The neurotransmitter serotonin has been at the center of depression research for decades, and SSRIs (selective serotonin reuptake inhibitor) are often the first drug to be tried for someone with depression.

Antidepressants are one of the most prescribed medications in the US, and their use has been risen quite a bit, especially in women, over the last decade.  Overall, the percentage of adults on antidepressants has risen 50% in the last 15 years.

Figure from the CDC showing the increase in antidepressant usage in the US since 1999.

Almost 25% of women over the age of 60 are now on antidepressants!

The questions that come to mind are: 1)  why are depression levels are on the rise, and  2) why are older people more susceptible?

Recent studies point to a fundamental environmental cause of depression that is often overlooked: disruption of the circadian rhythm.

Many core circadian clock gene mutations have been implicated in depression. Looking at which genetic mutations cause the disease is one way that researchers find the underlying cause. In the case of depression, it is clear that for a percentage of patients that the genetic susceptibility lies within the circadian system.  To create an animal model of depression, scientists can disrupt the animal's circadian rhythm.

Coming back to SSRI's and other antidepressants, many of these drugs change the user's circadian rhythm.

Back to my questions of 1) why is depression on the rise and 2) why are older people more susceptible:

1) A huge environmental change that we've seen over the past two decades is the ever-increasing amount of blue light that we are exposed to at night.  Blue light at night disrupts our circadian rhythm. Prior to electrical lights, humans were never exposed to the blue wavelengths except during the day. Incandescent light bulbs, from the early 1900s through the 1990s added just a little blue light to our nights. But the amount of blue light at night exploded with LED/CFL bulbs as well as laptops, tablets, smartphones, and TVs. Welcome to the 2000s.

2) As we age, our circadian rhythm is no longer as robust. Part of this is due to the formation of cataracts, filtering out our body's natural response to sunlight. And part is due to the aging of the brain, poor sleep quality, and a number of other factors. (study)

If the core circadian rhythm is at the root of depression for a lot of people, what can be done to cure it?

Bright light during the day has been shown to be a surprisingly simple, non-pharmacological way to increase serotonin levels.

A 2011 placebo-controlled randomized clinical trial investigated using bright light therapy for mild non-seasonal depression in adults aged 60 or older.  The study participants used bright light (7500 lux) that was 'pale blue' for one hour each morning for three weeks, while the control group was exposed to 50 lux of red light for an hour each morning. The results showed that exposure to bright light in the morning improved mood and sleep quality, while also increasing melatonin levels at night (81%) and decreasing cortisol levels at night (37%).  The effects lasted for another three weeks after the trial concluded.(study)

Bright light therapy also has been shown to work in adolescents. A trial using 2,500 lux of light in the morning for 1 week resulted in lower depression index scores for the patients. There was also an increase in melatonin levels at night and a decrease in melatonin during the morning. (study)

The American Psychiatric Association has listed bright light therapy as a first line treatment for both mild depression and seasonal depression since 2005.(study)

Seasonal affective disorder, or depression during the winter months, has long been treated very effectively with bright light therapy.(study)

Studies of brain levels of neurotransmitters are notoriously hard to do in living humans.  One study of over 100 men used blood samples from internal jugular veins to determine the concentration of serotonin metabolites. The study found that the "the rate of production of serotonin by the brain was directly related to the prevailing duration of bright sunlight (r=0.294, p=0.010), and rose rapidly with increased luminosity."(study) Another study used positron emission tomography to analyze the effect of light therapy on serotonin transporter binding. The results showed that light therapy in the winter specifically increased the amount of free serotonin.

Animal studies of brain levels of serotonin show that it both follows a circadian pattern and is regulated by light. Serotonin levels increase when light increases. (study)

So what exactly is happen when light hits your eye? (not like a big pizza pie, that's amore!)

In the retina, there are photoreceptors that form images (the rods and cones) and non-image forming receptors. Both image forming and non-image forming photoreceptors involve a photon (from light) exciting a pigment in the retina that then transmits a signal to the brain. One part of the brain that directly receives signals from the non-image forming photoreceptors is the suprachiasmatic nucleus, located in the hypothalamus and responsible for setting the core circadian rhythm. Another part of the brain, the dorsal raphe nucleus, has recently been shown to be directly impacted by light signaling through the image forming photoreceptors. This is important here because the dorsal raphe nucleus is where most of the serotonin in the brain is produced. (study)(study)  Both of these systems are thought to be involved in the effect of light on the increase in serotonin levels in the brain. (study)

Antidepressants are changing your circadian clock...

One thing that I found extremely interesting when previously looking into mood disorders and circadian clock disruption: a lot of antidepressants, including Celexa, Prozac, Paxil, and Zoloft, work by influencing your circadian rhythm. (study)(study)

Citalopram (Celexa) is an SSRI that increases the sensitivity of the circadian rhythm to light. A double-blind, placebo-controlled, within-subjects crossover trial found that melatonin suppression in the daylight (when it is supposed to be suppressed!) was increased by 47% when taking citalopram. Basically, it is making people happier by suppressing melatonin at the levels of indoor lighting (100 lux). (study)  This brings us back around to the idea that not only are we getting too much artificial light at night in this modern era, but we are also not getting outside as much in the daytime to get the full effect of daylight on our circadian system.

Fluoxetine (Prozac) is an SSRI that advances the phase of the core circadian clock, but only if there is enough serotonin available. (study) In an animal study using fluoxetine, researchers found that the circadian period was longer in treated animals than in control. The study concludes, "We here provide first evidence that fluoxetine treatment normalizes disrupted circadian rhythms and altered hippocampal clock gene expression in a genetic animal model of high trait anxiety and depression." (study)

Paroxetine (Paxil) is another SSRI linked to circadian changes. (study) It has been found to help with sleep problems in cancer patients. (study) Animal and cell culture studies show that paroxetine, as well as Celexa, Prozac, and Zoloft, all change the circadian oscillation of the core circadian clock genes. (study)

Agomelatine is a newer antidepressant that is on the market in Europe and Australia (but not in the US) for major depressive disorder. It is a melatonin receptor agonist and a serotonin receptor antagonist, so it is directly acting on the circadian system. A recent meta-analysis of antidepressants found that agomelatine ranked highly as 'more effective' and 'more tolerable'. (study)

Summary:
1) The research is clear that depression and circadian rhythm disruption go hand-in-hand.

2) Blocking blue light at night is half of the equation.

3) Getting lots of light during the day is the other half of the equation.

Action steps:

  • Studies on depression usually use bright light (7500 lux or brighter) for 30 minutes to an hour, first thing in the morning.
  • There are light boxes made for seasonal affective disorder that you can use.
  • There are light therapy lamps as well that are a little more stylish.
  • The obvious, FREE option is to go outside as soon as the sun comes up. Drink your coffee on your deck, walk to work, etc.

Common sense disclaimer:  This information is provided here is based on research studies and is for informational and educational purposes. Don't put off seeing a medical professional if you need medical help with depression.