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They drank it at health spas, they put it in 7 up. They even used it for mania and depression. Lithium was the elixir of the early 1900s, until Big Food tried to sell it as a table salt. That was one step too far. Welcome to the Carlat Psychiatry podcast, Keeping psychiatry honest since 2003.
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I'm Chris Akin, the editor in chief of the Carlat Psychiatry Report.
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And I'm Kelly Newsom, a psychiatric NP and a dedicated reader of every issue. Our recent episodes traced a lineage of psychiatric revolutions, from Freud to dbt, from Carl Jung to Alcoholics Anonymous. These pioneers drew from a deep well, their own struggles with depression, psychosis, and addiction. Other trailblazers were inspired by what they witnessed in family members. And that's the spark that lit the way for lithium.
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Lithium had a lot of false starts in medicine, but it finally caught on in the 1950s, when a Danish psychiatrist named Morgan Shue began studying lithium for depression and bipolar disorder. Shue went to medical school with one goal to understand mood disorders. His own brother suffered from severe recurrent depressions, depressions that came on every spring. And eventually his went into remission on lithium. But how did Dr. Xu get the idea to try lithium in the first place, fresh out of residency training? That's where the story gets tangled. There's no straight line here. It winds through spas, Victorian literature, and a dangerous theory about crystals in the blood. We're going to start this tale at an unlikely source. Gout. Back in the 1840s, the English physician Alfred Baring Garrad discovered that gout was caused by elevated uric acid crystals. This was a landmark moment. Medicine was just beginning to move away from ancient Greco Roman theories and toward an empirical science. And like a lot of exciting discoveries, physicians stretched it as far as it would go. Suddenly, uric acid wasn't just the cause of gout. This crystal, they believed, was building up everywhere. In the joints, in the blood, in the brain, causing headaches, asthma, high blood pressure and epilepsy. And since alcoholism is one pathway to gout and gouty, patients seemed moody and irritable. The theory jumped to psychiatry. Terms like gout brain, gouty mania and gouty melancholia entered the medical lexicon and slipped into popular culture, where gouty became a synonym for irritable and irrational.
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You can hear it in Victorian fiction. Charles Dickens wrote of a gouty old gentleman who. Who cursed and swore at the servants. George Eliot tells of a gouty character so irritable that no one dared approach him. And William Thackeray describes the old gouty officer, peevish and out of humor with all the world.
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Dr. Girard's next discovery added to the fervor. And this is where lithium enters. He found that lithium dissolved uric acid crystals in a test tube. So the thinking went, maybe lithium would dissolve those crystals inside the body. The evidence here was shaky, but the idea took off. Doctors started prescribing lithium orally for gout and for the whole constellation of disorders where uric acid was supposedly the culprit.
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What doctors stretching a theory beyond its therapeutic reach. We would never do that today unless we're using off label anticonvulsants to target the kindling theory of bipolar mania.
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Right. That's another example still around today that really doesn't work. Or you could add to that the anti inflammatories to target the inflammatory theory of depression. Sure a few of those treatments work, but many do not. Have you ever seen a patient come in on low dose naltrexone like 2-5mg for depression in low doses, naltrexone has anti inflammatory properties and it has some promising data in inflammatory disorders like multiple sclerosis and fibromyalgia. And that has led some clinicians to prescribe it for depression. It's actually quite widespread. But here's a research the first adequately powered randomized trial of low dose naltrexone and depression just came out and it was negative, adding to an earlier trial that was way too small to draw conclusions. With only 12 patients. This one used a placebo control and still small, but had 37 patients totally negative, no signal on secondary measures. The medication didn't even lower markers of inflammation.
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But the inflammatory theory has produced positive results in other areas. The NSAID celecoxib, for example, has 31 randomized control trials in depression and several in bipolar. Enough to earn it a chapter in Dr. Akin's new textbook Difficult to treat depression. Let's pause for a preview of the CMA quiz for this episode. Earn CME for each episode through the link in the show notes what led to lithium's reclassification from a wellness supplement to a prescription medicine. A discovery of its antimanic effects B confirmation of its anti gout effects C false advertising by the lithium industry D reports of toxicity from lithium salt.
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But even when the theory is wrong, it can still lead to treatments that work. When physicians treated gout with lithium, they noticed their patients moods improved. By the 1880s, clinicians like Alexander Haig and the Lang brothers Carl and Frederick Lang were were using lithium specifically for mania and depression. They described their findings in books and medical journals. Carl Lang was a prominent neurologist, and his theory that emotions arise out of bodily processes neurophysiology was cited by Freud. Lang's paper also made its way to Emil Kraeplin, the German psychiatrist who first described manic depression in 1899, bringing together different types of mood disorders under one umbrella and separating them from schizophrenia. Anyway, Kraeplin read Lang's paper on lithium but rejected lithium. Never tried it, believing the uric acid theory that it was based on was just a bunch of bunk.
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Kraeplin's rejection of lithium may have also been a reaction to the fattish quackery that sprung up around it. By the early 1900s, the uric acid theory had jumped from medicine into wellness culture, and lithium came along with it. People flocked to lithium spas, hoping to dissolve the uric acid poison that gave them headaches, fatigue and indigestion. Lithium beer was marketed as a healthier alternative to alcohol. And if you drank too much, you could try 7up, marketed as a cure for hangovers. That takes the ouch out of the grouch. 7up took its name from the molecular weight of Lithium 7, which serves as a helpful reminder of Lithium's current FDA approval. It is approved for bipolar disorder in children and adults all the way down to age 7.
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This wellness craze around uric acid crystals ran for nearly 75 years, until a dash of table salt brought it down. As doctors grew concerned about high sodium diets and hypertension, they searched for a salt substitute. And what better candidate than the celebrated health elixir lithium? So in 1948, the Foster Milbram Company in Buffalo, New York, began marketing lithium table salt. Within a year, reports of fatal toxicity were making national headlines and landing on the COVID of JAMA as people sprinkled the salt a little too liberally on their food. In response, the FDA took lithium off the food shelves, ending its career in sodas, spas and salt shakers. Eventually, Foster Milburn was brought down by lawsuits, and their former Buffalo headquarters are now occupied by the Spectrum Behavioral Health Clinic.
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And here's where the story pivots. Five months after the lithium toxicity scare, a Melbourne psychiatrist named John Cade published a small case series in an obscure Australian medical journal. The title Lithium Salts in the Treatment of Psychotic Excitement. The medical establishment had every reason to ignore it. It was based on the now discredited uric acid theory. The study was uncontrolled and the drug itself was now considered a dangerous toxin. But the paper found its way to Mogen's shoe. Remember Dr. Shue, the Danish psychiatrist whose brother had suffered those crushing spring depressions? And that is where the lithium spark finally caught fire.
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In the decades since, researchers have uncovered a remarkable range of benefits from lithium. None have anything to do with uric acid. Lithium stabilizes circadian rhythms. It has anti aging effects, protecting the telomeres at the ends of our DNA from from degradation as we age. Lithium is neuroprotective and in epidemiologic studies it is linked to a lower risk of dementia. In the 1980s, lithium's antiviral properties were discovered, first against herpes and now across more than a dozen viruses, including controlled trials in COVID 19. These antiviral trials use the same serum levels that we target for mood disorders, 0.6 to 0.8. There is also preliminary data suggesting lithium may reduce the risk of stroke and cancer. And the most recent finding? While SSRIs and SNRIs are tied to bone loss osteopenia, lithium appears to do the opposite. It seems to protect the bones as people age. In both laboratory and epidemiologic studies, lithium
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is no longer used for gout, as physicians realised in the late 1800s that the amount of lithium they'd need to give someone to dissolve uric acid crystals was toxic. But the mania gout story came back with a modern twist. Researchers at the nimh, including Carlos Zarate and Hussain Manji, have linked bipolar disorder to abnormal purine metabolism. That connection led to trials of allopurinol, an anti gout medication in acute mania. It worked. We now have five positive randomized controlled trials supporting allopurinol as an adjunct in mania. I've used it as a last resort in mania and with some success, and we'll cover it next month in an article on off label therapies for mania in the Carlat report's print edition. Dr. Akin's new book, Difficult to Treat Depression, features 15 antidotes for lithium side effects, including aspirin for sexual dysfunction, amiloride for nephrogenic diabetes insipidus and NAC to prevent renal disease. It's available in print or audio.