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.

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18 Comments »

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  1. Thank you for this entry, LivingWith! I’ve never tried chronotherapy, having by instinct an inkling that it might be a bad idea. I do know of people who’ve used it many times for its short-term results, without bad effect. They say the results last from a few days to a very few weeks. But, for me, the risk just ain’t worth it!

  2. I had always had DSPS for ages (related to anxiety I believe) and one doctor suggested chronotherapy. I did it and ever since then I have the most horrendous non-24 that never ends as if the chronotherapy destroyed my brain completely and made it impossible to settle and stop the brain clock. That was like 17 years ago of unstopable non-24 driving to madness in every sense.

  3. Daniel–
    I’m so sorry to hear that. I have had N24 since 1982 so I know how hellish it can be. Once it starts it can be unstoppable and it makes life so difficult.
    Some people are able to entrain their rhythms by using light and dark treatment. When your rhythm revolves around to where you’d like to keep it (for example getting up at 8am), you start to use a light box for an hour or two first thing upon awakening. Then in the evening, you start avoiding light (especially blue light) for about 6 hours before you want to go to sleep. Dark goggles or blue-blocking glasses can be use then. I had some success with that method, but it did not last and I eventually returned to N24. However a few others have had better results. But it is a very hard regimen to maintain, even when it works.
    Melatonin is another treatment that works for some N24s. It did not help me.
    Since you mention anxiety, I find that medications that are sedative and anti-anxiety initially help my N24, but over the long run they wear off and no longer help at all.
    Don’t give up. There is a lot of research going on about circadian rhythms and sleep that will hopefully pay off for people like us.
    (I’ll send you some more personalized suggestions via email.)
    –LivingwithN24

  4. […] – A Sleep Disorder: Charting the course of N24 DSPS – A Sleep Disorder: Chronotherapy: balancing benefit and risk DSPS – A Sleep Disorder: Melatonin: Less Is (Sometimes) More DSPS – A Sleep Disorder: A […]

  5. Hi living with N24 thanks for your advice I have found it helpful as I was considering starting chronotherapy as I have had DSPS for about 17 years but I don’t want to start anything that could potentially make it worse. I understand people can go through so much worse in their lives but I find this condition such a curse. Can you please tell me can you work a “normal” 9-5 job? I’m am trying but I am finding it so hard I’m just wondering what other people in my position do.

    Would it be possible for you to pass on the information you are giving to Daniel ?
    Thanks

  6. I have had great difficultly working for most of the time I have had N24, which is of course a major problem. Working a 9 to 5 job is difficult for most people with DSPS or N24. Some people are able to work at jobs that often have more flexible hours, such as computer programming. Others are able to work only with great suffering from lack of sleep and all its negative consequences.

    –LivingWithN24

  7. I did manage to work 9 to 5 jobs with DSPS for a very long time but major sleep deprivation during the week and sleeping in on the weekends (until noon minimum)were standard. I find that as I get older the delay has become longer. I don’t get sleepy until 4, sometimes 6 am, when it used to be 2 to 3 am. I have my own business and can work my own hours, (much to my lark husband’s chagrin) so now I find that I won’t get up with an alarm if I don’t have to. I sleep until I wake up naturally, usually noon, sometimes 2 pm. This has become a bit of a problem in my marriage and business, that’s why I came back to this site. I have to educate my husband and at the same time try to see if I can find a solution. After reading this blog again, I think the world may just have to adapt to my schedule. I sleep like a log in the morning, even if there is full sunlight in the room. It is out of my control. Good Luck!

  8. Thank you for your comment, Judith. It does seem that for many people who have DSPS as adults that the delay seems to get greater over time and it becomes more difficult to cope with. You are fortunate to have your own business so that you can, to some extent, set your own hours, but, as you know, that doesn’t solve the problem entirely. Many DSPS people who are self-employed still find that their are many daytime obligations — such as meeting with clients — that are difficult to fulfill. The risk of chronotherapy, is that it can turn this into N24, which is even more difficult to reconcile with such obligations. Good luck to you, too!
    –LivingWithN24

  9. Does anyone have information on the risks of ASPS person undergoing chronotherapy?

  10. I don’t have any information about that. ASPS appears to be more rare than DSPS and there is less known about treatment. In some cases lightbox use in the evening may help. I have not read of any cases of chronotherapy being used for ASPS. I assumed you would plan to rotate your sleep around the clock but by a series of advances (i.e. to earlier times) rather than delays.

  11. Thanks for your response “L”,
    There was one successful ASPS case treated by chronotherapy.See: http://www.journalsleep.org/ViewAbstract.aspx?pid=24561
    I tried the light therapy (FeelBrightLigt.com) visor along with melatonin: didn’t work for me.
    Yes, I’m going in the opposite direction, started with 8 pm bedtime, 2 days later: 5 pm…
    I’ve done quite a bit of research on chronotherapy. Some of the more valuable citations are below:

    Resetting the Clock:
    http://www.journalsleep.org/ViewAbstract.aspx?pid=25443

    Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders
    An American Academy of Sleep Medicine Report
    http://www.journalsleep.org/ViewAbstract.aspx?pid=26986

    Sleep Medicine Reviews (2007) 11, 485–496
    CLINICAL REVIEW
    Circadian rhythm sleep disorders: Characteristics
    and entrainment pathology in delayed sleep phase
    and non-24 sleep–wake syndrome$
    Masako Okawaa,_, Makoto Uchiyamab

    Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A,
    Murphy PJ, et al. Familial advanced sleep-phase syndrome:
    a short-period circadian rhythm variant in humans.
    Nat Med 1999;5:1062–5.

    http://www.chronobiology.ch/otherDocuments/Okawa_07.pdf
    Cheers & Happy New Year,
    Al

  12. Oh, that’s right! I have a copy of the article about using chronotherapy for ASPS but it it had been so long since I’d read it I had forgotten. (I have the other articles as well.)
     
    It’s hard to say whether advancing chronotherapy has the same risks as the delaying form. Non-24 hour sleep wake cycle disorder with a period shorter than 24 hours is very rare, although it has been reported (but not as a result of chronotherapy.) But then ASPS is also very rare, ASPS seems to be produced by a shorter than normal period in the endogenous circadian clock, as demonstrated by isolation experiments in Murphy et al., and so might predispose to developing short-period N24 after chronotherapy. But since there have been so few cases of treating ASPS with chronotherapy the degree of risk is unclear.
     

    Incidentally the Moldofsky article mentions an early entry into REM sleep in the subject. They connect that to possible narcolepsy or depression. What they do not mention, since it was not understood at the time, is the the circadian rhythm of REM propensity is controlled by the Dorsomedial SCN which also regulates the temperature rhythm. If the patient has an endogenous temperature cycle shorter than 24 hours it might be expected he would entrain with his temperature rhythm in a relatively advanced phase which would also account for the early REM entry. Normally REM sleep is more prominent in the second half of the night but if he was forcing himself to stay awake in the evening his REM rhythm might have been advanced relative to his sleep onset time.

     
    The other possibility, that the ASPS in his case was related to narcolepsy or depression, is also interesting. I know a number of people with narcolepsy who developed secondary DSPS. Perhaps secondary ASPS is possible.

     
    The larger studies of familial ASPS did not show any signs of narcolepsy and the advance of REM sleep was the same as that of sleep onset in most cases.

     
    Although ASPS is more rare than DSPS, the molecular basis of ASPS is better understood due to the the strong heritability factor in certain family lines. At least two mutations, one in the per2 gene and one in casein kinase 1 delta have been pinpointed as the cause in different families. Other families have as yet unknown causes.

     
    Is ASPS something that runs in your family?
     

    I would be interested in how your treatment goes. Please let us know. Thanks for commenting.
     

    -LivingwithN24

  13. LivingwithN24,
    I will be glad to share my cronotherapy ASPS treatment experience if we go off line (you have my email address) and you share who you are and what is your involvement with all this, besides the seeming obvious that you experiencing N24.
    If you want to find out more about me, go to my domain name website and click author.
    Al

  14. N24, i have a question…if you only sleep 5 hours, you also go to sleep 1.30 2 hours later.? Well i have dsps since 16 years old, my mom obligate to go to school, and in one moment,when i was going to sleep knowing,that i would sleep 3 or 4 hours, i put very very nervous with anxiety that directly i dont sleep nothing. I passed 3 years only sleeping in weekends. Well these driving me, to phobia social, ddepression, and other stuff. Then i drink a lot of alcohol to sleep in a normal way, and it makes worst. I start to became addicted to alcohol and cigarettes. Well actually when i know that i have to wake up in the morning, directly i dont sleep. Also i have a very good resistence to dont sleep, but also then break me. I think seriously to do chronoterapy, but then i think that it will be worse and dont like me. Well i apolagize my english, im from argentina. Now we are in summer, and i take a course to impove my english. Well a big hug, from. Here.

  15. “L”, My son was diagnosed with DSPS at age 13. At that time, the doctor prescribed chronotherapy and a second phase with light therapy and melatonin. We did it. Well, that turned onto N24! I had to take him out of school and home school him. Now, he’s 18 trying to find his first job and this condition makes it almost impossible. He’s too young to work alone in his own business. I think he should have a regular job first. In searching for solutions today, I found out about the link between Chronotherapy and N24. I’m outraged. The doctor NEVER mentioned the risk that we would be taking. It’s medical malpractice!

  16. I am very sorry to hear what happened to your son. This risk has been known for years so you both should have been told that the development of N24 was a possibility.

  17. So sorry to hear that. I think this happened to my son. We were not able to discuss things with the doctors as once your kids turn 16 in the UK you have no say in any treatments.


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