A simple drug, a complex mechanism of action

Lithium levels in drinking water and risk of suicide.
Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N.
Br J Psychiatry. 2009 May;194(5):464-5

A group of Japanese researchers have suggested that lithium in drinking water could decrease the risk of suicide in the general population. The researchers did a systematic study of lithium content of drinking water in 18 municipalities in the prefecture of Oita, Kyushu, Japan. They compared the drinking water lithium levels and the suicide rate in the municipalities during 2002 to 2004. They found that lithium in drinking water was significantly negatively correlated to suicide in the general population.

Lithium has potent mood stabilizing properties and is widely used in psychiatric practice in the treatment of serious mood disorders. It is known to reduce the risk of suicide in such patients. However, its presence in drinking water and its effect on suicide risk in the general population had not been established yet. An earlier study done in 27 counties in Texas had also suggested that lithium in drinking water significantly reduced the incidence of suicides (Shrauzer et al., 1990). Other studies, however, have not supported this claim (Oliver et al., 1976).

The authors of this paper have called for further research to confirm their findings in other countries but they stopped short of any suggestion that lithium be added to drinking water. The discussion around adding fluoride to water to improve dental health has proved controversial and has been criticized by many as mass involuntary medication.

Lithium is perhaps the only metal that is used in the treatment of organic disease. Its therapeutic properties were discovered by Dr. John Cade. As with all landmark discoveries, the discovery of lithium had its fair share of serendipity and happy coincidences.

Dr. John Cade was a World War II veteran having served in the Australian Army Medical Corps. After the fall of Singapore to Japan in 1942, he spent three years as a prisoner of war in the Changi Prison in Singapore. During his stay in the prison, Dr. Cade observed many of his fellow inmates suffer from strange vacillating behavior that he believed was caused by a toxin that was excreted in the urine.

After the war, the battle scarred doctor returned to work in the Bundoora Repatriation Mental Hospital in Melbourne. Here, he converted an unused kitchen in the hospital into a laboratory where he performed experiments that would eventually lead to the discovery of the therapeutic properties of lithium. Dr. Cade believed that a toxin that is excreted in the urine was responsible for mental illnesses like schizophrenia and depression. He injected the urine of mentally ill patients into the peritoneal cavity of guinea pigs. He found that the urine of mentally ill patients was more toxic to the animals compared to that from healthy controls. The prevailing belief that uric acid present in urine had important effects on neuronal function lead Dr. Cade to investigate the effects of intraperitoneal injections of uric acid. In an effort to increase the solubility of uric acid, he used a lithium salt of urate. He found that lithium urate had a remarkable calming effect on the guinea pigs. However, due the careful use of controls, Dr. Cade was able to conclude that the calming effect was a property of the lithium ion itself. He published his finding in the Australian Medical Journal in 1949.

The discovery of lithium was landmark in treatment of psychiatric disorders. It provided a valuable alternative to shock treatments, lobotomies and Freudian psychotherapy which were the main treatments for depression at that time. However the use of lithium as a drug was not welcomed by all, especially the drug companies. Lithium was a cheap and commonly available metal that could not be patented. It was not a drug that could rake in the big bucks for the pharmaceutical industry. It was not until 1970 (20 years after Dr. Cade’s discovery) that FDA approved the use of lithium in the treatment of bipolar disorders in the USA.

Despite the use of lithium for well over five decades now, its mechanism of action has not been fully elucidated. Some theories that have been put forward are:

1. Lithium may produce its effects by interacting with the transport of monovalent or divalent cations in neurons. However, because it is a poor substrate at the sodium pump, it cannot maintain a membrane potential and only sustains a small gradient across biological membranes.

2. Lithium may deactivate the glycogen synthase kinase 3B (GSK-3B) enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. When GSK-3B is activated, the protein Bmal1 is unable to reset the "master clock" inside the brain. As a result, the body's natural circadian cycle is disrupted. When the cycle is disrupted, the routine schedules of many functions (metabolism, sleep, body temperature) are disturbed. This may explain many of the features of mania and depression. Lithium, by inhibiting GSK-3B, may restore normal brain function after it is disrupted in some people.

3. Lithium treatment has been found to inhibit the enzyme inositol monophosphatase leading to disruption of the phosphoinositide cycle. This interferes in the formation of phosphoinositide diphosphate which is important in the intracellular signaling pathway of several neurotransmitters.

Evidence from both in vitro and in vivo studies has demonstrated that lithium exerts multiple effects on neurotransmitter/receptor-mediated signaling, ion transport, signal transduction cascades, hormonal and circadian regulation, and profoundly alters gene expression. It is surprising that a small ion like lithium that has many properties that are similar to sodium could exert such diverse effects.

References:
Oliver SL, Comstock GW, Helsing KJ. 1976. Mood and lithium in drinking water. Arch Environ Health. Mar-Apr;31(2):92-5.

Schrauzer GN, Shrestha KP. 1990. Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res. May; 25(2):105-13.