Lithium and Therapeutic Targeting of GSK-3

Evidence Supporting GSK-3 as a Lithium Target

Direct Targets of Lithium

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Therapeutic Uses of Lithium Salts

Lithium salts have been a part of the therapeutic toolbox, for better or worse, since the 19th century. They have been claimed to help with conditions like gout, hangovers, and insomnia, and there were early suggestions that lithium might improve psychiatric disorders. However, it was the remarkable effects of lithium reported by John Cade and later by Mogens Schou that revolutionized the treatment of bipolar disorder.
The known molecular targets of lithium are surprisingly few, including the signaling kinase glycogen synthase kinase-3 (GSK-3) and a group of related phosphomonoesterases, including inositol monophosphatases and phosphoglucomutase. GSK-3 is a therapeutic target for various diseases, including bipolar disorder, cancer, and coronavirus infections.

History of Lithium Treatment

Lithium was discovered as a new element (atomic number 3) in 1817. It is an alkali metal, the lightest solid element, and a monovalent cation in solution. It is used therapeutically mainly as lithium carbonate, but also in other forms such as acetate, citrate, chloride, or sulfate salts. Lithium salts first gained pharmacological popularity in the 19th century as treatments for gout and other conditions thought to be caused by excessive uric acid, since lithium carbonate can dissolve uric acid in vitro. By 1859, Sir Alfred Baring Garrod included recommendations for lithium to treat “brain gout,” which included mania.

In 1871, Danish psychiatrists Carl and Frederik Lange recommended lithium carbonate as maintenance therapy for periodic depression, which they believed was caused by uric acid. The “uric acid diathesis” hypothesis of disease was largely abandoned in the early 1900s. Lithia water and lithium tablets were popular patent medicines and health supplements in the late 19th and early 20th centuries. Studies claimed lithium water treatments prevented or treated ailments caused by uric acid. The carbonated beverage now known as 7Up was initially marketed as “Bib-Label Lithiated Lemon-Lime Soda” and promoted as a hangover cure. Although lithium toxicity was described in several studies, lithium salts remained popular in the United States until the FDA restricted patent medicines.

In 1948, lithium chloride (LiCl) was marketed as a table salt substitute for low-sodium diets, leading to multiple reports of lithium toxicity, including several fatalities by 1949. In 1949, Australian psychiatrist John Cade successfully used lithium citrate to treat patients institutionalized for mania, having observed a sedative effect of lithium on guinea pigs in uric acid experiments and assessed its safety through self-administration. Longitudinal studies showed that lithium acts as a mood stabilizer, preventing recurrent manic and depressive episodes. The development of a simple assay for plasma lithium levels established a therapeutic range for lithium, demonstrating that it has a narrow therapeutic window. The US FDA approved lithium for the treatment of mania in 1970, becoming the 50th country to do so, and later approved it for maintenance therapy in 1974.

The specific direct targets of lithium in psychiatry are not fully known, but research has identified several viable candidates. While lithium induces a wide range of physiological and developmental effects, it directly inhibits a few known targets. Identifying which of these targets is responsible for a specific effect of lithium can be challenging, particularly for its therapeutic effects in humans. Validating direct targets of lithium involves several criteria:

• (1) inhibition of the target enzyme at therapeutically relevant concentrations of lithium in vitro and in vivo;
• (2) structurally distinct inhibitors of the proposed target mimicking the effects of lithium;
• (3) genetic loss-of-function of the proposed target producing effects similar to those of lithium;
• (4) the effects of lithium being reversed by restoring target function or a downstream effector.

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