The Metal Marvel That Has Mended Brains for 50 Years

Lithium—a simple metal and the oldest drug in psychiatry—might protect the brain against mental illness, Alzheimer’s, and other diseases. One problem: There’s no profit in it.

By Paul Raeburn, Monica Heger|Monday, December 27, 2010
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Lithium is as puzzling as it is potent. It was the first drug used to treat mental illness, and more than 50 years later, it is still one of the most widely used psychiatric medications. But the doctors who prescribe lithium to their patients still do not know how it works or even why it works. “It is the most mysterious drug in psychiatry,” says De-Maw Chuang, a biologist at the National Institute of Mental Health. “It’s so small, but it is so powerful.”

Unlike other psychoactive chemicals—large, complex molecules like Prozac (fluoxetine) or Abilify (aripiprazole)—lithium is extremely simple. It is an element, the lightest of the metals, and its chemical properties are similar to those of the sodium in table salt. Nonetheless, researchers have recently found that lithium could be something close to a psychiatric wonder drug. It has two remarkable powers in the brains of mentally ill patients: protecting neurons from damage and death and alleviating existing damage by spurring new nerve cell growth. Far beyond its current application as a mood stabilizer, lithium could be helpful in treating or preventing Alzheimer’s disease, schizophrenia, stroke, glaucoma, Lou Gehrig’s disease (amyotrophic lateral sclerosis), and Huntington’s disease—an impressive tally that earned it the nickname “the aspirin of the brain” in the journal Nature.

The mood-stabilizing powers of lithium were discovered by accident in the 1940s by John F. J. Cade, a lone psychiatrist working in Melbourne, Australia. Cade had noticed that some substance in the urine of patients with mania was particularly toxic and was investigating uric acid as the potential culprit. He added lithium to the uric acid so it would dissolve more easily in water and injected it into mice. The lithium appeared to have a protective effect against the uric acid. Cade also noticed that the injections made the animals extremely lethargic and unresponsive. That response made him wonder: Might lithium also neutralize his patients’ mania?

After giving himself a shot of lithium to be sure it was safe, Cade injected it into 10 patients with manic depression, the roller-coaster psychiatric condition (also known as bipolar disorder) in which people experience bleak depression alternating with agitated, frenzied highs. The results were spectacular: All 10 improved. One man, who had been in “a state of chronic manic excitement for five years, restless, dirty, destructive, mischievous, and interfering,” improved in three weeks. He left the hospital and resumed his job.

In the United States, lithium is now the first-line treatment for bipolar disorder, a dangerous condition with the highest suicide rate of any psychiatric illness. Lithium compounds, usually given as lithium carbonate or lithium citrate, have three beneficial effects on bipolar patients: preventing mania, easing acute manic episodes, and, to a lesser extent, lifting depression.

Picking up Cade’s work decades later, Chuang has found that lithium protects neurons from damage. In one of his first experiments, he and a colleague treated nerve cells in a test tube with glutamate, which stimulates neurons to fire off an electric signal. Glutamate is a natural brain chemical, and we could not survive without it. But it has a dark side: When the brain is injured by trauma or stroke, cells die and release a massive amount of glutamate, which then excites other cells to death. An excess of glutamate is also found in patients with Huntington’s disease, the incurable degenerative condition that killed the folksinger Woody Guthrie.

When Chuang added glutamate to his laboratory cultures of nerve cells, the cells were wiped out. The story was very different when he put lithium in the dishes before adding the glutamate. “The neurons were almost completely protected,” he says. Even better, the protective effect occurred at low concentrations, similar to the doses already being used in psychiatric patients. Chuang repeated the experiment using Prozac and other anti­depressants to see if they had the same protective effect. None of them did. The mysterious little lithium ion was unique.

Next Chuang wanted to know if the compound could protect cells in an actual living brain. So he gave rats lithium for a couple of weeks, then artificially triggered strokes by blocking a brain artery. Lithium reduced the resulting brain damage by half compared with other rats in a control group. It even helped prevent damage when given after an artificial stroke, suggesting an important new medical application. The lithium had to be given quickly after the stroke to save brain cells—probably within a few hours—but hospital emergency room staff could easily be trained to do that.

Chuang has found that the compound has other powers that may make it useful in Huntington’s disease, a genetic illness that causes cell death in a part of the brain called the striatum. By injecting an excitotoxin—a chemical that destroys neurons by overstimulating them—into the striatum of rats, he was able to cause effects similar to those seen in Huntington’s: jerky movements and cognitive problems. When Chuang first administered lithium to the rats, however, the damage caused by the toxin was sharply reduced. He is now studying the effects of lithium in genetically altered mouse models of Huntington’s disease to see whether the drug might be beneficial.

A research group at the Eve Topf and National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research in Haifa, Israel, found in 2004 that lithium has a similar protective effect in mouse models of Parkinson’s disease. Chuang thinks that the metal might also prevent neuron death in other diseases in which the brain gradually loses function, such as Lou Gehrig’s disease.

If this were all lithium did, it would be impressive. But it also seems to promote cell growth, according to studies by Husseini Manji, a psychiatrist previously at the National Institute of Mental Health and now at Johnson & Johnson. Manji, who has long been interested in bipolar disorder, was studying lithium compounds to gain fresh insights into the cause of the illness. “We thought these drugs were probably working by turning on or off certain genes,” Manji says. His hunch was correct, but he and his colleagues were surprised to learn which genes were involved: Lithium seemed to be affecting the behavior of a so-called cancer gene, BCl-2, which is mutated in certain kinds of leukemia.

Other researchers had found that mutations in the BCl-2 gene were related to the excessive cell growth of leukemia. Manji decided to investigate whether BCl-2 could also be altering the growth of brain cells in bipolar disorder. He collected a group of volunteers with bipolar disorder who were not doing well on medication, and he took them off their drugs completely. He then scanned their brains with magnetic resonance imaging (MRI), which depicts brain anatomy, put them on lithium for four weeks, and scanned them again.

Postmortem studies of bipolar brains have shown that patients’ frontal lobes, regions that control higher cognitive functions, are smaller than normal. The disease causes nerve cells in the frontal lobes to shrivel, their branches and limbs withering like dried flowers. But Manji’s second round of scans—done after the patients had been put on lithium—were remarkable. “We were astounded to see increases in gray matter,” Manji says. In normal volunteers, the drug did not produce any nerve cell growth. “It’s not causing brain cells to grow unregulated, but it’s correcting damage,” Manji says.

These findings point to a deeper understanding of bipolar disorder: They imply that the disorder may arise when nerve cells shrink to the point at which they can no longer communicate effectively with one another, although it’s not clear whether the shrinkage is a cause or a symptom of the condition. Lithium may act like a natural nerve-growth factor, helping the damaged cells reestablish connections and restore the circuits, Manji theorizes. Other drugs, including SSRIs—the class of antidepressants that includes Prozac and Zoloft—also prompt brain-cell growth, which might partly explain how they work.

Manji’s findings about cell regrowth suggest that lithium treatment might be able to prevent or treat other diseases that involve the ongoing death of brain cells. The BCl-2 gene has also been shown to affect the growth of cells in the optic nerve, the bundle of fibers leading from the eyeball to the brain. Glaucoma damages the end of the optic nerve that connects to the retina, causing a gradual loss of vision. Laboratory experiments conducted by Dong Feng Chen at Harvard suggest that lithium, by boosting the expression of BCl-2, might not only prevent glaucoma damage but also aid the regeneration of damaged nerve cells, restoring vision. Chen’s experiments show that when mice with damaged optic nerves are given lithium in conjunction with a drug that reduces scarring, they will regenerate some cells.

The resurgent excitement about lithium has prompted researchers in Melbourne—the site of John Cade’s pioneering experiments—to test it to see if it might prevent schizophrenia, another disease marked by the withering and death of brain cells. “This is not a treatment for schizophrenia,” cautions one of the researchers, Gregor Berger, a psychiatrist now with Integrated Psychiatry Winterthur in Zurich, Switzerland, but formerly at the University of Melbourne. (His office was just a few hundred yards from Cade’s laboratory, which has since been torn down.) “We want to use lithium in the same way as cholesterol-lowering drugs—as a prevention.”

The symptoms of schizophrenia (hallucinations, delusions, apathy, and cognitive problems) usually appear in late adolescence or early adulthood. So Berger and his colleagues aimed young, identifying teenagers who were at risk because they had schizophrenia in their families or had mild symptoms of psychosis, such as imagining they heard their names being called. He performed proton magnetic resonance spectroscopy scans of these at-risk young people before any of them developed schizophrenia, and again after some of them did. His studies documented a clear decrease in brain volume, probably due to a loss of neurons. The question then became this: Could lithium prevent that cell death, and in doing so prevent the illness?

So far, Berger and his colleagues have given lithium to 30 teenagers and young adults at high risk for schizophrenia. “They have fewer symptoms and feel better with lithium, but it is too early to draw any conclusions,” he says. If his study succeeds, it still will not offer help to patients who already have the disorder. But preventing even a small percentage of cases would be a major achievement against a devastating, lifelong disease that is difficult to treat.

In the process of exploring what lithium does, Peter Klein, a developmental biologist at the University of Pennsylvania, identified another promising application. He noticed that lithium blocked the action of a protein called GSK-3. That discovery immediately suggested a link with Alzheimer’s disease. The brains of people with Alzheimer’s disease contain two kinds of abnormal structures: braided fibers known as neurofibrillary tangles and hard, flat growths called amyloid plaques. The two abnormalities are formed in different ways, but GSK-3 is implicated in both processes and both are suppressed by the application of lithium. Klein believes that lithium’s neuroprotective effects could also reduce the loss of neurons seen in Alzheimer’s disease. Only a few trials have tested the compound in Alzheimer’s patients, and results have been mixed so far. Some researchers think it would be more likely to prevent Alzheimer’s rather than improve the cognitive abilities of those who already have the disease.

Lithium is not a perfect drug. In its early years, while researchers and clinicians were still figuring it out, they discovered that the dosage window was extremely narrow. “With many medications you can take four times the normal dose and you’d have some side effects, but nothing that bad,” Manji says. “With lithium, even just 30 percent more can cause serious problems.” People who take it develop a slight shaking of the hands and fingers. It can affect the kidneys and the thyroid gland, and an overdose can be lethal. Most of these side effects can be managed reasonably well by capable doctors who know enough to carefully adjust the dose, however.

Perhaps a bigger obstacle is lithium’s status as intellectual property. Nobody has a patent on the drug. It’s freely available to anyone. If Merck or Pfizer spent millions to prove that lithium protects against schizophrenia or prevents the worst symptoms of Alzheimer’s disease, any other company could sell the drug, profiting from the research done by its competitor. “This is a huge problem,” Manji says. “It’s very difficult to do these clinical studies without a lot of money. The NIH can provide some of that money, but it’s the pharmaceutical industry that must spend the millions of dollars. And they aren’t going to fund it.” Human studies of lithium are stalled out for the most part, he says, because the costs are so high.

As a result, some scientists have had to turn to natural experiments to gain a better understanding of lithium’s potential. Roughly 20 years ago, researchers at the University of California, San Diego, found that the counties in Texas with the highest levels of lithium in the water had the lowest rates of mental hospital admissions for psychosis, neurosis, and personality disorders. Other studies suggested that crime rates were lower in areas where lithium was present in drinking water. In Japan, researchers at Oita University found a correlation between the levels of lithium in drinking water and rates of suicide.

Nobody is yet suggesting that we start dumping the mineral into our water supply. But if the brain-protecting promise of lithium truly pans out, this humble element might become something close to a modern panacea.

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