TMAP: they knew…

Posted on Friday 3 June 2011

The TMAP/Janssen suit in Texas [coming this month: TMAP finally goes on trial…] has been postponed yet again from June 21st to sometime in November. Meanwhile, I’ve been thinking about the state of things back in those early TMAP days. From today’s perspective, the TMAP Schizophrenia Algorithm seems absurd. It isn’t really an algorithm. It’s more like a command – "USE ATYPICAL ANTIPSYCHOTICS." They claimed that it was based on a series of "facts" – determined by authors John A. Chiles and Alexander L. Miller:
Only three of those "facts" would point towards choosing the expensive Atypicals over the older neuroleptics [in red]. We now know that there are some other parameters – weight gain and diabetes for example. I’ve already covered Quitepine [Seroquel] and Olanzapine [Zyprexa]. In the case of Zyprexa, the weight gain was known early, though the propensity towards diabetes was downplayed. With Seroquel, AstraZeneca did its best to deny both. But I never reviewed the approval studies for Risperdal, mainly because I couldn’t find them on the FDA site. That site is spotty, posting irratically, and all I found was safety information – not efficacy. I went back and looked and discovered that the original studies were there [at least partially] in a later review

They submitted two identical studies: USA-79 and INT-6. They were both Active Comparator Trials [Risperdal versus Haldol]. In USA-79, Risperdal won in both the time to relapse race [primary outcome] and in the PANSS scores, significantly beating Haldol in both positive and negative symptom reduction [secondary outcome]:

In INT-6, there was no significant statistical difference between Risperdal and Haldol in anything. That was interpreted as evidence of efficacy, but not of superiority to Haldol:

reformatted to match USA-79

Adverse events were pooled for the two studies:

As they say, the adverse events due to drug effects are similar [EPSris>EPShal].

So when it’s all said and done, in the initial Risperdal studies available at the time, Risperdal only really fit one of the "facts" – "…reduces the likelihood of tardive dyskinesia". At that point, the weight gain and diabetes potential was not publicly apparent.

We, of course, knew a lot more later. With CATIE [Clinical Antipsychotic Trials in Intervention Effectiveness][an N.I.M.H. funded study][2005]  and the European schizophrenia outpatient health outcomes study [financed by Eli Lilly][2010], the efficacy comparisons were finally solidified:



And as for EPS and TD:



Then in February 2004, the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity collectively issued a Consensus Development Statement from a Panel in November 2003 concerning weight gain and Diabetes:
Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes
American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity
Diabetes Care 27:596–601, 2004.

The SGAs are of great benefit to a wide variety of people with psychiatric disorders. As with all drugs, SGAs are associated with undesirable side effects. One constellation of adverse effects is an increased risk for obesity, diabetes, and dyslipidemia. The etiology of the increased risk for metabolic abnormalities is uncertain, but their prevalence seems correlated to an increase in body weight often seen in patients taking an SGA. Direct drug effects on β-cell function and insulin action could also be involved, since there is insufficient information to rule out this possibility. In the general population, being overweight or obese also carries a much higher risk of diabetes and dyslipidemia. These three adverse conditions are closely linked, and their prevalence appears to differ depending on the SGA used. Clozapine and olanzapine are associated with the greatest weight gain and highest occurrence of diabetes and dyslipidemia. Risperidone and quetiapine appear to have intermediate effects. Aripiprozole and ziprasidone are associated with little or no significant weight gain, diabetes, or dyslipidemia, although they have not been used as extensively as the other agents.

Drug Weight Diabetes  Lipids

Clozapine +++ + +
Olanzapine +++ + +
Risperidone ++ D D
Quetiapine ++ D D
Aripiprazole * +/−
Ziprasidone * +/−

+ = increase effect; − = no effect; D = discrepant results
* = Newer drugs with limited long-term data.

The choice of SGA for a specific patient depends on many factors. The likelihood of developing severe metabolic disease should also be an important consideration. When prescribing an SGA, a commitment to baseline screening and follow-up monitoring is essential in order to mitigate the likelihood of developing CVD, diabetes, or other diabetes complications.
CATIE confirmed the weight gain hierarchy:
My apologies for so much posting of old news, but there’s a point I’m trying to make and I wanted all the points visible. In those original trials for Risperdal, they already knew the things that others had to spend millions to prove later. They knew about the weight gain. They knew that the "negative symptom" success couldn’t be reproduced in the second study. They knew that the incidence of EPS was similar to the typical antipsychotics. They knew that the incidence of Tardive Dyskinesia was decreased, but significant [the same in USA-79 as in the EUR SCHIZ study]. As was the case later with Zyprexa and Seroquel [TMAP: a devil in this machine…], what they told us about their drugs was what we wanted to hear, and what they wished was true – not what was true, even in their earliest studies. Further, the authors of the TMAP Schizophrenia Algorithm surely must’ve known the truth…

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