Grand Rounds (week 3): A.J.Lewy on Circadian Rhythm/Melatonin
Lewy, MD, PhD, been studying melatonin and light effects on sleep and depression xlongtime
cartoon: "Portland weather calls for severe depression with a 30% chance of suicide."
pearls:
give melatonin (.5mg) in morning, light in evening-->phase delay (for early risers)
give melatonin in evening, light in morning-->phase advance (for night owls)
keep melatonin by bedside for those who wake in night, take only after 1am (phase advanced usu)
alarm clock to remind of dosing
phase advanced more in older folks
phase delayed more in younger
phase shift enhanced when exogenous mel pulse overlaps with either onset of endogenous mel production or offset of mel prod, or by spillover effect
MELATONIN
= 5-methoxy-N-acetyletryptamine
made by pineal gland, SCN = suprachiasmatic nucleus also controls cortisol pattern
pineal glands calcify but that doesn't affect function
melatonin measured in blood or saliva
pineal @ top of head in reptiles, in center of brain in higher mammals
secretes into CSF and bloodstream
innervated by sympathetic NS via nerves from spinal cord that enter brain
B1 andrenergic receptors on pineal
conversion of ser to n-acetyl ser is rate limiting step
there is no negative feedback loop: giving mel doesn't inhibit endogenous production
ser levels and tryptophan don't affect mel levels
amount of mel made controlled by dihydroxyindole-o-methyltransferase
snips in mothers of autistic children? research ongoing
reg by melatonin production:
hibernation, migration, estrus cycle (fall vs spring breeders)
robustness of seasonal rhythms increases with larger difference in day/night length
LIGHT THERAPY
begins to be effective in 4 days, fully effective in 10 days
need 2 hours light exposure daily
may need more or longer light if no response
or may be the other type
lux origin? luxuriant from Latin, rich
without daylight most pts rhythm drifts later, to ~25 hour rhythm
or 24.7 hours (tau)
sunny 100,000 lux
cloudy day 10,0000
bright artificial light 2,000
ordinary room light 200 lux
Herbert Kern had winter depression
wanted mel levels measured
not suppressing production with normal light
1500 lux causes suppression in most everyone
some pts need 5x brighter light to suppress mel prod
therapeutic tx: bright light
key distance of eyes from light fixture, no UV, 45 deg angle
MELATONIN
production suppressed by bright light, dawn
napping does not affect melatonin levels
dark pulse during the day has no effect on phase
blind person, case study
had melatonin surge in daytime
on 24.7 hour cycle, surge shifts over a matter of a few weeks
recurrent depression
in legally blind, tau range 23.86-25.08, only one pt had less than 24 hour cycle
blind pts should take mel every day for the rest of their lives
bedtime 3-10mg melatonin makes about 1/3 of the pop sleep better
2/3 don't notice this dose
Bob Sack led research for a while
things you can tx with melatonin
advance sleep phase syndrome
delayed sleep phase syndrome
jet la
shift work
blindness
THERAPEUTIC LIGHT
2,000 lux or more, he uses 10K lux
wavelength close to blue light, 509nM is peak
timing is important: SAD not related to seasons but to 24h clock and time of dawn or dusk but not both
must know if they are phase advanced or phase delayed
measure with basal body temp, increases too early if phase advanced
light pulse in first half of night causes phase delay
earlier light pulse in 2nd half of night causes phase advance
morning light phase advances, evening light phase delays
PHASE ADVANCES AND DELAYS
phase advance
adaptation to night work
east to west jet lag
atypical SAD
phase delay
monday morning blues
prototypical winter depressoin
west to east jet lag
SCIENCE
DLMO = dim light melatonin onset
start dim light at 5pm
do not give light in middle of night
give at dawn or before bed
DLMO is ~14 hrs after getting light, if up 7am then it's 9pm
give mel 3 hours before DLMO?
circadian time zero is when you wake up in the morning
give mel in morning, light in evening-->phase delay
give mel in evening, light in morning-->phase advance
entrainment = synch with daylight
free running vs entrained
free running = sleep pattern not based on daylight
another study 24.2-24.9 taus
low dose .5mg mb more effective than 10 or 20mg
he thinks .3-.6mg is optimal dose range
pts become phase delayed in winter when depressed
bright light antidepressive by provind corrective phase advance
don't lengthen day in pm, just light in am for phase advance
atypical in winter to be phase advanced but some are
am & pm light ineffective: do just one
SAD
5x more in women of childbearing age
5% of pop severely affected, 15% have sub syndromal sad
hypersomnia, fatigue, incr appetite, carb preference, weight gain
begins as children
increased sleep duration in winter
usu phase delayed, greater depression with greater delay
inc alc, coffee/tea, junk food intake
workup
find out when: get up, go to bed, when go outside
another study
first v low dose mel 3pm .125mg
another low dose closer to bedtime
can give .5-.6 mg mel in afternoon without making anyone sleepy
approx 1/3 of pts phase advanced
nonseasonal depression
also with anxiety
shorter phase angle differences PADs assoc w worth depressive sx
later the DLMO-->greater depression
he doesn't believe that norepi and dopa have to do with depression
jet lag / travel
can tx by light and mel
schedule light exposure at correct time of day
east to west get night light, take morning melatonin
west to east get morning light, take evening melatonin
big gap get light in middle of day
going to europe: avoid light in morning
see chart in powerpoint for scheduling melatonin doses
Monday morning blues
.3-.6mg mel in evening on sat and sun will prevent
shift work
ideal: stay on same sleep/wake cycle all the time
not a good way to deal with their problems integrating timewise
want to feel best at work, or when off?
autism connection?
mel levels frequently low in kids
dad levels normal, mom levels low
look at genes in mothers
answer will be out in a few weeks
big dose of mel to autist in pm-->better sleep but no change in autism
damage was done during preg??
give mel to preg mothers? no answer yet, could prevent autism
newborns have no discernable sleep wake cycle
baby doesn't make mel at night until 12mo post conception/3 months after birth
cannot use light dark cycle to synchronize sleep until around 16 weeks
uses mother's melatonin via placenta or breastmilk
sundown brand mel on amazon recommended
FDA may soon approve salivary mel level test
new study on blind pts nationwide
melatonin onsets vary but generally progress, are phase advancing
more in females than in males
women more susceptible to social cues than men
no known dietary effects on melatonin
comment: taking high dose mel can decrease ser. he denies this.
mel for sleep maintenance
(trouble staying asleep)
don't take mel in afternoon or at bedtime, not even SR formulation
take .5-5mg at bedside and take only after 1am
probably have advanced phase syndrome
www.sltbr.org
society for light tx and biorhythms
he is founding president
has list of accredited manufacturers
cool white fluorescent light, don't want full spectrum
cancer tx
studied x40yrs
he hasn't been convinced that it works
it is antioxidant
BOOK in NCNM library on same topic:
The body clock guide to better health
by Michael Smolensky and Lynne Lamberg
cartoon: "Portland weather calls for severe depression with a 30% chance of suicide."
pearls:
give melatonin (.5mg) in morning, light in evening-->phase delay (for early risers)
give melatonin in evening, light in morning-->phase advance (for night owls)
keep melatonin by bedside for those who wake in night, take only after 1am (phase advanced usu)
alarm clock to remind of dosing
phase advanced more in older folks
phase delayed more in younger
phase shift enhanced when exogenous mel pulse overlaps with either onset of endogenous mel production or offset of mel prod, or by spillover effect
MELATONIN
= 5-methoxy-N-acetyletryptamine
made by pineal gland, SCN = suprachiasmatic nucleus also controls cortisol pattern
pineal glands calcify but that doesn't affect function
melatonin measured in blood or saliva
pineal @ top of head in reptiles, in center of brain in higher mammals
secretes into CSF and bloodstream
innervated by sympathetic NS via nerves from spinal cord that enter brain
B1 andrenergic receptors on pineal
conversion of ser to n-acetyl ser is rate limiting step
there is no negative feedback loop: giving mel doesn't inhibit endogenous production
ser levels and tryptophan don't affect mel levels
amount of mel made controlled by dihydroxyindole-o-methyltransferase
snips in mothers of autistic children? research ongoing
reg by melatonin production:
hibernation, migration, estrus cycle (fall vs spring breeders)
robustness of seasonal rhythms increases with larger difference in day/night length
LIGHT THERAPY
begins to be effective in 4 days, fully effective in 10 days
need 2 hours light exposure daily
may need more or longer light if no response
or may be the other type
lux origin? luxuriant from Latin, rich
without daylight most pts rhythm drifts later, to ~25 hour rhythm
or 24.7 hours (tau)
sunny 100,000 lux
cloudy day 10,0000
bright artificial light 2,000
ordinary room light 200 lux
Herbert Kern had winter depression
wanted mel levels measured
not suppressing production with normal light
1500 lux causes suppression in most everyone
some pts need 5x brighter light to suppress mel prod
therapeutic tx: bright light
key distance of eyes from light fixture, no UV, 45 deg angle
MELATONIN
production suppressed by bright light, dawn
napping does not affect melatonin levels
dark pulse during the day has no effect on phase
blind person, case study
had melatonin surge in daytime
on 24.7 hour cycle, surge shifts over a matter of a few weeks
recurrent depression
in legally blind, tau range 23.86-25.08, only one pt had less than 24 hour cycle
blind pts should take mel every day for the rest of their lives
bedtime 3-10mg melatonin makes about 1/3 of the pop sleep better
2/3 don't notice this dose
Bob Sack led research for a while
things you can tx with melatonin
advance sleep phase syndrome
delayed sleep phase syndrome
jet la
shift work
blindness
THERAPEUTIC LIGHT
2,000 lux or more, he uses 10K lux
wavelength close to blue light, 509nM is peak
timing is important: SAD not related to seasons but to 24h clock and time of dawn or dusk but not both
must know if they are phase advanced or phase delayed
measure with basal body temp, increases too early if phase advanced
light pulse in first half of night causes phase delay
earlier light pulse in 2nd half of night causes phase advance
morning light phase advances, evening light phase delays
PHASE ADVANCES AND DELAYS
phase advance
adaptation to night work
east to west jet lag
atypical SAD
phase delay
monday morning blues
prototypical winter depressoin
west to east jet lag
SCIENCE
DLMO = dim light melatonin onset
start dim light at 5pm
do not give light in middle of night
give at dawn or before bed
DLMO is ~14 hrs after getting light, if up 7am then it's 9pm
give mel 3 hours before DLMO?
circadian time zero is when you wake up in the morning
give mel in morning, light in evening-->phase delay
give mel in evening, light in morning-->phase advance
entrainment = synch with daylight
free running vs entrained
free running = sleep pattern not based on daylight
another study 24.2-24.9 taus
low dose .5mg mb more effective than 10 or 20mg
he thinks .3-.6mg is optimal dose range
pts become phase delayed in winter when depressed
bright light antidepressive by provind corrective phase advance
don't lengthen day in pm, just light in am for phase advance
atypical in winter to be phase advanced but some are
am & pm light ineffective: do just one
SAD
5x more in women of childbearing age
5% of pop severely affected, 15% have sub syndromal sad
hypersomnia, fatigue, incr appetite, carb preference, weight gain
begins as children
increased sleep duration in winter
usu phase delayed, greater depression with greater delay
inc alc, coffee/tea, junk food intake
workup
find out when: get up, go to bed, when go outside
another study
first v low dose mel 3pm .125mg
another low dose closer to bedtime
can give .5-.6 mg mel in afternoon without making anyone sleepy
approx 1/3 of pts phase advanced
nonseasonal depression
also with anxiety
shorter phase angle differences PADs assoc w worth depressive sx
later the DLMO-->greater depression
he doesn't believe that norepi and dopa have to do with depression
jet lag / travel
can tx by light and mel
schedule light exposure at correct time of day
east to west get night light, take morning melatonin
west to east get morning light, take evening melatonin
big gap get light in middle of day
going to europe: avoid light in morning
see chart in powerpoint for scheduling melatonin doses
Monday morning blues
.3-.6mg mel in evening on sat and sun will prevent
shift work
ideal: stay on same sleep/wake cycle all the time
not a good way to deal with their problems integrating timewise
want to feel best at work, or when off?
autism connection?
mel levels frequently low in kids
dad levels normal, mom levels low
look at genes in mothers
answer will be out in a few weeks
big dose of mel to autist in pm-->better sleep but no change in autism
damage was done during preg??
give mel to preg mothers? no answer yet, could prevent autism
newborns have no discernable sleep wake cycle
baby doesn't make mel at night until 12mo post conception/3 months after birth
cannot use light dark cycle to synchronize sleep until around 16 weeks
uses mother's melatonin via placenta or breastmilk
sundown brand mel on amazon recommended
FDA may soon approve salivary mel level test
new study on blind pts nationwide
melatonin onsets vary but generally progress, are phase advancing
more in females than in males
women more susceptible to social cues than men
no known dietary effects on melatonin
comment: taking high dose mel can decrease ser. he denies this.
mel for sleep maintenance
(trouble staying asleep)
don't take mel in afternoon or at bedtime, not even SR formulation
take .5-5mg at bedside and take only after 1am
probably have advanced phase syndrome
www.sltbr.org
society for light tx and biorhythms
he is founding president
has list of accredited manufacturers
cool white fluorescent light, don't want full spectrum
cancer tx
studied x40yrs
he hasn't been convinced that it works
it is antioxidant
BOOK in NCNM library on same topic:
The body clock guide to better health
by Michael Smolensky and Lynne Lamberg