Circadian Rhythm Connections: Part 1 – Mood Disorders

Roosters crowing at the first crack of daylight. Morning glories unfurling their blooms as the sun rises in the sky. Lightning bugs flickering just as dusk falls.

Most people intuitively understand that plants respond to sunlight, using photosynthesis to produce energy and store sugar during daylight.  It is easy to also apply the thought of daily rhythms to animals, with nocturnal mice scurrying around at night and diurnal birds chirping in the morning.

What is often more difficult to understand is how deeply circadian rhythms are hardwired into us, humans. While evolutionary biologist may argue exactly how the circadian clocks evolved through different species, there is no argument that all animals and plants are governed by circadian rhythms, from blue-green algae preparing for sunrise to much more complex organisms with nocturnal and diurnal patterns.[ref]

Why is it so hard for us to understand that humans also are affected by light and dark?

Human hubris?  We are superior, beyond the animal rhythms of nature.  We craft tools for extending light into the night, and our society now functions 24 hours a day. Take back the night. Light it up; party all night.

But it seems that our chickens have come home to roost (pun intended).  This human determination to conquer the night, a 24-hour society of hustling and bustling, is probably at the root of so many diseases including mood disorders, cancers, heart disease, dementia, and diabetes.  In fact, over the course of this multi-part series of articles, I will make the case that research studies are showing that circadian disruption is at the heart of most of our chronic health problems.

Before you mentally check out and decide that this article doesn’t apply to you, I challenge you to read to the end and check out the overwhelming evidence for yourself.

This isn’t hippie-dippie, crackpot, wacko stuff. There is a true abundance of evidence that ignoring our circadian rhythm is fundamentally detrimental to our health.

This goes much deeper than just the standard, oft-repeated advice that you should sleep well. Everyone knows that they should sleep well – and most ignore it.  Sleep is involved, but I think I can make the case that good sleep is a byproduct of good circadian function.

The flow of science usually starts with observing a phenomenon. It is talked about, poked-and-prodded, and theories fly. But a true understanding of a phenomenon or a disease comes with understanding the mechanisms that cause it, reverse-engineering it. One way of reverse-engineering chronic diseases is to look at the genes that cause an increased risk for a disease. Modeling the disease state can then happen in an animal model using genetic manipulation, or knocking out a gene to see the effect.  It isn’t as neat and straightforward in biology as it is in engineering, but the principle remains the same.

My path into investigating the impact of circadian rhythms started with diving into genetics and a fascination with the genes that control our core circadian clocks. Humans (like all animals) have a few core genes that regulate our internal rhythms such as the rise and fall of our hormones, enzymes level fluctuation, cellular repair, body temperature, and the sleep/wake cycle.

Our core circadian rhythm is set by the rising levels of two proteins, CLOCK and BMAL1, that join together each day. Levels of CLOCK and BMAL1 rise over the daylight hours, eventually getting to a high enough level that they inhibit themselves, thus allowing the subsequent increase of the other half of our circadian genes: PER (period) and CRY (cryptochrome).  This feedback loop runs on approximately a 24-hour rhythm.

Notice the word approximately. Circadian comes from the Latin words circa (about) and dia (day). About a day. The daily fluctuations of our circadian rhythms usually take a little over 24 hours for humans kept in total darkness, and other animals may have slightly shorter than 24 hour periods. The CLOCK and BMAL1 timing needs to be regularly set and adjusted.

So what sets the beginning of our daily rhythm: morning sunlight.

The shorter wavelengths of sunlight in the 450-480nm wavelengths, what we perceive as blue light, are exciting a non-image forming photoreceptor in the retina of the eye that signals the beginning of the day. Like a lock and key, the specific wavelength of blue light causes the excitation of the molecule, triggering the signal for our circadian clock. (If you think back to plant biology, this same mechanism is at  work in photosynthesis with a specific wavelength of light exciting the chlorophyll pigment inside the chloroplast.)

If you are thinking back to high school biology and only rods and cones in the retina that form images, you may be surprised to find that there is a third type of photoreceptor in the eye known as intrinsically photosensitive retinal ganglion cells (ipRGC’s). The blue light-sensitive pigment in these cells is known as melanopsin, and it has only been known for less than 20 years.[ref]

So if our eyes are not supposed to be exposed to light at night, what about the fact that we have had light at night ever since our caveman ancestors first lit up a fire to keep their caves toasty at night? Good question. Firelight (and light from candles, oil lamps, etc) gives a nice warm glow; it is mainly light in the yellow and red end of the visible light spectrum without any of the shorter, blue wavelengths.

Over 100 years ago we conquered the night with electric lights, but these incandescent bulbs also cast a warm, yellowish light with only a little in the blue wavelength spectrum. Black and white TV’s came into living rooms in the ‘50’s, and by the 1980’s everyone had color TV’s pouring blue flickering light out into the night as we sat glued to the Duke of Hazard and The A-Team.

Fast forward thirty more years to our current era of ubiquitous devices such as cell phones, tablets, and laptops, all glowing with light in the shorter, blue wavelengths.  Add in the effects of LED and compact fluorescent light bulbs, which both have sharp peaks of blue wavelengths in their spectrum – the pure white light includes a lot of blue light in it. (Anyone else here see the irony of the government banning incandescent light bulb production in favor of the lights that are increasing our chronic health problems?)

We are now bombarding the receptors in our retinas at night with light in the exact wavelength (480nm) that signals to our brain that it is daytime.

All of this core circadian oscillation is taking place in a region of the brain called the suprachiasmatic nucleus (SCN).  Located in the hypothalamus the SCN is connected to the retina and receives the signal from the ipRGC’s. One interesting fact about the SCN is that when it is isolated from the rest of the brain, the cells still maintain electrical and molecular rhythms – the clock keeps on ticking.[ref]

It helps to visualize the rise and fall of the circadian genes like a sine wave, with the amplitude (height) of the wave being important as well as the phase (length of time) affecting us.

Let’s get into some of the scientific studies that investigate the importance of our circadian rhythm.

Mood Disorders:
In 2005, the NIH estimated that 9.5% of the adult population suffered from mood disorders.[ref] The 2016 statistics show that 18.3% of US adults suffer from a mental illness (which is a bit broader of a category than just mood disorder).[ref]  This topic is relevant to so many of us, and the science linking mood disorders to circadian dysfunction leads us to new solutions and alternatives to the psychiatric medications that so often come with side effects.

Seasonal Affective Disorder:
Let’s start with an easy and obvious example:  Seasonal Affective Disorder (SAD) is a well-known disorder that involves the onset of depressive symptoms with the changing amount of daylight in the fall or winter. SAD affects between 2 – 9% of the population, depending on the latitude. It is now thought that the decreased intensity or brightness of the light is what triggers SAD rather than a shorter period of daylight. One effective therapy for seasonal affective disorder is bright light therapy.[ref]  More to read: Genetics of Seasonal Affective Disorder

A study of diurnal (active during daylight) rats found that decreasing the intensity of light could effectively cause anxiety-like behavior. In other words, dim light was causal for mood disturbance. The researchers also found that the decreased light intensity caused a disruption to the HPA axis with increased corticosterone production.[ref]  Corticosterone in rodents is equivalent to cortisol production in humans.

Bipolar disorder:
The link between circadian disruption and bipolar disorder has been known since before the 1970’s. Bipolar patients with a shortened circadian period are the ones who respond to lithium carbonate[ref], which has recently been shown to inhibit GSK3beta, directly impacting the core clock genes. Lithium also causes an increase in the amplitude of the production core circadian protein PER2[ref]

The worldwide lifetime risk of bipolar disorder is a little over 2%, with onset most likely occurring between the ages of 17-27.  One mutation in the gene, CLOCK, causes people to be more likely to stay up a little later in the evenings (evening chronotype); it is also linked to a doubling of the risk of bipolar disease.  [ref]

Major depressive disorder (MDD) has also been linked to circadian disruption. Our neurotransmitter levels of serotonin, norepinephrine, and dopamine all fluctuate with a circadian rhythm over the day. Moreover, MAOA (monoamine oxidase A), which terminates dopamine signaling, is a transcriptional target of the core circadian genes, BMAL1 and PER2.[ref]

It is interesting to look at how antidepressants work. Studies show that SSRI’s shorten or advanced the circadian period, and fluoxetine (Prozac) also causes phase advances.[ref] It is thought that SSRI’s are increasing serotonin in the SCN (suprachiasmatic nucleus), and part of the reason that it takes a little time for them to be effective is that they are changing the body’s circadian rhythm which takes a little while to adjust.[ref]

This brings us back to the chicken or the egg argument. Are mood disorders causing the changes in circadian rhythms or are alter circadian rhythms causing mood disorders?[ref] There seem to be arguments on both sides, and it could be that both sides are correct in that the interrelated feedback loops could keep driving the dysfunction.[ref]

One strong argument for circadian dysfunction causing mood disorders is that genetic variants in the core circadian genes are linked to increased risk of major depressive disorder, bipolar disorder, and anxiety. Another strong link is that altering the CLOCK gene in mice can produce a mouse model of depression. One specific strain, called CLOCKdelta19 mice, causes a longer circadian period with mania and anxiety during daylight and euthymia in darkness[ref] Knockdown of BMAL1 in the SCN of mice induced helplessness, behavioral despair, anxiety and weight gain.[ref]

But not all circadian gene mutations cause mood disorders. Per1 and Per2 mouse mutant strains have altered circadian rhythms without mood alterations. This has led some to hypothesize that light, rather than circadian rhythm, plays a causal role in mood disorders.[ref] While a genetic variant of the CLOCK gene may double the risk of bipolar disorder, obviously not everyone with the variant will become bipolar.[ref]

Looking at animal models of depression adds more fuel to both sides of the argument.  Chronic mild stress causes a dampening in the amplitude of circadian rhythms in mice. It also causes a damping of amplitudes of daily temperature variations and of corticosterone production.[ref]

What do human studies show?
Shift workers who alter their schedules for work are at an increased risk for depression.[ref] While the numbers vary depending on the study, a 2017 meta-analysis came up with a conservative estimate of a 43% increase in the risk of depression for those who work the night shift.[ref]

A number of human core clock genes are associated with the risk for MDD and seasonal affective disorder. Again, finding that circadian gene variants can cause mood disorders is a strong indicator that circadian disruption drives mood disorders.  Recently, it was shown that a PER3 mutation that causes Familial Advanced Sleep Phase Disorder (people who have this naturally want to go to sleep very early in the evening and get up extremely early in the morning) also is causal for seasonal affective disorder. The same study created a mouse model that decreased PER3 expression, which showed that not only were the mice depressed, but the severity of depression was worse with a shorter photoperiod. [ref]

A study of patients with depression looked at the gene expression at the time of death (you can’t do a lot of in vivo studies on gene expression in the brain with people who are living). The study found that compared to non-depressed, people with depression controls who had died at the same time of day showed a phase delay in gene expression, strongly linking circadian rhythm changes to depression.  [ref]

Sleep disturbance goes along with altered circadian rhythms, and sleep disturbances are a hallmark of both bipolar disorder and depression. It is theorized that dampened and shifted circadian rhythms can explain the sleep disturbances in mood disorders. Indeed, dampened temperature fluctuations (our body temperature is supposed to drop at night) and dampened hormonal rhythms are a big part of depression. In bipolar patients, it has been shown that circadian gene expression is phase advanced in manic states and delayed during periods of depression. [ref]

A recent study of blue-blocking glasses for bipolar patients had very positive results.  The study used two groups of patients, one group wearing blue-blocking glasses from 6 pm to 8 am for seven days, while the other group wore clear lenses. After seven days, the group wearing blue-blocking glasses had a drop in the Young Mania Rating Scale of 14.1 compared to the placebo group which had a drop of 1.7.[ref]  Simple, inexpensive, and effective – blocking blue light in the evenings had a significant impact after only a week.

Let me wrap this up by pointing out some things that may seem obvious now:

  • We are a society that is chronically somewhat stressed.
  • Most of us spend the majority of our day inside with low amounts of light (compared to sunlight).
  • We are constantly telling our body that it is morning instead of night by our use of electronic devices with blue light hitting our eyes at night.
  • All of this is having a deleterious effect on our circadian rhythm.


Block the Blue Light at Night:  
Blue-blocking glasses (amber or orange colored lenses) in the evening for a couple of hours before bedtime.  This means wearing them constantly since less than a minute of blue light can delay melatonin onset for quite a while. One study found a 50% increase in melatonin production after just two weeks of wearing blue-blocking glasses. [ref] Be sure to look for ones that block 100% of the blue light wavelengths.

Alternatively, you could stop watching TV in the evenings, avoid reading from a lighted eReader, and refrain from looking at your cell phones, tablets, and laptops. Couple the avoidance of all electronics with low lighting in your house from bulbs that have a red hue and you are on the right track to resetting your circadian clock.

Bright Light During the Day:
Sunlight during the daytime is really important. There is just no way to get enough brightness from normal light bulbs during the day. Try eating your breakfast and lunch outside, or park farther from work and walk in the sunshine for a bit before your day begins. Just make it a priority to get some sunlight. A study shows that even sitting next to a window in your office can help. [ref]  Another study found that increasing morning light decreased depression and increased sleep quality. [ref]

Light therapy devices are becoming more and more prevalent, and the studies on them are showing efficacy for more than just seasonal affective disorder. One recent clinical trial found light therapy effective for postpartum depression [ref], and another in dementia patients also found bright light therapy effective.[ref] There are literally a couple thousand studies available on light therapy for depression, so I would encourage you to research the topic. Note that for most studies on depressed patients, the participants continue their current depression medication during the trial. If you are currently on medication, please don’t just throw out your bottle of pills and turn on a bright light—talk with your doctor and come up with a plan.

Darkness at Night:
Dark Therapy has been tried for some bipolar patients, with forced darkness for 10 hours per night leading to stabilization in mood.[ref] Along those same lines, all of us can benefit from blocking out all light sources in our bedrooms while we sleep. Get some blackout curtains (inexpensive on Amazon), and cover up all the little LED lights on chargers, etc.

Final thoughts:
Read and learn more,  pay attention to your circadian rhythm, and realize that the inconvenience of staying on a normal sleep/wake routine more than pays off in benefits for your long-term mental and physical health.


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