The Zyprexa Chronicles: Mauricio Tohen, Part 1

I was poking around Google Scholar and PubMed as is my wont, and ran into something interesting. Mauricio Tohen, an MD and DPh, is listed as author on numerous research papers investigating Zyprexa. Tohen is a major thought leader in the psych research world. He is listed as an author on 435 papers in his career--apparently, the man has no social life--and that includes 39 papers since January 2004. I admire his industry.

In addition, his papers on bipolar disorder, schizophrenia and the use of Zyprexa are cited by one of the largest number of fellow researchers that I have ever seen. In some cases, a paper will have been cited by more than 80 other papers. That's vast influence. He's also the doctor who designs many of the Zyprexa studies (see below).

I give Tohen the title of Dr. Zyprexa or, perhaps, Lord Atypical. At the same time, Tohen is a faculty member at Harvard School of Medicine and works for Eli Lilly in Indianapolis, Ind. Lilly makes Zyprexa. Zyprexa has kind of been in the news of late.

The Harvard/Lilly cross-alliance is an interesting arrangement, one confirmed by looking at Harvard's online phone directory and papers on which he's listed as being Harvard's man in I-Town. In 2003, Tohen told "Special Topics": "Six years ago I joined Lilly Research Laboratories as an investigator, in order to design the studies addressing the use of olanzapine in bipolar disorder. In collaboration with a number of experts in bipolar disorder around the world, I am currently involved in a number of clinical trials that will determine the risks and benefits of the use of olanzapine in the different phases of bipolar disorder."

So, Tohen has been at Lilly since 1997, almost 10 years by now. Why is someone on an academic faculty working at a pharma company and designing studies on Zyprexa and then turning around and co-authoring papers with other prominent researchers, including Harvard's Gary Sachs and Joseph Biderman? Why was he saying in 2003 that he would still need to "determine the risks" of using Zyprexa in bipolar disorder when as early as 1999 he was writing in other papers that Zyprexa was associated with lots of weight gain? Sure, some of those studies were done on schizophrenics, but many were done on bipolars as well. You cannot make the argument that weight gain in schizophrenics wouldn't likely correlate with weight gain in bipolars. In fact, I was told as much by one the CATIE investigators last year. The risks of weight gain and its various consequences were well-known by 2003, as one of the recent New York Times articles traces various marketing memos about weight gain back to 1999.

Two things: one, click on the extended entry link to see a selection of papers Tohen has authored while working for Lilly, Harvard or both; and, two, come back later today when I will have another post on Tohen. We start with some non-Zyprexa papers.

"1995: Is clozapine a mood stabilizer?" He was asking about atypicals as mood stabilizers in 1995. QUOTE: "CONCLUSION: Clozapine monotherapy is an effective mood stabilizer, reducing both the number of affective episodes and rehospitalizations in patients with severe refractory bipolar illness."

Why, yes, yes it is. Assuming you can get past the white-count issues and the death issues.

"1996: Risperidone in the treatment of mania." QUOTE: "Further studies need to be conducted."

And, they were.

1997:"Risperidone in the elderly: a pharmacoepidemiologic study." QUOTE: "Risperidone appeared to be effective and may be safe for many elderly psychiatric patients with comorbid medical conditions provided that doses are low and increased slowly. Particular caution is advised in the presence of cardiovascular disease or cotreatment with other psychotropic agents."

How could it be safe when the study states: "Adverse events occurred in 32% of the patients (36% of those discontinued). These adverse events included hypotension (29%) or symptomatic orthostasis (10%), cardiac arrest (1.6%) with fatality (0.8%), and extrapyramidal effects (11%) or delirium (1.6%)."

1997: "Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment." QUOTE: "Most patients who remained stable for 6 months continued to do so for long periods without medication, indicating clinical heterogeneity."

In other words, psychiatry isn't one size fits all, even in schizophrenia. Makes you wonder about the TIMA, doesn't it? It's not clear which meds were used in this meta-study.

1998: "Clinical predictors of acute response with olanzapine in psychotic mood disorders." QUOTE: "Olanzapine may be a useful alternative or adjunctive treatment for patients with bipolar disorder." AND: "METHOD: In a naturalistic setting, by reviewing medical records, we assessed response to olanzapine and factors associated with response to olanzapine in 150 consecutive patients newly treated with the drug at a nonprofit academic psychiatric hospital."

That hospital? I bet it was McLean. Tohen was working for Lilly at this point.

1998:"Antipsychotic agents and bipolar disorder." QUOTE: "The focus is on neuroleptic drugs, the atypical antipsychotic drugs (risperidone and clozapine), and two (sic) fo the new atypical antipsychotic drugs that were recently approved."

Fo' Shizzle.

1999: "Olanzapine Versus Haloperidol Treatment in First-Episode Psychosis" QUOTE: "In patients experiencing first-episode psychosis, olanzapine had a risk-benefit profile significantly superior to that of haloperidol. The study results suggest that novel antipsychotic agents such as olanzapine should be considered as a preferred option in first-episode psychosis, on the basis of both safety and efficacy advantages."

OK, someone on Lilly's payroll can say this ("preferred option") in a paper he co-authors with Jeff Lieberman (main PI of CATIE study)? Has Lieberman's tune changed?

2000: "Efficacy of Olanzapine in Acute Bipolar Mania" QUOTE: "Olanzapine-treated patients had a statistically significant greater mean (± SD) weight gain than placebo-treated patients (2.1 ± 2.8 vs 0.45 ± 2.3 kg, respectively)."

2001: "A Prospective Open-Label Treatment Trial of Olanzapine Monotherapy in Children and Adolescents with Bipolar Disorder." QUOTE: "Body weight increased significantly over the study (5.0 ± 2.3 kg, p < 0.001)."

Joe Biderman, the child psychiatrist at Harvard is a co-author on this study. He sits on the advisory board of the Child and Adolescent Bipolar Foundation. The study concludes that "Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted." One child in the study was five-years-old. A five-year-old with mania? Average weight gain of 10 pounds?

2001: "Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study." QUOTE: "Forty-one percent of patients were maintained on olanzapine monotherapy. The most common treatment-emergent adverse events reported were somnolence (46.0%), depression (38.9%), and weight gain (36.3%)."

A 49-week continuation study. Of 113 patients, only 46 made it to the end. Similar to the Zyprexa drop out rate in the CATIE study.

2002: "Olanzapine Versus Divalproex in the Treatment of Acute Mania" QUOTE: "Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex."

It's interesting that "54.4% of olanzapine-treated patients responded (>=50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale <=12), compared to 34.1% of divalproex-treated patients." That's not particularly impressive response or remission considering that it was a 3-week study.

2003: "Olanzapine Versus Divalproex Sodium for the Treatment of Acute Mania and Maintenance of Remission: A 47-Week Study" QUOTE: "There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness."

A 47-week study.

2003: "Comparative Efficacy and Safety of Atypical and Conventional Antipsychotic Drugs in First-Episode Psychosis: A Randomized, Double-Blind Trial of Olanzapine Versus Haloperidol" QUOTE: "Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients."

Jeff Lieberman, the main PI on the CATIE study, is lead auhtor of this paper.

2003: "Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome."
QUOTE: "Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients (p<.001). CONCLUSIONS: This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients."

Ten pounds in 8 weeks?

2003: "A 12-Week, Double-blind Comparison of Olanzapine vs Haloperidol in the Treatment of Acute Mania." QUOTE: "These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with weight gain."

That's stating the obvious.

2003: "The McLean-Harvard First-Episode Mania Study: Prediction of Recovery and First Recurrence." QUOTE: "Within 2–4 years of first lifetime hospitalization for mania, all but 2% of patients experienced syndromal recovery, but 28% remained symptomatic, only 43% achieved functional recovery, and 57% switched or had new illness episodes."

It is interesting that this study was cited by 32 different papers, including seven papers investigating Zyprexa. Three of the citations belong to Joe Calabrese, another big player in the bipolar research world, who's done many of the studies around Seroquel.

2004: "Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone." QUOTE: "Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy."

This paper has Joe Calabrese, Charles Bowden, Gary Sachs (Harvard) and Nassir Ghaemi (Harvard) listed as co-authors, all of them bipolar big shots, two of them from the same faculty of which Tohen is a member.

So if we weren't seeing syndrome remission, then why are these same docs still pushing for atypicals to be used as mood stabilizers?

More to come.

Posted by Philip Dawdy at December 19, 2006 10:40 AM
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