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.


Next post: 60. Charting the Course of N24


xii. Circadian rhythm disorders

27 November 2005 at 11:14 | Posted in Circadian rhythm | 6 Comments
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There are a great many sleep disorders. I read recently that an official list of them had been pared down to about 70. Many have to do with not getting enough sleep, or getting sleep of poor quality by several criteria. Some have obvious causes, such as chronic pain, frequent stops in breathing etc.

My interest is in the timing of sleep as my sleep seems otherwise normal. As the experts put it, I have normal “sleep architecture”. (For a good, short explanation of sleep architecture — stages and brain waves — see this page from Feinberg School of Medicine at Northwestern University in the USA.)

Nearly all of us can reset our clocks daily, adjusting the various rhythms to 24 hours. As much as I’ve read about it, I’ve not found a good enough explanation for being able to adjust to 24 hours while not being able to adjust to sleeping midnight to eight or so.

I’m not immune to the light/dark cycle. I need to get up at noon. I fly 8 hours east or west, go through jet lag like anyone else and within days I need to get up at noon in the new location. This is built in. I’m not the only one. I’d just like to understand it better.

A Japanese paper (2004) suggests these possible mechanisms:

  • reduced sensitivity of the oscillator to photic entrainment,
  • an intrinsic period beyond the range of entrainment to the 24 hour day, and
  • abnormal coupling of the sleep/wake cycle to the circadian rhythm.


The least common and most debilitating circadian disorder is the one where body temperature, melatonin secretion, sleep and other rhythms vary several times a day, in and out of phase with one another, so called Irregular Sleep/Wake Disorder. This has been reported in humans who’ve been in accidents and had physical injuries to the hypothalamus. It’s also been provoked by surgery in lab animals.

One of the most rare disorders which occurs naturally is called Non-24. Sufferers simply(?) live on a 23, 25 or 26 hour cycle, getting up one hour later each day for example, thus coming in sync with the earth’s rotation every few weeks. Their rhythms are in sync internally, just not with the light/dark cycle outside. Most, but not all, of these people are blind. 

ASPS, Advanced Sleep-Phase Syndrome, is also rare. These people fall asleep and awaken much earlier than normal. The disorder runs in families, and an American family has been studied intensively the last few years. Research on their genetic mutation was published in 2001. “Detailed sequence studies of the candidate human gene, hPer2, in the affected family members, revealed a key change in a single amino acid — from serine to glycine — at position 662 in the hPer2 protein.” The alteration “occurred in the portion of the hPer2 protein that governed binding to an enzyme called casein kinase one-epsilon (CK1e ).” In animal models, this enzyme regulates “proteins involved in controlling the length of circadian rhythms.”

Now this is beyond me, but it would appear that these disorders may be genetically programmed. Though ASPS is rare, it seems reasonable that researchers start there, since one can compare the DNA of people who are related to one other.

DSPS, Delayed Sleep-Phase Syndrome, is a bit more common. Studies indicate that somewhat more than one in a thousand adults have DSPS (Japan 0.13%, Norway 0.17%). It runs less commonly in families, but it doesn’t seem unreasonable to guess that its cause may be similar to that of ASPS.
Clearly, anyone whose health cannot tolerate frequent forced awakening earlier than 10 a.m., will have few real choices in our society. Thus, hardcore (inflexible) DSPS must be considered a disability.

Another disorder which may be related to the others is Seasonal Affective Disorder, SAD. Sufferers are normal in summer, have problems of mood, weight gain etc. when days get shorter and can often be treated successfully by bright light therapy. It seems likely that they may have a mild form of ASPS or DSPS which is “treated” by morning/evening daylight when days are long.

Diurnal preference, spoken of as “morningness”, larks, and “eveningness”, owls, is also a subject of study, the field of chronobiology. This is, reasonably enough, connected to one’s circadian rhythms. However, it does not appear that ASPS is an extreme morningness chronotype nor DSPS an extreme eveningness chronotype. The internal relationships among the various rhythms do not place these conditions on a simple continuum.


Next post:  xiii. DSPS-sleep


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