DSPS, a sleep disorder

55. Chronotherapy: balancing benefit and risk

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 aka “L“

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.