Sleep Basics: Melatonin

Melatonin is a hormone produced by the pineal gland from the precursor, serotonin. During daylight hours, serotonin is stored and is unavailable for use. As darkness sets in, an enzyme is activated which converts serotonin to melatonin. Through its changing concentration (high at night and low during the day), melatonin plays a significant role in the human circadian rhythm.

After synthesis, melatonin is released into the blood stream and cerebrospinal fluid, where it acts on receptors found in many different targets in the human body including the suprachiasmatic nucleus (SCN) in the hypothalamus. In the SCN, melatonin inhibits the firing of certain neurons, which may contribute to it’s sleep-promoting effects.

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Melatonin is produced by the pineal gland (red) and acts on the suprachiasmatic nucleus (green). Image here.

A few things we know about melatonin:

  1. Melatonin secretion starts when human infants are 3-4 months of age. This is the same time infants begin sleeping through the night.
  2. Nocturnal melatonin production decreases over the human lifespan. Peak concentrations in 70 year olds are only 25% of the peak concentrations in younger adults and may contribute to sleep difficulties in older adults. (Fun fact: this decrease may be related to the calcification of the pineal gland with time. Calcification = decreased synthetic capability = less melatonin).
  3. Certain substances (i.e. caffeine and ethanol) can lead to decreases in melatonin concentrations. (Recommendations on caffeine and ethanol intake can be found here).
  4. Very dim light (i.e. 100-200 lux) such as that from the darkest of overcast days or from light-emitting devices (i.e. iPhones) can suppress melatonin production and can lead to feeling less sleepy before bed, increased time to fall asleep, and increased grogginess the next morning 1.

As an over-the-counter supplement, melatonin has an indication for treatment of age-associated insomnia (such as elderly people with decreased melatonin production), jet lag, and shift work. Its primary efficacy is for sleep-initiation and has not been show to have significant effects on sleep-maintenance or early morning awakening 2.

We know that melatonin receptors are highly sensitive to desensitization and that supraphysiologic doses of melatonin may lead to this. As such, optimal dosing of melatonin has not been clearly established. Anecdotally, I have had neurologists and psychiatrists recommend a starting dose of 3mg (such as from this preparation), however from my reading and literature review it seems that lower doses may be preferable. UpToDate, a widely trusted medical resource, recommends starting doses as low as 0.3mg, whereas the European Food Safety Authority recommends that “in order to obtain the claimed effect, 1 mg of melatonin should be consumed close to bedtime”3.

The take home? Melatonin is relativey safe, has few to no addictive properties, and has an indication for sleep-onset insomnia. If you have trouble falling asleep, it is reasonable to try a melatonin supplement with a starting dose of 1 mg. LabDoor provides rankings of the top 10 melatonin supplements, and as I have heard from other physicians, the Nature Made brand ranks near the top for product purity and ingredient safety. What do I take? I buy the 3mg Nature Made brand, break it in half, take it 30 minutes before bedtime, and it helps me fall asleep.

Inflammation, Depression, and … Statins?

There are multiple theories regarding the pathophysiology of depression. The most common (and the one you’ve probably heard about) is the monoamine hypothesis. This theory posits that depression is an imbalance (or depletion) of certain key neurotransmitters in the brain. The imbalance of these key neurotransmitters, namely dopamine, serotonin, and norepinephrine, is believed to cause depression. As such, most common antidepressants fit into classes that limit the uptake and/or breakdown of serotonin (SSRIs), serotonin and norepinephrine (SNRIs and TCAs), or serotonin, norepinephrine, and dopamine (MAOIs).

Today, we’re interested in a different hypothesis involving inflammatory proteins called cytokines. Cytokines are increased within our body when we are having an immune response and with inflammation in general. In patients with depression, certain cytokines have been found to be elevated before treatment (associated with a pro-inflammatory state) and decreased after treatment 1. This implies that cytokines and other inflammatory molecules may cause a pro-inflammatory state that causes our brain to be “inflamed,” thus causing depression. If there were a way to decrease inflammation in our body, perhaps depressive symptoms would improve as well.

On to statins. Statins (think Lipitor, Crestor) are commonly prescribed to treat high cholesterol. Incidentally, they are also believed to have anti-inflammatory properties. This is believed to be the reason why statins decrease the risk for stroke and heart attack independent of their cholesterol lowering effect.

A recent study in Denmark followed 872,216 SSRI users (of whom 113,108 (13.0%) used a statin concomitantly) over the course of 15 years 2. It found that patients who took SSRIs while on a statin had fewer depression-related hospital visits and depression-related hospitalizations. As such, the article concluded that “concomitant treatment with SSRIs and statins resulted in robust advantages compared with SSRIs alone.”

So does this prove the cytokine hypothesis of depression? Should you be taking a statin if you’re depressed? Not quite. Statins are not benign drugs, and the evidence isn’t there yet to recommend augmenting antidepressant treatment with a statin. Regardless, this study represents one more step in the right direction. Here’s to eventually finding a cure (and a satisfying explanation) for the millions of people worldwide who are afflicted with depression.

References:
  1. Cytokines and Depression
  2. Statins and Depression