Lithium: The Cinderella Drug

This breakthrough treatment costs a fraction of more expensive, less effective drugs
BY Joe D. Haines Jr TIMEJuly 17, 2022 PRINT

Dr. Walter Brown begins his 2020 book “Lithium, a Doctor, a Drug and a Breakthrough,” by asking, “What do Abraham Lincoln, Winston Churchill, and Ernest Hemingway have in common?” The answer is bipolar disorder, previously known as manic-depressive illness.

Bipolar disorder is a serious mental illness characterized by extreme mood swings, including extreme excitement (mania) phases and extreme depressive feelings.

Bipolar is one of the more common mental illnesses in the United States., affecting more than 3 million people. However, the number is likely higher due to underdiagnosis and misdiagnosis (i.e. major depression). Lithium has been found to result in a 10-fold decrease in the rate of suicide, an amazing discovery.  Interestingly, communities with higher levels of lithium in the drinking water are associated with a low rate of suicide.

“Using data for 27 Texas counties from 1978-1987, it is shown that the incidence rates of suicide, homicide, and rape are significantly higher in counties whose drinking water supplies contain little or no lithium than in counties with water lithium levels ranging from 70-170 micrograms/L,” notes one study published in Biological Trace Element Research in 1990.

There was little effective treatment for bipolar disorder until Dr. John Cade began using lithium in 1948. His discovery is perhaps one of the most important, yet largely unsung, medical innovations of the modern era. It would come to save an untold number of lives and launch a pharmacological revolution—all based on a miraculous metal rescued from decades of stigmatization. Cade’s discovery was responsible for ending insulin comas, lobotomy, and incarceration, and exile in those suffering from bipolar disorder.

The New York Times recently described lithium as the “Cinderella” of psychiatric drugs. Beyond lives, lithium has also saved billions of dollars in health care costs. And to think it was almost lost to mankind. The story behind this breakthrough treatment is both unlikely and remarkable.

Chemists tell us that lithium has an atomic number of 3 and exists as a soft white metal in its natural forms of lithium carbonate and lithium chloride. Lithium is a highly reactive element, serving as an essential ingredient in hydrogen bombs and nuclear reactors. It’s better known as a component of batteries.

In the 19th century, lithium was unsuccessfully tried as a treatment for illnesses caused by elevated uric acid in the body. Lithium had a brief resurgence in the late 1940s as a salt substitute for patients with cardiovascular disease who needed to restrict their sodium intake. Unfortunately, the amount of salt substitute recommended to take was not specified, so patients taking in an excessive amount of lithium became toxic, and some died. The FDA pulled the lithium salt substitute off the market. However, the damage was done, as lithium now had a reputation for toxicity. The medical uses of lithium fell out of favor until the mid-20th century when Cade began his investigations.

Shortly after Cade completed his psychiatry training, World War II broke out and he was shipped out to Malaysia as a general medical officer. The Australian and British troops were forced to surrender to the Japanese and were subsequently incarcerated at the infamous Changi Prison in Singapore. While in prison, Cade thought a good deal about the cause of manic-depressive illness (now called bipolar disorder), which he observed in some of his fellow war prisoners.

After the war, Cade returned to his home in Australia, weighing only 90 lbs due to severe malnutrition. After recuperating, he took a position at a small 200-bed mental hospital. Cade began experimenting on guinea pigs in a primitive laboratory he created in an unused kitchen he commandeered on the grounds of his mental hospital. It was equipped with a bench and some jars of chemicals.

Cade quickly discovered that lithium tranquilized the guinea pigs. He then moved on to human trials, experimenting on himself then with 10 manic patients and had remarkably good results. Thus the first effective treatment for manic depressive illness was born. Danish psychiatrist Dr. Mogens Schou became an enthusiastic advocate of Cade’s work.

In the words of Dr. Walter Brown: “Cade’s research in 1948 and 1949 revolutionized the treatment of manic-depressive illness and the outlook for its victims. Cade is rightly credited for launching the ‘psychopharmaceutical revolution’ for showing a drug can relieve mental symptoms.”

Brown further describes why there was a 20-year delay before psychiatrists accepted and routinely prescribed lithium. As Brown states: “Why the slow acceptance of lithium? First, since lithium is a natural substance, drug companies could not patent it, so it was of no commercial interest and no drug company promoted it. Second, drug companies vigorously marketed the antipsychotic drugs that came on the scene soon after lithium, and the psychiatric community seized on these new agents.” These new agents became all the rage.

The FDA finally granted authorization for lithium use in 1970, followed by approval as a prophylactic for mania, a major step toward full acceptance.

In 1995, Valproic acid (Depakote) was approved by the FDA to treat mania. Even though it was shown to have no advantage over lithium and was even found to be less effective, Abbott Labs marketed Depakote heavily to both physicians and consumers. Needless to say, the marketing was very effective and lithium use subsequently declined.

That shift isn’t without consequence. Lithium isn’t without its own complications, but it’s a fraction of the cost and generally favored by patients. Meanwhile, a 2007 study published in Developmental Medicine and Child Neurology linked Depakote with autism, finding an 8.9 percent rate of developing autism among children exposed to the drug before birth, compared to a 1 percent rate among the general population.

And while drugs like Depakote take teams of researchers and millions of dollars to create, Cade’s discovery “was made by an unknown psychiatrist, working alone in a small chronic hospital, with no research training, primitive techniques and negligible equipment. … [This] was hardly likely to be compellingly persuasive, especially in the U.S.,” notes Brown.

Today, largely due to the effective marketing campaigns of drug companies, lithium prescribing has been far surpassed by newer and more profitable agents. A recent study estimated that lithium has fallen to approximately 23 percent usage compared to a previous level of 60 percent. Lithium isn’t only far less expensive than newer drugs, ($0.15 per pill compared to $3.77 for Depakote) but it has also been shown to be just as effective therapeutically if not more so compared to the newer agents. As far as safety, monitoring periodic lithium blood levels has demonstrated that lithium toxicity is easily avoided.

Thus, an obscure psychiatrist in Australia, Dr. John Cade, was responsible for discovering one of the most important treatments in psychiatry. Content with his lithium findings, Cade produced no further research. However, with his lithium discovery, Cade revolutionized the treatment of bipolar disorder.

Joe D. Haines, Jr, MD, MPH, FAAFP is a board-certified family practitioner. In addition to family medicine, he also completed an aerospace medicine residency and received an MPH while serving in the US Navy. Dr. Haines has practiced medicine for 40 years and remains active with medical expert witness work and writing. He is a veteran of the Afghanistan War, serving as the Wing Surgeon for the Marine Corps in 2011 He has over 200 publications in a wide variety of journals.
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