Lithium treatment for bipolar disorder.

Psychiatry is a relative newcomer to the pantheon of medical specialties. While this discipline possesses a venerable heritage of keen observation and description -- as exemplified by the writings of Burton (1), Pinel (2) and Kraepelin (3) -- the pathophysiological processes underlying the "functional" psychoses such as schizophrenia and bipolar disorder (manic-depressive illness) still remain elusive. However, despite the lack of understanding about the etiological processes involved, major advances in treatment were achieved in the 20th century. Prominent among these was John Cade's discovery of lithium's effectiveness in the treatment of mania (4-6). At the time of his discovery, John Cade was a 37-year-old medical officer working in a war veterans' repatriation hospital for chronic psychiatric illnesses, in an outer suburb of Melbourne, Australia. The son of a psychiatrist, who had himself suffered from depression, Cade had recently returned from three years' incarceration in the Changi prisoner-of-war camp in Singapore. There he had found that all of his patients with psychiatric illness who had died (and were examined post mortem) had some significant pathology, such as a tumour. This observation impressed upon him the strong likelihood of an underlying physical cause for manic-depressive illness, particularly as he saw no apparent relationship between stress and psychiatric presentations in the camp (7). In 1947, Cade wrote of his hypothesis that "manic-depressive insanity" was analogous to states of hyper- and hypothyroidism, with mania being "a state of intoxication of a normal product of the body circulating in excess", while "melancholia is the corresponding deprivative condition" (8). With the limited investigative techniques of the day -- his laboratory was a converted wooden shed in the grounds of the hospital -- he began to search for the hypothesized "toxic agent" in the urine of manic patients. The fact that he was undertaking animal studies in a psychiatric hospital in the 1940s is remarkable in itself. To examine for the pharmacological effect in animals of any such toxin, he injected guinea-pigs intraperitoneally with the urine of patients with mania, schizophrenia and melancholia, as well as that of normal subjects. He found that the urine of manic patients was particularly toxic, animals being killed by much lower amounts than by urine from patients with other disorders. Cade then injected the animals with pure forms of the main nitrogenous constituents of urine to identify the specific lethal compound. He found that injections of urea led to exactly the same mode of death as observed with whole urine. He was, however, unable to explain the greater toxicity of the urine of manic patients in terms of higher concentrations of urea. Thus, he began to search for substances that could modify the toxic effect of urea, either by diminution or by enhancement. Cade noted in his 1947 article that uric acid appeared to have a "slightly enhancing" effect on the toxicity of urea. His 1949 paper (4), reproduced here, described the fruition of the research presaged in his earlier work. He had continued the search for the postulated compound that enhanced the toxicity of urea. Further study of uric acid was difficult, though, as it was relatively insoluble in water. To overcome this problem, he fortuitously chose lithium urate, the most soluble of the urates. To Cade's surprise, when he injected the guinea-pigs with lithium urate in conjunction with urea, the toxicity was reduced rather than enhanced, suggesting that the lithium may have been protective. Cade further explored this lead by injecting the guinea-pigs with lithium carbonate in conjunction with urea, and once more observed reduced toxicity. He concluded that lithium itself provided a protective effect against the action of urea. This belief then caused him to wonder whether lithium per se would have an effect on his guinea-pigs. …