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Cade (1949) reasoned that mania was caused by a normal product of the body circulating in excess. He found that concentrated fresh urine of manic patients injected intraperitoneally into guinea pigs was often found to kill more readily than urine from normal persons, schizophrenics or melancholics. Urea was identified as the toxic substance and in trying to establish how much uric acid increased the toxicity of urea, lithium urate, as the most soluble urate, was injected with a urea solution into guinea pigs, seeming to produce a protective effect. To determine whether lithium salts by themselves had any discernible effects, lithium carbonate was injected and after a period of about two hours the animals, although fully conscious, became extremely lethargic and unresponsive to stimuli for a few hours before once again becoming normally active. As Cade himself admits "It may seem a long way from lethargy in guinea pigs to the control of manic excitement, but as these investigations had commenced in an attempt to demonstrate some possibly excreted toxin in the urine of manic patients, the association of ideas is explicable", even if totally fallacious. It can be conjectured that the docility of the guinea pigs was due to lithium toxicity. Not unusually in medicine, lithium was introduced through a mistaken hypothesis.

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