Lithium Therapy: History of

   (from 1949)

   Prehistory: On the basis of his views about excess uric acid causing depression (see Depression: Emergence: periodical melancholia [1886]), Danish physician Carl Georg Lange (1834–1900) described in 1886 the systematic use of lithium in endogenous depression. His younger brother psychiatrist Frederik Lange (1842–1907), in a book published in Danish in 1894 entitled The Most Important Groups of Insanity, described treating acute depression with lithium carbonate alone. However, with the decline of theories about uric acid diathesis, these early attempts were forgotten.

   Cade’s discovery (1949). John F. J. Cade (1912–1980), who first rediscovered the therapeutic efficacy of lithium in mania, received his medical degree from Melbourne University medical school in 1934, then trained in psychiatry before going off to war in 1940 (he was a prisoner of war between 1942 and 1945). Upon returning home, in 1946 he became superintendent of the Repatriation Mental Hospital in Bundoora, Australia. Here he discovered, through a combination of serendipity in experimenting with guinea pigs and a keen observational mind, that lithium carbonate provided relief in the treatment of psychotic excitement, thus publishing an article in the Medical Journal of Australia in 1949. The observation about the therapeutics of mania went largely unheeded. Mogens Schou’s trial (1954). Mogens Schou (pronounced SKOW) (1918–), who confirmed the efficacy of lithium therapy in mania and argued for its prophylatic value in preventing further recurrences of depression and mania, was born in Copenhagen, the son of psychiatrist Hans Jacob Schou (who himself had manic-depressive illness). He graduated in medicine from Copenhagen University in 1944, then trained in psychiatry, in part at the Aarhus university clinic in Risskov. In 1952, Erik Strömgren, the head of the clinic, read Cade’s paper and suggested that he and Schou look into lithium, as to have an alternative to electroconvulsive therapy and the barbiturates. Colleagues in the clinic therefore organized a double-blind trial, one of the first in psychiatry, giving one group of patients the active treatment, the other identical placebo tablets compounded by the hospital pharmacy. (The patients were randomized by the flip of a coin.) "We had accordingly established under strictly controlled circumstances that lithium exerted an antimanic action," said Schou later (in Samson, ed., The Neurosciences: Paths of Discovery, II, p. 153). Schou, Strömgren, and the others published their findings in 1954 in the Journal of Neurology, Neurosurgery, and Psychiatry. Schou was greatly helped in this work by the availability of the recently introduced Beckman flame photometer, which let him measure lithium concentrations in the patients’ blood (because otherwise, lithium can be quite toxic). In 1979, Schou determined that lithium was highly effective in treatment-refractory depression (Archives of General Psychiatry). Indeed, there are psychiatrists today who consider it something of a miracle drug for this indication. In 1987, Schou won a Lasker Award for "his landmark systematic clinical trials of lithim as therapy and prophylaxis for manic-depressive illness."

   Lithium in the prophylaxis of depression (1963 and after). In 1959–1960, Geoffrey Philip Hartigan (M.B. 1941) at St. Augustine’s Hospital in Chatham, Kent, England, and Poul Christian Baastrup (1918–2001), a staff psychiatrist at the psychiatric hospital in Glostrup, Denmark, independently of each other, both contacted Schou asking if lithium might not serve in the prevention of further episodes of depression. Schou urged them to publish their limited observations, which they did, Hartigan in the British Journal of Psychiatry in 1963 with a note of Schou’s appearing alongside, and Baastrup in Comprehensive Psychiatry in 1964. All three papers went "largely unnoticed," as Schou later said. Then, Schou and Baastrup together undertook a longterm study (not double-blinded) on lithium prophylaxis of mania and depression; they presented it at an international congress in 1966 and published it in 1967 in the Archives of General Psychiatry. The findings in bipolar patients with mania and depression, and in unipolar depressive patients, were quite striking. (Michael Shepherd at the Institute of Psychiatry, however, remained unconvinced and touched off a major international controversy that interested readers may follow in interviews that David Healy did with Schou and Shepherd, published in The Psychopharmacologists, vol. III.) To confound the doubters, Baastrup, Schou, and two other trialists published a double-blind study in 1970 in the Lancet on manic-depressive and recurrent depressive disorders, showing the efficacy of lithium prophylaxis. In 1979, Schou published in the Archives of General Psychiatry a trial showing the results of lithium vs. placebo and antidepressants vs. placebo in the treatment of unipolar affective illness: whereas only 22% of those on lithium relapsed within a year, 65% of the placebo patients did so. (By contrast, 35% of the patients on antidepressants relapsed vs. 68% of the placebo patients in that arm of the trial.) Schou’s lifetime advocacy resulted in the general acceptance of lithium prophylaxis in many parts of the world.