Neurology & Psychiatry · 1949
Cade's lithium for mania
In 1948, John Cade was working as a psychiatrist at the Repatriation General Hospital in Bundoora, a veterans' institution near Melbourne, with minimal laboratory resources and no research funding. He had a theory that manic illness might result from a circulating toxin, and he was trying to identify it by injecting urine concentrates from manic patients into guinea pigs. One constituent of urine, uric acid, was toxic to the animals at high doses. To dissolve it, Cade used lithium salts, the most soluble available. He noticed that guinea pigs receiving lithium urate, compared with controls, appeared unusually placid and difficult to provoke.
The observation was oblique and could have been ignored. Instead, Cade followed it. He administered lithium carbonate to the guinea pigs at doses that did not cause obvious toxicity, confirmed the calming effect, and then decided to try it in his most difficult patients. His first subject, W.B., was a 51-year-old man who had been in a state of chronic manic excitement for five years, incontinent, destructive, and unmanageable on the ward. After several days of lithium carbonate, he was calm enough to carry on a conversation. He was eventually discharged and held a job, though he relapsed when he stopped taking the medication.
The September 1949 paper in the Medical Journal of Australia reported all 10 manic patients improved, 6 with depressive illness showed no benefit, and 3 with chronic schizophrenia showed modest and temporary improvement. The selectivity of the response, mania responding where other conditions did not, was itself a signal. Lithium was not simply sedating; it appeared to act on something specific to the manic state, though what that was remained unknown and remains incompletely characterized today.
The path to acceptance was slow and was nearly derailed by a separate accident. During the same period, lithium chloride had been widely marketed in the United States as a salt substitute for patients on sodium-restricted diets. Several deaths from lithium toxicity resulted, and the FDA withdrew it from the market in 1949. That history made American physicians reluctant to revisit the drug despite Cade's results. Mogens Schou, a Danish psychiatrist whose own brother had bipolar disorder, ran controlled trials in the 1950s and 1960s that confirmed efficacy and, crucially, established the relationship between serum concentration and therapeutic effect, creating a framework for safe monitoring.
Lithium's antisuicidal effect, distinct from its mood-stabilizing action, became apparent in observational data over subsequent decades. Meta-analyses published from the 1990s onward found that lithium reduced completed suicide rates in bipolar disorder by roughly half compared with no mood stabilizer. The drug entered clinical use before any of its mechanisms were known, and its central mechanism in bipolar disorder remains the subject of active investigation involving inositol signaling, glycogen synthase kinase-3, and neuroprotective pathways. It remains a first-line agent in current international treatment guidelines.
Key People
- John Cade — Melbourne psychiatrist who first treated manic patients with lithium carbonate
- Mogens Schou — Danish psychiatrist who conducted controlled trials confirming lithium's efficacy
Med J Aust. 1949
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