Tags: Adolescent, Depression, Diagnosis, Non-24, Sleep disorder, Treatment
I’ve been reading an interesting article on a case of psychiatric misdiagnosis of N24 in a 14-year old. This poor kid was given a long list of severe and pejorative psychiatric diagnoses, all of which resolved completely when his circadian rhythms were normalized with melatonin treatment. He had dropped out of school for two years and was sent to a child psychiatric hospital. After treatment was able to return to school and do well. This case shows how easily N24 (and DSPS) can be misdiagnosed. The boy was also lucky he responded to melatonin as many N24s do not.
Here is the description of his case before proper diagnosis and treatment:
During the 4 years before referral,
the patient suffered from major functioning difficulties
including conflicts with teachers, parents, and peers. He
was described by a licensed child psychologist as being
extremely introverted with severe narcissistic traits, poverty
of thought, and disturbed thinking, including
thoughts with persecutory content and self-destruction
that led to a paralyzing anxiety, anhedonia, social isolation,
and withdrawal. Assessment of learning disabilities
revealed difficulties with written language and poor
visual and auditory memory. Assessment also revealed
above-average performances in verbal comprehension
and abstract reasoning.
Two years before referral, the patient dropped out of
school and was sent to an inpatient child psychiatry center.
Three months of psychiatric evaluation yielded diagnoses
of atypical depressive disorder with possible
schizotypal personality disorder. He was described as
sleepy and passive, especially in the mornings.
The patient was diagnosed using actigraphy (a wrist monitor that measures movement) and with 24 hour sampling of melatonin and temperature rhythms. This is his actigraphy chart showing the classic N24 pattern in which the waking period shifts later each day. The black peaks on the chart show movement, indicating the time of day or night during which he was awake.
Treatment with 5mg of melatonin (a large dose) at 8pm resulted in a normalization of his circadian rhythms within a month.
Here is how he was described after proper diagnosis and treatment:
The patient returned to school after a 1 years absence
and succeeded in filling the gaps of missing studies. At the
end of the first semester, his school report showed excellent
results. His parents also reported an improvement in
the patients relationship with his family and peers.
In a psychiatric evaluation by licensed psychiatrists,
none of the previously described severe diagnoses were
present, and the boy showed no evidence of psychopathology,
as was previously thought.
One wonders how many adolescents — and adults — are misdiagnosed with various severe psychiatric disorders simply because no one looked for a circadian rhythm sleep disorder. The case was reported by Yaron Dagan and Liat Ayalon two of the best researchers on the clinical manifestations of N24 .
1. Dagan Y, Ayalon L. Case study: psychiatric misdiagnosis of non-24-hours sleep-wake schedule disorder resolved by melatonin. J Am Acad Child Adolesc Psychiatry. 2005 Dec;44(12):1271-5.
–Posted by LivingWithN24 (James Fadden)
Next post: 63. Sleep research in the USA
Tags: Body clock, Circadian rhythm, Depression, Diagnosis, Genetic mutation, Treatment
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….
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.
Next post: 60. Charting the Course of N24
Tags: Body clock, Chronotherapy, Circadian rhythm, DSPS, Non-24, Treatment
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 . 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 . 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 . 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 . 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)
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.
Tags: Melatonin, Treatment
Melatonin is often suggested as a remedy for those of us who have N24 or DSPS. It works for some people, but not for others. (So far I seem to be in the latter category.) For some people it doesn’t work because — well because it doesn’t work for them — we can’t always tell why. But for other people it does not work because they are using the wrong dose. Melatonin dosing can be a bit tricky.
When speaking of hormone dosing, there are two terms that often arise: physiological dose and pharmacological dose.
The physiological dose of a hormone is the dose the replicates the level of the hormone normally found in the body. For example, people with Addison’s disease, a deficiency of the hormone cortisol, will usually take 15 to 25 mg of cortisol a day, which results in a serum level of cortisol similar to that of a healthy person. Another phrase to describe the physiological dose is the “replacement dose” which means essentially the same thing.
The pharmacological dose of a hormone is the dose required to produce a specific desired effect. In some cases the pharmacological dose is much higher than the physiological dose. Cortisol for example has an immune system suppressing effect at high doses, so people with auto-immune conditions are often prescribed cortisol (or cortisol analogs) in much higher doses than the replacement doses used for Adddison’s disease. There is nothing necessarily wrong with using such high doses. They are often the best treatment for a disease. But they do have a much greater risk of side effects, since you are introducing a hormone at much higher doses than the body is used to.
Melatonin is a hormone produced at night, and in humans aids in consolidating sleep at night. As such melatonin can have a sedative effect. Melatonin levels during the day are very low, typically 1- 10pg/ml, and often undetectable. At night melatonin levels rise to much higher levels, usually 40-100 pg/ml or roughly 10 to 40 times the daytime level.
You will often see recommendations to take melatonin doses at night of 3mgs. Such a dose of melatonin will not only produce levels much higher than the daytime levels, but will produce levels much higher even than those found normally at night. If the nighttime level of melatonin is around 10-40 times that found in the day, 3mg of melatonin will produce levels approximately 10-40 times higher than even the nighttime levels (or over 100 times that normally occurring during the day). The serum level would be around 1000 pg/ml.
Why are such high doses suggested? One reason is because this high dose maximizes the sedative effect of melatonin. For most people the more you take the greater the immediate sedative effect. This is a pharmacological dose — it is maximizing the effect of a hormone by taking very large doses that produce a drug-like effect.
Well, what’s wrong with that? If you want to get to sleep don’t you want to maximize the sedative effect? Well, maybe, maybe not. You see in the treatment of N24 or DSPS a sedative effect is not the whole answer. If it were then any sedating pill could treat these conditions, and that is not the case. Most sedatives in fact don’t work very well for circadian disorders. What we are looking for in using melatonin is a phase shift in the timing of sleep, not just an acute sedative effect and for that too much melatonin can be harmful.
Melatonin taken in the evening produces a phase advancing effect, while melatonin taken after the midpoint of sleep (roughly) produces a phase delaying effect. Keep in mind that melatonin taken orally has a half-life in the blood that can range from 30 minutes to 2 hours (depending on the individual and the study method). If you take 3 mg you are getting blood levels in the evening that are extremely high and it’s going to take many hours for those levels to get back down. And that’s the problem. You will still have melatonin in your system the next morning, when it will produce a phase delay. This spillover effect is nicely illustrated in a graph produced by Lewy et al in a study which showed the advantages of lower doses of melatonin. They found they could entrain a blind patient to 24hrs with 0.5mg of melatonin but not with 10mg. As one can see from the graph this is because the 10 mg dose caused melatonin levels to remain elevated during the phase delay portion of the phase response curve (PRC).
(Graph from Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int. 2002 May;19(3):649-58.)
In addition to the spillover effect from high doses of melatonin, the immediate sedative effect of a large dose can cause other problems. With any kind of sedative the phenomenon of acute tolerance can occur, which means as the sedative effect wears off later in the night the person may find themselves awakening again in the middle of their normal sleep period.
To achieve physiologically normal levels of melatonin in the blood an oral dose should be around 0.1 to 0.2 mg (100 – 200 mcg). This will produce levels mimicing those normally present in the body. For N24 or DSPD we don’t necessarily want very high levels, we just need the melatonin to be produced at an earlier time. For N24 you should take this low dose at the same time each night, about an hour or two before you want to fall asleep — possibly even several hours earlier. The aim is to stabilize the time of sleep onset. For DSPS (aka DSPD) you will want to take it a several hours ahead of your normal bedtime to try to pull your sleep to an earlier time. (The timing of melatonin is complex as well so I can’t cover it in detail today. In general earlier melatonin produces greater phase advances, but may also cause sleepiness immediately after the dose, which can be problematic during the day.)
There may be some individuals who need high doses of melatonin because they are insensitive to its effects or they require an acute sedative effect. I would not discourage anyone from trying higher doses. But if a higher dose doesn’t work or causes problems, consider going low dose. That’s the point of this post.
Will these lower doses of melatonin work for you if you have N24 or DSPS? I wish I could promise they will. For some people they do work or at least help. They are often helpful for blind people with N24; less so for sighted people. But for many others melatonin does not work. There are several possible reasons. Taking melatonin early in the evening produces the equivalent of a very long winter night and this can result in depression-like symptoms in many people. It may also be that the spillover effect of melatonin is more pronounced in some people. It also may be that the underlying cause of N24 or DSPD in many people has nothing to do with melatonin itself, and therefore manipulating melatonin levels accomplishes nothing for them.
I know that melatonin often makes me feel very tired and lethargic the next day — not what I am trying to achieve, needless to say. Lately I’ve been experimenting with even smaller doses. I put around 125mcg (0.125mg) of melatonin in liquid form in a glass of water and sip small amounts of it for an hour or two before bed. I probably get only around 25-50mcg (less than half a glass) in total. I’m not sure if this is helping yet (and even such a low dose may have made me more lethargic at times).
But while I can’t promise melatonin will work, if you are going to try it you are better off trying the right dose. At the right dose it may work, and at least if it does not you work will know that melatonin is not the answer for you, not that you just took the wrong dose.
Remember, for melatonin less is (sometimes) more.
Posted by LivingwithN24 (James Fadden).
Next post: #52. 2010: sleep logs