Michael V. Vitiello - US grants

Human sleep/waking patterns undergo significant changes with advancing age. Decreased stage 4 and REM sleep and increased nighttime wakefulness are consistent findings in sleep studies of the aged. We hypothesize that this age-related disruption in sleep patterns, observed even in very healthy non-complaining aged individuals, may be related to an age-change in sympathetic nervous system (SNS) activity. There is considerable anatomical, physiological and pharmacological evidence that indicates the central mechanisms regulating sleep/waking patterns and SNS outflow may interact. Plasma norepinephrine (NE) levels, which increase with age, are thought to be markers of SNS activity; plasma NE is increased following SNS activation by a variety of stimuli and decreased by pharmacological inhibition. Individual levels of nighttime plasma NE correlate with degree of disturbed sleep among aged individuals, while experimentally induced alterations of sleep patterns do not affect plasma NE levels. Finally, increasing SNS activity via hypovolemia induced by low sodium diet results in both increased plasma NE and disruption of sleep patterns in preliminary studies of young adults. The proposed study will examine the effects of low, normal and high levels of dietary sodium on the sleep and nighttime physiology of young and aged normal men. This will test our hypothesis that central SNS activity level affects sleep. We predict that increased SNS activity induced by hypovolemia (resulting from low sodium diet) will be associated with higher plasma NE and disturbed sleep. Conversely, inhibiting SNS activity by high sodium diet should decrease plasma NE and either improve, or have no effect on sleep patterns. If altering SNS activity is found to affect sleep patterns, this would suggest new approaches to the treatment of sleep complaints in some aged populations.

As much as 30% of the geriatric population complains of poor sleep quality, a complaint that is validated by objective findings showing reduced slow wave sleep (SWS) and increased time and frequency of awakenings during sleep in elderly compared to younger individuals. The physiological consequences of age impaired sleep are poorly understood, but may include impaired anabolic hormone status and damped circadian rhythms. Poor sleep may also account for the disproportionate prescription of sedative hypnotics in the elderly population. Hypnotic medication offers only short term efficacy and in the long term may itself disrupt sleep. Hypnotic use may also lead to exacerbation of sleep apnea and daytime carryover effects such as sedation, falls, cognitive impairment and anterograde amnesia and has been associated with increased morbidity and mortality. Non- pharmacological interventions to improve sleep quality in the elderly population are obviously needed. One such treatment might be regular exercise leading to increased aerobic fitness. Physical fitness in older individuals has been associated with decreased incidence of coronary heart disease, increased strength and vigor, improvements in cognitive functioning and attenuates and perhaps reverses age-related declines in physiological and psychological functioning which may be at least partially the result of inactivity. Daytime exercise has been shown to increase nighttime SWS in young physically fit individuals. Young unfit individuals show enhancement of SWS following a period of physical training. Surprisingly, the effects of improved aerobic fitness on sleep have never been examined in the elderly. The proposed study will examine the effects of improved aerobic fitness resulting from a six month (3 day/week) aerobic training program on objective and subjective sleep quality and on physiological correlates of sleep (circadian temperature rhythm, nighttime growth hormone secretion (and basal daytime somatomedin-c levels) and basal nighttime plasma norepinephrine levels) of 30 men, 60 to 80 years of age, compared to a matched control group of 30 men who participate in a six month (3 day/week) program of relaxation/stretching. Improved aerobic fitness is hypothesized to be associated with improved objective and subjective sleep quality, increased circadian temperature amplitude, increased growth hormone and somatomedin-c levels and decreased nighttime norepinephrine levels.

This is a resubmission for K02 MH01158, a Research Scientist Development Award application for Michael V. Vitiello, Ph.D. It will support Dr. Vitiello's research efforts which center on understanding the causes and consequences of age-related changes in sleep and circadian rhythms and provide him with the opportunity to expand his collaborative relationships and develop additional expertise relevant to his research interests. Dr. Vitiello proposes to examine the feasibility of possible interventions at three levels: first, to continue his study of the effects of fitness training. on the sleep quality and nighttime physiology of the elderly; second, to begin a new series of studies designed to evaluate the usefulness of anabolic hormones in improving sleep quality; and third, to develop a new collaborative relationship with the ultimate goal of examining the possibility of improving the sleep quality of the elderly with melatonin administration. Dr. Vitiello is currently conducting a study of the effects of fitness training on the sleep of the elderly. Preliminary analyses of the sleep and fitness project data set indicate that neither regular endurance nor stretching/flexibility training improves objective sleep quality in healthy elderly men and women. However, improvements in subjective sleep quality, circadian core body temperature rhythm and secretory patterns of growth hormone and plasma norepinephrine were observed. Analyses of this data set and those of the ancillary studies developed in conjunction with this study will continue. Dr. Vitiello also plans to examine the relationship between anabolic status and sleep quality in two studies. The first, a correlational study, will examine the relationships between anabolic status and sleep quality in a sample of healthy elderly men. The second, a prospective intervention, will examine the sleep quality of healthy elderly men and women before and after three months of treatment with growth hormone releasing factor or placebo. Dr. Vitiello will also develop a collaboration with Dr. Robert Sack and develop expertise in the circadian melatonin rhythm with the ultimate goal of examining this endocrine system as another possible intervention for age-related sleep disturbance.

growth hormone releasing hormone; hormone regulation /control mechanism; secretion

We propose to examine the effects of five months of treatment with GEREF vs. placebo on the sleep quality, 24-hour secretory pattern of growth hormone, and insulin-like growth factor-1 concentrations of three groups of healthy older subjects: men, women not on estrogen replacement therapy and women on estrogen replacement therapy. The inclusion of women on ERT as a separate group is important because estrogen interacts in numerous ways with the GH-IGF-1 axis and because an increasing proportion of older women are on chronic ERT.

This is a competing renewal of Dr. Michael V. Vitiello's NIMH Independent Scientist Award, K02-MH01158, Age-Related Sleep Disturbance Possible Interventions. As much as 40% of the older population complains of significant, chronic sleep disturbance. Sleep complaints often lead to chronic sedative hypnotic use and the elderly receive a disproportionate number of such prescriptions. Sedative-hypnotics offer short-term relief but their long-term efficacy is unclear and chronic use has been associated with increased morbidity and mortality. A recent NIH Consensus Conference concluded that chronic hypnotic use is inappropriate and that non-sedative interventions for sleep disruption are sorely needed. Dr. Vitiello proposes three specific aims that will examine possible non-sedative hypnotic approaches to improving the sleep quality of the elderly: Specific Aim 1: Examine the usefulness of fitness training interventions to improve the sleep quality of older men and women. Specific Aim 2: Examine the usefulness of neuroendocrine interventions (e.g., growth hormone releasing hormone, estrogen, and testosterone supplementation) to improve the sleep quality of older men and women. Specific Aim 3: Examine the usefulness of cognitive behavioral techniques to improve the sleep quality of older men and women in a number of different settings. While pursuing these aims, Dr. Vitiello will develop additional expertise in the interactions of sex steroids and sleep quality, ambulatory monitoring of sleep and respiration, actigraphic recording of rest/activity rhythms and cognitive behavioral interventions for sleep disturbance in the elderly. Each of these proposed lines of research has considerable significance for our understanding of the causes of,and potential treatments for, sleep disturbance in the aged. Effective non- sedative interventions may significantly improve not only sleep quality but also overall the quality of life in the elderly. Further, such interventions may have significant impact in decreasing morbidity and mortality directly related to such sleep disturbance or its inappropriate treatment with chronic hypnotic medications.

Sleep complaints increase significantly with age in women. Many older women experience difficulty falling asleep, more night-time awakenings, and less restful sleep. Sleep studies verify that disturbed sleep patterns are observed even in healthy older women. Sleep disturbances are associated with increased daytime drowsiness, increased accident risk, increased use of health care, and reduced quality of life. Older women receive a disproportionate number of sedative-hypnotic medications, which can exacerbate sleep apnea and have daytime carryover effects such as sedation, falls and subsequent fractures, and cognitive impairment. A better understanding of the sleep changes experienced by older women is sorely needed. One contributing factor may be menopause-related changes in sex steroids such as estrogen and progesterone. Research attention has focused on estrogen. However, progesterone may also participate in the control of sleep. Clinical reports indicate that women often feel drowsy after they take oral progesterone - an effect which is undesirable during the day, but may be positive at night. To date there are no published studies of progesterone's effect on the objectively-measured sleep and daytime drowsiness of older women. The proposed study will take a systematic, multi-dimensional approach to determining the effect of progesterone on the sleep and drowsiness of older women. Objective techniques (polysomnography, Multiple Sleep Latency Test) will be used to measure sleep and daytime drowsiness following evening or morning administration of 300 mg micronized progesterone, in 40 postmenopausal women who are at least 5 years past menopause and who are not experiencing hot flashes. Attention, memory, subjective sleepiness, and blood levels of progesterone and its metabolite (allopregnanolone) will also be measured. This study is part of a long-term research plan to assess (1) how the very low postmenopausal levels of estrogen and progesterone contribute to sleep difficulties of older women, and (2) how hormone replacement therapy affects the sleep of women. An ongoing placebo-controlled study is investigating the effects of estrogen on the sleep of older women. The proposed study will complement the estrogen study. It will enhance our limited understanding of the relationship between sex steroids and sleep, and the factors that contribute to sleep problems in older women.

DESCRIPTION (provided by applicant): This is a revision of NIH grant application 1 R01 AG025515-01, GHRH: Cognition in Aging and Mild Cognitive Impairment. The societal burden of Alzheimer's disease (AD) and other primary neurodegenerative dementias is monumental, with total annual costs estimated at $100 billion (1996 dollars) per year in the United States. The need to identify and treat individuals as early as possible in the Alzheimer's disease process is clear, and justifies intensification of studies of individuals with Mild Cognitive Impairment (MCI) who are at risk for progression to dementia within a few years. The FDA's recent hearings on the suitability of MCI as an indication for pharmacotherapy are major indicators of its importance as a public health concern. There is considerable and compelling evidence in the literature that the actions of the somatotrophic (growth hormone releasing hormone/ growth hormone/insulin-like growth factor I) hormonal axis have significant and predictable beneficial impact on cognitive function. Supplementation of the somatotrophic axis may likely be of direct benefit to individuals such as those with MCI, who are experiencing a mild but significant cognitive impairment and who may be at particular risk for continued cognitive decline and progression into AD. We have recently shown that a five-month growth hormone releasing hormone (GHRH) treatment improves cognitive function in healthy older men and women and preliminary evidence supports the expectation of a similar effect in individuals with MCI. We believe it important to replicate and significantly extend our initial GHRH finding in healthy older adults, using a much more comprehensive cognitive assessment battery, which includes measures of memory not included in our preliminary study. We also believe it crucial to extend our examination of the cognitive function enhancing effects of GHRH to a sample of older adults with MCI. Therefore we propose to conduct a prospective, double-blind, randomized placebo-controlled study of the effects of GHRH on the cognitive function of 80 healthy normal older men and women and of 80 older men and women diagnosed with MCI.

DESCRIPTION (provided by investigator): This is a revised submission of 1 R01 AG031126-01, Cognitive Behavioral Therapy for Arthritis Pain and Insomnia in Older Adults. Osteoarthritis (OA) pain affects half of all adults age 60 or older;the majority of whom also experience significant sleep disturbance. Since pain initiates and exacerbates sleep disturbance and poor sleep in turn maintains and exacerbates chronic pain, optimal interventions for OA should target both pain and sleep. While there is limited preliminary evidence that such an intervention may benefit both pain and sleep, a large, rigorous randomized controlled trial testing this hypothesis is lacking. The proposed study will determine whether an intervention that targets both pain and co-morbid sleep disturbance in older adults with painful OA and disturbed sleep yields substantially improved pain, sleep and functional outcomes relative to both an intervention targeting pain alone and a placebo-control. Older (>60 yrs) patients (N=5556 in current database) who have sought treatment for OA in a large health plan will be screened for significant chronic pain and co-morbid sleep disturbance. Three hundred seventy five patients will be randomized to one of three treatment groups: an 8-session Cognitive-Behavioral Therapy for Pain (CBT-P) program addressing pain dysfunction alone;an 8-session Cognitive-Behavioral Therapy for Pain and Insomnia (CBT- Principal Investigator) program addressing both pain and sleep disturbance;{or an 8-session Stress Management and Wellness (SMW) placebo-control group. The SMW condition is based on a placebo-control intervention previously demonstrated to have no effect on sleep quality or perceived pain. To control relevant information, all three groups (CBT-P, CBT-Principal Investigator and SMW) will receive the Arthritis Helpbook, which provides information on pain control, arthritis self-management, and sleep hygiene techniques. Subjects will be assessed at baseline, post-treatment (2-months) and at 6, 12 and 24-month follow-ups. We hypothesize that: 1) CBT-Principal Investigator will produce significantly greater initial and long-term improvements in sleep outcomes relative to both CBT-P and SMW;2) CBT-Principal Investigator, by improving sleep outcomes, will produce significantly greater initial and long-term reductions in OA pain than both CBT-P and SMW;3) CBT-Principal Investigator, by improving both sleep and pain outcomes, will produce greater initial and long-term improvements in pain-related activity limitations than both CBP-P and SMW;} and 4) CBT-Principal Investigator, by improving sleep, pain and functional outcomes, will produce long-term reductions in health care utilization and costs for a broad range of symptomatic conditions (including pain and sleep disturbance). The proposed trial will also provide the largest experimental evaluation to date assessing the effectiveness of conventional CBT for OA pain. Given recent limitations on pharmacologic options for management of OA pain, the proposed trial has important implications for improving management of both pain and co-morbid sleep disturbance in the rapidly growing population of older Americans with OA. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) pain debilitates half of all older adults, most of whom also experience significant sleep disturbance. This project will determine whether a cognitive-behavioral treatment targeting both pain and co- morbid sleep disturbance in older adults with painful OA results in substantially greater reductions in pain and improvements in sleep and functional outcomes compared to current standards of care. Given the recent limitations on pharmacologic options for effective management of OA pain, this project has major implications for improving management of both pain and co-morbid sleep disturbance in the rapidly growing population of older Americans suffering from OA.

Twenty-five percent of older adults experience significant osteoarthritis (OA)-related comorbid sleep disturbance. Insomnia is associated with substantial negative effects on function, mood, and medical resource utilization. Cognitive behavioral therapy for insomnia (CBT-I) is evidence- based and has been shown to be efficacious in populations with a variety of comorbid conditions including OA-related chronic pain. However, in-person CBT interventions are unlikely to be widely deployable in healthcare systems. Telephone delivery has the advantage of giving patients access to personalized, efficacious CBT-I interventions from home, increasing generalizability, and outreach to minority, rural, and other underserved populations. Previous small trials of telephone CBT-I have reported positive insomnia outcomes, but no large randomized trials have assessed its long-term efficacy, impact on related outcomes in a primary care patient population, or cost-effectiveness. This proposal builds upon our successful completion of two randomized trials of CBT for insomnia with older adults: Lifestyles, a trial of group CBT in older adults with OA-related insomnia and pain, and MsFLASH04, a trial of telephone CBT-I for insomnia in menopausal women with comorbid vasomotor symptoms. Older (60+ yrs) primary care patients across Washington State will be screened for severe persistent OA-related insomnia and pain. Two hundred and seventy patients will be randomized to either CBT-I or an education only attention control (EOC). Each treatment will consist of six 20-30 minute telephone-based sessions over an eight week period. Pre-treatment, post-treatment (2 months), and 9 and 18 month assessments will include measures of sleep, pain, fatigue, mood, and quality of life. A cost effectiveness evaluation of the intervention will also be conducted. We hypothesize: 1) CBT-I will produce significantly greater initial and long-term improvements in sleep outcomes relative to EOC; 2) CBT-I will produce significantly greater initial and long-term improvements in pain, fatigue and mood relative to EOC; and 3) CBT-I will produce long-term reductions in health care utilization and costs relative to EOC. We will also explore whether changes in insomnia severity explain observed effects of CBT-I on secondary outcomes (mediator analysis), and whether CBT-I effects on insomnia differ by baseline insomnia, pain, or depression symptom severity (moderator analysis). The proposed research will determine if telephone CBT-I improves OA insomnia and associated outcomes in a state-wide primary care population of older adults, and inform policy decisions about widespread dissemination of telephone CBT-I in this and related patient populations.