Daniel F. Kripke - US grants

This is a proposal for an ADAMHA Research Scientist Award, submitted as a competitive renewal, following ten years support of Dr. Daniel F. Kripke at RSDA Level II. First, clinical studies of patients with affective disorders will examine treatment effects of bright light, the role of melatonin, and the role of circadian phase disorders. The major clinical study is a controlled trial of bright light treatment of patients with major depressive disorders. Effects of seven days of treatment with 1500-2500 lux bright white light from 8:00 to 11:00 P.M. will be contrasted with effects on subjects randomized to a control treatment with dim red light. Initial results suggest that one week treatment with bright white light is somewhat more effective than one week treatment with amitryptyline. Second, VA-funded research examines related chronobiologic issues in rodent models. We will explore effects of lithium and clorgyline on circadian rhythms in wheel running activity, body temperature rhythm, and suprachiasmatic nucleus multiple unit firing. The influence of lithium and clorgyline on phase-response curves will also be examined. Third, studies of sleep apnea will be pursued primarily from an epidemiologic orientation. An ongoing study examines the mortality risk associated with sleep apnea in a medical in-patient sample of subjects over age 65.0. A second project in UCSD's Teaching Nursing Home explores the association of apnea in a nursing home sample with hypnotic drug use and with dementia.

In pilot experiments with 24 depressed patients, a single 1-hr. exposure to bright (1,000-2,000 lux) light from 2 hrs. to 1 hr. before the patient's usual time of arising reduced depressive symptoms. Results after exposure to bright white light were significantly better than after 1-hr. exposure to dim red light. These results are partially explained by the phase advance theory of depression and by a critical interval hypothesis utilizing a model analogous to rodent phtoperiodic responses. Thus, the suprachiasmatic nucleus, the pineal, and melatonin may be involved. To confirm these results with a 7-day duration of treatment, 36 inpatients with Major Depressive Disorders will be studied. After 2-day baseline, each patient will be treated with 1 week of bright light and 1 week of dim red light (in counterbalanced orders). Follow-up ratings will be obtained for an additional week. The light exposures will be given during a 5:00 A.M. - 6:00 A.M. awakening. EEG sleep recordings will be obtained throughout baseline, the light exposures and 2 nights of follow-up Hamilton and Beck depression ratings and a circadian mood self-rating will be obtained daily. Urine will be collected for 6-OH-melatonin-sulfate assays on 3 nights during each light treatment. This clinical trial is a step toward developing bright light as a clinical treatment for depression.

Sleep apnea is a repetitive process of respiratory cessation. Results of on-going studies now show that one quarter of independently living people age 65 years and older have sleep apnea. It might be that sleep apnea is normal among the elderly, but sleep clinic studies suggest that an excess of this "normal" process may be disabling or fatal. Our data show that among representative subjects 65 years and older, sleep apnea is associated with excessive daytime sleepiness, confusional spells automatic behaviors, and depression. A disorder of leg jerks (periodic movements during sleep, PMS) is also found in 42% of our senior citizen sample. This study will examine morbidity and mortality of subjects with sleep apnea. Eight hundred veterans at the San Diego Veterans Administration Medical Center, 65 years of age or over, will be randomly selected for all-night portable respiration recordings. All-night oximetry will also be recorded. All subjects will be followed up over a 5-year period to determine the mortality rate for those with and without sleep apnea. In addition, medical data will be collected to determine conditions associated with the presence of sleep apnea. A second study will also be done as a follow-up of the senior volunteers whose sleep has been recorded in our present 1981-1985 study. This will be done to study longitudinally the co-morbid conditions developing with sleep apnea. These studies will determine the morbidity and mortality associated with sleep apnea in order to indicate the extent to which sleep apnea in aged patients needs treatment.

This is a proposal for an ADAMHA Research Scientist Award, submitted as a competitive renewal, following ten years support of Dr. Daniel F. Kripke at RSDA Level II. First, clinical studies of patients with affective disorders will examine treatment effects of bright light, the role of melatonin, and the role of circadian phase disorders. The major clinical study is a controlled trial of bright light treatment of patients with major depressive disorders. Effects of seven days of treatment with 1500-2500 lux bright white light from 8:00 to 11:00 P.M. will be contrasted with effects on subjects randomized to a control treatment with dim red light. Initial results suggest that one week treatment with bright white light is somewhat more effective than one week treatment with amitryptyline. Second, VA-funded research examines related chronobiologic issues in rodent models. We will explore effects of lithium and clorgyline on circadian rhythms in wheel running activity, body temperature rhythm, and suprachiasmatic nucleus multiple unit firing. The influence of lithium and clorgyline on phase-response curves will also be examined. Third, studies of sleep apnea will be pursued primarily from an epidemiologic orientation. An ongoing study examines the mortality risk associated with sleep apnea in a medical in-patient sample of subjects over age 65.0. A second project in UCSD's Teaching Nursing Home explores the association of apnea in a nursing home sample with hypnotic drug use and with dementia.

This is a resubmission of proposal originally submitted for an NHLBI announcement (KW0715040). Sleep apnea is characterized by repetitive cessation of respiration during sleep, with consequent decreases in blood oxygen saturation, repetitive arousals, daytime somnolence, and complex cardiorespiratory disturbances. There is growing recognition that sleep apnea is a frequent cause of hypertension, cardiorespiratory failure premature death. We have shown that 24% of elderly have at least 5 apneas per hour of sleep, but the prevalence of sleep apnea among American adults under age 65 is unknown. We now propose 1) to determine the prevalence of sleep apnea among both sexes age 40 to 64; 2) to examine the longitudinal course of sleep apnea; and, 3) to examine associations of apneas, oxygen desaturations, snoring, high blood pressure, and other biomedical correlates. A structured random sample will be selected by random digit telephone dialing. Subjects will be studied in their homes. Some will followed yearly during the project. Each volunteer will give a brief sleep history and medical review, including blood pressure measurement, the National Interview Survey, And Quality of Well-being Scale. Blood oxygen saturation, pulse rate, snoring, and sleep duration will be recorded for 3 nights. State-of-the-art computerized pulse oximeters and microprocessor- based activity/light monitors will be used. Subjects found to have the most severe sleep respiratory disturbances will undergo laboratory polysomnograms to add descriptive data and to validate the survey methodology. The prevalence of respiratory disturbances in sleep will be analyzed as a function of age and sex. Associations with several aspects of morbidity will be determined. The longitudinal course of respiratory disturbances in sleep will be examined.

This is a resubmission of proposal originally submitted for an NHLBI announcement (KW0715040). Sleep apnea is characterized by repetitive cessation of respiration during sleep, with consequent decreases in blood oxygen saturation, repetitive arousals, daytime somnolence, and complex cardiorespiratory disturbances. There is growing recognition that sleep apnea is a frequent cause of hypertension, cardiorespiratory failure premature death. We have shown that 24% of elderly have at least 5 apneas per hour of sleep, but the prevalence of sleep apnea among American adults under age 65 is unknown. We now propose 1) to determine the prevalence of sleep apnea among both sexes age 40 to 64; 2) to examine the longitudinal course of sleep apnea; and, 3) to examine associations of apneas, oxygen desaturations, snoring, high blood pressure, and other biomedical correlates. A structured random sample will be selected by random digit telephone dialing. Subjects will be studied in their homes. Some will followed yearly during the project. Each volunteer will give a brief sleep history and medical review, including blood pressure measurement, the National Interview Survey, And Quality of Well-being Scale. Blood oxygen saturation, pulse rate, snoring, and sleep duration will be recorded for 3 nights. State-of-the-art computerized pulse oximeters and microprocessor- based activity/light monitors will be used. Subjects found to have the most severe sleep respiratory disturbances will undergo laboratory polysomnograms to add descriptive data and to validate the survey methodology. The prevalence of respiratory disturbances in sleep will be analyzed as a function of age and sex. Associations with several aspects of morbidity will be determined. The longitudinal course of respiratory disturbances in sleep will be examined.

Most aging Americans experience increased objective disturbances of initiating and maintaining sleep. Insomnia complaints are among the most important risk factors for institutionalization and early death among the elderly. likewise, depressive symptoms are colon and highly disabling, and the rate of suicide is increasing among elderly Americans. An ongoing survey shows that inadequate daylight exposures are associated with insomnia and depressive symptoms among adults 40-64 year of age. Preliminary studies and theoretical arguments indicate that insomnia and depression in aging Americans are partly caused by inadequate light exposure. This study will survey the prevalence of low illumination exposure in a representative sample of the San Diego population ages 60-79 years and will assess the epidemiologic associations of illumination with sleep and depressive symptoms. In a laboratory clinical trial, 135 volunteer subjects ages 60-79 will spend 5 nights and 4 days under controlled lighting conditions. With stratified randomization, 1/3 of subjects will be assigned to each of two experimental treatments using 3000 lux bright light for 4 hours each day. The final 1/3 of subjects will receive control 50 lux lighting and placebo dim red light treatment. Each subject will be monitored polysomnographically during the 8-hour sleep periods to determine the benefits of bright light treatment on objective sleep disturbances. Urine collections will be obtained to determine treatment effects on the circadian rhythm of melatonin excretion. Subjective sleep logs and mood self-ratings will assess subjective benefits of the treatments. By demonstrating casual benefits of bright light, this experiment will develop treatments with potentially high impact for millions of elderly Americans.

Both reported short sleep and reported long sleep are major predictors of excess mortality risk, but the import of reported sleep duration as a risk factor is not yet known. Sleep-related risks are of special interest to The Women's Health Initiative (WHI), because insomnia increases among women at menopause, and because WHI's hormone replacement therapy (HRT) and dietary modification (DM) may influence sleep. The WHI will be an exciting opportunity to examine whether risks associated with reported sleep durations can be explained by a selection of intercurrent conditions, but the broad WHI design will not control for important potential confounders. Explicitly, the broad WHI design by itself cannot determine if behaviorally-modifiable objective sleep durations are the primary risk factor. This ancillary project will supplement th WHI Observational Study (OS) by performing additional examinations on 600 San Diego OS women. These volunteers will undergo home sleep recordings, hormone measurement, and detailed psychiatric interviews. To facilitate distinction of affective and sleep factors in WHI outcomes, the types and severity of depression in the OS subsample and the validity and reliability of sleep items i questionnaires given to WHI women will be examined. The ancillary studies will determine whether objectively recorded sleep durations are mortality risk factors, whether sleep duration can be distinguished from depression as a risk factor in WHI data, and whether sleep-associated risks are attributable to specific pathophysiologic processes such as sleep apnea, circadian rhythm phase advances, deficiencies of melatonin, or deficiencies of melatonin, or deficiencies of reproductive steroids.

This is a small grant proposal in response to RFA ES-06-007, "Biological effects of power frequency EMF." It has been hypothesized that EMF (electro-magnetic fields) may suppress melatonin, and through this mechanism, EMF might mediate morbidity and mortality. The problem may be particularly severe for elderly people who have low melatonin. The hypothesis that melatonin prevents aging, e.g., aging related to free-radical damage and cancer, has recently received sensational news coverage. Millions of Americans fearful of melatonin deficiency may be buying products from health food stores labeled as melatonin. The investigators propose to critically test whether EMF in the bedroom influences daily melatonin excretion. This small grant will permit the investigators to collect home EMF recordings to combine with data being collected for other projects on melatonin excretion and bedtime light levels. The correlation of EMF resultant vector strength and nightly melatonin excretion will be determine, to establish if EMF could be a substantial regulator of melatonin production. Statistical controls for age, gender, light levels, and drug intake will be implemented. This study will establish whether EMF could be an important source of variance in melatonin excretion. In conjunction with ongoing studies, possible indirect EMF effects through melatonin on morbidity and mortality will be considered.

To test whether pulsatile release of luteinizing hormone which is controlled by episodic release of gonadotropin releasing hormone by hypothalamic arcuate cells is associated with the occurrence of daytime fantasies.

DESCRIPTION (adapted from investigator's abstract): The investigator's laboratory has discovered an appalling prevalence of malsynchronization of circadian rhythms among volunteers averaging 70 years of age. Aging people may be abnormally resistant to the circadian synchronizing effects of bright light. If so, we may need to develop alternative methods by which older Americans can synchronize their circadian rhythms to the environment. Recent studies indicate that exercise may shift circadian rhythms in young adults, but nothing is known about the value of exercise for regulating circadian rhythms in the aging population. It seems crucial to extend our understanding of exercise effects on the circadian system and, specifically, to compare the potential values of exercise and bright light for correcting the circadian malsynchronization of older Americans. The project will establish circadian phase response curves both for exercise and for bright light in 96 volunteers, ages 18-30 plus 128 older volunteers ages 60-75 years. Volunteers will be recorded for 4.8 to 4.6 days while following an ultra-short sleep-wake cycle, consisting of 30 minutes for sleeping, followed by 60 minutes for waking. Baseline circadian phases of urinary 6-sulphatoxymelatonin, urinary free cortisol, temperature and sleep propensity will be assessed every 90 min. Oral temperature will be sampled every 30 min. Volunteers will be given experimental phase-shifting treatments (exercise or bright light) for 3 days. Resultant circadian phases will then be determined to compute the phase response curves, in order to examine interactions of stimulus (exercise vs. light), age, and gender on circadian responsiveness.

DESCRIPTION (adapted from investigator's abstract): Most older Americans are troubled by low-level depression or sleep disturbances, which are often intimately intertwined. In the first 5 years of AG12364, they have been examining the etiologies of depression and insomnia in aging volunteers. Their findings suggest an appalling degree of circadian malsynchronization among aging Americans, which possibly explains part of their insomnia and low mood. Further, their volunteers displayed surprisingly weak circadian and clinical responses to 4 days of bright light treatment, indicating possible light resistance. In this renewal, they will test more extended 4-week bright light treatments in the home, to determine if light resistance in volunteers ages 60-79 years can be overcome with a longer duration of treatment. One hundred fifty volunteers with significant depressive complaints will be recruited for a trial consisting of one-week placebo baseline terminating in a half-night sleep deprivation, followed by 4 weeks randomized assignment to 10,000 lux white light or 10 lux red light placebo. Phase-typing during baseline will determine before randomization whether treatment should best be given in the morning, mid-day, or evening. Fractional urine samples for 6-sulphatoxymelatonin will be collected for 48 hours at the end of baseline and for 48 hours at the end of the randomized treatment, to determine if 10,000 lux treatments successfully normalize malsynchronized circadian phase adjustments. The success of the treatment in lowering the GDS depression score and in reducing sleep complaints will be examined.

DESCRIPTION (provided by applicant): Proposed is a collaboration of UCSD sleep disorders and genetics investigators with the NHLBI PGA Analytical Genomics Center in Tucson. In circadian rhythm sleep disorders (CRSD), the patient's preferred sleeping time is malsynchronized with the sleep phase controlled by the circadian system. The CRSD arise partly from genetic variants in circadian system genes. Nevertheless, in humans, relatively little is known about the nature and prevalence of functional sequence variations in the genes which might produce CRSD susceptibility, nor have epistatic interactions been studied. A total of 200 evening-type patients will be recruited according to the Horne-Ostberg scale plus strict inclusion and exclusion criteria. Each patient's phenotype will be characterized by clinical data, questionnaires, and a 2-week recording of wrist activity to objectively determine sleep timing. Then 200 controls will be selected, matched to cases by age, gender, and ethnicity. Blood samples will be drawn to immortalize lymphoblastoids for DNA preservation. An additional sample of 92 Scandinavian subjects will also be used. From DNA of 40 evening-type patients, the sequences of exons and adjacent promoter and intronic regions will be determined for 10 circadian system genes. SNPs and other variants will be discovered, published in the NCBI dbSNP data base, and tabulated. The variants will then be genotyped in all 200 CRSD patients, 200 matched controls, and the Scandinavian sample, to recognize associations of CRSD with particular SNP alleles, haplotypes, and epistatic interactions. This proposal is likely to identify many of the common variants in the major genes of the human circadian system. Moreover, understanding more about the phenotypes and genetic causes of CRSD will lead to clinical diagnostic methods for CRSD, progress toward alleviating suffering due to genetic susceptibilities, and increased basic science understanding of the circadian system.

DESCRIPTION (provided by applicant): Exciting recent data from our laboratory show that bright light stimulates secretion of luteinizing hormone (LH, lutropin), the pituitary hormone which regulates testosterone, estrogen production and ovulation. The basic science significance of the finding may be that photoperiodic mechanisms are active in humans. One hour of bright light stimulation per day from 0500-0600 produced a 69.5 percent increase in urinary luteinizing hormone (LH) excretion in young men. It is possible to replicate and extend these findings in conjunction with ongoing studies. The investigators are currently testing bright light effects in three protocols: A) a study of circadian phase response curves in adults ages 18-30 and 60-75, B) a clinical trial of bright light for depressed patients 60-79, and C) a study of early-night versus early-morning light stimulation in patients with premenstrual dysphoric disorder and normal controls. For this project, 8792 urine samples already being collected for these three protocols will be assayed for LH, using radioimmunoassay. In each study, 24-hour urinary LH excretion will be measured both before and after bright light treatment. Results will be analyzed to determine the optimal times of day for light stimulation of LH, to compare the responsiveness of young men and menstruating women versus older men and menopausal women, and to consider the relationship of LH response to baseline depression ratings and to remission of depressive symptoms. Bright light effects on LH may ultimately be useful for augmenting testosterone in men and for stimulating ovulation in women, for regulating puberty, menarche and menopause, and for reducing endocrine risk factors for mood disorders, heart disease, and cancer.