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In the 1950s, Mogan Shu was fresh out of residency training. He staked his career and his family on a mineral most of his colleagues dismissed as dangerous nonsense. This is the story of how lithium went from a fringe wellness fad to the gold standard for bipolar disorder and the bitter scientific battle that nearly derailed it. Welcome to the Carlite Psychiatry podcast, Keeping psychiatry honest since 2003.
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I'm Chris Aiken, the editor in chief of the Carlat Psychiatry Report.
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And I'm Kelly Newsom, a psychiatric NP and a dedicated reader of every issue.
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But first, a correction. I've realized we have pronounced Dr. Sco's name incorrectly on this podcast. At times, the correct pronunciation is Moen Scoe. There's a silent G in Moen. The year is 1951. Mogan Shue has just read a report on 10 patients whose mania resolved with lithium. The young Danish psychiatrist had enrolled in medical school hoping to find a way to treat mood disorders, inspired in part by his brother's experience with recurrent depression. Dr. Xu's father, himself a prominent psychiatrist, had delivered pointed lectures, dismissing lithium as a useless fad built on an erroneous theory. But his father's generation had not discovered anything else for mania. Antipsychotics were still a few years away. Shue figured lithium was worthy of further investigation, and he knew of a new method to test randomization.
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Three years earlier, Austin Bradford Hill had published the first randomized control trial, a 1948 study of streptomycin and tuberculosis. But no one had taken randomization to psychiatry, and Xu decided to change that. Using a coin flip, he randomly allocated 38 manic patients to lithium or placebo. After two weeks, lithium worked, surpassing placebo on a crude three point scale of mania. And then Xu noticed something else in the data that still holds up as one of the most useful pearls in lithium therapy. Dr. Xu divided the patients into classic and atypical bipolars. The classic cases looked like textbook manic depression, pure manias, an episodic course, clear recovery between episodes. The atypical cases had mood, incongruent delusions, catatonia, and less distinct episodes. Lithium worked in 90% of the classic cases, but only 60% of the atypical ones. This observation has become one of the most replicative findings in lithium research. About one in three patients with bipolar disorder fits this classic type, and they may be bipolar one or bipolar two. But when you see it, the euphoric manias are hypomanias, followed by depression. Lithium is very likely to work and keep working.
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These classic Bipolar patients tend to have onset in their teenage years around 15 to 20. They have long periods of euthymia between episodes and a pattern where depression tends to follow. The manias or hypomanias, as if following the law of what comes up must come down. The atypical patients, they might still respond to lithium, but they're less likely to achieve a full recovery on it. These atypical cases often have an earlier onset in childhood or around puberty. They don't recover all the way between episodes, whether because of temperamental instability, continuous residual symptoms, often a mixed in nature, or because of comorbidities like anxiety, ocd, eating disorders, personality disorders or substance use. All of those things are more common in the atypical bipolar cases. So they have a lot of mixed states and early onset and they don't tend to recover all the way. These are the patients who tell us, I don't know what normal is.
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Lithium was slow to catch on. By 1959, Shu had counted only 359 reports of patients on lithium in the medical literature. But that was about to change. The invention of the Coleman flame photometer in 1958 made it possible to measure lithium levels more accurately and easily. Lithium spread. The first reported use in the US came out of the University of Michigan in ANN ARBOR In 1960, at least the first non bromide lithium. As he worked with it, Hsu came to believe lithium was more than a symptomatic treatment. Patients who stayed on it had long recoveries. A few complained of emotional or cognitive blunting, something we still see today when the dose is too high. But lithium didn't affect emotions the way barbiturates or stimulants did. That comparison mattered because the most popular treatment for manic depression in the 1950s was a barbiturate amphetamine combination pill branded as dexamil. Dextroamphetamine paired with amobarbital. It was even called a mood stabilizer. At the time. The amphetamine treated the depression. The amobarbital sedated the mania. Xu observed that patients felt better on this combination, but they didn't function better. They didn't have the long term stability he was seeing with lithium. So Dr. Xu coined a new term, mood normalizer, to distinguish lithium and set out to test its long term effects in clinical trials.
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The landmark paper was a long time coming. In 1967, Hsu and colleagues published the first long term mirror image study of lithium, so called because it looked at episode rates before and after starting the drug. A mirror image the results were striking. Lithium reduced the frequency and duration of new episodes five to ten fold, and nearly 80% of patients on lithium had no relapses at all during their treatment. But to prove this conclusively, they needed a placebo control. That came in August 1970 with a double blind comparison of a discontinuation trial published in the Lancet. At first, the editors rejected the paper, thinking that lithium had already garnered too much publicity. But they changed their mind at the urging of other psychiatrists.
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Here's a preview of the CME quiz for this episode. Start earning CME through the link in the show. Notes. What is the main advantage of antipsychotics over lithium in acute mania? A faster onset B fewer side effects C greater benefits in depression D better functional outcomes. Every scientific revolution has its opponents. Leading the charge against lithium were two British psychiatrists from the Maudsley Hospital, Aubrey Lewis and Michael Shepard, and another Brit who had migrated to the University of Cincinnati, Barry Blackwell. Lewis was the most influential British psychiatrist of his era. He favored a psychosocial view of mental illness and thought lithium was dangerous nonsense, lumping it with other therapies. He disapproved of ECT and insulin coma therapy. His younger colleagues were more open to biological treatments, but preferred intramuscular chlorpromazine for mania, arguing that mania was a rare disorder and that manic patients would refuse oral medication. Every time Hsu's group published, the Maudsley gang swooped in to point out holes in the science. And after each criticism, Hsu returned with a better trial. In 1970, this back and forth culminated in a placebo controlled double blind trial, showing that lithium not only treated mania, but prevented it. But shepherd and Blackwell did not back down. They had one argument left and they used it, claiming the blind must have been broken. Patients, they wrote, could detect whether they were on lithium or placebo because of subliminal changes in mental state, specifically alterations in REM sleep.
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Today we call this functional unblinding. Blackwell used a more ominous phrase, calling it awareness of subterfuge. It sounds like a stretch here, arguing that lithium caused subtle improvements in sleep quality, which might have tipped off the subjects to the fact that they got the active treatment and not the placebo. And and then somehow this optimism sparked enough to prevent mania. What? It may be a stretch, but Blackwell does have a point. Functional unblinding is important in psychiatric research, including with lithium. Around 60 to 70% of patients taking lithium in a supposedly double blind trial can correctly identify their treatment. But if we discard trials on Those grounds we would have to discard just about every treatment in psychiatry. We see similar rates of unblinding with antidepressants in the 60 to 70% range and much higher rates approaching 95% with ketamine and psychedelics.
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A few years after running his first lithium trial in the 1950s, Shue's brother began taking the drug and experienced full remission from his debilitating cycles of yearly depressions. That family connection fueled Shue's work, but it also became a liability after he published the long term Mirror Image trial. Xu was so convinced of lithium's preventative benefits that he initially resisted testing it against placebo. He wrote that it might be unethical to subject patients, for example, my brother, to a 50% chance of receiving placebo and possibly facing a suicide. Eventually, Hsu relented, but when the attacks on lithium continued, he began to suspect that this familial connection was fueling the skepticism against him.
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Here's what he the crucial point in the conflict with Shepard and the Maudsley Group seems to have been reached when I told them how the disease course of my brother, who for 25 years had depressions every spring, changed drastically on lithium. To shepherd, this was apparently the final testimony of my folly and more or less proved that lithium was ineffective. He did not seem to understand that my personal involvement made me extra motivated to put the efficacy of the treatment on the firmest possible ground and to study closely its side effects and risks.
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The acrimony went further. Shepherd wrote editorials calling Mogan Xu an enthusiast, and rumors circulated within the Maudsley group that Hsu himself was taking lithium for manic depression. Xu was forced to respond, I am
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not a manic depressive and never was in lithium treatment, but what difference would it make should data, arguments and conclusions presented by an insane person be disregarded rather than judged on its own merits?
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The debate spilled into medical and cardiology journals. The acrimony was ugly, but the debates also drew attention to a drug that otherwise had no industry sponsor, no marketing budget, and no seat at the table. Without Shepherd's contrarian stance, Shue might never have conducted the placebo controlled trial that proved lithium's long term merits, tipping the balance as it moved through the fda.
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All of this debate played out in the late 1960s when lithium was not even available as a prescription medication in the US that changed in 1970 when the FDA approved lithium for acute mania, followed by an approval for prevention of bipolar in 1974. This was a rare example where the agency reclassified a natural substance as a prescription medicine. I don't know of any other examples of this in psychiatry, unless we count cannabidiol for seizures or psilocybin, that magical mushroom that actually isn't yet approved. Back then, approvals were not as costly, and two pharmaceutical companies paid for the application. Both of them had patents on a controlled release formulation of lithium. By the end of the 1970s, lithium's ability to prevent new episodes in bipolar disorder was well established. Fred Goodwin captured the state of the field in a 1979 paper comparing lithium to antipsychotics in mania. Antipsychotics worked faster, he concluded, but carried more side effects, while lithium produced better long term outcomes both in overall functioning and in episode recurrence. Those findings hold up today even as antipsychotics have expanded to treat both depression and mania in bipolar. Goodwin's conclusions are echoed in the new treatment guidelines from the International Society of Bipolar Disorders, which recommend lithium first line for new onset bipolar disorder, citing its superior ability to prevent new episodes and improve long term functioning.
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Mogan Xu died in 2005 at the age of 86. He worked up to his final day. When he passed, his computer was still on. He'd been planning a large long term trial to test whether lithium prevented new episodes in unipolar depression. Xu had a hunch that it did, as there were already 21 controlled trials showing this preventative benefit. I'm talking about 21 trials in recurrent unipolar depression, not bipolar, but Shue thought it needed a large trial to really be sure. Ironically, one of those small trials was conducted by his nemesis Matthew Shepard in 1984. Learn how to use lithium in unipolar depression in Dr. Akin's new book, Difficult to Treat Depression. Available in print and audio, the book also covers other mood stabilizers, lamotrigine, carbamazepine and valproate and explores whether they have a role in unipolar depression or better off deprescribed.