Rhythm and Blues: The Curious Case of Circadian Rhythms and Bipolar Disorder

By: Jessica Scott
Images by Jessica Scott

head clockWhen an activity or skill is second nature to someone, they might say confidently, “I could do it in my sleep!” Sleeping is the embodiment of comfort, rest, and routine for most people. Our internal biological clocks – known as circadian rhythms – silently direct the forces that make it possible for us to drift off or rise to face the new day. But for many people suffering from bipolar disorder, circadian rhythm imbalance may contribute to irregular sleep patterns and even to mood instability.

Bipolar disorder is a cyclical disorder. Patients experience phases of intense excitability or irritability known as manic phases, which cycle with depressive phases, periods of time in which sufferers experience depressed mood and low energy. In addition to abnormal mood cycling, people with bipolar disorder often find that their sleep cycle is mysteriously disrupted. They may sleep much less during manic phases and much more during depressive phases. What’s even more curious? At the heart of the story is the metal lithium, a common treatment for bipolar disorder.

Scientists don’t fully understand how bipolar disorder works, or how lithium works to treat it. The cool thing about that is that it presents researchers with a unique opportunity to work backwards! Instead of trying to sort out the many different root causes of bipolar disorder – genetic, environmental, life experiences – they can alternatively study how the treatment works in order to find the disease mechanism. In the case of lithium, scientists know that, somehow, it is able to steady the wayward cycles that characterize bipolar disorder.

In order to understand how lithium might affect the circadian clock, we need to understand a little about how the circadian clock actually works on a molecular level. At the center, controlling the cycles and rhythms of all the other components of the clock, are two proteins, BMAL and CLOCK. Ultimately, BMAL and CLOCK control the length of a day in your body (they are helped out by natural light). These proteins function as a unit – they can’t do their jobs if they’re apart. BMAL and CLOCK, like any good leaders, listen to their constituents. In the circadian world, this means that other proteins in the molecular clock can interact with and change the behavior of BMAL and CLOCK.

One particular protein, called Rev-erb, is especially important in this regard. BMAL and CLOCK, as the leaders of the cycle, provide the system with instructions to make more Rev-erb. In turn, Rev-erb provides the system with instructions to make less BMAL and CLOCK. To simplify, we’ll say that BMAL/CLOCK turn Rev-erb on and Rev-erb turns BMAL/CLOCK off. This is what we call a feedback loop.

You can think of this feedback system like the heating system in your house. In a home heating system, when the temperature drops below your thermostat setting, the heat turns on. Once the temperature reaches the set point, the heat sensor prevents the heat from running until the house cools back down a little. In our system, BMAL and CLOCK are like the heat and Rev-erb is like the heat sensor. When there is too much BMAL and CLOCK in the system, Rev-erb is activated and prevents more BMAL and CLOCK from being made. Like heat in a house, proteins don’t last forever, so eventually the supply of BMAL/CLOCK is depleted and Rev-erb stops blocking BMAL/CLOCK production. And instead of cycling between a heater being turned on and off, the BMAL/CLOCK/Rev-erb feedback loop provides your body with a pattern for sleeping and waking, and for other important things like neural activity and metabolism.

BMAL and CLOCK turn on Rev-erb, and Rev-erb turns off BMAL and CLOCK. This is called a feedback loop and creates cycling protein levels which contribute to your circadian rhythms.

BMAL and CLOCK turn on Rev-erb, and Rev-erb turns off BMAL and CLOCK. This is called a feedback loop and creates cycling protein levels which contribute to your circadian rhythms.

So here’s where it gets interesting. In 2006, a group of researchers in Pennsylvania discovered that yet another protein, called GSK3-beta, can help turn Rev-erb on. Coincidentally, researchers have known for a long time that lithium, the first effective treatment for bipolar disorder, inhibits GSK3-beta.  Thus, the group in Pennsylvania was able to develop a new understanding of the circadian clock, where lithium is inhibiting Rev-erb by inhibiting GSK3-beta. This means that BMAL and CLOCK are more active, and somehow this stabilizes the out-of-control circadian cycling. In short, it appears that lithium may be an effective treatment for bipolar disorder at least in part by restoring regular circadian rhythms to the body.

GSK3-beta turns Rev-erb on, and Lithium turns GSK3-beta off. The upshot of this is that Rev-erb is less active and BMAL/CLOCK is more active. In many patients this appears to normalize circadian rhythms.

GSK3-beta turns Rev-erb on, and Lithium turns GSK3-beta off. The upshot of this is that Rev-erb is less active and BMAL/CLOCK is more active. In many patients this appears to normalize circadian rhythms.

Although lithium was a breakthrough medication and continues to be extremely effective for many people, it isn’t a solution for everyone. It cannot be used by women who are pregnant or breastfeeding, and it can cause unpleasant side effects for some people. Understanding how lithium works could lead to better or more specific medications down the road. For instance, knowing that GSK3-beta targets Rev-erb opens an avenue for developing a new medication that specifically targets Rev-erb. Maybe this hypothetical new drug would have fewer side effects or be safer for more people.

Of course, this isn’t the whole story. Even though we know that lithium targets GSK3-beta, we also know lithium isn’t very specific – it targets a number of other molecules in the body as well. Even GSK3-beta isn’t very specific – it has effects not only on circadian rhythms, but also on growth and development and metabolism. So while Rev-erb might be one piece of the puzzle, it’s probably not the only piece. This is why researchers continue to study every little part of each little pathway. We are constantly learning more about how the body works at a molecular and cellular level… and even on a larger scale. The road to understanding bipolar disorder or any mental illness will be a long one, and it will take many scientists and physicians and patients, all with different ideas and questions and points of view, to get there.

Editor’s note: In order to make the science accessible to everyone, we tried to explain the molecular pathways in the simplest possible terms. This means we lost some of the intricacies that our fellow molecular biologists (and others) may be interested in. For instance, Rev-erb does not directly “turn off” BMAL/CLOCK; it is an orphan nuclear receptor which acts as a transcription factor. Furthermore, there are different subtypes of Rev-erb; the beta-subtype is actually a transcriptional activator rather than a repressor. (Aren’t you glad the entire post wasn’t like this?) If you’re interested in wrestling with the details, check out the links within the post, leave a comment, send us an email (science.aces15@gmail.com) or tweet at us (@scienceaces).

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