Lithium: Too Much Of A Good Thing

          Many people have heard of using lithium as a treatment for bipolar disorder, but many people don’t know how it works in the brain to help cope with the manic phases of bipolar disorder (BD). Those confused people are in luck because scientists aren’t even 100% sure about why lithium works to treat BD. Recently scientists have taken a look at other uses for lithium in nervous system related disorders. One recent example of this can be seen in the article Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. This study takes a look at how lithium functions in the brain and what types of pathways it affects. It also takes a look at lithium’s effect on multiple CNS diseases and concludes that lithium can be neuroprotective and antiapoptitic. Both of these outcomes result in better overall brain and CNS function for the disorder individual.

The two main ways that lithium works in the brain seem to be 1) by inhibition of the molecule GSK-3 and 2) preventing apoptosis. GSK-3 is a molecule in the brain/CNS that plays a role in many pathways. It is inactive when phosphorylated and usually leads to activation of multiple transcription factors when inactivated. One specific way this works can be seen in multiple sclerosis (MS). MS is a condition where neurons become un myelinated, which leads to loss of motor control. When lithium is used as a treatment, it is able to inhibit GSK-3, which in turn activated transcription factors that are able to aid in remyelination of damaged nerves. This is an important because remyelination can help lead to regain of motor control for MS patients. The other main way lithium works in the brain is through preventing apoptosis, or cell death.

If lithium seems to do so many good things, why isn’t it used for the go to treatment for more conditions instead if as a second, or even last, resort? In looking at the pathways that lithium effects, I think it would be safety say lithium might be dangerous since it has so many possible effects.

(a few notes about the picture… Lines ending with arrows indicate connections that activate molecules. Lines ending with a flat line mean that the starting molecule inhibits the molecule where the line ends. Dashed lines mean that lithium treatment inhibits/decreases that pathway when used as a treatment.)

          Take for example the previously discussed example of GSK-3 inhibition activating a transcription factor to aid in MS, how can we be so sure that only that specific transcription factor will be activated? The picture of the many pathways clearly shows multiple effects of GSK-3 inhibition. It has even more effects that aren’t actually listed in the diagram. Now think about lithium’s inhibition of apoptosis and all the ways pictures to get to that goal. What might happen if the wrong transcription factors for disease treatment become active due to GSK-3 inhibition? What might happen if too many cells stay alive due to the lack of apoptosis and form tumors?  Both if these questions seem to lack answers, at least in the discussed paper. Thinking about the widespread pathways that lithium effects lead to the discussion of these two questions which made me question if lithium is really the best treatment on the market. It seems that the multiple pathway modification aspect of this drug is unsafe. I think it might be a better idea to treat diseases by targeting a molecule further down in its specific pathway in order to allow for more precision and less possibilities for error.

                One really interesting thing I learned from the lithium week discussion in my class was that the mechanism of lithium’s action in bipolar is pretty unknown. As a future pharmacist, it’s interesting to see that doctors prescribe this drug without understanding why it works. I also think it’s pretty strange that other mechanisms of lithium’s action are very well studied, but the reason it works for bipolar disorder (one of its very first uses) is still quite unknown.