Sleeping (or Not) by the Wrong Clock

[Cees Binkhorst]

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April 19, 2010, 9:15 pm
Sleeping (or Not) by the Wrong Clock
http://opinionator.blogs.nytimes.com/2010/04/19/sleeping-or-not-by-the-wrong-clock/
By MICHAEL TERMAN

All-NightersAll-Nighters is an exploration of insomnia, sleep and the
nocturnal life.
Tags:

chronotherapy, circadian rhythm, insomnia, melatonin

Despite his best efforts, Cliff, 28, could not get to sleep until about
7 a.m. It had been this way since he was a teenager. He was a healthy
and successful young scientist — except that he didn’t arrive at the lab
until 5 p.m., just as his co-workers were preparing to leave. Although
he got his work done by pulling all-nighters, he became isolated from
the group. Sleeping pills didn’t work. Nighttime alcohol bouts got him
to sleep sooner, but only by two to three hours — a bummer on many
levels. Significantly, Cliff was not depressed.

George, a 34 year-old paralegal, had a much more common experience. He
could rarely sleep until 1:30 a.m. Inured to sleeping pills, he would
get into bed at midnight, hoping for the best. He had to be awake at
7:30 in order to make it in by 9, but it was a losing battle. Almost
always late, he remained foggy until afternoon, and suffered headaches.
Unlike Cliff, George was mildly depressed.

Cliff and George, whose names have been changed here to protect their
privacy, are two of hundreds of patients we’ve treated at the Center for
Light Treatment and Biological Rhythms at Columbia University Medical
Center (where I serve as clinic director), and in research trials
supported by the National Institute of Mental Health and the Sleep
Research Society Foundation at the New York State Psychiatric Institute
(where I have been a principal investigator).

Both Cliff and George were treated using chronotherapeutics — methods
designed to reset the internal circadian clock.[1], [2] George was
dealing with sleep onset insomnia, a problem for millions of people. We
inferred clinically that his circadian clock signal for sleeping was
delayed relative to local time. People sleep best when the internal
clock is in sync with the workday rest/activity cycle. When there is a
mismatch, the likely results are insomnia, depressed mood and daytime
fatigue.

An unbalanced circadian rhythm can be returned to equilibrium through
the application of light to a sleeper’s retina near the end of a
person’s “internal night.” Internal night? Yes — it may be night
outside, but if your circadian clock is not prepared for sleep, internal
night may not start until late and last well into morning. Biologically,
it coincides with the secretion of melatonin by the brain’s pineal
gland. It is difficult to know where your internal night lies if you
artificially force sleep earlier, for example with sleeping pills. You
can estimate internal night with a quick chronotype questionnaire [3]
that helps determine when light exposure will be most effective for
syncing your circadian rhythm with external reality.

George began therapy at 8 a.m every day with 30 minutes of 10,000 lux
bright light. [4] This had no effect. But when we switched the timing to
7:30, he immediately started getting to sleep an hour earlier, by 12:30
a.m. However, he began waking up far too early, before 6 a.m. This
indicated an overdose of light. When we reduced light exposure to 15
minutes, still at 7:30 a.m., he began falling asleep at midnight and
waking up just before alarm (a few minutes before the scheduled light
exposure). Within a week of starting treatment, his depression lifted,
he was more alert in the morning and his headaches vanished. Lesson
learned: just as with drugs, light therapy needs to be individually
dosed, which may require a clinician’s guidance.
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Cliff, who usually slept between 7 a.m. and 3 p.m., was following his
internal clock, though he was out of sync with the outer world. His
sleep problem cleared up in two weeks using a combination of three
chronotherapeutic methods. First, he began light therapy upon waking in
mid-afternoon. As his internal clock began to respond, he was able to
wake up earlier for the lights in 30-minute steps.

Second, we administered a minute dose (0.2 milligrams) of
sustained-release melatonin about five hours before bedtime, mimicking
the action of the pineal gland, before it begins its nightly cycle. [4]
This dosage is in sharp contrast to over-the-counter melatonin, which
usually comes in megadoses (3 to 5 milligrams) that deliver far more
hormone than the pineal gland ever produces. The mini-dose does not act
like a sleeping pill, so you spend the evening awake and alert. Rather,
it communicates with the circadian clock in the same way as morning
light exposure, shifting internal night earlier.

Finally, after taking melatonin, Cliff wore specially filtered
wraparound glasses [1] that prevent inappropriate evening light from
acting against morning light exposure. He soon found it easy to sleep
from 11:30 p.m. to 7:30 a.m. Then he was off to the gym and into the
lab. He was incredulous: “I thought my circadian clock was permanently
damaged!”

Cliff’s case is instructive because even with greatly delayed sleep
onset, he was not depressed; his sleep patterns obeyed his internal
clock. George, by contrast, struggled to sleep earlier on a biologically
inappropriate schedule — often a major factor underlying depression.
With light and melatonin therapies, we can shift the internal night into
congruence with local time and the workday schedule, with dual
antidepressant and sleep-enhancing results.

Depression, of course, can become overwhelming, far more severe that it
was for George. And sleep itself actively feeds severe depression — a
vicious cycle that needs to be broken. A therapeutic full night awake
under observation in a hospital setting instantly relieves the
depression in about 60 percent of patients. This is one of the major,
surprising findings of biological psychiatry. The problem is, after the
next day’s recovery sleep the depression is likely to return. So the
benefit is only ephemeral.

To counter the relapse, we begin daily light therapy at the end of the
wake therapy night, enabling the circadian clock to readjust, with the
result of sustained remission. [1] The benefit is enhanced with a very
early bedtime the night after wake therapy, and early rising after
recovery sleep. In patients with bipolar disorder, the effect is further
magnified by the use of lithium carbonate, the mood-stabilizing drug.[5]
A manic reaction is very rare, but it can be quickly dampened by staying
in a darkened room for 14 hours. Such dark therapy can be just as
effective as anti-manic (anti-psychotic) medication.[6]

In American psychiatry, chronotherapeutics is a new kid on the block,
viewed by some as a counter-intuitive departure from conventional
medication. By contrast, in Europe, where it is already well
established, it is seen as compatible with medication and a means for
expediting improvement with fewer residual symptoms. Residual symptoms
are harbingers of relapse. To protect our patients, we should be pulling
out all the stops.

Footnotes:

[1]. Anna Wirz-Justice, Francesco Benedetti, Michael Terman,
“Chronotherapeutics for Affective Disorders: A Clinician’s Manual for
Light and Wake Therapy,” Basel, S. Karger, 2009.

[2] Olivia Judson, “Enter the Chronotherapists,” New York Times,
December 22, 2009.

[3] Michael Terman, Thomas White, Joy Jacobs, “Automated
morningness-eveningness questionnaire.”
http://www.cet.org/en/index.html?/en/Questionnaire.html
Downloadable Self-Assessments without automated feedback.
http://www.cet.org/en/pdf-ass-english.html

[4] Michael Terman, Jiuan Su Terman, “Light therapy, in Principles and
Practice of Sleep Medicine,” 5th ed., Meir Kryger, Thomas Roth and
William Dement (Eds.), Philadelphia, Elsevier, 1682-1695, 2010.

[5] Cristina Colombo, Adelio Lucca, Francesco Benedetti, Barbara
Barbini, Euridice Campori, Enrico Smeraldi, “Total sleep deprivation
combined with lithium and light therapy in the treatment of bipolar
depression: replication of main effects and interaction,” Psychiatry
Research 95(1), 43-53, 2000.

[6] Barbara Barbini, Francesco Benedetti, Cristina Colombo, Danilo
Datoli, Alessandro Bernasconi, Mara Ciagala-Fulgosi, Marcello Florita,
Enrico Smeraldi, “Dark therapy for mania: a pilot study,” Bipolar
Disorders 7(1), 98-101, 2005.

Michael Terman is Professor of Clinical Psychology in Psychiatry at
Columbia University’s College of Physicians and Surgeons. He directs the
Center for Light Treatment and Biological Rhythms at Columbia University
Medical Center, and is president of the Center for Environmental
Therapeutics, a nonprofit agency dedicated to research and education in
non-pharmaceutical interventions for depression and sleep disorders.
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  December 22, 2009, 9:30 pm
Enter the Chronotherapists
http://opinionator.blogs.nytimes.com/2009/12/22/enter-the-chronotherapists/
By OLIVIA JUDSON

Olivia JudsonOlivia Judson on the influence of science and biology on
modern life.
Tags:

breast milk, cancer, circadian rhythm, light, obesity, sleep

Here’s my prediction for the Next Big Thing in health care:
chronotherapy, or therapy by the clock. Yes, in the future, your
medicines, your operations, your mealtimes and when you step onto the
treadmill or the badminton court — all will be overseen by your personal
chronoconsultant.

It’s been known for ages that our bodies have daily, or “circadian,”
rhythms. Body temperature is lower in the morning than it is in the
afternoon. Blood pressure is low during the night, and rises just before
you wake. Muscles are stronger in the afternoon than they are in the
morning, and you may have greater dexterity then, too. Badminton players
tend to serve more accurately in the afternoon, for example.

But now it’s clear that the body clock is in charge of many other, more
subtle processes as well. The content of human breast milk changes
during the day. Evening milk is full of compounds that make a baby
sleepy; morning milk isn’t. The liver, too, has a strong daily rhythm:
many of its activities shut down during the night. Levels of several
hormones, including melatonin (involved in sleep) and ghrelin (involved
in appetite), rise at night. Testosterone, in contrast, is highest in
the morning and lowest in the late afternoon. Cholesterol is made more
rapidly at night. Even cancers have a rhythm: breast cancers, for
instance, grow faster during the day.

The implications of all this are huge. Living against your body clock —
as so many of us do — can affect your health and well-being in myriad
ways. Some of these are trivial: unless you’re professional (or
super-competitive), it probably doesn’t matter if your badminton serve
is a little off in your morning games. Besides, your opponent’s will be,
too. (It may, however, be better for your heart if you play in the
afternoon.)

But living against the clock can also lead to major health problems.
Obesity, breast cancer and certain kinds of mental illness are all
associated with circadian disruption.

Disruption can be a consequence of shiftwork or jetlag — or of not
spending enough time sleeping, or in the dark. Darkness is important
because even a brief exposure to light during sleep-time can be enough
to reduce melatonin levels and reset the body clock. Exposure to light
in the night has been linked to breast cancer; consistent with this,
women who are totally blind have a lower incidence of breast cancer than
those who can see even a little bit.

Badly timed light isn’t the only troublemaker. Eating at the wrong
moments — like the middle of the night — makes it harder for the body to
process food and leads to weight gain. A recent experiment shows this
nicely. Two groups of mice were fed identical diets but on different
schedules: one group was allowed to eat only during normal waking hours,
while the other was restricted to eating during normal sleeping hours.
After six weeks, the mice allowed to eat only during sleep-time were
significantly fatter than the wake-time eaters — a result that may help
explain why obesity is so common among shift-workers who, because of
their jobs, are forced to eat against their clocks.

In fact, sleep itself has been implicated in obesity: not sleeping
enough is associated with getting fat. (Which suggests the sleep diet:
stack those Zs and see the pounds melt away!) More worrying: obesity may
actually interfere with the clock mechanism. In mice, the genes involved
in regulating the body clock function differently in obese animals as
compared to thin ones: the clocks of obese animals are less rhythmic.
Perhaps, then, one way to treat (or prevent) obesity would be to impose
a strong circadian rhythm on mealtimes and bedtimes.

To my knowledge, chronotherapy has not yet been tried for obesity; but
it has, with great success, been used in psychiatry. Several mental
disorders, including bipolar disorder, can be rapidly ameliorated by a
resetting of the body clock. Indeed, it’s been argued that manipulating
the body clock affects the same parts of the brain as antidepressant
drugs — but that chronotherapy works faster and with fewer side effects.

Even conventional medicines work better when the body clock is taken
into account. For example, evidence suggests that some statins — drugs
that help people reduce their cholesterol levels — are more effective
when taken before bedtime. Several of the drugs used in chemotherapy
also have a “best” time of day: give the drug at the right moment, and
you can take a smaller dosage, get a greater benefit and have a lower
risk of unpleasant side effects. Sounds good. But don’t forget: regular
good sleep in a nice dark room can inhibit tumors, and may thus help you
avoid chemo in the first place.

Much more, no doubt, remains to be discovered, and it may, in fact, be a
while before a chronotherapist opens an office near you. (That’s often
the nature of the Next Big Thing — you see it on the horizon ages before
it arrives.) But while we’re waiting for medicine by the hourglass,
there are still steps that can be taken. I don’t know about you, but I’m
going to darken my bedroom, cancel the midnight feasts and put sleep at
the top of my list of things to do. It’s about time.

Notes:

The circadian rhythm of body temperature is well known — and easy to
verify for oneself. For the circadian rhythm of blood pressure, see
Smolensky, M. H. et al. 2007. “Role of sleep-wake cycle on blood
pressure circadian rhythms and hypertension.” Sleep Medicine 8: 668-680.
For an overview of muscle strength being higher in the afternoon, see
Reilly, T. and Waterhouse, J. 2009. “Sports performance: is there
evidence that the body clock plays a role?” European Journal of Applied
Physiology 106: 321-332; see also the references therein. For badminton
serves being better in the afternoon, see Edwards, B. J., Lindsay, K.
and Waterhouse, J. 2005. “Effect of time of day on the accuracy and
consistency of the badminton serve.” Ergonomics 48: 1488-1498.

For the content of breast milk fluctuating through the day, see Sánchez,
C. L. et al. 2009. “The possible role of human milk nucleotides as sleep
inducers.” Nutritional Neuroscience 12: 2-8; and Cubero, J. et al. 2005.
“The circadian rhythm of tryptophan in breast milk affects the rhythms
of 6-sulfatoxymelatonin and sleep in newborn.” Neuroendocrinology
Letters 26: 657-661. For the liver having a strong circadian rhythm, see
Reddy, A. B. et al. 2006. “Circadian orchestration of the hepatic
proteome.” Current Biology 16: 1107-1115. The behavior of melatonin is
well-known; but for a good overview of how it works, see Blask, D. E.
2008. “Melatonin, sleep disturbance and cancer risk.” Sleep Medicine
Reviews 13: 257-264. This paper also reviews the association between
cancers and shift-work, and between cancers and exposure to light at
night. The author also advocates spending time sleeping and in total
darkness as a possible anti-cancer therapy.

For ghrelin being higher at night, see Yildiz, B. O. et al. 2004.
“Alterations in the dynamics of circulating ghrelin, adiponectin, and
leptin in human obesity.” Proceedings of the National Academy of
Sciences USA 101: 10434-10439. For testosterone being higher in the
morning, see Brambilla, D. J. et al. 2009. “The effect of diurnal
variation on clinical measurement of serum testosterone and other sex
hormone levels in men.” Journal of Clinical Endocrinology and Metabolism
94: 907-913. For cholesterol synthesis, see the paper by Crispim et al.
2007, listed below. For breast cancers growing more during the day, see
Brainard, G. C. et al. 2005. “Melatonin-depleted blood from
premenopausal women exposed to light at night stimulates growth of human
breast cancer xenografts in nude rats.” Cancer Research 65: 11174-11184.

For a review of light-at-night as a risk factor for breast cancer see,
for example, Stevens, R. G. 2009. “Light-at-night, circadian disruption
and breast cancer: assessment of existing evidence.” International
Journal of Epidemiology 38: 963-970. For blindness and breast cancer
see, for example, Flynn-Evans, E. E. et al. 2009. “Total visual
blindness is protective against breast cancer.” Cancer Causes and
Control 20: 1753-1756.

For obesity and circadian disruptions, see Laposky, A. D. et al. 2008.
“Sleep and circadian rhythms: key components in the regulation of energy
metabolism.” FEBS Letters 582: 142-151. For mice gaining weight when
they eat during sleep time, see Arble, D. M. et al. 2009. “Circadian
timing of food intake contributes to weight gain.” Obesity 17: 2100-2102.

For sleep deprivation being a risk factor in obesity see, for example,
Crispim, C. A. et al. 2007. “The influence of sleep and sleep loss upon
food intake and metabolism.” Nutrition Research Reviews 20: 195-212;
also see this paper for a review of the circadian rhythm of cholesterol
synthesis. These authors argue for more sleep as one way to help prevent
obesity.

For obesity interfering with the body clock in mice, see Kaneko, K. et
al. 2009. “Obesity alters circadian expressions of molecular clock genes
in the brainstem.” Brain Research 1263: 58-68. A google search on
“chrononutrition” reveals a French diet that purports to work by timing
food consumption; however, I was unable to find any papers about it in
the standard scientific databases, so I couldn’t assess how well it works.

For the treatment of psychiatric disorders by means of chronotherapy,
see Wirz-Justic, A. 2009. “From the basic neuroscience of circadian
clock function to light therapy for depression: On the emergence of
chronotherapeutics.” Journal of Affective Disorders 116: 159-160. See
also Benedetti, F. et al. 2007. “Chronotherapeutics in a psychiatric
ward.” Sleep Medicine Reviews 11: 509-522. A treatment manual is also
now available: see http://www.chronotherapeutics.org/Index.html.

For statins and time of day, see Plakogiannis, R. and Cohen, H. 2007.
“Optimal low-density lipoprotein cholesterol lowering: Morning versus
evening statin administration.” Annals of Pharmacotherapy 41: 106-110.
For time of day and chemotherapy, see Kobayashi, M., Wood, P. A. and
Hrushesky, W. J. M. 2002. “Circadian chemotherapy for gynecological and
genitourinary cancers.” Chronobiology International 19: 237-251. See
also Mormont, M.-C. and Levi, F. 2003. “Cancer chronotherapy:
Principles, applications, and perspectives.” Cancer 97: 155-169.

Many thanks to Jonathan Swire for insights, comments and suggestions.

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