64. Circadian Sleep Disorders Network

28 November 2011 at 22:00 | Posted in Circadian rhythm | 5 Comments
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UPDATE:

CSD-N is now set up to accept paying members.  Charter membership (before 31 March 2012) is just US$25.  The organization needs many members to increase its clout in working for its goals.  See the “Join us” page on the website. 

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There’s a new organization for us:  Circadian Sleep Disorders Network – advocating for people with misaligned body clocks.  It’s incorporated as a non-profit in the USA and very soon will be accepting paying members.

Its mission statement:

  • Circadian Sleep Disorders Network is a non-profit organization dedicated to improving the lives of people with chronic circadian rhythm disorders.
  • We aim to increase awareness within the medical community and among the general public, to provide emotional support and practical ideas for people living with these disorders, to encourage research into circadian rhythms, and to advocate for accommodations in education and employment for people with circadian rhythm sleep disorders.

The website, under construction, is at CSD-N.org.  There you’ll find a two-sided brochure which may be downloaded and freely distributed; it is available in both A4 format and 8.5×11 letter size.

Here’s wishing the new organization a long and useful life.

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Next post:  65.  Sleep inertia

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61. Questions and answers about Non-24

17 February 2011 at 13:56 | Posted in Circadian rhythm | 18 Comments
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About 50% of the totally blind have Non-24-hour Sleep-Wake Cycle Disorder while it is very rare among sighted people.  People with Non-24 cannot adjust to the environmental 24-hour cycle.

If Hayakawa et al. are to be believed, there have been only 96 cases of N24 in sighted people reported in studies, worldwide, ever.  The first 39 were reported in 26 separate studies dated 1970-2003.  Hayakawa’s group reported on 57 cases in a report in 2005*.  These 57 were diagnosed in Japan in 1991-2001.  So what have I learned from that paper?

Are there equally many men and women?  No, there are more than two and a half times as many men.

Is Non-24 about as common as the other Circadian Rhythm Disorders (CRDs)?  No, the other CRDs together, primarily DSPS, are six times as common.

Do people with Non-24 have anything else in common physically?  No.  Eye examinations, blood counts, serum biochemistry, electrocardiography, electroencephalography and brain MRIs show nothing special.

Socially?  89% were unmarried and 39% were unemployed.

Had they any health problems in common before the onset of free-running?  28% had psychiatric problems (obsessive-compulsive, adjustment, schizoprenia, anxiety or depression and often associated social withdrawal), not remarkably higher than the general population.  But more than a fourth had DSPS before developing Non-24.

How old were they at the onset of Non-24?  86% were ten to twenty-nine years old, none younger than ten.  Sex had no effect on the age of onset.  (None of the subjects was over 50.)

Do the hours of sleep correlate to the length of the endogenous circadian cycle?  Most of the subjects’ cycles were between 24.5 and 25.5 hours, with only one having a cycle longer than 26.5 hours.  Subjects slept between less than 7 hours to more than 12, with the majority sleeping 9-11 hours.  But there was no correlation between the period of the sleep-wake cycle and sleep length, and neither was affected by sex nor employment status.

How debilitating is the disorder?  “98% had a history of disturbed social functioning due to inability to regularly attend school or work.”

Do people with Non-24 often develop psychiatric problems after the onset of the disorder.  Yes, but depression only, not the other disorders.  “It is possible that these patients had tried to adapt themselves to their social life and failed, leading to psychological stresses that could have precipitated their depression.”

How does Non-24 in sighted people differ from that of people who are blind?  The blind generally have a shorter circadian period, and it doesn’t fluctuate over time.  In sighted people, the period tends to be longer when sleep onset is in the daytime than when a person falls asleep during nighttime.

*Tatsuro Hayakawa, Makoto Uchiyama, Yuichi Kamei et al.  Clinical Analyses of Sighted Patients with Non-24-Hour Sleep-Wake Syndrome: A Study of 57 Consecutively Diagnosed Cases.   SLEEP 2005;28(8):945-952

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Next post:  62.  Psychiatric misdiagnosis of N24

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59. Clock genes at the heart of depression

24 October 2010 at 02:25 | Posted in Circadian rhythm | 8 Comments
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Which came first: the chicken or the egg?  The circadian rhythm dysregulation or the depression?

Traditionally, it has been claimed (assumed) that depression causes sleep problems including sleeping too early (the thinking in the 1980s) or too late (more recently).  We who have circadian rhythm disorders (CRDs) have always thought that depression and other mood disorders can be a result of circadian rhythm misalignment or disruption, rather than a cause.

Now a review* suggests that polymorphisms in some of the 18 clock genes may cause both depression and CRDs.

  • [T]reatment strategies or drugs aimed at restoring ‘normal’ circadian rhythmicity may be clinically useful.
  • [W]e may predict that new antidepressant drugs will emerge that (…) target and correct abnormalities in the circadian timing system. 

 

A recent careful study of patients with delayed sleep phase syndrome (DSPS) showed that

  • patients who also showed depressive symptoms had an even later peak in the 6-sulphatoxymelatonin rhythm than patients with no depression. 

 

Even research on rodents provides evidence

  • for a role of clock genes in behaviours that are relevant to mood disorders.

 

Much of the genetic info in this review goes way over my head, but this bit sounds reasonable:

  • The endogenous rythmicity within the master biological clock in the brain … is generated by interlinked positive and negative feedback loops of gene transcription and translation.  If there is to be a role of circadian rhythmicity in mood disorders then it almost certainly involves these genes….

 

Practical results?

I’m hoping that these ideas represent a turning point in circadian rhythm research.  I hope that, here on in, the researchers search for realistic and practical treatments, as well as useful diagnostic tests, for CRDs.

 

* Kennaway, David J. (2010) Review: Clock genes at the heart of depression.  Journal of Psychopharmacology Vol. 24 No. 5

The illustration is borrowed from a blogpost by Jeff Pruett.

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Next post: 60. Charting the Course of N24

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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.

54. Take a Nap!

30 June 2010 at 18:27 | Posted in Circadian rhythm | Leave a comment
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Sleep researcher Sara C. Mednick has written the book Take a Nap! Change your life.  (Workman Publishing, NY, 2006)

 Yes, it  continues in the over-enthusiastic, cheer-leading tone seen in the title, and no, it doesn’t address circadian rhythm disorders.  The book is so popularized that it doesn’t even have an index.  But it’s interesting and it’s based on solid science.  It tells about sleep stages, what they are for and their circadian rhythms.

Though we spend about half our total sleep time in Stage 2 sleep, it’s been known for some time that most deep sleep appears in the first half of one’s night, and most rapid eye movement (REM) sleep appears in the last half.  Here’s a hypnogram from Wikipedia  showing a normal night’s sleep with its sleep stages:

Deep sleep (slow wave sleep) is stages 3 and 4 where Stage 3 includes 20-50% delta waves and Stage 4 includes over 50% delta waves.  The illustration clearly shows deep sleep in the early part of the night (more clearly than a more modern one might, as stages 3 and 4 often are combined into one, at least in the USA).

It would never have occurred to me, but Dr. Mednick has shown that this early night/late night division into predominantly deep sleep and predominantly REM sleep is just part of a whole circadian cycle: a morning nap will include more REM sleep while an afternoon/evening nap offers more slow wave sleep.  Sleep cycles generally contain the lowest amount of REM a couple of hours before bedtime and the greatest amount twelve hours later.  I’ve tried to illustrate this here:

And should we care which sleep stages we are getting in a nap?  In a nap of 20 minutes or less, the answer is no, as that nap includes only stages 1 and 2.  But in a longer nap, up to an hour and a half or so, we go through a whole sleep cycle and it may indeed matter which type of sleep we are wanting.

The short “Stage 2 nap” increases alertness, stamina and physical dexterity.  Drowsy drivers have a lot to gain from a 15-20-minute nap. 

The morning nap, with more REM-sleep, inspires creative insight, heightens sensory perception and consolidates newly learned material including spacial orientation.  The evening nap, with more deep sleep, provides tissue repair, improves memory and clears the mind (“prunes deadwood”).

On one point, Dr. Mednick disagrees with other experts.  She says a nap no longer than three hours ending no later than three hours before bedtime will not interfere with nocturnal sleep and may even improve it!

Take a Nap! provides detailed instructions for planning your ideal nap.  NB!  if you are not well-rested, sleep debt will demand the repaying of SWS first, whether or not that’s what you want most of.  See also Mednick’s website:  www.takeanap.info

( posted by D )

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Next post: #55.  Chronotherapy: balancing benefit and risk

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