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

When John Cade’s four-page paper “Lithium salts in the treatment of psychotic excitement” appeared in the Medical Journal of Australia in September 1949, it described ten manic patients who had calmed while taking a simple salt of the lightest metal. It could easily have been forgotten. The same year brought reports of lithium poisoning among heart patients in the United States who had used lithium chloride as a table-salt substitute, and Cade’s own first patient, W.B., died of lithium poisoning in 1950. What turned a small Australian observation into one of the most studied medicines in psychiatry was the work of other people: a handful of Australian colleagues who kept treating patients and learned to measure lithium in the blood, and above all the Danish psychiatrist Mogens Schou and his co-workers, who tested it in a controlled trial and then asked whether it could prevent new episodes rather than only quiet a current one.

This page follows that story forward from 1949. It covers the early Australian follow-up, the move to measuring blood lithium, Schou’s 1954 Danish trial, the shift from treatment to prevention, the sharp scientific argument of 1968 over whether prevention was real, the 1970 double-blind trial that settled much of that argument, and the arrival of lithium on the American market the same year. It then sets out what modern trials and reviews have found about preventing mood episodes and about suicide, what large reviews have found about lithium’s effects on the kidney, thyroid, parathyroid glands and pregnancy, and how researchers marking the 75th anniversary of Cade’s paper have reassessed it. Cade’s life, the 1949 discovery itself and lithium as a mineral each have their own page in this wing, linked under Connections. Findings are reported as findings; this page gives no advice about any medicine.

Table of Contents

  1. Australian Follow-Up: Noack and Trautner
  2. Measuring Blood Lithium
  3. Mogens Schou’s Danish Trial (1954)
  4. From Treatment to Prevention: Baastrup and Schou
  5. The ‘Therapeutic Myth’ Debate
  6. The 1970 Discontinuation Trial and US Approval
  7. Preventing Mood Episodes: Modern Trials
  8. Lithium and Suicide
  9. Safety Findings: Kidney, Thyroid, Parathyroid and Pregnancy
  10. Seventy-Five Years On
  11. Key Research Papers
  12. Connections

1. Australian Follow-Up: Noack and Trautner

Cade’s paper did not spread quickly. Melbourne in 1949 was a long way from the centres of psychiatric research, the Medical Journal of Australia was little read abroad, and Cade himself, according to the historians who have reviewed his biographies, turned to salts of rubidium, cerium and strontium without therapeutic success and then set lithium aside after W.B.’s death. The work was carried forward, at first, by other Australians.

In a 1999 review for the 50th anniversary, the psychiatrists G.D. Burrows and J.W. Tiller traced this early Australian research. They describe Cade’s discovery as a progression from a metabolic hypothesis of mania, through animal studies, to patients, and they note that further reports on lithium appeared in the Medical Journal of Australia in 1950 and 1951, along with other Australian studies of the drug.

The most substantial of these was a 1951 paper by C.H. Noack and E.M. Trautner, titled “The lithium treatment of maniacal psychosis”. As its title says, it reported on the lithium treatment of manic patients, and it appeared in the same journal as Cade’s original. Its importance lay partly in who read it. The historian Johan Schioldann, in his history of lithium in medicine, writes that it was the Noack and Trautner paper that drew the English psychiatrist Rice to lithium — one of the threads by which the Australian observations reached Europe.

Why a second group mattered

A single doctor’s report on a few patients is a starting point, not proof. A second, independent group treating more patients and finding the same calming effect in mania was the first sign that Cade had seen something real rather than a run of chance improvements. The early Australian follow-up also kept running into the same obstacle Cade had met: the amount of lithium that calmed a manic patient was not far from the amount that made a person ill.

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2. Measuring Blood Lithium

The poisonings of 1949 made the central problem plain. In March of that year the Journal of the American Medical Association published two reports — one by A.C. Corcoran, R.D. Taylor and I.H. Page on “lithium poisoning from the use of salt substitutes”, the other by L.W. Hanlon and M. Romaine on lithium chloride as a substitute for sodium chloride in the diet and its toxicity. People with heart disease on low-sodium diets had used lithium chloride sold as a table-salt substitute, and some had been seriously poisoned; there were deaths. Within a year Cade’s own first patient had died of lithium poisoning. Lithium could clearly help, and it could clearly harm, and the dose alone did not tell a doctor which would happen in a given person.

Trautner’s group in Melbourne took up the question of what the body does with lithium. In 1955 E.M. Trautner, R. Morris, C.H. Noack and S. Gershon published “The excretion and retention of ingested lithium and its effect on the ionic balance of man” in the Medical Journal of Australia. As the title states, the study followed how ingested lithium is excreted by the kidneys and retained in the body, and how it affects the balance of other ions such as sodium. This was the early groundwork for the idea that what matters is not how many tablets a person takes but how much lithium is circulating in the blood.

From blood levels to routine monitoring

The principle that lithium treatment is guided by blood measurements became the standard practice of the following decades. Looking back in 1997, Mogens Schou wrote in his review “Forty years of lithium treatment” that systematically collected data did not show that long-term lithium treatment induces renal insufficiency, and he called for regular monitoring of serum lithium and serum creatinine (a marker of kidney function). The narrow gap between the effective and the toxic range, first exposed by the salt-substitute poisonings and W.B.’s death, is the reason blood-level measurement became inseparable from the medicine.

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3. Mogens Schou’s Danish Trial (1954)

Mogens Schou (1918–2005) was a Danish psychiatrist working at the psychiatric hospital in Risskov, near Aarhus. He came across Cade’s report and, with colleagues, set out to test it more rigorously than a series of individual case notes could. In 1954 Schou, N. Juel-Nielsen, E. Strömgren and H. Voldby published “The treatment of manic psychoses by the administration of lithium salts” in the Journal of Neurology, Neurosurgery and Psychiatry.

Accounts of the trial’s design differ in their wording. Schou himself, in a 1999 review of the early European lithium studies, called it a Danish controlled trial; the historian Edward Shorter describes it as a controlled study; and popular summaries sometimes describe it as double-blind and placebo-controlled throughout. The most careful reading is that it was a controlled trial in which part of the comparison was made against placebo. What all the sources agree on is the result: in Schou’s words, the Danish controlled trial confirmed Cade’s observation that lithium had an anti-manic effect.

Schou’s view of the guinea pigs

Schou’s confirmation came with a twist. In his 1957 review of the biology and pharmacology of the lithium ion, and in later writing quoted by Schioldann, Schou held that his group could not reproduce a specific calming effect of lithium in animals, and he believed Cade’s guinea pigs had been lethargic because they had received a toxic dose. Schou nevertheless gave Cade full credit for the clinical discovery. Schioldann quotes him writing, in 2001, that “to make therapeutic discoveries on the basis of misinterpreted experiments requires curiosity, daring, luck and compassion for patients!” The dispute over the animal experiments is covered in more depth on the page about the 1949 discovery.

The two men later shared an honour: in 1974 Cade and Schou jointly received the Kittay International Award for their work on lithium.

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4. From Treatment to Prevention: Baastrup and Schou

Manic-depressive illness, now called bipolar disorder, is a recurrent condition: a person who recovers from one episode of mania or depression is at risk of another. Treating an episode once it has started is only part of the problem. The question that came to define lithium’s second chapter was whether taking it continuously, between episodes, could reduce the number of new ones.

Schou and the Danish psychiatrist P.C. Baastrup pursued this idea with patients who stayed on lithium over long periods. In 1967 they published their findings in the Archives of General Psychiatry under the title “Lithium as a prophylactic agents. Its effect against recurrent depressions and manic-depressive psychosis” (the grammatical slip is in the original record). As the title states, they reported that continued lithium had a preventive (prophylactic) effect not only against manic episodes but also against recurrent depressions.

In his 1999 review, Schou recalled that this prophylactic action was then confirmed by a collaborative Swiss–Czech–Danish trial. The claim was a large one. It meant that lithium was not simply a sedative for excited patients, as Cade had judged it, but a medicine that might change the long-term course of a recurring illness.

Why the claim was hard to prove

Uncontrolled observations of patients over time are open to a familiar objection in a recurrent illness. Episodes come and go unpredictably, and patients often enter treatment at a bad time, so a quieter period afterwards can reflect the natural ebb of the illness rather than the drug. Doctors and patients who expect a benefit may also see one. These weaknesses set the stage for the controversy that followed.

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5. The ‘Therapeutic Myth’ Debate

In 1968 B. Blackwell and M. Shepherd published a paper in The Lancet titled “Prophylactic lithium: another therapeutic myth? An examination of the evidence to date.” As the title indicates, they examined the published evidence for lithium’s preventive effect and questioned whether it was strong enough to support the claim.

The paper set off one of the best-known debates in the history of psychopharmacology, conducted in journal articles and letters. Edward Shorter, in his 2009 history of lithium therapy, writes that lithium was “almost derailed” by a small group of opponents based at London’s Maudsley Hospital. G.S. Malhi and E. Bell, writing for the 75th anniversary in 2024, offer a two-sided view of the British role: British research reinforced Cade’s findings, while critical British opinion likely held back lithium’s use in clinical practice.

What the argument achieved

However it felt at the time, the challenge set a clear test. If lithium truly prevented episodes, then patients who were well on lithium and were switched, without knowing it, to an identical-looking placebo would relapse more often than those who stayed on lithium. That is the design Schou’s group adopted next.

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6. The 1970 Discontinuation Trial and US Approval

In 1970 Baastrup, J.C. Poulsen, Schou, K. Thomsen and A. Amdisen published “Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders” in The Lancet. Patients who had been taking lithium long term were randomly assigned either to continue lithium or to switch to placebo, with neither patients nor the doctors assessing them knowing who received which. The trial included both people with manic-depressive illness and people with recurrent depression.

Schou’s 1999 review states the outcome plainly: the Danish double-blind discontinuation trial established the prophylactic action of lithium. For much of the field, this answered the question the 1968 paper had raised.

The United States, 1970

The same year, lithium reached the American market. Shorter notes that the United States was the 50th country to admit lithium — more than two decades after Cade’s paper and well behind much of Europe.

By 1970, then, the essential shape of lithium treatment was in place: an anti-manic effect first reported by Cade and confirmed by Schou, a preventive effect reported by Baastrup and Schou and tested in a double-blind trial, and treatment guided by blood levels because of the narrow margin between help and harm.

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7. Preventing Mood Episodes: Modern Trials

Later decades brought newer medicines for bipolar disorder — anticonvulsants such as valproate and several antipsychotic drugs — often grouped together as “mood stabilizers”. Shorter’s history observes that lithium’s status came under threat from these newer drugs. Researchers responded with larger trials and systematic reviews.

Severus and colleagues, 2014

A systematic review and meta-analysis by E. Severus, J.R. Geddes and colleagues, published in the International Journal of Bipolar Disorders in 2014, pooled seven randomised controlled trials with 1,580 participants comparing lithium with placebo for the prevention of mood episodes. Lithium was associated with fewer mood episodes overall (risk ratio 0.66) and with fewer manic episodes (risk ratio 0.52). For depressive episodes the estimate also favoured lithium (risk ratio 0.78), but in the random-effects analysis the confidence interval (0.59 to 1.03) crossed 1, so that result was not statistically clear.

The BALANCE trial, 2010

The BALANCE trial, published in The Lancet in 2010, was a randomised open-label study of 330 people with bipolar I disorder. It compared lithium alone, valproate alone, and the two combined for preventing relapse. The investigators reported that lithium alone and the lithium–valproate combination were both more likely to prevent relapse than valproate alone; for lithium versus valproate the hazard ratio was 0.71 (confidence interval 0.51 to 1.00). Whether the combination did better than lithium alone was neither confirmed nor refuted by the trial.

What these findings show and leave open

Taken together, these studies support Baastrup and Schou’s central claim that lithium reduces new episodes, with the clearest effect against mania. They also show the limits: the effect on depressive episodes is less certain, and BALANCE was open-label, meaning patients and doctors knew which treatment was given. These are reported here as research findings.

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8. Lithium and Suicide

One of the most discussed findings about lithium concerns suicide. People with bipolar disorder and severe recurrent depression face a markedly raised risk of suicide, so any effect on that risk is of great importance. Schou himself, in his 1997 review, discussed a possible anti-suicidal effect of long-term lithium.

In 2013 A. Cipriani, K. Hawton, S. Stockton and J.R. Geddes published an updated systematic review and meta-analysis in the BMJ, “Lithium in the prevention of suicide in mood disorders”. It drew on 48 randomised controlled trials with 6,674 participants. Compared with placebo, lithium was associated with fewer suicides (odds ratio 0.13, confidence interval 0.03 to 0.66) and fewer deaths from any cause (odds ratio 0.38). For deliberate self-harm, the review found no clear benefit: the estimate (odds ratio 0.60) had a confidence interval that crossed 1.

Reading the numbers

Suicide is, fortunately, rare even in high-risk groups, so the trials recorded few suicides in total; that is why the confidence interval around the odds ratio is so wide. The direction of the finding was consistent, and it is one reason researchers continue to study lithium closely. The separate question of whether the small, natural amounts of lithium found in some drinking water are linked to suicide rates in whole populations is covered on the page about lithium as a mineral.

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9. Safety Findings: Kidney, Thyroid, Parathyroid and Pregnancy

From the salt-substitute poisonings of 1949 onward, lithium’s risks have been studied as closely as its benefits. Two large reviews summarise much of what is known.

McKnight and colleagues, 2012

R.F. McKnight, J.R. Geddes and colleagues published “Lithium toxicity profile: a systematic review and meta-analysis” in The Lancet in 2012, drawing on 385 studies. Their main findings were:

Munk-Olsen and colleagues, 2018: pregnancy

Pregnancy was examined more closely in an international collaborative meta-analysis of six cohort studies by T. Munk-Olsen, V. Bergink and colleagues, published in Lancet Psychiatry in 2018. It included 727 pregnancies exposed to lithium. First-trimester exposure was associated with a higher rate of major malformations than in unexposed pregnancies (7.4% versus 4.3%; adjusted odds ratio 1.71, confidence interval 1.07 to 2.72). The difference in cardiac malformations was not statistically significant. Babies exposed to lithium were also more often readmitted to hospital in the newborn period.

How these findings fit together

The two reviews reached different results on malformations; the 2018 analysis was a dedicated study of pregnancy outcomes across six cohorts, while the 2012 review covered lithium’s whole toxicity profile. The general picture from the research is of a medicine with real effects on the kidneys, thyroid and parathyroid glands that are detected through regular blood tests, which is why the site’s pages on kidney function and thyroid tests are linked below.

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10. Seventy-Five Years On

Cade’s paper reached its 75th anniversary in September 2024, and several researchers used the occasion to look back. G.S. Malhi had already written in 2014 of “Cade’s lithium: an extraordinary experiment with a not-so-ordinary element”, and in 2024 Malhi, C. Davey and E. Bell published an editorial in the Australian and New Zealand Journal of Psychiatry, “John Cade’s lithium: A granular look at his achievement”. In the British Journal of Psychiatry, Malhi and Bell traced the British contributions to lithium’s therapeutic use, concluding that British research reinforced Cade’s findings while critical British opinion likely impeded its clinical uptake.

The earlier 50th-anniversary literature of 1999 had already set the frame for these reassessments. Schou’s review of the early European studies ends with his personal memories of Cade; Burrows and Tiller recorded the Australian follow-up; and Shorter’s 2009 history credits Cade with reintroducing lithium to psychiatry in 1949 while noting that its psychiatric use went back to the mid-19th century before being forgotten.

A chain of people

Looking across the whole story, lithium’s path from a pantry laboratory at Bundoora to a medicine used around the world ran through a chain of people rather than a single moment: Cade’s hypothesis and first patients; Noack and Trautner’s confirmation and Trautner’s blood-level work; Schou’s controlled trial; Baastrup and Schou’s idea of prevention; the critics who demanded a better test; and the double-blind trial that supplied it. Modern meta-analyses have added numbers to their claims, and modern safety reviews have measured the costs that the 1949 poisonings first revealed. Cade’s lithium — a simple salt of an element found in rock, seawater and spring water — remains, three-quarters of a century later, one of the most closely studied medicines in psychiatry.

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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. Burrows GD, Tiller JW. Cade’s observation of the antimanic effect of lithium and early Australian research. Aust N Z J Psychiatry. 1999;33 Suppl:S27-31. PubMed PMID: 10622176
  3. Noack CH, Trautner EM. The lithium treatment of maniacal psychosis. Med J Aust. 1951;2(7):219-22. PubMed PMID: 14881840
  4. 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
  5. Hanlon LW, Romaine M 3rd. Lithium chloride as a substitute for sodium chloride in the diet; observations on its toxicity. J Am Med Assoc. 1949;139(11):688-92. PubMed PMID: 18128981
  6. 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
  7. 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
  8. Baastrup PC, Schou M. Lithium as a prophylactic agents. Its effect against recurrent depressions and manic-depressive psychosis. Arch Gen Psychiatry. 1967;16(2):162-72. PubMed PMID: 6019331
  9. Blackwell B, Shepherd M. Prophylactic lithium: another therapeutic myth? An examination of the evidence to date. Lancet. 1968;1(7549):968-71. PubMed PMID: 4171596
  10. 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
  11. Schou M. The early European lithium studies. Aust N Z J Psychiatry. 1999;33 Suppl:S39-47. PubMed PMID: 10622179
  12. Shorter E. The history of lithium therapy. Bipolar Disord. 2009;11 Suppl 2:4-9. PubMed PMID: 19538681
  13. Schou M. Forty years of lithium treatment. Arch Gen Psychiatry. 1997;54(1):9-13. PubMed PMID: 9006394
  14. Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, Geddes JR. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord. 2014;2:15. PubMed PMID: 25530932
  15. BALANCE investigators and collaborators, Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, Morriss R, Alder N, Juszczak E. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385-95. PubMed PMID: 20092882
  16. 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
  17. 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
  18. Munk-Olsen T, Liu X, Viktorin A, Brown HK, Di Florio A, D’Onofrio BM, Gomes T, Howard LM, Khalifeh H, Krohn H, Larsson H, Lichtenstein P, Taylor CL, Van Kamp I, Wesseloo R, Meltzer-Brody S, Vigod SN, Bergink V. Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies. Lancet Psychiatry. 2018;5(8):644-652. PubMed PMID: 29929874
  19. Malhi GS. Cade’s lithium: an extraordinary experiment with a not-so-ordinary element. Med J Aust. 2014;201(1):24-5. PubMed PMID: 24999881
  20. 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
  21. Malhi GS, Davey C, Bell E. John Cade’s lithium: A granular look at his achievement. Aust N Z J Psychiatry. 2024;58(9):733-737. PubMed PMID: 39175139

PubMed Topic Searches

  1. Mogens Schou and lithium
  2. History of lithium prophylaxis in bipolar disorder
  3. Lithium and suicide: meta-analyses
  4. Lithium: kidney, thyroid and parathyroid effects
  5. Lithium in pregnancy and malformations

Further Reading

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Connections