A J Lees

What’s in the 7 Up?

Lithium: A Doctor, a Drug, and a Breakthrough

By

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Lithium is a silvery-white metal that is so light it can float on water and so soft it can be cut with a butter knife. Along with hydrogen and helium it was produced during the Big Bang and so formed the universe before the emergence of the galaxies. It is employed to harden glass and to thicken grease, but its best-known industrial use is in the manufacture of rechargeable batteries. Lithium salts are found in considerable quantities in brine and igneous granite and the element is present in trace quantities in the human body. Lithium is also one of the few metals – along with platinum for cancer, gold for rheumatoid arthritis and bismuth for dyspepsia – that are used as medicines.

In 1949, a 37-year-old Australian doctor called John Cade produced a paper reporting that lithium quietened patients suffering from acute manic excitement. He reminded readers that lithium salts had been commonly used in the 19th century to treat gout and other disorders believed to be associated with high uric acid levels but had disappeared from the pharmacopoeia due to safety concerns. He then went on to describe a series of preclinical experiments he had carried out in a disused kitchen that had led him to consider lithium as a treatment for both manic depression (now often called bipolar disorder) and epilepsy. When injected into guinea pigs, urine collected from patients with mania caused more convulsions and fatalities in the animals than urine from healthy volunteers. Cade suspected that urea might be the toxin responsible for this but was unable to show that the patients with mania had higher levels of it in their urine. Undeterred, he carried out further experiments, which showed that uric acid enhanced the poisonous effects of urea and also neutralised the protective effects of urinary creatinine. Based on knowledge from the existing literature that lithium could dissolve kidney stones containing uric acid, he then injected urea, saturated with lithium urate, into the guinea pigs. The animals did not convulse or die; they became docile and immobile for several hours before fully recovering. Encouraged by this finding, he then started to take lithium salts himself to test their safety, before proceeding with observational trials in patients with life-threatening mania.

Cade had been brought up in the grounds of the mental hospitals where his father worked as a medical superintendent. During the Second World War, he spent three and a half years interned in a Japanese prisoner-of-war camp, serving as a medical officer specialising in mental health. On his return to Australia he was brimming with ideas about psychiatry. He strongly believed that all serious mental illnesses were due to biochemical abnormalities in the brain and that psychoanalysis was useless. He also considered that it was the obligation of all psychiatrists to carry out clinical research in the course of their work.

The Medical Journal of Australia, in which Cade’s paper on lithium was published, was a respected platform for medical research but was not on the radar of the leading figures in American academic psychiatry. Nevertheless, the article was noticed by a few doctors with curious minds. Further small clinical trials in Australia, France and England largely confirmed lithium’s promise. Unfortunately, two patients died, including one of the ten participants in Cade’s original trial. Cade stopped using lithium until the introduction of the measurement of lithium levels in the blood improved safety and further independent trials validated his findings.

During the 1950s and 1960s, an academic psychiatrist called Mogens Schou became lithium’s main champion. In collaboration with Danish colleagues, he carried out a large number of clinical trials that showed that lithium could not only relieve acute mania but also reduce the frequency of relapses of bipolar disorder. In the course of his research he treated twenty-four artists (a mixture of writers, composers and painters). By measuring productivity levels and the quality of their work, he showed that in those who had very severe bipolar disorder (of the type that affected Robert Lowell throughout his life), lithium enhanced their ability to create. Despite the steadily mounting evidence that lithium was a miracle drug that could salvage lives, it remained on the fringes of psychiatric practice, with many leading psychiatrists reluctant to use it. The US Food and Drug Administration (FDA) did not approve its use for the treatment of manic depressive psychosis until 1970.

Walter Brown, a psychiatrist at Brown University with forty years of clinical experience, first witnessed lithium’s positive effects shortly after the drug’s approval. He writes with sadness that the FDA’s tardiness deprived thousands of American citizens throughout the 1960s of a treatment capable of preventing devastating mood swings and reducing the risk of suicide. He states that it was probably no coincidence that company-backed tranquilisers (such as Thorazine), monoamine oxidase inhibitors for treating agitation and depression (such as Nardil and Parnate) and the tricyclic anti-depressants Tofranil and Tryptizol were, by contrast, all rapidly approved by the FDA. Lithium became the Cinderella of the psychotropics, an unpatentable and unprofitable orphan.

Just before Cade’s article was published, Westsal, a substitute for table salt containing 25 per cent lithium chloride, had begun to be sold in the United States. The low-sodium diet recommended for people with heart failure was so bland and unpalatable that a number of them started to spice up their food with large quantities of this new ‘safe’ salt. Some suffered tremors, lethargy and nausea, and after it was implicated in three deaths it was withdrawn from the market. The resulting concerns over lithium’s toxicity and the fact that its mode of action was unclear counted against it with regulators. A risk-averse attitude can prevent tragedies but it can also do harm. Brown tells us that in the twenty years after lithium was finally launched on the market it saved the US economy an estimated $145 billion.

Important breakthroughs in medicine frequently come from the most unlikely  people and places. The main modern challenger to lithium’s primacy as first-line treatment for bipolar disorder is a rebranded anticonvulsant, sodium valproate. Cade was an artist dabbling in science, a dilettante who relied on observation, intuition and a fertile imagination to make inspired connections. After his paper received belated acclaim, he wrote:

I might most kindly describe myself as an enthusiastic amateur, full of curiosity, with fair determination, golden opportunities, inadequate knowledge and woeful technique. But even the small boy, fishing after school in a muddy pond with string and bent pin, occasionally hauls forth a handsome fish.

In the fifty years since lithium was first marketed there have been no major insights into the pathogenesis of bipolar disorder and no major advances into its treatment. Society needs to ask why. Cade put his own success down to academic freedom:

I was able to go my own way unhindered by advice, criticism or caution. This is important. I don’t think it would happen these days. One would be suffocated by hospital boards, research committees, ethical committees and heads of department. Instead I was answering only to my own conscience and personal drive.

Unfortunately, overregulation and the big battalions that dominate modern medical research are making it hard for the ‘little man’ to be heard. Brown warns that ‘such spirits cannot be decanted into a neat cost structure’ but should be fostered when they come along by the scientific community. His beautifully written and insightful book deserves to be widely read by poets and novelists, among whom instances of bipolar disorder are above average, and, more importantly, by all those involved in the regulation and provision of medicines.

In 1929, a lemon-lime soda called Bib-Label containing lithium citrate was launched on the market as a calmative. It was soon renamed 7 Up and became a popular beverage. At around the same time, Lithia Springs in Georgia, USA, grew into a spa resort on the strength of its lithium-rich waters, attracting a number of US presidents. In 1948, when the lithium table salt scare broke, the producers of 7 Up removed lithium from the beverage. With the recent discovery that regions of the world with higher levels of lithium usage have lower suicide rates, it may be time to add a soupçon of lithium into 7 Up again and market it once more as a restorative and tonic. There is certainly as much to commend it as microdosing with psychedelics, a practice now in vogue.

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