Lithium and bipolar disorder: from the 1940s to treatment today
- Kosma Sakrajda
- 9 hours ago
- 5 min read
From lithium's (re)discovery to a gold standard in treatment: how an Australian psychiatrist's bold experiment reshaped psychiatry
During the last few years, my studies focused on the lithium mechanism of action in bipolar disorder. Despite its usage in modern psychiatry started over 75 years ago, lithium is still a widely used mood stabiliser recommended in all major treatment recommendations. I am Kosma Sakrajda, a researcher focused on neuroscience and psychopharmacology and a Board Member of  ECNP Early Career Academy (ECA). Today, I want to tell you how it all started – or maybe just re-started?
In 1936, Dr John Cade (1912–1980), then a 24-year-old son of a psychiatrist, who spent all his youth living within the grounds of mental health facilities and observed patients struggling with mental illness daily, began his tenure as a Medical Officer at Beechwood Mental Hospital (Beechworth Lunatic Asylum, State of Victoria, Australia).
However, the 1930s were not propitious. In 1939, Australia joined Britain in World War II and in 1941, John Cade joined war efforts as an army doctor. During the war, he became a prisoner of war for three and a half years in the Changi prison camp in Singapore, and set up a mental health unit. Cade carefully observed fellow prisoners of war (POWs) falling into strange and vacillating behaviour, which he later described as similar to that he had followed in Beechwood Hospital. That experience led him to the idea that mental illnesses – schizophrenia and manic depression (nowadays called bipolar disorder) – might have an organic, physical cause. That was in contrast with the long-held belief that mental conditions were caused by a poor upbringing.
Demobilised in 1946, Cade became medical superintendent and psychiatrist at Bundoora Repatriation Mental Hospital. At the time when insulin shock therapy, electroconvulsive therapy and lobotomy (that is, a neurosurgical procedure used for mental health conditions) were the standard treatments in psychiatric disorders, Dr Cade started his pioneering experiments, leading to a breakthrough in modern psychiatry.
His idea was that during a manic episode, certain chemicals are released, which leads to metabolic disturbances and manifestation of the disorder (such as elevated or irritable mood, agitation, impulsivity, decreased need for sleep). Using the kitchen of the unoccupied ward as his improvised laboratory, Cade injected the urine from manic patients into the abdominal cavities of guinea pigs, which caused a lethal effect. John Cade first believed that extensive amounts of uric acid – a metabolite whose elevation is caused, among other things, by kidney failure or gout. caused the observed effect. As uric acid doesn't dissolve in water by itself, to help it dissolve, Cade added lithium, creating a solution called lithium urate.Â
The lithium salts administered to animals resulted in reduced toxicity and also a calming effect. Later, he obtained the same calming and tranquillising effects using lithium carbonate, which has been used in medicine to treat gout since the nineteenth century.
Similar results were previously obtained but overlooked by science. In 1886, a Danish scientist named Carl Lange suggested that a buildup of uric acid in the blood might cause recurring depression. He advocated using lithium carbonate as a potential drug to normalise the uric acid levels in the blood. His claims were discarded by the psychiatric community of his time, and the lithium treatment of mood disorders was abandoned, till Cade's experiments. Surprisingly, although his concept of a role of the uric acid was later abandoned, Lange's proposed treatment used doses of lithium that are comparable to those currently used in psychopharmacology.
Cade's primary results led him to start testing the pharmacological use of lithium treatment. He started testing the safe dose on guinea pigs and also on himself. After that, Cade began lithium treatment of ten manic patients, and in September 1949, he reported improvements in all of the patients in an article published in the Medical Journal of Australia. Unfortunately, Cade's discovery remained mostly unnoticed at that time.
Cade abandoned further studies in 1950 as a result of the death of one of his patients, William Brand, due to lithium poisoning. In retrospect, the effect observed in his guinea pigs’ experiments is suspected as a first symptom of lithium intoxication (that is, too much lithium in the body causing harmful side effects, including lethargy (feeling very tired, or lacking energy) which is now considered a warning sign of lithium overdose. Therefore, it is suspected that Cade was wrong when concluding that guinea pigs were tranquilised by lithium. But his accidental rediscovery of lithium use in psychiatry became the basis of a modern mood disorder treatment. More about Dr Cade's life and work can be found in the video published by Bundoora Homestead Heritage.
Fortunately, Cade's experiments on lithium treatment and his 1949 paper were followed in the next decades by, among others, Danish psychiatrist Mogens Schou (1918–2005). From the 1950s, intrigued by Cade's results and in order to help his brother, who had bipolar disorder, he described the preventive effect of lithium in manic-depressive illness. After teaming up with Poul Christian Baastrup (1918-2001), they conducted a study that confirmed their preliminary results. They claimed that lithium is "the first prophylactic [that is, it can prevent] agent against major psychosis". Later criticism of the proposed lithium treatment from the British psychiatry led Shou and Baastrup to conduct a study where neither the participants nor the researchers knew who got the real treatment or a placebo, and the results were tracked over time. This was the first in-depth analysis of the lithium treatment effect on bipolar disorder patients and was published in The Lancet in 1970.
Today, over 75 years after Cade first introduced lithium into contemporary psychiatry, and after 75 years of extensive research on its effect in affective disorders, lithium carbonate is a commonly used drug. Its strong antimanic and moderate antidepressant properties, and also described effectiveness as an augmenting agent for antidepressants, are well-proven and have revolutionised the treatment of mood disorders, contributing to the psychopharmacological revolution.
However, scientists still don’t fully understand the exact ways lithium works, and many research centres are continuing to study it.  As research advances, lithium remains a key treatment in mental health care, offering hope and improving the lives of patients around the world.