Lithium (medication)

• 1. Introduction

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  Lithium, now a standard medication for bipolar disorder, was once advertised in a lemon-lime soda. Charles Leiper Grigg, who ran The Howdy Corporation in St. Louis, devised the soda's formula in 1920. The product launched two weeks before the Wall Street Crash of 1929 under the name 7Up Lithiated Lemon Soda. It claimed to contain lithium citrate, a mood stabilizer. It did not. All references to lithium were removed in 1937, after it became clear that the drink held none. The real substance went on to a far stranger career. Lithium carbonate is on the World Health Organization's List of Essential Medicines. In 2023 it was the 187th most commonly prescribed medication in the United States, with more than 2 million prescriptions. It has also turned up in songs by Nirvana and Evanescence, and characters in American Psycho and Garden State take it. How did a substance sold in soft drinks become a prescription for mood disorders? Why does it work? And why do doctors test the blood of anyone who takes it?

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• 2. Gout and Salt

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  In the nineteenth century, scientists found that lithium could dissolve uric acid crystals taken from kidneys, at least in the laboratory. Doctors used it for gout, and also for epilepsy and cancer. The levels needed to dissolve urate inside a living body, however, were toxic. Theories of the day linked excess uric acid to many disorders, including depression and mania. On that basis, Carl Lange in Denmark and William Alexander Hammond in New York City treated mania with lithium from the 1870s onwards. Those theories are now discredited. By the turn of the twentieth century, so-called brain gout had disappeared as a medical entity, and psychiatry had largely abandoned lithium. Manufacturers still produced lithium preparations for kidney stones and uric acid diathesis. Then a new idea took hold. As evidence mounted that excess sodium contributed to hypertension and heart disease, patients were given lithium salts to use in place of table salt. Reports of side effects and deaths followed. In February 1949, the United States banned both this practice and the sale of lithium itself. That same year, an Australian psychiatrist published a paper that sent lithium in a new direction.

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• 3. Cade's Guinea Pigs

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  At the Bundoora Repatriation Mental Hospital in Melbourne in 1948, the psychiatrist John Cade was injecting guinea pigs with urine extracts taken from manic patients. He hoped to isolate a metabolic compound that might be causing their symptoms. Uric acid in gout was known to be psychoactive, so he needed a soluble urate as a control. He chose lithium urate, already known as the most soluble urate compound. The guinea pigs became tranquil. Cade traced the effect to the lithium ion itself. He then swallowed lithium himself to check that it was safe for humans, and proposed lithium salts as tranquilizers. In 1949 he published the Medical Journal of Australia paper "Lithium salts in the treatment of psychotic excitement". He soon controlled mania in chronically hospitalized patients. It was one of the first successful uses of a drug against mental illness. The triumph did not last. In 1950, one of his first patients died of lithium toxicity, after Cade had treated him successfully and sent him home. Cade abandoned the work and tested rubidium, cerium and strontium instead. The wider world was slow to adopt lithium, largely because even minor overdoses killed people. Table salt substitutes made from lithium chloride had already caused such deaths. Still, other scientists had read the 1949 paper. In 1951, Edward Trautner and colleagues at the University of Melbourne used flame photometry to identify a range of blood levels that was safe for patients. By 1952 Cade was superintendent of Royal Park Hospital in Melbourne, and he banned lithium there, even though he had discovered its use. By 1953 he had changed his mind. He hired the biochemist Shirley Andrews to run the clinical laboratory and measure patients' lithium levels with a flame photometer. Andrews also became well known for her work on Australian folk dance and for Aboriginal rights activism. Both she and Cade later received the Order of Australia, hers for folk dance and his for lithium.

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• 4. Proving It Works

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  In 1954, Mogens Schou of Denmark and his colleagues ran a randomized, double-blind, placebo-controlled study that confirmed lithium's effect. Schou and Paul Baastrup then organized further studies and published a stream of research papers over the following decades. At the time, barbiturates were the standard treatment for mania, so lithium was a major advance. British psychiatry pushed back hard. Aubrey Lewis and Michael Shepherd of the Institute of Psychiatry at Maudsley Hospital called lithium "dangerous nonsense". Shepherd and Harry Blackwell named it a "therapeutic myth". The Maudsley psychiatrists had a history of debunking ineffective treatments, and they accused Schou of bias. His brother had suffered recurrent depressions since childhood and responded dramatically to lithium. Schou felt that it had cured him. Resistance slowly gave way through the efforts of Schou and Baastrup in Europe, and Samuel Gershon and Baron Shopsin in the United States. The American Psychiatric Association set up a lithium task force chaired by Irvin M. Cohen. Its members were William Bunney, Jonathan Cole, Ronald R. Fieve, Samuel Gershon, Robert Prien and Joseph Tupin. The task force recommended approving lithium. The Food and Drug Administration approved it for manic illness in 1970, making the United States the 50th nation to do so. Lithium is unusual among medications because academics developed it without pharmaceutical company sponsorship. As a natural element, it cannot be patented.

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• 5. What It Treats

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  Bipolar disorder remains lithium's main use in the United States. Doctors prescribe it chiefly as a maintenance drug that stabilizes mood and prevents manic episodes. It also treats acute mania, and it works within the first 7 days of treatment. For acute bipolar depression, the evidence that it beats placebo is low-quality, and atypical antipsychotics are considered more effective. It does prevent depressive episodes over the long term. Doctors once thought it unsuitable for children. More recent studies show it works for early-onset bipolar disorder in children as young as eight. People with bipolar disorder face three times the usual risk of dementia, and lithium cuts that risk by 50% in this group. In major depression, lithium has been prescribed off-label since the 1980s to boost antidepressants that have not fully worked. A 2019 systematic review found it much more effective than placebo in that role. The same review found lithium alone just as effective as antidepressants alone. For schizophrenic disorders, it is recommended only after other antipsychotics have failed. Studies also suggest good results in preventing cluster headaches, migraine and hypnic headache. The strongest claim concerns suicide. In randomized, double-blind, placebo-controlled trials, lithium reduced suicide risk in mood disorders by 87%, to close to the level of the general population. Some meta-analyses found no significant association, though others dispute them. Despite this, lithium appears to be underused in older people and in certain countries, partly because of patients' negative beliefs about it. A curious correlation points the same way. Areas with more trace lithium in drinking water have lower suicide rates, especially among men, and lower rates of homicide, rape and drug arrests.

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• 6. A Narrow Margin

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  For long-term maintenance of bipolar disorder, international guidelines recommend a blood level of 0.6-0.8 mmol/L. Levels of 1.2-1.5 mmol/L are borderline toxic, and anything above 1.5 mmol/L is toxic. Above 2.0 mmol/L, a person may suffer disorientation, renal failure, seizures and coma. In older patients, signs of toxicity can appear at half the levels seen in younger ones. This low therapeutic index is why blood tests run through the whole treatment. Levels are checked every 1-2 weeks until the target is reached, then every 2-3 months for six months. Once stable, they are checked every 6-12 months, usually 12 hours after the last dose. Acute toxicity mostly brings vomiting and diarrhea. Chronic toxicity is more neurological, with tremor, unsteady movement and changes in mental state. Other medicines can push levels up. Loop diuretics, thiazides, ibuprofen and other NSAIDs, and ACE inhibitors such as captopril, enalapril and lisinopril all raise lithium concentrations. Caffeine, theophylline and acetazolamide do the opposite, and more dietary sodium may lower levels. Dehydration, made worse by heat, also raises them. Lithium blocks the action of the hormone that lets the kidney reabsorb water. This causes thirst, heavy urination and, at least half the time in chronic users, a weakened ability to concentrate urine. Chronic kidney disease occurs in 1-5% of people after 10-20 years of treatment. End-stage kidney disease affects 0.53% of people on lithium, against 0.2% in the general population. Taking the dose once a day at night appears to limit kidney harm. The thyroid is also affected, with hypothyroidism about six times more common in people taking lithium. Hand tremor affects 27% of users. Stopping is risky too. After sudden withdrawal, there is a 50% chance of mania within a month. In the first year, the rate of suicide or attempted suicide can rise up to 20-fold. Gradual tapering is therefore recommended.

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• 7. Pregnancy Decisions

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  Lithium is a teratogen, meaning it can cause birth defects, and the worry centers on the first trimester. Case reports and several retrospective studies point to a possible rise in congenital heart defects, including Ebstein's anomaly. The risk depends on dose. The 2017 AMX registry study put the relative risk of any malformation at 1.11 for up to 600 mg of lithium carbonate daily. It was 1.60 for 601-900 mg and 3.22 above 900 mg. The first two figures were not statistically significant. A 2018 meta-analysis found a significant 62% increase in congenital malformations overall, but the 54% increase in cardiac malformations was not significant. Exposure during pregnancy is also tied to a slight rise in preterm birth and in babies born larger than usual. Yet lithium also prevents relapse during and after pregnancy, and stopping it carries real danger. Some patients are therefore advised to continue, after weighing risks and benefits with a psychiatric physician. The decision should come before conception, since there is no reason to stop once pregnancy has begun. Those who continue routinely have fetal echocardiography. Pregnancy lowers blood lithium, especially in the first and second trimesters, so monitoring becomes more frequent and the dose may rise. A higher level in the third trimester may help prevent postpartum psychosis. Starting lithium right after delivery also protects against postpartum psychosis and relapse. The American Academy of Pediatrics lists lithium as contraindicated for both pregnancy and lactation. Breast milk carries only small amounts, but safety data are limited and many international authorities advise against breastfeeding.

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• 8. An Unsolved Mechanism

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  In healthy people at therapeutic concentrations, lithium produces no obvious psychotropic effect such as euphoria. The specific biochemical mechanism by which it steadies mood remains unknown. Lithium carbonate itself is a white, odorless, alkaline powder. Researchers have proposed many targets. One is the enzyme GSK3 beta, which lithium inhibits. That activates mTOR and strengthens neuroprotective signaling. Another idea is that lithium depletes inositol by inhibiting the enzyme inositol monophosphatase. A third involves glutamate. During mania glutamate levels rise, and lithium may compete with magnesium at the NMDA receptor. Lithium also raises levels of the inhibitory messenger GABA, and it may protect against oxidative stress by boosting complexes I and II of the mitochondrial electron transport chain. Over time, lithium treatment increases expression of BDNF, a neurotrophic factor. Chronic treatment is linked to greater grey matter volume in brain areas for emotional processing and cognitive control. Bipolar patients on lithium also show higher white matter integrity than those on other drugs. A further neurotrophic factor, MANF, rises as well. The effects on the NMDA receptor appear exclusive to lithium and have not been seen with rubidium or cesium. A search for a lithium-specific receptor is still ongoing, though the high concentrations lithium needs make mainstream researchers doubt that one exists.

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