31 minute read
Feature Story: Lithium: Battering mania
Lithium:
Battering Mania
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Rebecca J. Anderson, PhD
While working as a prison warden’s administrative assistant in 1985, Risdon Slate began suffering from insomnia. Because the South Carolina prison had just performed a couple of executions in quick succession, Slate was diagnosed with “situational depression” by his family physician, who prescribed the antidepressant, amitriptyline (1, 2).
In 1986, Slate took a job as a probation officer (1-3). After some stressful encounters with a parolee, he again experienced insomnia and began selfmedicating with alcohol (2).
While in Miami for federal probation officer training, Slate got into an argument with a man at the hotel bar. Slate thought he was in an episode of the 1980s TV drama, Miami Vice, and that the man was an actor (1-3).
When police arrived, Slate insisted on speaking only to Sonny Crockett, the central character in Miami Vice (3). Within two weeks, Slate resigned his job for medical reasons, and his wife announced she was divorcing him (1).
A South Carolina psychiatrist finally got to the source of Slate’s problems. His diagnosis was bipolar
disorder, and he told Slate that amitriptyline was the wrong medicine. Antidepressants exacerbate mania. “It’s like putting jet fuel on the fire” (1). Instead, he prescribed lithium.
Salt of the Earth
Lithium is an alkaline metal. It was discovered in 1817 in mineral ore in Sweden. Although the name comes from lithos, the Greek word for stone, lithium is also found in seawater, mineral springs, and meteorites (4-6). There are also tiny amounts in both plant and animal matter (5).
In 1818, scientists found that powdered lithium glows crimson red when ignited, making it a key ingredient in red fireworks (4, 5). Its chief use today is in electronics and lithium-ion batteries, but it has long been used in medicine.
In 1859, Alfred Baring Garrod reported using lithium carbonate as a remedy for gout (7-9). If blood uric acid is high (for example, from eating purine-rich foods like meat and fish), uric acid crystalizes in the joints causing pain, and, in the kidneys, forming stones.
The idea behind Garrod’s treatment was that lithium salts are very soluble and could dissolve the uric acid deposits around gouty joints (10, 11). Physicians came to believe that excess uric acid was responsible for many other maladies, and they prescribed lithium as the treatment (7, 10).
When lithium was discovered in mineral springs, people sought those natural waters to cure rheumatism, diabetes, asthma, and other ailments, as well as gout. Among the high-profile spas in the US was Lithia Springs, Georgia, whose clientele included the Vanderbilts, Mark Twain, and Presidents Cleveland, Taft, McKinley, and Theodore Roosevelt (7).
In 1894, the Danish brothers Carl and Fritz Lange reported favorable results using lithium carbonate in 35 patients with mild depression. They attributed their success to the alleged effect on uric acid (7-10). Interestingly, they chose doses of lithium that are comparable to those currently used for bipolar illness (7).
The Lange brothers published in Danish, later translated only into German. So, few practitioners outside of Denmark knew about their work. Even in Denmark, doctors discounted the results, because by then, studies had shown that ingesting lithium had no effect on uric acid (6, 7, 10).
7-Up
Lithium beer was brewed and marketed in Wisconsin (4, 7). In 1929, a patent medicine called “BibLabel Lithiated Lemon-Lime Soda” was introduced as a mood booster and cure for hangover (4, 7, 8). Lithium citrate was one of its seven ingredients, and in 1936, the name was shortened to 7-Up (6, 7).
By the mid-20th century, the medical community had discarded lithium as a credible treatment for anything, and the US Food and Drug Administration (FDA) banned lithium from beer and soft drinks (6, 7).
Re-introducing lithium as a bona fide medicine took the valiant efforts of a free-spirited Australian and a persistent Dane.
Common Cause
From an early age, John Cade and Mogens Schou were familiar with mentally ill patients. Their fathers were both psychiatrists. The Cade family’s home was on the grounds of Mont Park Hospital for the Insane, where the senior Cade was superintendent. Schou’s father was director of two psychiatric hospitals in Denmark, and several of his relatives suffered from mental illness (6, 7, 12).
In the 1930s, Cade and Schou followed their fathers and became physicians. Their training included Emil Kraepelin’s seminal Compendium of Psychiatry. Kraepelin, widely regarded as the founder of modern psychiatry, developed a method for classifying psychiatric disorders that is still used today (7). In the second volume of his Compendium, he described “manic-depressive insanity,” which was later renamed manic-depressive illness, and more recently, bipolar disorder (6).
Many treatments for mental illness were tried, mostly with minimal success. Insulin-induced comas could temporarily alleviate schizophrenia
symptoms but were less effective in manic-depressive illness, especially in the depressed phase (7). Electroconvulsive therapy (ECT), introduced in 1938, calmed patients suffering from mania and shortened attacks of depression. ECT remains an effective treatment for depression, but it does not prevent future attacks, which require repeated ECT (7, 9, 13).
Cade and Schou were also familiar with Freudian psychoanalysis, the prevailing dogma at the time. But they both sought biochemical causes of mental illness (6). If biochemical abnormalities could be identified, then it might be possible to find truly effective pharmacological treatments.
Cade’s Journey
After graduating from medical school, Cade was appointed medical officer at Beechworth Mental Hospital (6). In parallel, he pursued postgraduate work for an MD. At that time in Australia, the MD was analogous to a PhD and meant for doctors wishing to pursue clinical research (6, 7). The graduate work required in-depth knowledge of physiology, pathology, immunology, and clinical medicine, including the history of medicine.
One of Cade’s first research efforts,albeit observational, was investigating the extensive bruising on some of the patients at Beechworth. Others might have dismissed this as unnecessary force by the staff or patient-inflicted assaults. But Cade investigated the bruises methodically from a medical perspective, rather than psychiatry, and found a lack of vitamin C in the patients’ diet (6, 7). Further review of patients at Beechworth and Mont Park Mental Hospital, where his father was superintendent, revealed that scurvy from lack of vitamin C was widespread (6, 7). Through Cade’s efforts, fresh fruits and vegetables were added to the meals at all of the mental hospitals in the state of Victoria.
Australian psychiatrist John Cade discovered the use of lithium as a treatment for bipolar disorder.
Changi POW
Cade received his MD in 1938 and simultaneously moved to Bundoora Repatriation Mental Hospital as a junior medical officer. Unfortunately, his plans to continue research were interrupted in 1939 when Australia entered World War II. Although Cade was married with two sons, he enlisted and was posted to the 2nd/9th Field Ambulance as a captain (6, 7).
Shortly after his unit’s arrival on the Malay Peninsula, Cade was promoted to major. When Japan invaded Malaya, Cade, along with thousands of Australian and British troops, became prisoners of war (POWs) at Changi prison camp on the island of Singapore (6, 14).
Officially, Cade was a regimental medical officer, but because of his experience with mental illness, he was put in charge of Changi’s small psychiatric ward. He also consulted on psychiatric cases in the general hospital wards. The troops affectionately called him the “Mad Major” (6, 7).
Cade did his best to treat a wide range of problems with limited resources. The meager rice rations caused many cases of beriberi, pellagra, and painful rashes. Cade and his medical colleagues devised several concoctions, attempting to provide essential vitamins, and conducted controlled studies to assess their relative benefits. A local grass proved to be rich in riboflavin, and they used it to make a bitter, light orange soup. The men called it Tiger’s Piss (6, 7).
Cade’s views on mental illness were profoundly influenced by his experiences in Changi (6). He kept detailed records, and when patients who had exhibited apparent mental illness died, he conducted autopsies. A manic soldier had suffered a massive subdural hematoma. In an uncoordinated hysterical sergeant, Cade saw extensive loss of myelin in the central nervous system (6, 7).
Cade was probably wrong when he thought guinea pigs were tranquilized by lithium. But he saw something remarkable, and his nimble mind concluded that lithium was worth pursuing—in patients.
Cade found psychoanalysis of limited value. He once defined it as “the art of describing the commonplace in terms of the incomprehensible” (7). Many of the POWs were demoralized and distressed, but stress alone did not seem to cause mental illness. And trying to alter psychiatric symptoms with psychoanalysis was an “absolute failure” (6).
This, along with his autopsy results and the nutrition experiments, convinced Cade that mental illness resulted from an underlying biological or physical problem. “I could see that so many of the psychiatric patients suffering from the so-called functional psychoses appeared to be sick people in the medical sense. This fired my ambition to discover their etiology” (7).
Despite the horrors of Changi, Cade did everything he could to protect his men and keep up their morale. His colleagues admired his medical and psychiatric expertise. The troops held him in high regard for his level-headedness, resilience, courage, honesty, and compassion (7).
Formerly robust and athletic, Cade returned from Changi in 1945, after three and a half years as a POW, weighing about 90 pounds (7, 14). He was frustrated at the lost time away from his family and profession.
He told his wife:“The old brain box is simmering with ideas. I believe this long period of waiting has allowed many of my notions in psychiatry to crystallize, and I’m just bursting to put them to the test. If they work out, they would represent a great advance in the knowledge of manic-depressive insanity and primary dementia” (7).
Testing Urine
After a few months’ recuperation, Cade returned to Bundoora Repatriation Mental Hospital and lived with his family in a house on the hospital grounds (6, 14). Most of his patients were ex-soldiers.
He was a prodigious reader, and his now-classic experiments began with reading Recent Advances in Endocrinology (6). He was intrigued by the effect of thyroid hormones on behavior. An overactive thyroid gland can cause agitation and restless thought. An underactive thyroid causes sluggishness, impaired memory, and depression.
This reinforced his notion that brain function should be viewed biochemically (6). He had already seen psychological changes in his patients due to vitamin deficiencies, and his autopsies revealed pathologies in the brains of mentally disturbed POWs.
Cade speculated that an excess of some unknown chemical made patients manic, and perhaps a deficiency of this same chemical caused depression (6, 7). Because he had limited resources, he began by examining urine, looking for excess of some chemical component in manic patients (15).
He worked in his garage, but as the jars of urine accumulated, he looked for better facilities. Fortunately, there was an empty pantry in a ward that had just been built but not yet occupied (6). It had a bench, sink, and hot and cold water but no refrigeration. Cade stored the jars of urine on the top shelf of the family’s refrigerator, and he set up his guinea pig pens in the family’s garden (6, 7).
Cade injected guinea pigs with the patients’ urine in stepwise amounts to determine the lethal dose. Large volumes of urine always killed the guinea pigs, but he found that urine from the manic patients was particularly toxic (6, 7, 10). This turned out to be false. The urine of manic patients is actually no more lethal than any other sort of urine (6). But this observation spurred him to continue.
Next, he tried to determine the substance in urine that was responsible for toxicity. Of urine’s major components, urea seemed to kill the guinea pigs similar to whole urine. Unfortunately, the urine from his manic patients contained no more urea than the urine from other patients (6, 7, 10).
In a somewhat illogical leap, he then imagined that some other chemical might be enhancing the toxicity of urea. Of the chemicals he tested, uric acid slightly enhanced urea’s toxicity. Unfortunately, he could not complete the dose-response curve, because uric acid is only sparingly soluble in water (3, 6, 7, 10). To
overcome this, he switched to lithium urate, the most soluble salt of uric acid.
A Right from Two Wrongs
To his surprise, lithium urate reduced the toxicity of urea (3, 7, 10). So, he repeated the experiment using lithium carbonate, to see if lithium might be responsible for this unexpected finding (3, 10). An 8% solution of urea caused five of ten guinea pigs to die. When he added lithium carbonate to the urea solution, all ten guinea pigs survived (15).
In his next experiment, Cade tested the effect of lithium carbonate alone. Guinea pigs have a robust startle response. But after injecting lithium carbonate, he could turn them on their backs, and instead of their usual frantic righting reflex, they merely lay there placidly (15).
Later, other investigators were unable to reproduce Cade’s results unless they injected animals with large, toxic doses of lithium. Rather than a beneficial tranquilizing effect, Cade’s guinea pigs were probably showing early signs of lithium poisoning (6, 7).
Cade was wrong when he concluded that urine from manic patients was more toxic than other urine. He was also probably wrong when he thought guinea pigs were tranquilized by lithium. But he saw something remarkable, and his nimble mind concluded that lithium was worth pursuing, in patients (6, 7).
Clinical Proof
After ingesting lithium himself to ensure that it was safe, Cade began his groundbreaking clinical studies (3, 10). The first subject was Bill Brand, a 51-yearold man who had suffered manic-depressive illness for 30 years. He had been admitted to Bundoora in September 1943 and was considered the most troublesome patient on the ward (15). Initially, Bill responded well to ECT treatment, but after a few months his mania returned. Repeated ECT had no effect (6). By the start of 1948, Bill was in a more-orless continuous manic state (15).
On March 6, 1948, Cade noted that Bill’s blood uric acid was “extremely high,” which he used to justify lithium treatment (6).
On March 29, 1948, Cade began administering lithium citrate, using the historical literature on the treatment of gout to guide his dose selection (15). Within days, Bill was noticeably quieter, and he steadily improved. Because lithium citrate caused nausea and vomiting, Cade switched to lithium carbonate. On July 9, 1948, Bill was discharged, perfectly well, with instructions to take a maintenance dose of 300 mg lithium carbonate, twice daily (15).
Cade proceeded to treat nine additional manic patients with lithium. Many had been in and out of asylums their entire lives, and they all improved to some degree on lithium (15).
Cade also administered lithium to six schizophrenic patients, but he saw “no fundamental improvement” (15). Three of them had been unusually restless, noisy, and shouting nonsensical abuse. During lithium treatment, they became quiet and agreeable, and Cade could discontinue their routinely prescribed doses of nighttime sedatives. When lithium treatment was stopped, they reverted to their previous schizophrenic state (15).
Cade was concerned that lithium might precipitate a depressive episode in patients who suffered recurrent depression. But he saw no evidence of that (15).
Cade conducted his animal and clinical studies alone (6). But he did discuss his findings with colleagues at medical meetings, and he published his results in September 1949 (15).
BIPOLAR DISORDER
Typically, bipolar disorder first appears in late adolescence or early adulthood. Manic episodes might last for days, weeks, or months. The person might experience recurring manic episodes or, just as likely, plummets into a profound state of depression and despair. Between episodes, the person is perfectly well and can function normally for months or years. But then, inevitably, another attack occurs. In untreated manic-depression, early death is common, and suicide rates are high.
A Salty Setback
Cade’s unprecedented results sparked curiosity, interest, and excitement among Australian psychiatrists (6). Some of them began treating their manic patients
with lithium. But his work received no notice beyond Australia, neither accolades nor criticism, for two reasons.
First, Cade published his findings in the Medical Journal of Australia, which was not widely circulated outside of Australia. So, the global medical community was largely unaware of his findings.
Second, and more impactful, were new reports of lithium toxicity, which were published concurrently in the US (5, 16).
In the late 1940s, doctors advised patients who suffered from hypertension to cut their salt consumption. Low-sodium diets are bland, and US companies devised alternatives to table salt that would satisfy the patients’ desire for a salty seasoning without increasing blood pressure (6, 7). At least four manufacturers came up with lithium chloride, which they marketed quite profitably in the US (6).
In March 1949, four papers appeared in JAMA suggesting that the lithium salt substitutes were toxic. From the time of Garrod and the treatment of gout, the narrow therapeutic window of lithium was well-known. Lithium can disturb thyroid activity and interfere with kidney function, leading to kidney failure (3, 7). High doses cause nausea, vomiting, and tremors, leading to seizures, coma, and death (7).
In general, using lithium chloride as a salt substitute was not harmful (5). But excessive consumption could be dangerous, especially in patients with comorbidities, such as congestive heart failure or cerebral arteriosclerosis. Patients on a low-sodium diet seemed to be especially susceptible to lithium toxicity (5, 11, 16).
Collectively, the JAMA reports described only 16 case histories (6). The three patients who died had consumed excessive amounts of lithium chloride, but widespread news coverage amplified the issue and caused a public outcry (6, 7). The FDA advised consumers to “Stop using this dangerous poison at once,” and US manufacturers withdrew their salt substitute products (6, 8, 11).
Cade’s Caution
When Cade submitted his 1949 paper, he may not have been aware of the publicity in the US, but he was certainly aware of lithium’s side effects. His paper reported his observations of abdominal pain, anorexia, nausea, vomiting, mild diarrhea, giddiness, tremors, ataxia, slurred speech, and muscle twitches (15). He advised close monitoring of patients and adjusting the lithium dose accordingly.
Bill Brand’s case exemplified how difficult it was to maintain a patient within that narrow therapeutic window. After Cade’s paper appeared, Bill’s manic episodes re-emerged, and Cade increased the lithium dose, which caused burning abdominal pain and nausea. Stopping treatment eased the side effects, but Bill relapsed (6). For months, Bill and Cade were at odds, vacillating between higher doses of lithium (which controlled Bill’s mania but caused great discomfort) and stopping treatment (which eased the side effects but triggered a relapse).
Cade’s final round of treatment in the spring of 1950 was a massive 2.6 grams of lithium three times daily (6). It calmed Bill’s manic symptoms, but he lapsed into a semi-coma and had three seizures (7). Bill died on May 23, 1950 (6, 7). There was no autopsy, but Cade reported to the coroner that Bill’s death was due to a combination of lithium toxicity and chronic mania (6).
A handful of Australian psychiatrists (mostly at longterm mental hospitals) were successfully treating their manic-depressive patients with lithium. But around the same time as Bill’s death, they reported that two additional Australian patients had died from lithium toxicity (6, 7).
Those patient deaths, along with the salt substitute cases in the US, convinced Cade that lithium’s potential for harm outweighed its benefits, and he stopped using it (7). In 1952, Cade became superintendent at Melbourne’s prestigious Royal Park Mental Hospital, and he banned lithium’s use there. He conducted no further research on lithium, but he actively solicited and compiled reports from psychiatrists on the efficacy and toxicity of lithium (7).
Flaming Success
Among the Australian clinicians who were successfully treating patients with lithium were Edward
Trautner and Charles Noack (6, 7). Trautner, a refugee from Nazi Germany, had earned his medical degree in Berlin and obtained an appointment in the physiology department at the University of Melbourne. He was a scientific polymath with research expertise ranging from animal and plant physiology to brain biochemistry (7).
Noack, a new psychiatrist at Melbourne’s Mont Park Hospital and a former student of Trautner’s, had seen Cade’s paper and was interested in trying lithium. Noack asked Trautner for advice, and together they conducted a clinical study (7).
They gave lithium to over 100 psychiatric patients, including more than 30 with mania (7). Mindful of lithium’s toxicity and the recent lithium fatalities, Trautner arranged for blood level measurements.
Victor Wynn, a research fellow in the physiology department, had developed a method for accurately measuring potassium, sodium, and calcium levels using flame photometry, a new technology at the time. Trautner asked Wynn to use his flame photometer to measure lithium in the patients’ blood samples (7).
Noack and Trautner’s results, which were published in August 1951, were consistent with Cade’s findings. Thanks to their blood level measurements, they could define the therapeutic window, which they reported to be between 0.6 and 1.2 mEq/l (7, 17). None of their patients died or developed serious toxicity.
Blood level monitoring was a major breakthrough. Doctors could now titrate the therapeutic dose of lithium.
Following Noack’s study, Trautner teamed with Samuel Gershon to conduct a series of clinical studies (6, 7, 17). Polish by birth, Gershon was educated in Australia, including a residency in psychiatry and fellowships in physiology and pharmacology (17). By the end of 1952, Gershon and Trautner were administering lithium to patients at numerous hospitals around Melbourne.
At Royal Park Mental Hospital, Cade eased his restriction and allowed his psychiatrists to dispense
lithium. Because of diligent blood level monitoring, no lithium-related deaths were reported in the Australian state of Victoria after 1953 (6).
Schou’s Journey
Meanwhile, in Denmark, Erik Strömgren, the head of Aarhus University’s Risskov Psychiatric Hospital, had seen Noack and Trautner’s paper. He referred the paper to Mogens Schou, who had recently arrived at the clinic as a research associate and was looking for a biological research topic (7, 10, 12). Schou received his medical degree from the University of Copenhagen in 1944 and then served residencies in clinical psychiatry at several Scandinavian hospitals (7). In addition to Trautner’s work, Schou soon found Cade’s paper, and he was impressed with the lithium results. But the Australian authors merely described observational cases. Schou and Strömgren realized that a randomized, placebocontrolled clinical trial was still lacking (7, 10, 12). Their study, published in 1954, was the first Schou’s study, controlled trial of lithium published in 1954, in mania, and perhaps, the was the first first randomized controlled clinical trial in psychiatry controlled trial of (7). They treated 38 manic lithium in mania, patients and measured and perhaps, the lithium blood levels (11). Their results were consistent first randomized with the Australian reports. controlled clinical trial Similar to Trautner’s findings, in psychiatry. Schou found the therapeutic window to be between 0.5 and 2.0 mEq/l (11). Like Cade, Schou collected information and reprints about lithium and maintained a database. But unlike Cade, Schou continued clinical trials with lithium, which was the focus of his research for the rest of his career. Because of the stability of the Danish population, he was able to follow his patients for many years (12).
Preventing Attacks
In the early 1960s, Schou received word from two investigators who, though working independently, had both observed that chronic lithium treatment seemed to
prevent recurrence of both manic and depressive episodes in bipolar patients (12).
In his 1954 study, Schou described a patient in whom lithium had stopped outbreaks of both mania and depression, but he had not paid attention to the possible preventative action of the drug (7). Similarly, Cade had anecdotally described the benefits of continuous lithium treatment in Bill Brand and several other patients (14). But subsequently, psychiatrists focused on suppressing manic attacks, and no one had systematically studied the effects of lithium on depressive episodes (7).
In view of these new reports, Schou decided to take another look. He collaborated with Poul Baastrup, a psychiatrist in Glostrup, Denmark. Over the next 6 years, they treated 88 bipolar and unipolar patients at Glostrup Psychiatric Hospital. During lithium treatment, the patients experienced markedly fewer manic and depressive episodes (12). Patients who stopped taking lithium suffered recurrences.
Best Buddies
In late 1963, Schou sent a letter to John Cade (6, 7). He explained that his brother had suffered from unstable moods and had been in and out of mental asylums for 25 years. Every spring, he suffered an episode, which lasted for several months and rendered him unable to work. ECT and other drugs had failed, but within weeks of starting lithium treatment, he improved. Maintenance doses of lithium completely prevented the annual relapses, and he was functionally cured (6, 7).
Schou’s clinical studies impressed Cade. Over the years, they developed a deep friendship and mutually praised each other’s work. They also hosted each other’s visits to Denmark and Australia (6, 7).
Countering Criticism
Schou and Baastrup published their findings in 1967 (7). Soon, psychiatrists throughout Scandinavia and continental Europe were prescribing lithium as a prophylactic treatment, and they confirmed the Danish results (12).
Unlike Schou’s 1954 study, the 1967 prophylaxis study had started on an exploratory basis and gradually grew, so it was not randomized or placebo-controlled (12). This left Schou and Baastrup open to criticism, and the harshest critics were Michael Shephard and Barry Blackwell at Maudsley Hospital in London.
In the decades before evidence-based medicine, the Maudsley psychiatrists prided themselves on rigorous evaluation of alleged psychiatric treatments, and in fact, they had debunked a number of bogus treatments (6, 7). Although they never conducted lithium studies themselves, they published a harsh critique of Schou’s study in The Lancet in 1968 (13, 18).
Shephard and Blackwell faulted Schou’s patient selection criteria, statistics, criteria for establishing prophylaxis, lack of blinding, and lack of placebo control (18). Those criticisms were justified, but the Maudsley group went further, accusing Schou of bias, because he had successfully treated his brother with lithium, making him a “believer” who lacked scientific objectivity (12).
Schou and Baastrup acknowledged the deficiencies in their open-label, observational study. They followed up with a controlled trial, but they agonized over using a placebo control. They didn’t want to prolong patient suffering and possibly trigger suicides by withholding a drug that they were convinced was highly beneficial (19). They finally settled on a double-blind discontinuation protocol as the most ethical option.
The study enrolled 84 women with manicdepressive disorder or with recurrent depressive disorder at Glostrup Psychiatric Hospital. All of them had been well-managed on lithium for at least a year (12, 19). Under double-blind conditions, the patients were randomized to either continue taking lithium or switched to placebo. Patients who relapsed during the trial were given lithium, without telling the observers or patient whether she had been in the lithium or placebo group. This protocol design exposed the fewest patients to placebo for the shortest time (12).
The results were definitive. Of the 39 patients on placebo, 21 relapsed during the five-month trial, but none of the 45 patients in the lithium group relapsed (19). It was clear evidence that lithium prevented manic and depressive attacks.
The study was published in 1970, and over the next few years, investigators in other countries confirmed
the findings using various protocol designs (12, 13). Lithium soon became the prophylactic drug of choice worldwide (12). Today, this preventative effect is recognized as lithium’s most important benefit (7).
FDA Approval
By the mid-1960s, a number of European countries had approved lithium for manic-depressive illness (9). But the FDA lagged far behind, for two reasons.
First, during and after World War II, a large number of European psychotherapists immigrated to the US. Some of them had been in Freud’s inner circle. They reinforced America’s general acceptance of psychoanalysis as the gold standard for treating almost all mental illnesses. Some therapists believed that drugs actually interfered with the psychoanalysis process (7).
Second, FDA officials still remembered lithium toxicity from the salt substitute debacle, and lithium fell outside the usual procedure for drug approval. Lithium salts could not be patented and therefore offered no financial incentive to drug companies (7, 20). It was unclear who (if not a drug company) would file a New Drug Application (NDA) for lithium and what data it should contain (7).
Also, the first effective drugs for schizophrenia (chlorpromazine) and depression (imipramine) had been discovered in the mid-1950s. Drug companies vigorously marketed them, and psychiatrists readily prescribed them (7).
Despite the popularity of the new psychiatric drugs, a few psychiatrists remained lithium champions, including Samuel Gershon, who emigrated from Australia to the US in 1963 (17). As a Pfizer Fellow at the University of Michigan, Gershon and his colleagues bought kilograms of lithium from a chemical supply company for a trial funded by the National Institute of Mental Health (NIMH) (9).
Because lithium was an investigational drug, psychiatrists could use it legally only by submitting an Investigational New Drug (IND) application to the FDA. INDs were meant for researchers who intended to conduct clinical studies, but most psychiatrists simply wanted lithium to give to their patients. Hundreds of other psychiatrists formed a sort of “lithium underground,” prescribing it without bothering to file an IND (7, 9).
By the end of the 1960s, clinical reports on lithium were appearing in the American medical literature, and the American Psychiatric Association set up a lithium task force, including Gershon, to prepare prescribing recommendations (7). Gershon and others also lobbied the NIMH, FDA, and anyone else who would listen, pushing for general lithium availability (4, 7).
The American College of Neuropsychopharmacology (serving as the sponsor) began preparing an NDA for lithium. This became unnecessary when Pfizer and a small pharmaceutical company, Rowell Laboratories, submitted their own regulatory applications (7, 20). They gathered enough data, with the assistance of Gershon and four other psychiatrists, to show that lithium was effective in bipolar disorder and (with blood, thyroid, and kidney monitoring) was safe (4).
In 1970, the US became the 50th country to approve lithium for mania (3, 9, 10). One lithium advocate cynically suggested that FDA officials granted approval simply to avoid having to process the flood of IND applications from individual psychiatrists (7).
In 1974, on the strength of a large US study, the FDA extended its approval of lithium to include prophylactic treatment of recurrent manic-depressive illness (7, 9, 12). The FDA’s approval served as an endorsement and convinced clinics around the world to administer lithium. Research, publications, and treatment of manicdepressive illness with lithium skyrocketed (6, 7).
Recognition
Although some called Cade’s discovery serendipitous, Schou always defended his friend. “To make therapeutic discoveries on the basis of misinterpreted experiments,” he said, “required curiosity, daring, luck, and compassion for the patients” (7). Cade and Schou both lectured extensively on lithium to general practitioners, psychiatrists, hospital
physicians, and patient groups worldwide and received numerous awards (12).
In 1974, Cade and Schou shared the world’s richest prize in psychiatry, the International Kittay Scientific Foundation Award (6, 7). In 1987, Schou received the Lasker Award in Clinical Medical Research for his lithium work.
Stopping Suicide
Manic-depressive patients are 10 to 20 times more likely to kill themselves than the general population (7, 21). Depression poses the greatest risk, but impulsivity, agitation, and aggression are also contributing factors. These patients also suffer high rates of alcoholism and substance abuse and a higher death rate from natural causes, particularly cardiovascular disease (7).
As psychiatrists conducted further clinical studies, they found that lithium-treated patients were 10 to 15 times less likely to attempt or complete a suicide (7, 8, 12). Although individual study results vary, a recent meta-analysis of clinical data from the past 40 years concluded that “the evidence to date is overwhelmingly in favor of lithium as an antisuicidal agent” (22). No other psychiatric drug has demonstrated this anti-suicidal effect (3, 7, 12).
Other Treatments
Despite its superior efficacy and low cost, only about 10% of American bipolar patients take lithium. In the mid-1980s, psychiatrists began prescribing the anticonvulsant, valproate, off-label (7, 0).
Later, clinical trials showed that valproate was effective in alleviating mania and preventing manicdepressive episodes. It was less effective than lithium and does not appear to have lithium’s anti-suicide effect. But it has a wider safety margin and does not require blood, thyroid, and kidney monitoring (7).
The FDA approved valproate for bipolar disorder in 1995 (7, 9). Like several other anticonvulsants, valproate can cause fetal abnormalities, but it was aggressively marketed for bipolar disorder and became more widely used in the US than lithium.
Despite lack of drug company marketing, the constant introduction of vigorously promoted but less effective alternative drugs, and the perception that lithium is tricky to use, research on lithium continues to affirm its unique value (7).
Risdon Slate took lithium for 30 years and relapsed only once, when he was taken off lithium for 2 months (1). He married again, got a job teaching at a community college, and earned his PhD in criminal justice. He is currently a criminology professor at Florida Southern College, advocates for the decriminalization of mental illness, and helps to train law enforcement officers in skills for compassionately managing those in mental crisis. He recently switched to valproate, because his kidney function was worsening. But he says, “Lithium saved my life” (1).
References
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Biosketch:
Rebecca J. Anderson holds a bachelor’s in chemistry from Coe College and earned her doctorate in pharmacology from Georgetown University. She has 25 years of experience in pharmaceutical research and development and now works as a technical writer. Her most recent book is Nevirapine and the Quest to End Pediatric AIDS. Email rebeccanderson@msn.com.
In the next issue of The Pharmacologist…
Dr. Anderson will feature American biochemist, pharmacologist and Nobel Prize recipient Gertrude Elion
