There is increasing evidence that circadian rhythm abnormalities are important in the pathophysiology of some affective and sleep disorders. The mechanism of aciton of antidepressant drugs may involve correction of circadian rhythm abnormalities. However, assessing the chronobiologic effects of drugs in humans has been impeded by problems with imprecise markers for circadian rhythms and by the confounding influence of time cues which entrain circadian rhythms to a 24-hour day. In blind people, the entraining effects of the light-dark cycle are eliminated, often resulting in autonomous (free-running) rhythms which reflect the intrinsic period of the endogenous biological clock (usually about 25 hours). Measuring melatonin onsets at biweekly intervals provides a convenient and efficient way to monitor the free-running rhythms. Our pilot studies have shown that the period (tau) of the free-running melatonin rhythm is remarkably consistent making it possible to efficiently detect drug-induced changes in the rhythm. Thus we were able to show that bedtime administration of both melatonin and triazolam phase advanced the rhythm (shifted it to an earier time). In this project we will identify blind people with free-running rhythms and will measure the effects of acute and prolonged administration of triazolam, melatonin and lithium on the melatonin rhythm. We anticipate that these chronobiologic effects of drugs in humans. This may lead to treatments for blind people who suffer bouts of insomnia and daytime sleepiness as a result of free-running rhythms. This information will also lead to new insight into the mechanism of action of psychotropic drugs which will potentially benefit sighted people who suffer circadian rhythm disturbances associated with sleep and mood disorders, shift work and jet lag.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH043016-03
Application #
3474648
Study Section
Treatment Development and Assessment Research Review Committee (TDA)
Project Start
1987-08-01
Project End
1990-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Sack, R L; Blood, M L; Lewy, A J (1992) Melatonin rhythms in night shift workers. Sleep 15:434-41
Sack, R L; Lewy, A J; Blood, M L et al. (1992) Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab 75:127-34
Sack, R L; Lewy, A J; Blood, M L et al. (1991) Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms 6:249-61
Lewy, A J; Sack, R L (1989) The dim light melatonin onset as a marker for circadian phase position. Chronobiol Int 6:93-102