Lithium, Circadian Clocks and Bipolar Disorder

Lithium, Circadian Clocks and Bipolar Disorder
I have previously only touched on the immensely interesting topic of the possible connection between circadian clocks and the Bipolar Disorder. A recent paper prompted me to look into this in a little more detail.

Lithium Affects the Circadian Clock

First, let's go a little bit into the past, the early history of chronobiology. During the 1940s and 1950s, while the field was still in its pioneering spirit and little was known about the circadian clocks, many researchers were using survey (or shot-gun) approaches to the studies of biological rhythms: studying as many organisms as they could get their hands on in order to come up with generalities and evolutionary answers, surgically removing every possible organ or brain region in order to find locations of clocks in various organisms, exposing the organisms to every possible light regimen imaginable in order to study the oscillatory properties of biological clocks, etc.

One of the approaches was to administer to animals every chemical one could find on the lab-shelf to see how it affects the circadian rhythms. This line of work yielded a big surprise - biological clocks are amazingly resistant to pharmacological agents. The few substances that had an effect were hormone melatonin (naturally, as it is the main signaling molecule of the circadian system), heavy water (deuterium oxide) and lithium (a few others were found much later, including sex steroid hormones). Lithium had the same effect - slowing down the clock, i.e., increasing the period - in a number of philogenetically very distant organisms.

Lithium affects the Bipolar Disorder

At the same time, lithium was one of the most prescribed drugs for treating bipolar disorder (at that time usually called "manic-depressive disorder"). Soon enough, people started making the links between effects of lithium on bipolar dissorder and the effects of lithium on the circadian clock. Is the bipolar disorder essentialy a circadian clock disorder?

During periods of depression, the circadian rhythms are phase-advanced.
Lithium is supposed to phase-delay the phase-advanced rhythms, i.e., bring them back to the normal phase. Here is an actograph of the sleep-wake cycle of a bipolar patient treated with various drugs, including lithium, as well as phase-shifts of the light-dark cycle, over a long period of time.
Lithium Affects Circadian Pacemaker Cells in a dish

Much more recently, it was discovered that each individual pacemaker cell (in the suprachiasmatic nucleus of the hypothalamus) in the mammalian circadian system responds to lithium. In other words, the effects of lithium are not at the system level (e.g., interfering with cell-cell communication), but on the level of the cell. This suggests that lithium may act on a particular clock gene and the search for the gene in question commenced.

To make things easier, the candidate clock-gene target of lithium is likely not to be limited to mammals, or vertebrates, as lithium has the same effects on rhtyhms in other organisms, including the fruitfly Drosophila melanogaster. Thus, it is likely that the target clock gene is one that is shared by the circadian clocks in Invertebrates and Vertebrates, thus somewhat narrowing down the list of candidates.

Molecular Mechanism of Circadian Rhythm Generation in Mammals

Let me now try to explain how the mammalian circadian clock works on the molecular level in as simple way as possible, so the non-scientists reading this can - hopefully - understand. Biologists can follow the links for more detailed information if so inclined. In order to do this, I will first give a super-simple primer on molecular biology (I hope I don't make any stupid mistakes on this part as I type it very fast in order to get to the cool new stuff). This is an oversimplification, so I hope molecular biologists do not chastise me for omitting all the extraneous details, as much as they may be important. This is BIO 101.

We are all composed of billions of cells. All of the genetic material - DNA - is found in the nucleus of each cell. DNA is a very long linear molecule, built like a chain out of many, many links. The links in the chain are the nucleotides, each made of a sugar molecule, a phosphate and a nucleic acid. There are four types of nucleic acids in the DNA: adenine, thymine, cytosine and guanine (A, T, C and G). The order of links with different types of nucleic acids on the DNA chain is the "code".

Genes involved in the generation of circadian rhythms can be loosely classified into core clock genes and associated clock genes. The core clock genes are almost all transcription factors. Their proteins act by inhibiting or stimulating transcription of other core clock genes (as well as regulating expression of other - downstream - genes that serve as functional outputs of the cell, i.e., telling the body when to relase a hormone and when not, when to sleep, when to wake up, etc.).

If core clock genes were all there is, the circadian cycle would last only a couple of hours, at best. That is how long it takes for all the players to switch on and off each other once. In order to prolong the cycle to be closer to 24 hours, oter genes are associated with the clock. Their protein products act as modifiers - they may add or remove phosphate groups on core clock genes, inhibit or stimulate expression of some of the core clock genes, degrade the core clock proteins either spontaneusly or upon receiving a signal that the retinae have perceived light, etc.

How lithium affects the molecular clock?

A couple of years ago, it was proposed that the protein involved in the clock mechanism that is sensitive to lithium is not one of the core clock genes, but one of the accessory genes - namely Glycogen Synthase Kinase 3ß (GSK3), which, in turn, acts on Rev-Erb, which in turn acts on Bmal.

Now, a new paper came out with more evidence that this is so:
Nuclear Receptor Rev-erb{alpha} Is a Critical Lithium-Sensitive Component of the Circadian Clock by Lei Yin, Jing Wang, Peter S. Klein and Mitchell A. Lazar. You can find the press-release and excellent media commentary here, here, here, here, and here.

According to this paper, lithium inhibits GSK3. GSK3 normally protects Rev-Erb from destruction. Rev-Erb normally inhibits expression of the core-clock gene Bmal (and perhaps also Period). Thus, when lithium is present, there is no GSK3 to protect Rev-Erb from being broken down. Without Rev-Erb, Bmal and Period get expressed again.

Perhaps this all means that in the Bipolar Disorder the clock gets "stuck" in some way. Perhaps Rev-Erb accumulates and stops the clock from running. Lithium indirectly aids the distruction of Rev-Erb, thus allowing the circadian cycle to proceed.

As they say:
"These results point to Rev-erb as a lithium-sensitive component of the human clock and therefore a possible target for developing new circadian-disorder drugs. Some patients taking lithium have developed kidney toxicity and other problems. Lazar surmises that new treatments that lead to the destruction of Rev-erb would have the potential of providing another point of entry into the circadian pathway."

from http://circadiana.blogspot.com/2006/...d-bipolar.html

City Attorney Silent on San Diego Cannabis Regulations

Hope Unlimited has asked the City Attorney's office to clarify the guidelines for cultivating and possessing medical cannabis in the City of San Diego. Patients are forced deal with San Diego law enforcement officials on a daily basis who have a variety of opinions on the current law regarding medical marijuana.
The City Attorney's office has the power to take a public stand for State Law.

Hope Unlimited members have contacted the City Attorney's office over 100 times requesting clarification on what the
current guidelines are for growing medical cannabis in the city of San Diego.  We have had no response from Mike Aguirre or his staff. 
His office has been informed that there are over 80 Hope members who are legitimate medical cannabis patients who deserve an answer.
They know that many of our members have families need to know they are within the established limits for possession and cultivation of medical cannabis.

If more Hope Unlimited members contact the City Attorney we can make it harder to ignore us!


You can either write an email or give her a phone call. --below find a script to send by email or read to his office.

REMEMBER EVEN A FEW PHONE CALLS or emails  MAKES A DIFFERENCE!

Office of the City Attorney
Civic Center Plaza
1200 Third Ave., #1620
San Diego, CA 92101
Phone: (619) 236-6220
TDD/TTY: (619) 702-7198
Fax: (619) 236-7215
E-mail: cityattorney@sandiego.gov


SAMPLE SCRIPT

Mr Aguirre,

Hope Unlimited is a group of patients and caregivers using cannabis for relief of chronic medical
conditions. Our group is concerned with following established guidelines for medical marijuana use. We are seeking
clarification from the City’s Attorney’s office on current policy towards medical marijuana in the City.
Patients and law enforcement officials need clear guidelines for this program to be successful.
We are operating under guidelines established in September of 2003: Adult marijuana patients with the approval of a San
Diego County doctor may keep up to 1 pound of marijuana and grow up to 24 plants. Under the measure,
caregivers can keep up to 2 pounds of marijuana and grow up to 48 plants for as many as four patients. Are
these still acceptable guidelines?

The suit by the County of San Diego to avoid issuing medical marijuana ID cards has now moved to appellate
court. It is our view that this suit has a slim chance of being decided in the County’s favor. What action
can we expect on ID cards from the City/County after this ruling?

Thank you

Anecdotal Evidence for Treatment of Bipolar with Cannabis

Scientific and medical research of medical cannabis has been limited by the Food and Drug Administration's (FDA) classification of marijuana as a Schedule I drug. A schedule I drug is one with a high potential for abuse and NO MEDICAL VALUE. Crack, PCP, heroin and meth are schedule II drugs. This category is reserved for drugs with a potential for abuse but with legitimate medical uses. Psilocybin (magic mushroom) is another Schedule I drug. The FDA is telling us marijuana and mushrooms are much more dangerous than Crack, PCP, heroin and meth. If you don't believe me read it for yourself,

FDA Drug Schedule / DEA Shopping List


So why are California doctors recommending medical marijuana if it has no value? Why are they not recommending a drug our government thinks has medical value... medical meth perhaps? The answer lies in anecdotal evidence. When you get past the rhetoric and talk to actual bipolar sufferers you find a surprising number who medicate with marijuana. Cannabis is by no means a panacea for everyone with bipolar disorder. But anecdotal evidence clearly shows that it gives significant relief to sufferers of bipolar.

The scientific/medical community sees it as a chicken and the egg question. Do sufferers of depression smoke marijuana because they are depressed or are they depressed because they smoke marijuana? It's an easy question to answer for most people.... marijuana provides relief for their symptoms. For those who feel they are depressed because they are smoking marijuana there are a huge number of well-funded organizations out there to help them. Here is a very small sample:

Marijuana Addiction Drug Rehab
Marijauna Addiction Treatment
How to Stop Smoking Marijuana.com
Marijuana Anonymous


Clearly there are a huge number of free resources available to anyone who feels marijuana is detrimental to their health. Those who experience a benefit from medical marijuana are not so lucky. The 70-year prohibition of marijuana in America has made it difficult for many patients to be honest with their doctors about their use. However, that hasn't stopped them from searching out other patients on the internet. Bipolar sufferers in particular have sought to build the knowledge of cannabis as a treatment method. The following are examples of that effort:

"Numerous patients report significant improvement and stabilization with their bipolar disorder when they utilize adjunctive therapy with medical cannabis. While some mental health professionals worry about the impact of cannabis on aggravating manic states, most bipolar patients trying cannabis find they "cycle" less often and find significant improvement in overall mood. Bipolar disorders vary tremendously in the time spent in the depressive versus manic states. Those who experience extended depressive episodes are more likely to be helped with cannabis.

Patients who use cannabis to "relax" may be treating the anxiousness sometimes associated with depression. Cannabis aids the insomnia sometimes present in depression and can improve appetite. Better pain control with cannabis can reduce chronic pain related depression. While cannabis cannot yet be considered a primary treatment of major depression it may improve mood when used under physicians supervision and in combination with therapy and/or SSRI’s.

There is currently a debate as to which "strain" of cannabis is most appropriate for the adjunctive treatment of depression. Since symptoms are so individualistic it is hard to determine what strain is right expect empirically. In general Sativa dominant strains tend to be more "up" and Indica dominant strains more relaxing.

Patients themselves are often the best judges of whether or not cannabis helps relieve the symptoms of depression. A poorly educated or narrow-minded physician may think any use of cannabis to be a substance abuse related aspect of depression. More enlightened psychiatrists (i.e. Lester Grinspoon of Harvard Medical School) appreciate the often beneficial aspects of cannabis therapy.

Perhaps the most reliable yardstick of the efficacy of medical cannabis in the treatment of depression is whether or not specific aspects of functionality improve. Functionality includes aspects such as self-care ability, job or school attendance, social interaction, normal sleeping, and cognitive skills." source

"I find marijuana the right drug for me, because it helps lower my BP, prevents me from being quite so obsesive and relaxes me. I have Epilepsey, stress related seizures and Bipolar Disorder NOS and last but not least, Post Tramatic Stress Disorder. I believe it helps me control all of my disorders."

"Good for Mania, not for Depression I am fortunate enough to live in a state that allows medical Cannabis. I use it for the severe nausea of Menieres Disease and have to smoke it several times a day. I also am manic depressive though considered what they call,"borderline". I find that great when I need to chill out and calm down from a mania phase. However if you've ever smoked pot, you should remember that when you are high...it makes you think a lot. Sometimes thinking about your problem over and over can make you feel worse. Pot can make you do just that. So beware. Also count on being treated like a second class citizen if you choose to medicate with cannabis. In some counties of California, they actually do arrest and take away all a patients medicine......and feel it is up to the courts to figure it out. So expect to be treated like a criminal no matter where you live.....except San Francisco." source


"I use cannabis as a herbal alternative to pills. I suffer from acute depression or clinical depression aka bipolar disorder (anxiety, mood swings). Also suffer from recurring pain in my lower back and both knees from a car crash. One... What state should I move to? To get a medical card.. Two what strains would be the best for treatment? Three.. does anyone else suffer from bipolar disorder?"

"I also use cannabis as a safer alternative to the pills. In Alaska it is legal to own/cultivate for personal use. If you are goin for medical strains, i would suggest bubblegum, jock horror, or white widow.... anything with an abundance of THC... Hey good luck, and i know what its like to be bipolar.. this shit really helps doesn't it!"


"That is exactly what I use cannabis for. I hate taking pills."

"My wife is bi-polar and has taken so many meds over the years I can't remember them all. Right now she is down to Clonazapam and smoking AK47. This seems to be working well at this time. She has also used Cinderella 99. Both strains create a positive mental attitude...we live in Oregon and you can get a medical card here."


"I am extremely bi-polar, diagnosed at age 12 with the rapid cycling type of disease. Seroquel helps more than anything, I take 500mg a day. But weed definetly helps with the depression part." source