Circadian Rhythm Disruption and Depression

Following several recent tragic celebrity deaths, like the beloved Anthony Bourdain, last week I spoke a little about this morose topic with Dan and Maddie during a humanOS trip. An important fact to understand is that the passing of people in this way is worryingly commonplace: Suicide is the second leading cause of death globally among 15- to 29-year-olds. Knowing that I wrote a book chapter on how circadian rhythm disruption is a juncture at the crossroads that link depression with diabetes, Dan suggested that I share some thoughts on whether mistiming of the biological clock contributes to mood disorders. So that’s what I’m doing today.

To be clear, I’m not making inferences about anybody in particular. Nor am I saying that I think that circadian rhythm disruption is at the heart of this matter. But such celebrities frequently engaged in activities (like trans-meridian travel) that are known to propagate biological clockwork breakdown. By the end of this post I hope you’ll recognize some of the many relationships between how well your body’s clock works and how you feel. Most important, I’ll also review a few promising ways of targeting circadian rhythm disruption in dealing with depression.

I overview how the biological clocks in our bodies work in the second humanOS course on circadian rhythms (available to Pro users), so I’ll just briefly outline relevant concepts here.

Our circadian rhythms emerge from systems of biological clocks in all cells in our bodies. Such rhythms optimize our biology and according to time of day and therefore help us anticipate and adapt to predictable changes in the environment, like the rising sun each morning. Most people’s biological clocks are not precisely 24 hours, so these clocks must be reset each day. The main time cue that resets our clocks is the light/dark cycle, which synchronizes a “master clock” in the brain. Damage this clock and the whole timing system desynchronizes, the net result of which is an apparent loss of circadian rhythms in behavior.

The master clock relays information about photoperiod to a brain structure named the pineal gland, where the vast majority of melatonin is synthesized in humans. Light exposure nullifies melatonin synthesis, which is therefore the “hormone of darkness”. As a result, melatonin in blood and saliva is generally scarcely detectable during the day but is much higher at night. Circulating melatonin acts on its receptors in many tissues to convey information about time of day.

In addition to the melatonin rhythm, other rhythms such as cortisol (which should spike sharply in anticipation of waking each morning to ready the body for the day ahead) and core body temperature (which should peak in the mid-afternoon, resulting in peak physical power and strength at this time) are also important in synchronizing the circadian system. Finally, various nutrients seem to be important cues in setting the pace of clocks outside of the master clock, so consistent diet timing keeps your metabolism in order.

So, if you want to keep your clocks ticking at the right speed then your days should be bright and full of enough physical activity and dietary nutrients to nurture good health. Your nights should be dark, restful, and devoid of food. Just think about how your paleolithic ancestors probably lived.

The importance of all this is that a healthy circadian system supports both your ability to be at your best every moment of your waking day, as well as your ability to sleep well at night. Disrupt your biological clocks and you’ll accelerate the demise of your physical and hence psychological health (for more on all of this, check out this review I wrote a couple of years ago). Sorry, I know that’s morbid. But it’s true. Let’s now look at mental health specifically.

If we categorize psychologically healthy people as having ‘normal’ circadian rhythms, people afflicted by depression often have abnormal circadian rhythms. There are surely stark differences between people who have depression, but I’ll note some of the ways in which people with depression generally differ from others.

I’m sure you’ve noticed that you feel better at certain times of day than at others. As a morning person, I feel great shortly after waking, sometimes slip into a lunchtime lull, and become all but useless in the evening. But what about people who have depression?

Using information about time of death to compare the brains of deceased people who did or did not have depression has shown that daily changes in gene expression in various brain regions may be compromised in depression. It’s perhaps little surprise then that people who have depression may have unusual patterns of brain metabolism, as reflected by glucose uptake in their grey matter. And when you consider that it is these unfathomably complex patterns of brain activity from which our mental states emerge, it makes sense that people with depression often experience marked daily variation in mood, the profile of which appears to diverge from non-depressed people.

Other biological rhythms may differ in people with depression too. A study published this year explored physical activity data collected using activity monitors on more than 90,000 people. People with weaker circadian rhythms in physical activity were at higher risk of major depression and bipolar disorder, and they tended to experience greater fluctuations in mood and lower happiness.

It is common for people with depression to have flatter rhythms in core body temperature and cortisol too. In addition, average core body temperature and cortisol tend to be higher in depression. As I detailed in a previous blog, a night-time drop in core body temperature helps people fall asleep and stay asleep. So, raised nighttime core body temperature isn’t conducive to restorative sleep. Cortisol production increases in response to stressors to help us cope with threats to the integrity of our bodies. This is great during the daytime, but a chronic increase in this stress hormone also tends to compromise sleep. As if this wasn’t enough, the daily rise and fall in melatonin production tends to be diminished in depression. Melatonin isn’t really a sleep hormone, but a strong melatonin rhythm does help orchestrate the timing of key players in the symphony of activity that generates sleep.

As you probably know, sleep and mood are highly intertwined in a reciprocal relationship. Sleep loss reliably erodes the capacity to empathise with others and degrades how well people regulate their emotions, predisposing them to irritability, anxiety, and aggression. And especially concerning findings show that poor sleep is associated with thoughts about suicide, attempts at suicide, and ultimately suicide itself.

In turn, sleep problems are pervasive in mood disorders: As many as 90% of people with depression report sleep problems, such as insomnia and frustratingly early awakenings. The structure of the sleep stages that people with depression pass through also tends to deviate from people without this disorder.

You’ve probably noticed that your sleep timing fluctuates during the year – perhaps you sleep more in the winter and find yourself getting up earlier in the summer. This suggests that circadian rhythms are nested within seasonal changes in biology and raises questions about whether depression severity might vary according to time of year. I bet you know what’s coming next…

Many people don’t suffer from depression year-round. Instead, seasonal transitions may coincide with substantial changes in mood, a phenomenon known as seasonal affective disorder. Most commonly, with short days and long nights of winter comes worsened wellbeing, and the further north of the equator that people live, the more rampant seasonal affective disorder becomes. Scientists understand this disorder less well than you might expect, but I’ll note that a delay in circadian timing is common among people with seasonal affective disorder.

If mood disorders and circadian rhythm disruption go hand-in-hand, might the circadian system be a target in helping people suffering from pathologies like depression?

Interestingly, many medications commonly used to treat mood disorders appear to affect the circadian clock. These include monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (used to counter depression), as well as lithium (used to curb bipolar disorder).

Some of these drugs often result in side-effects concerning enough to deter people who have depression from taking them. But not all drugs are like this.

Melatonin has a remarkable safety profile and can be very helpful in helping people synchronize their circadian systems to the 24-hour day in circumstances such as jetlag and a rare disorder called non-24-hour sleep-wake disorder. Melatonin doesn’t seem to have antidepressant effects in humans though… but what about related compounds?

One exceptionally interesting drug is an analogue of melatonin named agomelatine (brand names Melitor, Thymanax, and Valdoxan). The structure of agomelatine is similar to melatonin, as is its safety profile. Melatonin almost exclusively binds to melatonin receptors. Agomelatine, however, also binds to two serotonin receptors (5-HT2B and 5-HT2C), blocking the interaction of serotonin with these targets. Serotonin is a neuromodulator that acts on a remarkably large variety of receptors (there are seven families of serotonin receptors) resulting in nuanced roles in things like appetite, mood, sexual function, and sleep. As a result of its unique pharmacology, agomelatine seems to be a very promising antidepressant, and it also reliably reduces anxiety.

Light exposure primarily sets the pace of the master clock and shapes the melatonin rhythm. Intelligent use of bright light therapy during the daytime tends to improve mood in people with seasonal affective disorder, and some people with major depression may benefit from light therapy too. Exactly how to use light depends on the person, and the duration, intensity, timing, and wavelength of light are all relevant. Check out the fourth circadian course for more on this.The course also outlines how to best eat and exercise to keep your clocks on time.

This post is only a taste of the buffet of research on this topic, but I hope that it clarifies that your body’s clock is a key determinant of your psychological wellbeing. We need far more research on circadian rhythm disruption and mood, and it will be valuable to study people who regularly experience disruptions to their bodies’ clocks (flight attendants, shift workers and their families, and so on). Although the subject is in its infancy, it seems that even the kind of minor, regular circadian rhythm disruption that many of us regularly experience may associate with risk of developing depression, so it’s probable that this is something that we should all consider. Depression is rife, and it’s about time people wake up to the importance of biological timekeeping in curbing this most crippling condition.

1) People who have depression often have abnormal circadian rhythms.

2) Strategies to enhance circadian system function may be useful adjuncts to depression treatments.

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