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Billions of Years Old, Lithium Still Has a Promising Future

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In a six-decade career spent researching and prescribing lithium ― a long-established therapy for bipolar disorder ― psychiatrist David Dunner, MD, has many stories about the treatment’s fraught path to mainstream acceptance and the schism it caused between colleagues devoted to a classically psychoanalytic approach to treating mental illness and those pushing psychiatry toward a biologically focused future. The one that still makes him scratch his head in disbelief, however, played out on his TV.

In 1976, word began to spread that an upcoming episode of the sitcom Maude would feature the titular character being diagnosed with manic-depressive illness (the term by which bipolar disorder was then known). What was even more newsworthy was that Maude would be prescribed lithium for her condition. Dunner eagerly awaited the moment, but it never arrived. The show’s producers, bowing to pressure from concerned psychiatrists, left any mention of lithium on the editing room floor.

“I found that kind of astounding that there was so much concern about emerging psychopharmacology as a treatment for mental disorders and the notion that this was going to be emphasized on a popular TV show that it caused somebody to literally edit it out,” recalled Dunner, now director of the Center for Anxiety and Depression in Mercer Island, Washington.

In my opinion, this is the most effective drug in all of psychiatry…
Dr Nassir Ghaemi

Lithium’s ultimate success eventually did away with its taboo reputation. In providing the first targeted therapeutic for a notoriously life-threatening disease, lithium has prevented millions of suicides. By the 1990s, its use was thought to have saved the US healthcare system nearly $150 billion in hospitalization costs. Lithium’s status as a gold-standard therapy is evident in guidance from the UK’s National Institute of Health and Clinical Excellence, which recommends it as a first-line, long-term pharmacologic treatment for bipolar disorder.

“In my opinion, this is the most effective drug in all of psychiatry,” said Nassir Ghaemi, MD, MPH, professor of psychiatry and pharmacology at Tufts University, Boston, Massachusetts, and a lecturer on psychiatry at Harvard Medical School. “It’s the only drug that affects the disease and [doesn’t] just treat symptoms.”

Bipolar disorder remains an enormous clinical challenge. It is listed by the World Health Organization as the sixth most common cause of disability globally. Yet the desire to treat it with lithium seems to be dwindling; usage rates have declined in both Europe and the United States. This has left some to wonder whether lithium is once again being edited out of the conversation.

An Elementary Treatment Finds an Unlikely Pioneer

Unlike laboratory-derived treatments, lithium has existed since the dawn of our universe. One of the three elements wrenched into existence by the Big Bang some 13.7 billion years ago — helium and hydrogen being the other two — lithium is variously distributed across the earth in rocks, bodies of water, plants, and animals. However, it was not identified until the early 1800s, when it was isolated in samples taken from a Swedish mine (the element is named for the Greek work lithos, meaning rock or stone).

The decades that followed saw lithium’s first medical applications, after it was observed to break down excess uric acid, then thought to incite various ailments and now known to be the cause of gout. Concurrently, there was a boom in commercial formulations of lithium in the form of bottled water, tablets, or salt substitutes. The latter caused well-publicized cases of toxicity and death, leading the US Food and Drug Administration (FDA) to remove the products from the market in 1949.



 

With enthusiasm for lithium sapped, its therapeutic future appeared nonexistent. The story of how it rose from these circumstances to forever change the treatment of mental illness is the subject of Walter A. Brown’s Lithium: A Doctor, a Drug, and a Breakthrough . At its center is John Cade (1912–1980), an Australian psychiatrist with no established research background and therefore an unlikely candidate to ignite psychiatry’s pharmacologic revolution.

“Cade is an iconic figure in the history of psychopharmacology, but your average practicing psychiatrist in this country doesn’t know his story,” said Brown, clinical professor emeritus of psychiatry at Brown University, Providence, Rhode Island.

With no research grants, no really formal research training, he nonetheless managed to come up with what is arguably one of the most important treatment discoveries in psychiatry…
Dr Walter Brown

Brown’s book suggests that Cade’s upbringing made him uniquely empathetic to the tolls of mental illness. Cade was the son of a physician who likely suffered with posttraumatic stress disorder from his combat experiences. His father’s work as a medical superintendent at various mental institutions meant that he spent his youth living on the grounds of these facilities, often in close contact with patients. While serving in the Pacific during World War II, Cade was captured by the Japanese and was placed in charge of the Changi Prison’s psychiatric ward. During his 3½ years of imprisonment, he began to reconsider accepted notions regarding the causes of mental illnesses.

“He firmly believed that serious mental illness, bipolar illness, and schizophrenia had a basis in a biological abnormality,” said Brown.

After returning from the war, Cade found a position as the director of a small mental hospital, where he began investigating his theories about the biological origins of mental illness. There was little in his professional history to suggest he’d make a successful go at such endeavors, which he conducted by himself in an ad hoc laboratory on the grounds of the asylum.

“With no research grants, no really formal research training, he nonetheless managed to come up with what is arguably one of the most important treatment discoveries in psychiatry, and he did it on a shoestring,” said Brown.

Cade began collecting and analyzing urine samples from patients with mania, depression, and schizophrenia. He then injected the urine into guinea pigs to determine various thresholds for lethality. As Brown writes in his book, Cade’s experiments “did not follow an entirely logical or readily understood sequence,” but they nonetheless brought him to his breakthrough discovery.

Cade noted that the urine of manic patients was particularly toxic. He hypothesized that uric acid might be the cause, which he began administering to the guinea pigs. To help dissolve the uric acid, Cade eventually added lithium carbonate, which seemed to protect the animals from death. From here, he moved to directly injecting lithium carbonate itself. He observed its apparently tranquilizing qualities, which may have simply been a sign of temporary illness.

“This was strictly accidental. He wasn’t looking to change their behavior,” said Brown. “There was a lot of serendipity in that.”

Operating in an era with decidedly different ethical standards, Cade quickly moved to clinical testing. In another stroke of good fortune, he settled on a dose of lithium carbonate that was within range of what is now known to be clinically safe and therapeutically efficacious. He administered it to himself for 2 weeks and reported no ill effects. In March 1948, he treated his first patient with lithium, a man who had suffered through decades-long bouts of mania and depression. After a week, the treatment’s remarkable effects began to become clear. The patient was discharged 2 months later with a prescription for lithium carbonate at a dosage of 300 mg twice daily. Cade treated additional patients with similarly dramatic results.

Cade’s moment at the forefront of lithium research would be brief. Soon after publishing his initial findings in September 1949, Cade’s first patient’s condition began to regress. The patient died from lithium-related toxicity in March 1950. Cade’s concerns about lithium’s toxicity soon caused him to stop using it altogether. He prohibited his colleagues from doing so as well from his new post as superintendent of the Royal Park Mental Hospital, Melbourne, Australia.

Keeping the Flame Alive

In the ensuing decades, lithium’s therapeutic future was passed like a baton among several researchers, whose perseverance kept it from becoming lost to psychiatric history.

“Various people in different countries picked up on this little finding, and everybody piggybacked on everybody else and just kept going,” said Brown.

Pivotal early findings were offered by John Talbot, who correlated symptoms of lithium toxicity with its serum concentration, and Edward Trautner, who developed a method of measuring blood levels of lithium and eventually established safe ranges at which it can be given.

Trautner and his colleagues’ work gained the attention of the Danish psychiatrist Mogens Schou, who arguably played the most prominent role in developing lithium as a treatment. Schou conducted the first randomized placebo-controlled trial of lithium ― perhaps the first of its kind in psychiatry. It confirmed lithium’s efficacy in alleviating mania. Later publications from Schou and others revealed that lithium could also prevent further episodes of both mania and depression and that it could be safely administered for years at a time.

Schou became a vocal advocate for lithium at a time when residual concerns regarding its toxicity and the introduction of new psychiatric drugs had left its status battered. For his efforts, Schou was publicly rebuked by the psychiatric community at London’s Maudsley Hospital. The ensuing decade-long dispute was acrimoniously dubbed, “the Battle of Britain.” Schou’s research methods were criticized. He was accused of bias for discussing having successfully treated his brother’s recurrent depression with lithium. It was even rumored that Schou did himself have manic-depression and was self-medicating.

Nonetheless, Schou’s work attracted partisans who used lithium successfully in England, Australia, France, Scandinavia, and elsewhere. In the United States, prominent researchers such as Sam Gershon and Ronald Fieve built a compelling case for lithium, but faced an uphill battle.

“There was no need for lithium in the United States in the ’60s because all patients with psychosis were diagnosed as having schizophrenia,” said Dunner, who worked closely with Fieve during this time.

Things began to change when manic-depressive disorder was renamed bipolar disorder in the DSM-III and with the FDA’s approval of lithium in 1970. Nevertheless, colleagues were still hesitant, preferring a more psychoanalytic approach.

“It was a different kind of psychiatry,” explained Dunner. “It was a 15-minute med check, a blood test, prescribing ― a medical approach. It was all of the things that these people weren’t doing as part of their training and practice, so it took a while.”

Why Lithium’s Declining Status?

Although the studies that first established lithium are now decades old, recent years have seen a wealth of additional data in support of its utility. In what was described as the largest register-based, real-world effectiveness study of pharmacotherapies for bipolar disorder yet, Finnish researchers found that of all the compounds studied, lithium was associated with the lowest risk for hospitalization for any cause. Multiple observational studies have reported the superiority of lithium over various pharmacologic agents as monotherapy maintenance treatment, with lower rates of hospital readmissions and suicide-related events. Once confined to adult patients, recent data have shown that youths with bipolar disorder experience similar benefits in decreased suicidality and depression when treated with lithium.

It’s not like patients take lithium and then they are suddenly better. They’re better and better over years and years…
Dr Nassir Ghaemi

Yet, the declining rates of lithium use indicate that such positive results are not swaying clinicians. This is of particular concern to Ghaemi, who traces the trend back to the emergence of alternative long-term treatments for bipolar therapy.



Billions of Years Old, Lithium Still Has a Promising Future 2

Dr Nassir Ghaemi

“My generation became skeptical partly because of the rise of anticonvulsants like Depakote [sodium valproate] and carbamazepine in the ’80s and ’90s,” he said. “The companies that made those drugs often tried to get on the market by bashing lithium.”

Although Ghaemi and colleagues have highlighted what they see as crucial flaws in the design of studies with competitor drugs, he noted that such arguments are at risk of being drowned out. A natural substance without a patent, lithium lacks the considerable financial resources of its competitors. Ghaemi believes decades of antilithium marketing have taken their toll on clinician perception.

“When you have a drug that’s effective, to knock it down and for people to ignore it has been, in my opinion, one of the huge public health disasters of the last few decades,” he said.

Unlike other treatments that address psychiatric symptoms quickly, lithium’s effects must build up over a relatively long period, which may also serve to dissuade clinicians from its use.

“It’s not like patients take lithium and then they are suddenly better. They’re better and better over years and years, so clinicians don’t connect it to lithium,” said Ghaemi. “I don’t think people see the clinical effects as clearly as the reality.”

There may also be residual concerns regarding lithium’s toxicity, although meta-analysis data suggest it does not pose a significant risk for impaired renal function in most patients. It is associated with a low rate of end-stage renal failure. Poven dosing strategies circumvent other side effects as well.

The increasing reticence to use lithium comes at a time when its therapeutic potential is being investigated for conditions other than bipolar depression. Randomized controlled trials have determined that lithium, particularly as an add-on therapy, is an effective treatment of unipolar major depressive disorder. Lithium’s ability to prevent suicide has been proven in double-blind, placebo-controlled randomized trials, a distinction that it holds alone among medications. Lithium also may contribute to a reduction in risk for dementia and exhibits neuroprotective qualities.

Multiple epidemiologic studies have shown that rates of dementia, suicide, and mood disorders are lower among populations whose water sources are rich in lithium. That these effects are obtained with concentrations of lithium far below those in therapeutic formulations indicates a possible role for low-dose therapy.

Whether these avenues of investigation will result in viable applications depends largely on a research community willing to take them up, although the financial restrictions to doing so are even greater than in the years following John Cade’s discovery. Yet, any researchers choosing to do so would be joining a storied lineage of those whose contributions, once seemingly minor, eventually coalesced into a revolutionary treatment.

As Cade himself once self-effacingly said, “I am not a scientist. I am only an old prospector who happened to pick up a nugget.”

Seventy years since his discovery, it appears that there is still much prospecting to be done.

John Watson is a freelance writer in Philadelphia, Pennsylvania.

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