Lithium is an interesting sort of mineral salt. It sits on the periodic table right above sodium, and can fool our kidneys into thinking they are the same molecule. Scientists first figured out lithium could help stabilize mood in the late 1800s (when it was also used to treat gout). And, turns out, El Paso, Texas has high levels of lithium in the water, but low rates of violence and mental hospital admissions compared to other cities (1). Lithium was the original "up" ingredient in 7-UP soda (pretty sure lithium is not in there anymore!). The first research paper on lithium didn't appear until 1949, when Australian psychiatrist John Cade made his mark on psychiatric history. However, Greek physicians thousands of years earlier were treating mental disorders with mineral water now thought to be high in lithium.
Before John Cade, mania was treated with electroshock therapy or lobotomy, so lithium was a terrific option - in fact it was the first successful pharmaceutical treatment for mental illness (thorazine wasn't used for several more years). It has huge downsides - toxic to the thyroid and kidneys (and heart in high amounts), fatal in overdose, and a lot of the time it simply doesn't work. But when lithium does work, it is a wonderful thing. Suicidal depression and mood swings relieved within days. To this day, lithium is one of the few medications proven to decrease the risk of suicide (3).
Despite the fame and long term, widespread use, no one knew what the heck lithium actually did. In medical school, I was taught that it had some effect on the regulation of second messenger systems within the neurons (4). Meaning, like every other psychotropic medication, it buffs up the communication in the brain, presumably to help it work all the more smoothly. (We psychiatrists have almost no lab tests and no imaging studies to help us - we just have to sit with someone and figure out what might be going on. A handicap which lends itself to the search for holistic, evolutionary solutions - but everyone knows my bias!)
The good Dr. Hale sent me a link to this article in Psychiatric News, which sheds more light on lithium's possible mechanisms of action. The article references this paper in The Journal of Lipid Research, and the story herein involves more unfortunate rats.
We learn first of all that bipolar disorder is a major mental illness worldwide, and is characterized by mood shifts from severe depression to mania. Examination of the post-mortem frontal cortex of those with bipolar disorder shows an increase in neuroinflammatory markers (I'm sure you're not surprised), and an increase in the enzymes that regulate the expression of arachidonic acid. (Arachidonic acid is the highly-unstaturated fatty acid (HUFA) made from the omega 6 polyunsaturated fatty acids (omega 6 PUFAs), otherwise known as essential nutrients but Standard American Diet Villain Extraordinaire).
In this study, rats were given lithium-laced food or lithium-free food for 6 weeks, and then their little brains were examined to see what happened (sorry, they did not use non-invasive methods. The rats were anesthetized, however, before the final insult.)
To summarize the results - lithium decreases arachidonic acid in the brain and increases the concentration of an antiinflammatory metabolite of DHA (yes! Fish oil!). 17-OH DHA inhibits all sorts of other inflammatory proteins in the brain, like TNF-alpha. (For the biochemistry nuts - LiCl seems to intervene at the level of cPLA2 and sPLA2 and COX). Famous inflammatory modulator aspirin has been postulated to help lithium work better in bipolar disorder (5)
Interestingly enough, lithium has been shown to be the only effective drug (at least to slow the progression down) in another inflammatory, progressive, and invariably fatal neurotoxic disease, ALS (6), and is being studied in HIV dementia and Alzheimer's disease.