The Zyprexa Chronicles: Mauricio Tohen, Part 2

Prevention has always been the goal of the psychcopharmacological revolution. Preventing relapses of mania, psychosis and depression, be they full-blown on sub-syndromal, is claimed as the chief good of the revolution and is certainly part and parcel of pharma advertising.

At the center of many studies, prospective or not, on assessing preventing relapses and, indeed, of preventing first occurrences has been Mauricio Tohen. He's a professor of psychiatry at Harvard and, at the same time, an employee of Eli Lilly, makers of Zyprexa among other psych meds. Tohen is variously described in Lilly documents as "Lilly Research Fellow and Leader of the Zyprexa Product Team" or as a "distinguished scientist." He is also described in at least one paper as a "major shareholder" of Eli Lilly. It is rare that any of his scientific papers note his stock ownership.

As I noted yesterday, he is a thought leader in the world of psychiatry, especially in regards to schizophrenia and bipolar disorder. He has published 435 papers and key findings are cited by by as many as 80-plus other papers. Tohen has vast influence in the psych world.

I appreciate his dedication to research on prevention, but I have my qualms about his research motivations playing out while he sits on an academic faculty and works for a major pharmaceutical corporation in which he owns many shares of stock and whose products he designs studies for and authors papers on. That's conflict of interest, straight, no-chaser.

Anyhow, let's take a look at two recent prevention studies in which Tohen was involved, since they are illustrative of many of the issues around that particular ideology. The first is controversial, the second damn interesting.

In the first, which I posted on in May, researchers at Yale gave Zyprexa to teens deemed to be at-risk of developing psychosis but who'd never had an episode. Tohen was a co-author of the study. As I noted at the time:

"Study authors concluded that the drug didn't prevent psychosis, but perhaps only delayed its onset. But they couldn't--or wouldn't--say for sure whether that alleged delaying (a few months, tops) was the result of some patients taking the drug and getting a benefit from it. But, then, only 16 percent of the patients who took the drug received a benefit at all....But, then, Eli Lilly paid for the study, so what do you expect the docs to say? You know what's coming. They called for further studies to bear out their findings. Why do these guys always act like the jury is still out on both a drug and class of medication that have been widely-discredited?"

In terms of prevention, the study failed. It also raised serious questions among other researchers about the study's ethics. From a letter to the American Journal of Psychiatry in October, written by a clinical professor at Oregon Health Sciences University:

"In addition to the patients’ average weight gain of 19 lbs, I am concerned with what other biopsychosocial repercussions there were for these young men and women after they were placed on the neuroleptic, without a clear indication, for a year. Isn’t our first and foremost obligation to 'do no harm'?"

The letter led to this response from the lead author, but you can bet it was cleared with Tohen (Lilly paid for the study):

"Prevention is a new concept to psychiatry. We are used to functioning as post hoc diagnosticians and interventionists. Prevention interventions are common in other medical specialties and, by definition, they involve prescribing active treatments to a mixture of true positive and false positive persons. The clearest example is cholesterol lowering pharmacotherapy. As prevention, the strategy treats risk (high cholesterol) not disorder (coronary heart disease), and the vast majority of those treated are false positives."

I, too, have major questions about the ethics of giving teens, children and adults psych meds before they are clearly indicated. Here's why: days after that exchange of letters in October, John McManamy passed along the following:

"Last night, I was at a gala NAMI fundraiser in DC. BMS was picking up the tab. The Pres or VP of BMS Neuroscience [Bristol Myers Squibb] got up to say his perfunctory two or three words, which turned out to be a shameless promotion for Abilify. Among other things, he mentioned psychiatric meds in the context of prevention. He specifically used as an example of patients who have never had a heart attack taking heart meds. One guess what he was driving at?

If we were talking about an illness we actually knew something about, in a population with a very high risk probability of onset, with drugs that were predictably effective and tolerable then the conversation would be a lot different."

I agree with John wholeheartedly, but then I guess such amusing arrogance coupled with commercial interests and advocacy is what you should expect from NAMI and Big Pharma these days. The sad truth of mental illness is that there will always be relapses and recurrences of symptoms. Which brings me to the second Tohen paper.

In July 2005, Tohen was lead author (along with Harvard's Gary Sachs, Case Wetsern's Joe Calabrese, UBC's Lakshmi Yatham and Texas's Charles Bowden, all major authors of bipolar disorder papers as well as folks who are heavily involved in deciding what bipolar disorder and its subtypes are) of a 12-month study of Zyprexa vs. Lithium in maintenance treatment of bipolar disorder. In essence, Tohen was testing whether Zyprexa was a mood stabilizer and whether it or Lithium could prevent relapses.

The study found that relapses occurred in 30 percent of Zyprexa treated patients and in 38.8 percent of Lithium treated patients. That strikes me as fairly prototypical of what most bipolars, especially those with bipolar 1, would see in the course of a year. It also strikes me that there was no essential difference between the two drugs in their preventative abilities. An 8 percent difference in the real world ain't shit.

Tohen reasoned differently:

"The noninferiority of olanzapine relative to lithium (primary objective) in preventing relapse/recurrence was met, since the lower limit of the 95% confidence interval on the 8.8% risk difference (–0.1% to 17.8%) exceeded the predefined noninferiority margin (–7.3%)....These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium cotreatment."

That's a stretch, especially since the paper does not note in any fashion Tohen's major shareholder status with Lilly. He does give a rather tangled statistical justification for his assertion in the paper and the stats-jock readers of this site are encouraged to review it.

As I noted above, relapses will always happen for almost anyone with a mental illness. As tasty a goal as prevention might sound to patients and as profitable as it might be for pharma companies, it is time for the mental health world to stop making that our collective polestar. Docs have been slapping patients with meds since the 1940s and researching newer ones along the way, yet nothing has changed no matter how bold the initial evidence might seem for a particular medication or class of drugs. I am not arguing that we give up, but that we spend our resources and efforts on more important and more easily-reachable goals.

The key is to keeping patients alive and in harnessing their human determination to move on with their lives and co-exist with their relapses. That strikes me as a more useful--and noble--goal than expecting patients to take meds that give them all manner of metabolic complaints, don't work especially well and cost hundreds of dollars a month.

Posted by Philip Dawdy at December 20, 2006 12:01 AM
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