55. Chronotherapy: balancing benefit and risk

2 August 2010 at 15:16 | Posted in Body clock, Circadian rhythm, DSPS | 18 Comments
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Treatments for circadian sleep disorders fall into three general categories. The first combines phototherapy and scototherapy, that is treatment with light and dark.  The second is pharmacotherapy, usually using melatonin or one of its drug analogs. The third treatment is what I will discuss today and is known as chronotherapy.

None of these forms of treatment is universally successful — or there would be little need for this blog.   Chronotherapy was the first treatment found to  be successful for some cases of DSPS and thus was a major advance in treatment [1].  The researchers who discovered it should be commended.  But many valuable medical treatments also carry inherent risks.  In particular anyone planning chronotherapy needs to know that it poses a risk of converting DSPS into the even more severe disorder known as non-24 hour sleep wake cycle disorder (N24).

This risk was first reported in a letter to the New England Journal of Medicine in 1992 by Dan Oren and Thomas Wehr of the NIH [2].  They described three patients who had long-standing DSPS and had attempted to treat it by means of chronotherapy. In each of those cases the result was a persisting case of N24.

I can vouch for the accuracy of the NEJM article for one of the cases described is actually mine. I had DSPS for over 15 years before attempting to treat it by chronotherapy.  That was the start of my current condition of N24.

The reason I am posting about this at this time is that I have gotten emails from people in recent years who have tried chronotherapy and who had also ended up as N24.  These  people were startled to find out that this risk was known 18 years ago. They were not aware of this risk prior to starting chronotherapy. Since chronotherapy is widely recommended, but the risk it poses is not widely known, I thought the subject needed to be addressed.

Two questions arise.  Why does chronotherapy cause N24 in some cases; and how often does it do so?

To address the “why” question, let’s first review the difference between DSPS and N24.  Someone with DSPS is unable to sleep except at a very delayed hour compared to most people.  For example someone who sleeps every day from 4am to noon and cannot advance their sleep to normal hours would have the diagnosis of DSPS.

N24 is somewhat different.  The sleeping time of someone with N24 changes from day to day. If they start out falling asleep at 4am, the next day they might not fall asleep until 6am, the following day at 8am, then 10am and so on, until they go around the clock. They might have a 26 hour day, as in that example, or any other day length longer than 24 hours, hence the name non-24 hour sleep-wake cycle disorder.

Returning to DSPS, while someone with DSPS cannot advance their sleep — cannot start going to bed at 2am if they are used to going to bed at 4am  — they often can delay their sleep if they try.  Thus it was proposed that they could normalize their sleep by going to bed later and later until they rolled around the clock to a normal sleep time.  If they started at 4am they would be told to go to sleep the next day at 7am, then 10am then 1pm and so on until they reached a normal bedtime.

Described this way, it’s easy to see that chronotherapy for DSPS consists of temporarily following a schedule like that of someone with N24.

This first phase of chronotherapy is supposed to be followed by a second stabilization phase once the desired sleep time is reached. In the stabilization phase the subject is supposed to rigidly stick to the new bedtime and wake time.

Sometimes this works.  Chronotherapy has been successful in some individuals.  But not always.  The N24 state, once entered into, is not so easy to reverse. In some persons, it is irreversible and they find that chronotherapy, far from curing their circadian problem, has instead converted it to a new, more impairing form.

There are two reasons why the transition to N24 can be difficult to reverse.

The first reason has to do with the relative phase of sleep compared to the phase of the body’s circadian rhythm which determines the phase response curve to light.  In many cases of DSPS the delay of the sleep cycle relative to the light PRC means that such “nite owls” are asleep during the time at which the body need to be exposed to light in order to advance the timing of the circadian rhythm.  When doing chronotherapy one goes to bed even later relative to the PRC. This decreases light exposure during the phase advance portion of the PRC and increases the light exposure during the phase delay portion of the PRC, causing a progressive delay of the circadian rhythm.  The circadian rhythm determines the rhythm of sleep propensity so that delays as well.  This sets up a positive feedback effect which tends to perpetuate the N24 state once it has been started.  To reverse N24 once this feedback loop is started is very difficult.

A second reason may relate to findings in studies of animals on non-24 hour schedules (produced by a non-24 hour zeitgeber such as lights that go on and off every 25 hours). It has been found that prolonged maintenance on such a schedule changes the apparent period of the circadian rhythm, so that even when released from the non-24 hour zeitgeber into an environment of constant light or dark they continue to show signs of their prior N24 schedule [3]. This was the reason cited in the original NEJM article.

How large is the risk of inducing N24 after chronotherapy?  The NEJM article mentions 3 patients, which seems small until one recalls that the original article on chronotherapy in 1981 only cited 5 successful cases [1]. There have been other reports of successful chronotherapy since then, but usually with small numbers of patients.  Published cases of chronotherapy leading to N24 have been fewer; but as I mentioned, I have heard personally from other people in whom this has happened.  There has been no systematic attempt to determine the relative risk.  But given the small numbers of reported chronotherapy successes, the even smaller numbers of conversion to N24 cannot be considered negligible.

It may be that this risk could be reduced by the additional use of light boxes and dark therapy during the stabilization phase of chronotherapy. But this is speculation.  The authors of the NEJM article suggest a slow advance of DSPS using light therapy as preferable to chronotherapy.

Of course not all DSPS patients will respond to slow phase advance by light therapy. For those who don’t the possibility of chronotherapy is tempting.

I am not someone who likes to make blanket statements. I would not suggest that chronotherapy be abandoned entirely. It does work for some.  Nor am I criticizing the researchers who invented chronotherapy.  Since prior to that there were no treatments at all for DSPS it was an important advance, and one that may still have its uses.  But what I would say is that anyone starting chronotherapy needs to know that there is a  risk it could make their circadian disorder worse. It is a calculated risk, although one in which we have little data to make that calculation accurately.

Many web sites and even medical texts mention the use of chronotherapy.  Very few mention the risk that it can induce N24.  One would have thought that an article in the prestigious New England Journal of Medicine would have been enough to get the word out, but clearly this aspect needs to be more widely discussed, which is why I am posting this.

—Posted by LivingWithN24 (James Fadden)

References:

1. Czeisler CA, Richardson GS, Coleman RM, Zimmerman JC, Moore-Ede MC, Dement WC, Weitzman ED. Chronotherapy: resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep. 1981;4(1):1-21.

2. Oren DA, Wehr TA. Hypernyctohemeral syndrome after chronotherapy for delayed sleep phase syndrome. N Engl J Med. 1992 Dec 10;327(24):1762.

3.Pittendrigh CS, Daan S. A functional analysis of circadian pacemakers in nocturnal rodents. 1. The stability and lability of spontaneous frequency. J Comp Physiol [AI 1976;106:223-52.

xxxii. Chronotherapies for DSPS

3 March 2007 at 07:06 | Posted in Circadian rhythm | 10 Comments
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There are two forms of chronotherapy in use as treatments for DSPS. Since it is difficult or impossible to move sleep time to earlier in the night, an attempt can be made to sleep later than usual, by the one or the other system, until sleep and wake times are as desired.

(Note: The term “chronotherapy” can also refer to the optimization of schedules for administering medication. That is unrelated to its use here.)

1. The traditional method has been to stay up two or three hours later each night until one has gone ’round the clock. One might on subsequent days go to sleep at 6 a.m., 9 a.m., noon, 3 p.m., 6 p.m. and 9 p.m. It would then be wise to establish a bedtime of 9 p.m. for some days before easing toward the desired bedtime of 10 or 11 p.m.

This requires a week or more of strict self-discipline and a cooperative family. Maintaining the new bedtime requires very rigid discipline, and most people find that the effects may last from a few days to a couple of months at best, before the natural late night sleep time reasserts itself. There are people who routinely prepare for a daytime seminar or a holiday trip to the in-laws in this way.

IMPORTANT UPDATE:  See also post no. 55 about chronotherapy.

2. An article from Sleep Review, 2003, tells of a lesser known form. There we learn of a 16-year-old boy who had had DSPS for years. He slept nicely from 3 a.m. to noon but his mother had trouble getting him up for school and he dozed during breakfast, on the ride to school and during morning classes. The boy’s history and sleep log showed classic DSPS. He was active, not shy and not depressed.

“DSPS would not be problematic in a world without appointments and schedules. It becomes an issue when it results in conflict at school or work, or with family. Some adolescents are content with their DSPS and have no real desire to change. This perspective presents a serious barrier to therapy. Ultimately, it falls on patients to decide whether they are willing to make the effort and sacrifices required. We stress to families up front that DSPS can be alleviated in a motivated teenager, but therapy is “active” and not “passive.” It cannot be imposed on someone who is not willing to make substantial changes in lifestyle and habits.”

A modified chronotherapy was devised by M. J. Thorpy et al in 1988, apparently specifically for adolescents. It is called controlled sleep deprivation with phase advance, SDPA, and it is designed to be less disruptive to families and the school or work schedule while still taking advantage of the fact that most people find it easier to stay up late than to fall asleep early.

SDPA, step one: the patient sleeps regularly for a week on his natural schedule, in order to start treatment rested.

Step two: a night of total sleep deprivation followed by advancing bedtime by 90 minutes.

Step three: the new bedtime is observed for six days to consolidate the pattern.

Step four: the process of one night of total sleep deprivation followed by advancing the bedtime by 90 minutes is repeated. The process is continued every week until a target bedtime and wake-up time are attained.

Step five calls for maintaining the regular bedtime and rise-time once reached, to prevent relapse of DSPS. 

Conclusion
“Our patient responded to a trial of SDPA, though success required three attempts. Social events and failing to refrain from naps during the day interfered with the first trial. During the next attempt, he developed some performance anxiety around falling asleep even after being sleep deprived. He would lie in bed and worry about not being able to fall asleep. In this circumstance, we felt justified in adding a short course of zolpidem at bedtime for 1 week in combination with SDPA, and he successfully reset his schedule to a 10:30 pm bedtime and 7:00 am rise-time. The family enlisted help from his friends to reschedule their social activities, and this helped the therapy plan move ahead as well. 

 

“It is likely that we have not heard the last from our young man. DSPS patients have a high rate of recidivism, particularly when opportunities to fall off schedule (vacation, travel, college, final examinations, social events, and jobs) present themselves. It is our hope that we succeeded at least in giving our patient the tools he needed to correct his sleep troubles and that he will remember them and know what he needs to do the next time problems arise.” 

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This was an interesting approach. It mirrors somewhat my own tactic which I call my 36-hour trick. At times, almost once a week, I feel a need for a long sleep, 11-12 hours. This can only be attained by staying up one whole night and going to bed very early the next night. It does not, however, get me to bed earlier the following nights. It just allows me to feel rested and healthy for a few days. I have my doubts that the “new” chronotherapy (no. 2) would last any longer than the old, without the aid of melatonin and a light box.  

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Next:  xxxiii. Owls of the World, Unite!

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