Resetting the Clock on Bipolar Disorder

I was flipping through an old issue of Science (Feb. 2006, so not that old) when I happened upon an article with relevance to bipolar disorder. Since I've know a few people with this condition, I was immediately taken by it.

Bipolar disorder is characterized by episodes of mania followed by a long depressive lull. The patient will often feel euphoric and very active during manic periods, usually going with little sleep, working tirelessly on projects, and talking often to themselves or others. Some argue that manic depressive disorder should not be treated, because the ideas that individuals touch upon during the manic phase are sometimes novel or useful. This phase usually only lasts a couple weeks though, and many feel it is not worth the months of depression that follow. In high contrast to the flitting, rapid speech of the manic phase, the patient will often speak more slowly during a depressive episode. The depressive phase is draining; the patient often feels worthless and unmotivated (Carlson, 533-534).

There are a few highly effective treatments of this disorder though, the most widely known being lithium carbonate. More specifically, it is the lithium in the mixture that is thought to be the active ingredient. Lithium is most effective when administered during the manic phase. It immediately brings the person back to a normal state of functioning and prevents the depressive lull that would normally follow the mania. The mental side effects of the drug are pretty much nonexistent; it does not impair cognitive functions or regular emotional responses to life. A patient on lithium, for example, can still feel depths of sadness or happiness appropriate to a situation, but does experience the prolonged, excessive mania or the months of depression that he or she may otherwise feel. Unfortunately, there are side effects for the body with prolonged use of lithium. Lithium carbonate is not always easy for the body to process! If the patient’s blood lithium levels are not carefully monitored, the individual could develop hand tremors, excessive thirst and urine production, and possible weight gain (Carlson, 535). Carbamazepine and other drugs have been developed in the hopes of producing similar effects to lithium, but without any of the related toxicity problems. Finding better drugs has been a difficult process though, because how lithium works and what cellular pathways it works on are not yet known! I recall reading just last semester in my physiological psychology text that researchers “…have not yet discovered the pharmacological effects of lithium that are responsible for its ability to eliminate mania.”(Carlson, 536).

This is where that article in Science magazine comes in! It appears that the lithium-sensitive component has been found, at least in vitro. According to Yin et al., the nuclear receptor Rev-erba is directly effected by lithium and activity of glycogen synthase kinase 3 (GSK3) is effected as well. GSK3 is the enzyme responsible for regulating circadian rhythm in several model organisms. Cellular circadian rhythms are maintained by interconnected transcriptional feedback of clock genes involved in multiple negative and positive feedback loops.

Initiated by signals from the hypothalamus, transcription factors BMAL1 and CLOCK activate the clock genes (Per1, Per2, Cry1, and Cry2), creating the corresponding PER and CRY proteins. These proteins form dimmers in the cytosol and return to the nucleus to inhibit there own transcription. It is GSK3 that directs the length of this process by degrading PER in the cytosol, lengthening the time before negative feedback begins. Another feedback loop involved in circadian rhythm includes Rev-erba. Rev-erba's primary target is the Bmal1 gene, which is active during the night phase of circadian rhythm. Like PER and CRY, Rev-erba inhibits its own transcription, so too much of the protein can lead to over inhibition, while too little may effect expression of Bmal1.

This study reveals that bipolar disorder is probably more a disorder of circadian rhythm than anything else, and traditional anti-depressants such as MAO inhibitors are not likely to help in the long run. It also provides possible hypothesizes for the cause of bipolar disorder; could it be that patients have an inability to degrade all of the Rev-erba protein, leading to ill-maintained oscillation of clock genes? Could it be some other mutation in the circadian pathway? Another exciting aspect of this research is that understanding the biological pathways behind the disorder will allow for development of better drugs, which act directly on target enzymes or genes, with reduced side effects.

Here is a link to the article: http://www.sciencemag.org/cgi/content/abstract/311/5763/1002

Sources: Carlson. Physiolgy of Behavior. 2003
Yin et al. "Nuclear Receptor Rev-erba is a Critical Lithium-Sensitive Component of the Circadian Clock." Science pg 1002. 17 feb 2006
Images: www.ecademy.com (masks)
www.bbc.co.uk/radio4/science/ (brain clock)