Ever since her senior year in high school, Kay Redfield Jamison has spent days and even weeks exploding with energy. She would stay up all night, sometimes for weeks in a row, feeling euphoric and productive. She would become lively, extroverted and impulsive. She would make bizarre purchases--a stuffed fox one day and a dozen snakebite kits the next.
Then, suddenly, it would end, and Jamison would descend into darkness. She would lose interest in work, friends and hobbies. She would feel listless, drained and totally alone. During these periods, thoughts of death and decay plagued her. More than once, she flirted with suicide. "From the time I woke up in the morning until the time I went to bed at night, I was unbearably miserable and seemingly incapable of any kind of joy," she wrote in her memoir, An Unquiet Mind (Alfred A. Knopf, 1995).
Jamison, 60, has long fought the extreme mood swings of bipolar disorder, also known as manic depression. Two to 3 percent of American adults share her torment. Like Jamison, they swing wildly from manic phases, in which they are ecstatic and energetic, to depressive periods, in which they are sad, dejected and hardly able to function. These radical fluctuations in behavior and emotion can ruin marriages, damage job or school performance, and often lead to suicide.
On supporting science journalism
If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.
On her doctor's advice, in 1974, Jamison began taking lithium salt, a so-called mood stabilizer. At first, she took her medicine sporadically. She disliked its troublesome side effects, which ranged from limb trembling and slurred speech to nausea, but mostly she missed the intoxicating highs of her former self. She finally decided to stick with the treatment after she attempted suicide, and her moods largely became stable. She is now a psychiatry professor at the Johns Hopkins School of Medicine. Her specialty: the disorder that plagues her.
Like Jamison, hundreds of thousands of people owe their mental stability to the alkali metal lithium. Patients take salts of this element, such as lithium carbonate, lithium sulfate or lithium citrate, that break down into ions in the body, including the positively charged lithium ion Li+, which is thought to be the active ingredient. In about two thirds of patients the treatment successfully suppresses their drastic emotional shifts.
The drug is unique in its ability to dramatically lower the suicide rate in patients with manic depression and other mood disorders. Up to 15 percent of patients with the disorder eventually succeed in committing suicide. Lithium can prevent about 60 percent of such tragedies, according to a 2005 report by John Geddes of the University of Oxford and his colleagues, in which the researchers analyzed the results of dozens of studies of the drug's efficacy.
Lithium may be more than just a wonder drug for many bipolar patients. New studies of its actions in the brain suggest that its job may not be limited to changing the way nerve cells respond to stimuli. It may also promote brain cell survival. If these preliminary findings hold up, doctors may one day be prescribing the drug for a variety of neurological disorders.
Salty Sedative
Lithium's powers as a psychoactive drug were first discovered in the 1940s, when Australian psychiatrist John Cade wondered whether the disorder then known as mania might result from intoxication by normal body products, such as those in urine. To test this curious idea, he injected guinea pigs with lithium urate, the most soluble of the simple urate salts. He found that the salt was not toxic but instead seemed to make the animals calmer. When Cade tested lithium urate on 10 manic patients, all of them became similarly more sedate.
Cade's report, which appeared in the Medical Journal of Australia in 1949, attracted little notice until Danish researcher Mogens Schou chanced on it in 1952. Seeking more solid support for Cade's hypothesis that lithium could pacify people with mania, Schou and his colleagues at Aarhus University conducted the first controlled studies of a psychotropic drug anywhere. They treated a group of manic patients, some of them with lithium and others with a placebo, and found that lithium was indeed more effective than placebo in treating the disorder, a result they published in 1954.
The medical community did not immediately embrace lithium or Schou's work. As late as the 1960s, many scientists and doctors attacked Schou and his findings in the scientific literature. The new drug had a particularly difficult time in the U.S, where lithium chloride had been used during the 1940s as a salt substitute, and toxic doses had killed several heart patients. Its use was banned in this country until Ronald Fieve, a psychopharmacologist at the Columbia College of Physicians and Surgeons, conducted a series of rigorous studies of lithium during the mid- to late 1960s. Fieve's work finally led to lithium's approval as a medication in the U.S. in 1970.
Boosting Brain Matter
For many years after lithium's powers were recognized, neuroscientists still had little notion of how the drug dampened the passions of patients with bipolar disorder. Many assumed that it somehow altered levels of neurotransmitters (chemical messengers) in the brain and thereby corrected a chemical imbalance that was presumed to underlie the mood disorder. Although that theory is still thought to be partially correct, it does not fully explain what lithium does to neurons. For one, despite the fact that lithium alters neurotransmitter concentrations quickly--within hours--it takes a week or longer to relieve symptoms of depression.
In the 1980s many researchers championed the idea that lithium works by inhibiting the production of the sugar inositol, which forms the backbone of a number of important signaling molecules within a cell. Lithium reduces the concentration of inositol in cultured cells and in the rodent brain. Such a deficit could, for example, alter the way a neuron responds to chemical signals from another neuron. It is unclear, however, whether inositol levels are too high in patients with bipolar disorder, and no one has been able to prove that lithium's effects are a result of reductions in inositol.
Over the past several years, researchers have begun to chase a different set of molecular targets for lithium, those that control not only neuronal signaling but also cell survival. For example, lithium helps to block the potentially lethal actions of the excitatory neurotransmitter glutamate; it also suppresses an enzyme called glycogen synthase kinase-3 (GSK-3), which can set in motion events that cause cell death [see box on next page]. In doing so, lithium may work to boost the number of neurons in the brain.
Relative to normal people, patients with bipolar disorder have notably less gray matter, which primarily consists of neuron cell bodies. Depending on the area of the brain, the shortfall is as much as 30 percent, either because nerve cells have died or because they have failed to develop in the first place. Lithium does seem to increase neuronal numbers to some extent. A team of researchers led by psychiatrist Husseini Manji, now at the National Institute of Mental Health (NIMH), used brain imaging to measure the volume of gray matter in patients with bipolar disorder before and after four weeks of treatment with lithium. They reported in 2000 that overall gray matter volume had increased as much as 8 percent after lithium treatment. The effect may be more pronounced in particular brain regions. In mice, Manji and his colleagues reported that the drug increased the number of neurons by 25 percent in a part of the hippocampus, a region involved in memory.
Salve for Sore Minds?
Such studies have led researchers to wonder whether lithium might be effective in treating classic neurodegenerative diseases, such as Alzheimer's or Huntington's, and other problems that lead to the death of neurons, such as stroke. So far a small number of animal and early-stage human studies support this notion.
For example, a research team led by Yuan Su at Lilly Research Laboratories in Indianapolis discovered that lithium abolished or reduced certain hallmarks of Alzheimer's in the brains of mice genetically prone to developing the disorder. Lithium is thought to thwart Alzheimer's disease processes, such as the accumulation of plaque in the brain, in part by inhibiting GSK-3.
In addition, preliminary data suggest that people with bipolar disorder who have been taking lithium for a long period may be less likely to acquire Alzheimer's than people who have not been taking the drug. In a 2006 study of the medical records of 1,423 elderly outpatients who visited a clinic at Oita University Faculty of Medicine in Japan, the patients who had received lithium treatment had higher scores on a test of mental function than people of the same age and sex who had never been prescribed lithium. But a 2005 study by Nick Dunn of the University of Southampton in England and his colleagues points in the opposite direction. Dunn's team found that patients who take lithium actually stand a greater chance than others of developing dementia.
Such contradictory results underscore the early stage of the field. "These are amazing findings," says psychiatry researcher Dietrich van Calker of the University Medical Center in Freiburg, Germany. But van Calker warns that taking lithium to prevent symptoms of Alzheimer's would be going "overboard."
At least one study in rats suggests lithium might also ameliorate the devastating symptoms of Huntington's, in which uncontrollable spasmodic motions are caused by cell death in the striate body, an area of the brain involved in the planning and control of movement. Later, further neuronal death degrades higher thought and memory functions. Neurobiologist De-Maw Chuang and his colleagues at the NIMH simulated early Huntington's in rats by infusing the rodent striate body with quinolinic acid, which triggers neuronal death. In 2004 Chuang's team reported that rats that received lithium before and soon after the acid treatment lost significantly fewer neurons than rats that received only the acid. Lithium blocked cell suicide signals and also seemed to spur the proliferation of neurons.
Defying Death
If lithium can attenuate cell death, it might also help reduce the damage from stroke, in which brain cells succumb after arteries feeding the brain rupture or become blocked. As the blood supply diminishes, the cells become starved of oxygen. This starvation, in turn, is thought to induce the excessive release of glutamate, thereby overstimulating certain receptors on other nerve cells and unleashing a cascade of events that culminates in cell death. Lithium may interfere with this fatal process, in part by binding to and inactivating NMDA, the receptor that ordinarily responds to glutamate.
Indeed, rat studies suggest that the drug may considerably reduce brain damage after a stroke. Chuang's team showed that lithium treatment reduced both brain damage and neurological problems in rats that had suffered experimental strokes. Lithium was effective if the rats received it within three hours after the brain injury, the researchers reported in 2003. Thus, the agent might work as an acute treatment for stroke as well as a way to limit the damage in patients at risk for having a stroke.
Through similar means, lithium might also lower the risk of brain damage from radiation treatment for brain tumors if taken before the treatment. Radiation can damage nerve cells, particularly those in the brain's hippocampus. In 2006 oncologist Dennis Hallahan of Vanderbilt University and his colleagues reported that giving lithium to rats before radiation exposure protected the rodents against neuron death in the hippocampus and preserved the animals' performance on mental function tests, such as navigating a maze, relative to irradiated rats that did not receive lithium.
Other surprising uses for lithium include the prevention of schizophrenia. Recent research suggests that schizophrenia may stem from the loss of certain brain cells and the failure of others to grow and develop--a process that lithium might conceivably counteract. Data to support that hypothesis come from psychiatrist Gregor Berger of the University of Melbourne in Australia. Berger and his colleagues treated 30 young adults at high genetic risk for schizophrenia or other psychoses with lithium for a year or longer. Statistically, a quarter of the test subjects should have begun to show signs of schizophrenia by now, but none of Berger's patients has exhibited any symptoms of the illness so far, hinting that lithium may have a prophylactic effect.
Still, lithium's promise in these diverse disorders must be borne out in further studies--ultimately, large ones done in humans--before anyone can consider it therapy for anything but bipolar disorder. "That's still way in the future," warns psychiatry researcher Michael Bauer, who studies mood disorders at Charit Medical School in Berlin. Not only are the findings to date highly preliminary in most cases, but lithium can also be toxic. For some patients, the therapeutic dose of the substance is dangerously close to the toxic dose. Doctors must closely monitor blood levels of lithium in their patients to minimize side effects, such as hand tremors, dry mouth, weight gain, blurred vision, confusion and seizures.
But perhaps lithium's largest liability is its very identity. As a chemical element, it cannot be patented or reap profits for pharmaceutical firms. Thus, drug company executives are disinclined to spend millions for the clinical trials needed to prove its efficacy in various neurological disorders. "[Drug companies] want to sell their own substances," Bauer points out, and industry scientists are trying to develop patentable mimics of the metal. In some ways, that seems like a pricey redundancy, because the natural material works so well. Jamison is proof of that. Without this medication, she penned in An Unquiet Mind, "I would be constantly beholden to the crushing movements of a mental sea; I would, unquestionably, be dead or insane."
