John Cade: Lithium and the Birth of Modern Psychopharmacology

John Frederick Joseph Cade (1912–1980) was an Australian psychiatrist who, in September 1949, published a four-page paper in the Medical Journal of Australia titled “Lithium salts in the treatment of psychotic excitement.” He reported that ten patients in the grip of mania had calmed within days to a couple of weeks of being given lithium citrate or lithium carbonate, and that they relapsed when the salt was stopped. The medicine he used was not a product of a modern chemistry laboratory. Lithium is a simple element, the lightest of all metals, present in small amounts in sea water, in many spring and river waters, and in grains and vegetables. Cade worked largely alone, with guinea pigs and his own hospital patients, after three and a half years as a prisoner of war in Changi.

His paper is now widely described as one of the starting points of modern psychopharmacology, the use of specific medicines to treat severe mental illness. The road from that paper to everyday use was long: lithium’s narrow margin between an effective and a toxic amount, a series of poisonings in the same year, and a long scientific debate all slowed it, until the Danish psychiatrist Mogens Schou and his colleagues tested it in controlled trials. This wing tells the story in four deep-dive articles. The overview below gives it on one page.

Table of Contents

  1. Deep-Dive Articles
  2. 1. Who John Cade Was
  3. 2. The 1949 Discovery on One Page
  4. 3. The Natural Source: A Mineral in Water and Stone
  5. 4. Timeline at a Glance
  6. 5. Later Significance
  7. 6. A Narrow Margin Between Help and Harm
  8. Key Research Papers
  9. Connections
  10. Featured Videos

Deep-Dive Articles

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John Cade: Life and Career

A country doctor’s son who became an asylum doctor, an army medical officer, a Changi prisoner of war and, for a quarter of a century, the superintendent of Royal Park Psychiatric Hospital in Melbourne.

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Lithium Salts and Mania: Cade’s 1949 Discovery

From a theory about a toxin in the urine, through guinea pigs and uric acid, to the first patient in 1948, the 1949 paper, and the dispute over what the animal experiments really showed.

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Lithium: The Mineral, Its Natural Sources and How It Acts

Element number three: where lithium occurs in rock, sea, food and tap water, the old gout and spring-water beliefs, the drinking-water studies, and the leading theories of how it acts.

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From Cade to Schou: Lithium’s Legacy and Later Research

Mogens Schou’s Danish trials, the prevention debate of the 1960s, the 1970 double-blind trial, and what modern reviews report about mood episodes, suicide and safety.

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1. Who John Cade Was

Cade was born on 18 January 1912 in country Victoria — at Horsham according to the Australian Dictionary of Biography, at Murtoa according to the Encyclopedia of Australian Science. His father, David Duncan Cade, was a medical practitioner who commanded a field ambulance in the First World War. The son was educated at Scotch College, Melbourne, and graduated in medicine from the University of Melbourne in 1934. After hospital residencies he became a medical officer in the Victorian state mental hospitals at Mont Park. In 1937 he married Jean Charles; they had four sons and a daughter.

In 1940 he joined the Australian Army Medical Corps and was posted with a field ambulance to Singapore. When Singapore fell in February 1942 he became a prisoner of war and spent the rest of the war, until September 1945, in Changi. His biographers write that he was put in charge of the camp’s psychiatric section and noticed the links between poor diet and disease among his fellow prisoners — beriberi and pellagra, the deficiency diseases of vitamin B1 and vitamin B3. Some writers have suggested that this wartime experience shaped his thinking about the body’s chemistry and the mind.

After demobilisation in 1946 he joined the Repatriation Mental Hospital at Bundoora, outside Melbourne, where the lithium work was done. From 1952 to 1977 he was psychiatrist superintendent of Royal Park Psychiatric Hospital and dean of its clinical school. He was federal president of the Australian and New Zealand College of Psychiatrists in 1969–70, shared the 1974 Kittay International Award with Mogens Schou, and was appointed an Officer of the Order of Australia in 1976. In a 1951 lecture, as quoted by the historian Johan Schioldann, he called himself “an enthusiastic amateur, full of curiosity, with fair determination, golden opportunities, inadequate knowledge and woeful technique.” He died of cancer in Melbourne on 16 November 1980. The full story is in John Cade: Life and Career.

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2. The 1949 Discovery on One Page

Cade’s starting idea was an old one in medicine: that mania might be a kind of self-poisoning, caused by a normal body substance circulating in excess. Working from an unused pantry at Bundoora with very little equipment, he injected concentrated urine from manic patients, from patients with other illnesses and from healthy people into guinea pigs. Any concentrated urine, given in enough quantity, killed the animals; but, as Schioldann quotes him, urine from manic patients “often killed much more readily.”

He traced the lethal substance to urea and began testing how other urine compounds changed its effect. Uric acid seemed to make urea slightly more toxic, but uric acid dissolves poorly in water, so he used its most soluble salt, lithium urate. To his surprise the lithium salt appeared to protect the animals. He then gave guinea pigs lithium carbonate on its own and reported that, after about two hours, they became lethargic and unresponsive while fully conscious. That observation led him to wonder whether lithium might calm manic patients.

He took lithium citrate and lithium carbonate himself first, by his later account, and noticed no ill effects. On 29 March 1948 he began giving lithium to a patient he identified only by the initials W.B., a man who had been in a state of manic excitement for years. W.B. improved within days. Cade went on to treat ten manic patients, six patients with schizophrenia and three with chronic depression. In the 1949 paper he reported that all ten manic patients improved, and that relapse followed when the lithium was stopped; the schizophrenic patients showed no fundamental improvement, though three became quieter, and the depressed patients neither improved nor worsened.

The paper drew little notice at first. In the same year, the Journal of the American Medical Association reported cases of lithium poisoning, including deaths, among heart patients on low-sodium diets who had used lithium chloride as a table-salt substitute. Cade’s own first patient, W.B., later died of lithium poisoning, and by the accounts of his biographers Cade stopped using lithium. Later researchers, including Schou, argued that Cade’s guinea pigs had been lethargic because of a toxic dose rather than a specific calming effect — a dispute covered in Lithium Salts and Mania: Cade’s 1949 Discovery. Cade himself later wrote, as quoted by Schioldann, that it was “not an accidental discovery” but “the inevitable though unforeseen product of a hypothesis and of a series of experiments.”

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3. The Natural Source: A Mineral in Water and Stone

Lithium is element number three in the periodic table, the lightest metal and the least dense solid element. The Swedish chemist Johan August Arfwedson discovered it in 1817 in the mineral petalite, and it was named from the Greek lithos, “stone.” It is mined from minerals such as spodumene, petalite and lepidolite, and sea water holds a fraction of a part per million. According to a 2002 review by the researcher G. N. Schrauzer, grains and vegetables are the main food sources, and drinking water can add a varying amount depending on where a person lives.

Lithium entered medicine long before Cade. In the nineteenth century the physician Alfred Baring Garrod used lithium salts for gout, because lithium urate is the most soluble salt of uric acid; “lithia” tablets and spring waters were later sold for many complaints. In his 1949 paper Cade reviewed this history and noted an old belief that certain wells helped people with mental illness, writing that it was “very likely that their supposed efficacy was a real efficacy and directly proportional to the lithium content of the waters” (as quoted by Schioldann). He also speculated that lithium “may well be an essential trace element.”

That question is still open. Schrauzer argued in 2002 that the evidence was enough to treat lithium as essential and proposed a provisional daily intake — one author’s proposal, not a recommendation by any official body. Studies comparing natural lithium in tap water between regions have reported associations with lower suicide rates, and a large Danish study reported a non-linear link with dementia (lower incidence at the highest levels, higher at a middle range); these are observational findings that cannot by themselves prove cause. How lithium acts in the brain is also unsettled; the two leading hypotheses involve inositol depletion and inhibition of the enzyme GSK-3. All of this is set out in Lithium: The Mineral, Its Natural Sources and How It Acts.

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4. Timeline at a Glance

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5. Later Significance

In Denmark, Mogens Schou and his colleagues at Risskov tested lithium in a controlled trial in mania, published in 1954. With his colleague Baastrup he then reported in 1967 that long-term lithium appeared to prevent new episodes of mania and depression. That claim was challenged in a 1968 Lancet paper by Blackwell and Shepherd titled “Prophylactic lithium: another therapeutic myth?”, and the Danish group answered with a double-blind discontinuation trial published in 1970, which Schou later described as establishing lithium’s preventive action. The historian Edward Shorter writes that lithium’s use in psychiatry actually reaches back to the mid-nineteenth century before being forgotten, and that Cade is credited with reintroducing it.

Modern reviews report findings that keep lithium central to research on bipolar disorder. A 2014 meta-analysis of seven randomised trials reported fewer mood episodes overall, and fewer manic episodes, with lithium than with placebo. A 2013 BMJ meta-analysis of 48 randomised trials reported fewer suicides and fewer deaths from any cause in people given lithium than in those given placebo. Safety findings are reported just as plainly: a 2012 Lancet review linked lithium with reduced urinary concentrating ability, hypothyroidism, raised calcium and parathyroid hormone, and weight gain, and a 2018 meta-analysis of six cohort studies reported more major malformations after first-trimester exposure. Writing for the 75th anniversary in 2024, Malhi and Bell described how British research reinforced Cade’s findings even as critical British opinion likely slowed clinical use. The full account is in From Cade to Schou: Lithium’s Legacy and Later Research.

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6. A Narrow Margin Between Help and Harm

Lithium’s history is also a history of its hazards. The amount that calms mania is not far from the amount that poisons, and the events of 1949 and 1950 showed it twice over: the American salt-substitute poisonings reported in JAMA, and the death of Cade’s own first patient from lithium poisoning. In a 1955 paper the Melbourne researchers E.M. Trautner, C.H. Noack and their colleagues reported on how the body excretes and retains ingested lithium and how it affects the balance of other ions, work that later researchers built on to make the medicine safer to study.

Schou’s 1957 review of the biology and pharmacology of the lithium ion gathered what was then known, and he raised the possibility that the apathy seen in animals given lithium reflected general intoxication. Four decades later, in a 1997 review of forty years of lithium treatment, Schou wrote that systematically collected data did not show lithium inducing kidney failure and stated that serum lithium and creatinine are monitored during treatment. The 2012 Lancet review reported the effects on kidney concentrating ability, thyroid and parathyroid listed above, with renal replacement therapy in 18 of 3,369 patients (0.5%) in the studies it pooled. These are findings from the research record; this site gives no guidance on lithium use.

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Key Research Papers

  1. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349-52. PubMed PMID: 18142718
  2. Mitchell PB, Hadzi-Pavlovic D. John Cade and the discovery of lithium treatment for manic depressive illness. Med J Aust. 1999;171(5):262-4. PubMed PMID: 10495760
  3. Cole N, Parker G. Cade’s identification of lithium for manic-depressive illness—the prospector who found a gold nugget. J Nerv Ment Dis. 2012;200(12):1101-4. PubMed PMID: 23197126
  4. Schioldann J. From guinea pigs to manic patients: Cade’s ‘story of lithium’. Aust N Z J Psychiatry. 2013;47(5):484-6. PubMed PMID: 23508681
  5. Corcoran AC, Taylor RD, Page IH. Lithium poisoning from the use of salt substitutes. J Am Med Assoc. 1949;139(11):685-8. PubMed PMID: 18110875
  6. Schou M, Juel-Nielsen N, Strömgren E, Voldby H. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry. 1954;17(4):250-60. PubMed PMID: 13212414
  7. Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet. 1970;2(7668):326-30. PubMed PMID: 4194439
  8. Trautner EM, Morris R, Noack CH, Gershon S. The excretion and retention of ingested lithium and its effect on the ionic balance of man. Med J Aust. 1955;42(8):280-91. PubMed PMID: 13264856
  9. Schou M. Biology and pharmacology of the lithium ion. Pharmacol Rev. 1957;9(1):17-58. PubMed PMID: 13431415
  10. Schou M. Forty years of lithium treatment. Arch Gen Psychiatry. 1997;54(1):9-13. PubMed PMID: 9006394
  11. Shorter E. The history of lithium therapy. Bipolar Disord. 2009;11 Suppl 2:4-9. PubMed PMID: 19538681
  12. Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 2002;21(1):14-21. PubMed PMID: 11838882
  13. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. PubMed PMID: 23814104
  14. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721-8. PubMed PMID: 22265699
  15. Malhi GS, Bell E. British contributions to the therapeutic use of John Cade’s lithium. Br J Psychiatry. 2024;225(3):353-356. PubMed PMID: 39364556
  16. Draaisma D. Lithium: the gripping history of a psychiatric success story. Nature. 2019;572:584-585. DOI: 10.1038/d41586-019-02480-0

PubMed Topic Searches

  1. John Cade lithium
  2. History of lithium therapy
  3. Schou and lithium prophylaxis
  4. Lithium in drinking water

Further Reading

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Connections