The history of lithium therapeutics

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Garrod described the medical use of lithium in 1859 for the treatment of rheumatic conditions and gout - and in particular 'brain gout'. The hypothesis behind the use of lithium at this point was based on its ability to dissolve nitrogen-containing compounds, called urates or uric acid, which were thought to build up in the body giving rise to many illnesses. This is certainly true for gout, but the idea was extended to include many other human physical disorders. By the 1880s, Carl Lange and others7 were using lithium for the treatment of BD, and lithium carbonate and citrate were described in the British Pharmacopoeia of 1885.

In addition to the treatment of patients, the urea hypothesis spurred the development of the lithium tonic and its increasing use in common food stuffs. The most notable today is 7 UP, originally introduced in 1929 as 'Bib-Label Lithiated Lemon-Lime Soda'. The lithium was removed in 1950. The decline of the urea hypothesis and the lack of a credible therapeutic mechanism for lithium lead to its disuse as a therapeutic agent until it was re-discovered in 1949 by John Cade.8 He was continuing the search for a toxin which may cause BD, and was working on the premise that these toxins may be excreted in the urine of BD patients. He thus injected concentrated urine samples from these patients and control subjects into the abdomen of Guinea pigs, and found that bipolar patient urine had greater toxicity than that of the control subject. To identify what this toxic compound was, he then tested different forms of nitrogen-containing compounds found in urine, and identified urea as being the most toxic. His line of reasoning continued, that dissolving this urea may alleviate the toxicity, so he tried co-injecting urea with alkali metals, only to find that lithium causes sedation and stupor in the animals. This suggested that lithium may have sedative or mood-control properties. Following testing of lithium toxicity on himself, he then administered it to BD, depressed and schizophrenic patients, and found huge improvements in the BD patient group. As no effective drug treatments existed at the time for any major psychiatric disease, this was an extremely exciting event and effectively places lithium as the first modern psychopharmacological agent.

Cade's work, however, rapidly became overshadowed by two events. First, on the same year as Cade's discovery, the Food and Drug Administration (FDA) banned lithium following the death of four US patients due to lithium overdose. It was thought at the time that lithium chloride could be used to reduce sodium chloride intake, and would therefore be useful in the treatment of hypertension. Doses of up to 14 g per day were used in these cases, which were extremely high compared with modern lithium use. The second event to overshadow Cade's re-discovery of lithium was the discovery of chlorpromazine, the first anti-psychotic. This molecule heralded a new era in the development of psychotropic drugs for the treatment of schizophrenia and major depression.

Fortunately, throughout the 1950s Schou9 and others continued to investigate the use of lithium and demonstrated that it could be used safely in the treatment of BD. It was re-approved by the FDA in 1972 and is now prescribed in over 50% of BD cases,10 although it is very common that it is used in combination with other drugs. It is marketed under a variety of names including Lithicarb®, Quilonum SR®, Lithotabs® and Librium®. It has also clearly been shown to reduce the risk of suicide in mood disorder patients,11 and it has considerable socioeconomic impact, e.g. it has been estimated that it has saved around $8 billion in the US alone in 1991.12

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