Bipolar disorder, depression, and circadian clock genes

Depression and bipolar disorder are often thought of as being caused by a lack of neurotransmitters. Many of us first learned about neurotransmitters by watching TV commercials for SSRI’s like the ones for Zoloft – watching the little round balls of neurotransmitters moving from nerve A to nerve B.

It turns out that depression and bipolar disorder may be more complicated than that Zoloft commercial leads us to believe.

New research shows that depression and bipolar disorder are linked with changes or disruption in circadian genes. And genetic variants in the circadian clock genes can increase your susceptibility to mood disorders.

This article will dig into those connections and give examples of just some of the many genetic variants in circadian genes that influence the risk of depression or bipolar disorder.

What causes depression and bipolar disorder?

First, a couple of quick facts to set the stage:

  • Major depressive disorder is defined as depression lasting more than a couple of weeks that affects a persons ability to function normally (e.g. loss of concentration, thoughts of death, problems sleeping). This affects about 16.2 million adults in the US (2016 data).[ref]
  • Bipolar disorder affects 1-3% of the US population.[ref]  This mood disorder involves episodes of manic highs and periods of depressive lows.

What is ‘circadian rhythm’:

Your circadian rhythm is the 24 hour cycle of changes that goes on in your body.  The first thing that comes to mind for most is the sleep/wake cycle.  In general, humans are diurnal and are active during the day and sleep at night. Other examples of your circadian rhythm include the fluctuation of body temperature, cortisol, melatonin production, etc over the course of the day.

In fact, a lot of the proteins and enzymes that your body makes fluctuate over the course of 24 hours. For example, you don’t need to produce lactase at night when you are sleeping since you don’t drink or eat dairy while you are asleep. This is true for a lot of processes in the body — some need to occur while you are awake and active, and others need to occur when you are asleep.

Messing with your circadian rhythm has severe consequences on long-term health and mental well-being.  If you’ve traveled long distances, think back to the first time you experienced jet lag. I bet you felt awful – like being hit by a train. Mentally foggy, physically drained and slightly ill, and your mood was probably pretty crappy. Now think of doing this on a regular (but smaller) basis, and you can imagine how important circadian rhythm can be to physical and mental health.

Investigating the root cause:

One way that researcher dig into the root causes any disease or disorder is to look at the genetic variants that are found more often in people with the disease. Sometimes this is through sequencing specific variants to see if they are more common in patients. Othertimes they look at huge amounts of genetic data for a large population compared with a patient group. This genome-wide approach gives researchers a lot of clues towards the various genes that affect a disease or disorder.

Genes that increase the probability of a disease clearly point toward the mechanisms or pathways involved in the disease. In the case of mood disorders such as depression and bipolar disorder, there are quite a few genes involved in the core circadian clock that are statistically linked to these mood disorders. [ref]

One question that genetic studies can help answer is cause vs. effect.  It has long been known that sleep problems and circadian disruption are hallmarks of bipolar and depressive disorders. But it wasn’t known if the circadian disruption caused mood disorders or if the mood disorders caused the circadian disruption.

The studies showing that the genetic variants that cause changes to the circadian clock also significantly increase the risk of depression answer the cause vs. effect question. This clearly shows that disrupting the circadian clock can cause bipolar disease and depression.

But let me make clear:  It is one of the causes. There are other causes of depression – and other genetic pathways that researchers have found.  Knowing where your susceptibility lies can help you to understand which solutions may work best for you.

Clock genes and mood disorders:

Studies show that bipolar disorder is linked to a shifted circadian phase and a peak of melatonin production later in the night. Along with shifted circadian gene expression, people with bipolar disorder also are more likely to have “irregularity of social rhythms, sleep/wake and activity patterns, and disruptions of social rhythms by life events”. [ref]

There are many animal studies that show that disrupting circadian rhythm causes depression and bipolar symptoms. A mouse model of bipolar disorder is created by a mutation in the CLOCK gene.  And mouse experiments show that light at night, even dim light, is enough to cause changes to circadian rhythm and induce depressive symptoms. [ref][ref][ref][ref]

Human population studies also clearly show that bipolar disorder is both highly heritable, which shows that it is highly influenced by genetics, and that it is related to circadian disruption. [ref]

Antidepressants and Circadian Clock Genes:

A lot of antidepressant prescription medications (both SSRI’s and tricyclic antidepressants) modify core circadian clock gene expression. [ref](There are a bunch of studies on this — I’ve listed some of them in the “more to read” section at the end.)

Am I saying that depression or bipolar disorder is always caused by a disruption in the circadian clock system?  No… Just that this can be a foundational part of these disorders for a large number of people. There are always exceptions, and that is where knowing your genetic variants comes into play.

Carrying the genetic variants associated with mood disorders doesn’t mean that you will have that disorder or get the disorder. It’s all just statistics and probabilities.

For most, mood disorders are a combo of genetic susceptibility and environmental factors (food, toxins, micronutrients, lifestyle, etc.).

If you carry some of the genetic variants below that are part of the core circadian clock system, then one of the environmental factors influencing you is, most likely, the activities and lifestyle choices that disrupt circadian rhythm. And this is something that you can modify through simple changes in lifestyle.

This isn’t a million-dollar miracle pill. Instead, it is free, powerful information that can change the quality of your life.


Clock gene variants related to depression and bipolar disorder:

Below is a sampling of genetic variants in circadian clock genes associated with bipolar disorder or depression. There are quite a few more variants that are not covered in 23andMe data.

PER3 gene:
The period genes (PER1, PER2, and PER3) are involved in the negative arm of the molecular circadian clock. These genes are expressed more in diurnal animals during the night hours.

Check your genetic data for rs707467 (23andMe v5 ):

  • C/C: increased risk of bipolar disorder [ref]
  • A/C: increased risk of bipolar disorder
  • A/A: normal

Check your genetic data for rs139315125 (23andMe v5):

  • A/A: normal
  • A/G: increased risk of depression, delayed sleep disorder[ref]
  • G/G: increased risk of depression, delayed sleep disorder

PER2 gene:

Check your genetic data for  rs4663868 (23andMe v4):

  • T/T: increased risk of bipolar disorder [ref]
  • C/T: increased risk of bipolar disorder
  • C/C: normal risk of bipolar disorder

CRY2 gene:
This gene is part of the ‘negative’ arm of the core circadian clock. Lower levels of CRY2 are found in people with seasonal depression and bipolar disorder.[ref]

Check your genetic data for rs3824872 (23andMe v4; AncestryDNA):

  • A/A: decreased risk of persistent mild depression [ref]
  • A/C: normal risk of depression
  • C/C: normal risk of depression

NPAS2 gene:
Analogous to the CLOCK gene (below), this gene is involved in the maintenance of the core molecular circadian clock in mammals.

Check your genetic data for rs11123857 (23andMe v4; AncestryDNA):

  • A/A: normal
  • A/G: slightly increased risk for bipolar disorder, depression
  • G/G: increased risk for bipolar disorder, depression[ref]

Check your genetic data for 23andMe data for rs13025524 (v4 only):

  • G/G: normal
  • A/G: slightly increased risk for bipolar disorder, depression
  • A/A: increased risk for bipolar disorder, depression[ref]

CLOCK gene:
Part of the core circadian clock, the CLOCK gene has several variants that are tied to depression and bipolar disorder.

Check your genetic data for rs1801260 (23andMe v4, v5; AncestryDNA):

  • G/G: increased frequency of manic episodes in bipolar disorder [ref][ref], increased evening preference (may or may not increase depression risk)[ref]
  • A/G: increased frequency of manic episodes in bipolar disorder,
  • A/A: normal

NR1D1 gene:
Also known as Rev-ErbA, this is a transcriptional regulator involved in both the core circadian clock and peripheral circadian rhythms (liver, skeletal muscles).

Check your genetic data for rs2314339 (23andMe v4, v5; AncestryDNA):

  • T/T: decrease risk of bipolar disorder
  • C/T: decreased risk of bipolar disorder
  • C/C: normal risk of bipolar [ref]

GNB3 gene:
Guanine nucleotide binding protein (GNB3) is a component of intracellular signaling and is expressed in the pituitary gland with a circadian rhythm.[ref]

Check your genetic data for rs5443 C825T (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of depression (more so in Asian populations)[ref]
  • C/T: slightly increased risk for depression
  • C/C: normal depression risk, significantly increased response to Zoloft[ref]

Lifehacks:

Before I even get started here, let me recommend that if you are under the care of a physician or psychiatrist for a mood disorder, you should always talk to your doctor before making any changes.  Like I mentioned in the intro to this article, many antidepressants work through modifying your circadian clock, so please consider these seemingly simple lifehacks in the same context as trying an antidepressant drug. 

The two biggest lifestyle factors for setting circadian rhythm are the timing of light exposure and the timing of eating. These are both considered ‘zeitgebers’ or ways of entraining the molecular circadian clock.

Light:

Light is foundational to your body’s circadian rhythm. For all of human history, the sun came up in the morning and set at night. Modern electrical lighting is messing with our circadian system. While we are resilient beings, chronic exposure to light at night is decreasing melatonin levels and disturbing our molecular clock.

Specifically, our eyes contain a photoreceptor that is sensitive to light in the blue spectrum (around 480 nm). Light in this wavelength causes signals from the retina to our brain, saying that it is daytime. All fine and dandy until the advent of color TV’s, laptops, smartphones, and LED / CFL / fluorescent light bulbs.  (The old-fashioned light bulbs that were yellowish in color didn’t emit much light in the blue spectrum.)

Two things are necessary to get your circadian system back in sync using lighting:

  1. Eliminate blue light at night while decreasing overall illumination.
  2. Get more light during the day, especially in the morning.
Eliminating blue light at night:

Blocking out blue wavelengths at night is the modern answer to our modern problem. There are lots of options for blue blocking glasses available these days if you are going to be exposed to blue light at night. You want ones that block 100% of blue light (orange or amber lenses) Wear the blue-blocking glasses for a couple of hours before bed each night.

Alternatively, if you don’t use electronics in the evening (TV, laptop, backlit eReader, phone), you could just turn off the overhead lights and light your home with lamps that use old-fashioned yellow light bulbs.

More light during the day:

The other half of the lighting equation is to increase your exposure to light during the day, especially first thing in the morning. This shuts down melatonin production and resets your clock for the day. Getting outside is the easiest way to do this. Take your coffee out on the deck each morning. Take a walk. Perhaps bike or walk to work. If you work in an office, sit as close as you can to the window during the day.

If you live in the northern latitudes, you may want to look into light therapy boxes for increased light exposure in the winter time.

Sleep is incredibly important:

Getting your circadian rhythm on track through optimizing lighting should improve your sleep quality. It is important to stay on a fairly regular sleep schedule. While the occasional delay in going to bed probably won’t hurt much (we are resilient, remember), the chronic lack of sleep is a definite problem for mood disorders. Get into a solid routine of blue-blocking glasses for a couple of hours, then go to sleep at a time that is 8 hours before you need to get up.  If you get up at 7 am, go to bed by 11 pm.  You can do the math…

Timing of eating:

I think we all understand that the quality of what we eat matters to our mood and overall health. Junk food is just not the way to go for good mental health.

It turns out that “when” we eat also matters a great deal.

Our organs have their own circadian clock systems that sync with our core circadian clock.[ref] So the other half of the circadian optimization equation is to eat when your body is best prepared for food – which is during the daytime. Your body is most insulin sensitive in the morning, and studies show that eating later in the evening or during the night is a mismatch to your circadian timing leading to insulin resistance. [ref][ref]

A simple rule would be to eat on a fairly consistent schedule and during the daylight. Everyone’s daily routine is different, but an example would be to eat breakfast each morning around 7:30 pm and finish with dinner by 6:30 pm. Stop snacking at night…

Depression, weight problems, and diabetes (or pre-diabetes) all go hand in hand. Restricting your eating ‘window’ to 10-12 hours and not eating at night is associated with gradual weight loss without needing to diet. [ref] [ref]

Fasting:
Several studies have found that fasting decreases depressive symptoms for some people.[ref] Most studies show that mood improved between days 2 and 7 of fasting.[ref]

One caveat here is that carriers of the rs5443 T/T genotype were found to have increased hunger and worsened mood during an 8 day medical fast (<350 kcal/day).[ref]

Conclusion and Challenge:

Yes, I have just told you that you need to go to bed on time and eat on a regular schedule. I know that this doesn’t sound like earth-shattering advice. If I had read this somewhere on a blog, I would probably just shrug it off and look for other information on a magical supplement or special super-duper diet.

But the science behind getting your circadian rhythm back on track is overwhelming.

So I challenge you: Give it a try for a solid two weeks. 

It won’t cost you much to get some blue blocking glasses or some Edison bulbs for your lamp. Timing your meals and a routine bedtime doesn’t cost you anything, but the benefits of getting your circadian clock genes in sync are priceless.

Why two weeks? It takes at least a week for the body to adjust the expression of the circadian clock genes. This is one reason that doctors have depressed patients try an antidepressant for several weeks…  turns out that many antidepressants work by modifying circadian gene expression.

More studies to read:

Chronic citalopram treatment ameliorates depressive behavior associated with light at night. — Light experiments on animals (light at night, dim light during the day) causes depressive-like behaviors. This study showing that the SSRI Celexa (citalopram) specifically works on the depression caused by dim light at night, but not on other depressive models.

The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose. A human study showing that Celexa increases the “sensitivity of the circadian system to light”.

Evening types demonstrate reduced SSRI treatment efficacy. “Selective serotonin reuptake inhibitors (SSRIs) have a profound effect on the circadian system’s response to environmental light, which may impact treatment outcomes for patients depending on their habitual light exposure patterns.”

Effects of Restricted Time in Bed on Antidepressant Treatment Response: A Randomized Controlled Trial. Study using Prozac and different sleep quantities and timing over an 8-week trial. The conclusion was that 8 hours ‘time in bed’ was more effective than shorter sleep times that pushed patients to sleep earlier or later.

Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response. A big study by 23andMe on Zyban (SSRI) efficacy found a genetic variant involved in circadian rhythm pathways.

Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior.  An animal study on how Prozac changes (lengthens) the circadian period.

Serotonin suppresses food anticipatory activity and synchronizes the food-entrainable oscillator during time-restricted feeding. Another animal study that used an SSRI, different feeding schedules, and different lighting schedules to find out how serotonin affects circadian clocks.

Aberrant light directly impairs mood and learning through melanopsin-expressing neurons.

Chronic unpredictable stress induces a reversible change of PER2 rhythm in the suprachiasmatic nucleus. To create an animal model of depression, researchers can use ‘chronic unpredictable stress’. This then causes a reduction in the amount of one of the core circadian clock genes (PER2). Researchers were able to reverse this reduction (and the depression) by using a tricyclic antidepressant.

Time of Administration of Acute or Chronic Doses of Imipramine Affects its Antidepressant Action in Rats. This animal study found that the timing of taking the tricyclic antidepressant Tofranil matter a lot as far as its effectiveness.

Prospective, Open Trial of Adjunctive Triple Chronotherapy for the Acute Treatment of Depression in Adolescent Inpatients.  This is one of several studies on humans using ‘triple chronotherapy’ for the remission of depression and bipolar disorder. In this study, 84% of the teens with moderate to severe depression were in remission for 1+ month after treatment. The treatment consists of resetting the circadian clock through one night of sleep deprivation and then three nights of controlled sleep timing and bright morning lighting.

Adjunctive Triple Chronotherapy (Combined Total Sleep Deprivation, Sleep Phase Advance, and Bright Light Therapy) Rapidly Improves Mood and Suicidality in Suicidal Depressed Inpatients: An Open Label Pilot Study  Another study on using triple chronotherapy for suicidal patients who had been committed to a psychiatric hospital. This study showed a 60% remission rate, which is pretty darn impressive.

Related articles:

Early to bed, early to rise – helps with weight loss and diabetes

Genetics of Seasonal Affective Disorder



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2 Comments on “Bipolar disorder, depression, and circadian clock genes

  1. When I check “PER3 gene: The period genes (PER1, PER2, and PER3) are involved in the negative arm of the molecular circadian clock. These genes are expressed more in diurnal animals during the night hours” against my 23 and me raw data, my genotype is expressed as A/C. How is that possible if the nitrogenous bases are G or T?

    • Hi Dana,
      Thanks so much for your comment. Normally, I list the alleles in the plus orientation, to match with 23andMe. But in this case, I missed noticing that the study referred to the bases in the minus orientation. (A = T and C = G). Thanks for letting me know. I’ll get it fixed so that everything matches with 23andMe.
      Debbie

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