreatment subjective and electroencephalographic sleep measures among depressed patients who remitted with psychotherapy alone and those who did not remit. METHODS Patients were 111 midlife women with recurrent major depressive disorder. Baseline psychiatric ratings and sleep studies were conducted prior to treatment with weekly interpersonal psychotherapy. Remission was defined as a score of < or = 7 for 3 consecutive weeks on the Hamilton Depression Rating Scale. Clinical and sleep measures were compared between remitters (n = 62) and nonremitters (n = 49) using t tests and random regression. Linear discriminant function analyses were used to categorize remitters and nonremitters on the basis of sleep measures. RESULTS Treatment nonremitters had significantly worse subjective sleep quality and significantly elevated phasic REM sleep as measured by multivariate and univariate analyses. The linear accumulation of REM activity during sleep occurred at a significantly higher rate in nonremitters than in remitters. Linear discriminant function analyses based on subjective sleep quality and REM activity correctly identified 68.3% of nonremitters and 68.5% of remitters. CONCLUSIONS These findings highlight the role of subjective and REM sleep measures as correlates of short-term psychotherapy treatment response in major depressive disorder. Disturbed sleep may be a physiological indicator of increased limbic and brain stem arousal.

Gray Matter Changes in Late Life Depression—a Structural MRI Analysis

Multiple brain morphometric changes have been reported in late-life depression (LLD), mostly in studies comparing volumes of circumscribed brain areas. The aim of our study is to characterize the volumetric changes of multiple gray matter regions in relation to age of onset/duration of illness. We predicted that the association of gray matter volumes with total duration of illness and age of onset would differ depending on whether the region was susceptible to the toxic effects of chronic exposure to cortisol or to the vascular/neurodegenerative changes accompanying prodromal dementia. Seventy-one elderly depressed subjects were studied along with thirty-two comparison subjects. High-resolution T1-weighted brain MRIs were processed using an automated labeling pathway technique. To protect against type-I error, we combined the right and left hemisphere volume data. We sampled 24 regions of interest (ROIs). We used the primary visual cortex volume to normalize for individual variations in brain size. LLD Subjects had smaller volumes than non-depressed subjects in 17 of the 24 examined ROIs. Shorter duration of illness and later age of onset was correlated with smaller volumes of parahippocampal area and parietal inferior area. A later age of onset was also correlated with smaller volumes of several frontal and temporal areas, cingulum, and putamen. Our findings support a dementia prodrome model more strongly than a toxic stress model in this group of subjects. However, it remains likely that both processes as well as other factors contribute to the heterogeneity of volumetric brain changes in LLD.

Maintenance Treatment of Depression in Old Age: A Randomized, Double-blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Donepezil Combined With Antidepressant Pharmacotherapy

CONTEXT Cognitive impairment in late-life depression is a core feature of the illness. OBJECTIVE To test whether donepezil hydrochloride and antidepressant therapy is superior to placebo and antidepressant therapy in improving cognitive performance and instrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment. DESIGN Randomized, double-blind, placebo-controlled maintenance trial. SETTING University clinic. PARTICIPANTS One hundred thirty older adults aged 65 years and older with recently remitted major depression. INTERVENTIONS Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo. MAIN OUTCOME MEASURES Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression. RESULTS Donepezil and antidepressant therapy temporarily improved global cognition (treatment × time interaction, F₂,₂₁₆ = 3.78; P = .03), but effect sizes were small (Cohen d = 0.27, group difference at 1 year). A marginal benefit to cognitive instrumental activities of daily living was also observed (treatment × time interaction, F₂,₁₃₇ = 2.94; P = .06). The donepezil group was more likely than the placebo group to experience recurrent major depression (35% [95% confidence interval {CI}, 24%-46%] vs 19% [95% CI, 9%-29%], respectively; log-rank χ² = 3.97; P = .05; hazard ratio = 2.09 [95% CI, 1.00-4.41]). Post hoc subgroup analyses showed that of 57 participants with mild cognitive impairment, 3 of 30 participants (10% [95% CI, 0%-21%]) receiving donepezil and 9 of 27 participants (33% [95% CI, 16%-51%]) receiving placebo had a conversion to dementia over 2 years (Fisher exact test, P = .05). The mild cognitive impairment subgroup had recurrence rates of major depression of 44% with donepezil vs 12% with placebo (likelihood ratio = 4.91; P = .03). The subgroup with normal cognition (n = 73) showed no benefit with donepezil and no increase in recurrence of major depression. CONCLUSIONS Whether a cholinesterase inhibitor should be used as augmentation in the maintenance treatment of late-life depression depends on a careful weighing of risks and benefits in those with mild cognitive impairment. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00177671.

What constitutes too long of a delay? Determining the cortisol awakening response (CAR) using self-report and PSG-assessed wake time.

The cortisol awakening response (CAR) is a burst of cortisol in response to awakening from sleep that is superimposed on the circadian rhythm of cortisol. Determination of the CAR is contingent on the timing of sample collection: a delay between waking and collection of the first sample may affect the rise of the CAR, and could explain equivocal findings reported in the literature. We evaluated the impact of a delay between wake time and collection of waking cortisol samples on the CAR. Two methods were used to identify wake time: polysomnography (PSG) and self-report (S-R). Participants (total n=207, mean age 74.0+/-7.2 years) included bereaved older adults (n=35), caregivers (n=50), patients with insomnia and co-morbid medical disorders (n=68), and the healthy older adults (n=54). We used ANOVA to test if a delay >15 min affected the CAR. We also fitted cubic spline models to assess expected cortisol levels, the expected CAR, and the expected decrease in CAR. Wake times measured by PSG and S-R did not differ significantly. Large delays were observed (for both PSG and S-R) between wake time and collection of the waking cortisol sample (24.8+/-32.2 min for PSG and 28.3+/-49.2 min for S-R). Both statistical methods indicated that a delay >15 min between wake time and first cortisol sample collection significantly affected the CAR (ps<.005); later collection times were associated with smaller CAR values. Later collection times and reduced CAR values may affect the interpretation of clinical associations. Our data also show that S-R assessments of wake time perform equally well to PSG for evaluating adherence with CAR sampling procedures.