A Brief History of Lithium - In Case You're Wondering Why Your Doctor Never Prescribed It
Last week, we discussed lithium in the novel context of a neuroprotective agent. This week, we will look at lithium in its traditional role as treatment for bipolar disorder.
The story typically begins in 1949, the year the Australian psychiatrist John Cade published his seminal research, but let’s fast-forward to 1999, the year I was diagnosed. By then, the pharmaceutical companies were in a full-court press marketing lithium’s competition - mood-stabilizers and new-generation (atypical) antipsychotics.
Let's start with mood stabilizers ...
The psychiatric historian (and psychiatrist) David Healy notes that the term, “mood stabilizer,” was dreamed up by marketers. These were anti-epileptic agents pressed into service to treat bipolar. They were mood stabilizers only in the industry’s imagination, as they displayed little or no efficacy in working both sides of the bipolar equation.
At the time of my diagnosis, the clinical trial evidence for mood-stabilizers ranged from sketchy to nonexistent to proved worthless. In brief:
The sketchy - In 1995, the FDA approved Depakote for the treatment of bipolar mania. The approval was based on two trials running just a few weeks.
The nonexistent- Tegretol, used off-label by doctors, never received an FDA indication for bipolar. Years later, a generic manufacturer gained approval for “Equetro” based on two three-week trials. Meanwhile, doctors were using Lamictal off-label for treating bipolar depression. Its manufacturer, GSK, ran a series of trials that failed to demonstrate efficacy. Only later, as part of a settlement, would these studies become public. The company later achieved an FDA bipolar indication based on two relapse prevention studies.
The worthless - In a 2004 settlement, Warner-Lambert (now part of Pfizer) agreed to pay $430 million in fines for its illegal off-label promotion of Neurontin. Clinical trials found the med of no value in treating mania. Also worthless, Topamax.
Meanwhile, on the antipsychotics front ...
Antipsychotics were originally indicated for the treatment of schizophrenia. When I was diagnosed in 1999, there were two newer-generation antipsychotics FDA-approved for treating mania in bipolar - Risperdal and Zyprexa, both based on trials lasting a few weeks. Another antipsychotic, Seroquel, was being used off-label for the purpose, and would eventually earn its FDA bipolar merit badge (for mania, and later bipolar depression).
Also, soon after my diagnosis, Geodon would hit the market, followed by Abilify a year or two later. Both drugs first received a schizophrenia indication, followed by a bipolar mania indication.
At the time, though the weight-gain effects of most of these meds were well-known, the metabolic and diabetes risks were not appreciated.
Meanwhile, regarding lithium ...
Inspired by John Cade’s discovery, the Danish psychiatrist Mogens Schou conducted his own studies into the safety and efficacy of lithium. The issue here was whether lithium was effective over the long-term at preventing relapse.
This is worth special emphasis. In the 1950s, Dr Schou produced evidence of short-term efficacy, equivalent to the type of data that drug manufacturers would produce decades later to obtain FDA approval for the likes of Depakote and Zyprexa.
Dr Schou’s results failed to impress the psychiatric establishment of the day. Part of this had to do with psychiatry’s love affair with Freud. But doctors also demanded evidence more convincing than a mere short-term fix. It was only when Schou produced that evidence (in the late sixties and 1970) that lithium gained respect. An FDA indication followed soon after.
The lithium saga continues ...
In an article in the British Journal of Psychiatry in 2001 - two years after I was diagnosed - the research tag team of Baldessarini and Tondo noted that the evidence for lithium as a long-term agent was supported by “at least 10” double-blind studies, which “far exceeds the available support for possible alternatives to lithium treatment.” Moreover, lithium was the only known agent shown to reduce the risk of suicide.
But there is a twist to the story. Studies conducted some two decades after Schou failed to match his stellar results or those of his contemporaries. (In one Schou study, only the patients in the placebo group relapsed.)
Lithium probably became the victim of its own success. Doctors were now far more liberal in applying the bipolar diagnosis, which translated to more problematic patients in their study cohorts.
Moreover, if you follow patients around long enough, you will find that they eventually relapse. This is essentially what Tondo and Balderassini discovered when they tracked patients on lithium over a number of years. These patients certainly fared better than patients not on lithium, but now the drug was becoming a victim of its own evidence.
In a 1998 journal article, Paul Groff went so far as to assert:
Thus, during the past two decades, the earlier perception of lithium as an effective and specific treatment has been changing from that of a highly valued, long-term treatment to a questionably useful substance of fleeting benefit.
Maybe you can see where this is leading ...
Because lithium is a naturally occurring element with no patent protection, it lacks an industry sponsor. The drug has no marketing budget. Drug reps do not hand out lithium samples to psychiatrists. Industry hacks do not plant pro-lithium “research” articles in medical journals. Academic superstars do not deliver industry-sponsored talks.
In addition, owing to its toxicity at high doses and its long-term effects on kidney and thyroid function, lithium poses a major challenge for clinicians.
By the time of my diagnosis, the drug had fallen out of favor - to the point that psychiatric residents were no longer being taught how to use it. This message was brought out loud and clear by Frederick Goodwin to a packed room at the 2002 American Psychiatric Association Annual Meeting.
Get ready, major irony alert ...
So, in 1999, fifty years after John Cade, thirty years after Mogens Schou’s battles with the establishment, psychiatry had done a complete backflip. Instead of a skeptical profession in thrall to Freud demanding convincing proof of the long-term evidence of a new drug, we now had a new breed of believers of biological psychiatry willing to listen to just about anything their visiting drug reps told them.
Back in the old days, any drug with a sedative effect was regarded as a mere temporary fix. Now the assumption was that the “drug that got you better would keep you better.”
So here I was, in early 1999, barely coherent. The doctor reaches for the prescription pad. On one hand, we have a drug with a long track record, backed by both short and long-term trial evidence, not to mention naturalistic studies, not to mention comprehensive knowledge of the drug’s side effects and risks.
On the other hand, we have a host of industry-sponsored drugs, with little or no clinical trial evidence - certainly none long-term, with incomplete knowledge of the long-term health risks.
Guess which drug I was not prescribed.
More to come ...