Tuesday, October 03, 2006

CUtLASS 1: Newer Antipsychotics Disappoint Again

In the Archives of General Psychiatry this month (October 2006), another blow is dealt to second generation antipsychotic medications. The study, known by the acronym CutLASS 1 indicated that outcomes, including quality of life as well as more traditional symptom-based measures such as the PANSS, were no different for patients taking first-generation antipsychotic medications (FGA) compared to those taking second-generation antipsychotics (SGA). Side effect data also indicated no differences between medication class. In fact, there was a nonsignificant trend favoring slightly better outcomes for those taking FGAs over SGAs.

Full text of the article is available free here.

The study is accompanied by two commentaries in the journal. I admit I was expecting at least one of them to come from an industry-entangled researcher whose conflicted interests would make for laughable pro-SGA flacking. I was wrong. Drs. Robert Rosenheck and Jeffrey Lieberman both aptly point out that the CUtLASS 1 findings are actually not particularly surprising. Indeed, when one considers the results of the CATIE trial (on which Lieberman and Rosenheck were both authors) as well as prior comparisons between FGAs and SGAs, the results from CUtLASS 1 meld in quite nicely. Rosenheck pointed out in a prior article (International Journal of Law and Psychiatry, Secp-Oct 2005) that two-thirds of trials comparing SGAs to haloperidol (Haldol; an FGA) did not allow prophylactic anticholinergic medication use for those taking Haldol. The problem is that Haldol, without concomitant anticholinergic meds, frequently causes side effects that result in early dropout “and can be mistaken for symptoms of schizophrenia” according to Rosenheck’s 2005 piece. Indeed, he pointed out that no study which allowed the recommended side effect control medication to be coadministered with Haldol has found it inferior to an SGA.

Rosenheck, in his current commentary, goes on to cite sources indicating that the cost of antipsychotic medications is currently over $10 billion annually, which is 70% paid by Medicaid (which is paid for by all of us). SGAs vary in cost, but at the extreme, they can cost 100 times as much as FGA’s, and in most cases, the difference is at least fifty-fold. Considering that they seem to have comparable efficacy and likely roughly equivalent safety (with the possible exception of extrapyramidal symptoms), one is left wondering why taxpayers are left footing such an exorbitant bill when equally efficacious medications are available at a fraction of the cost.

Lieberman was particularly quotable in his commentary, so let’s try on a few quotes for size:

First off, referring to the combined findings of CATIE and CUtLASS 1: “These studies found few differences in effectiveness between first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) in nonrefractory patients – a conclusion that runs counter to the impression of many clinicians and previous studies suggesting marked superiority of the SGAs and that belies the huge advantage in market share enjoyed by the SGAs in the United States and other parts of the world. However, the results are generally consistent with numerous meta-analyses carried out in the past decade in an effort to discern a clearer picture of the comparative effectiveness of antipsychotic drugs that could be derived from any previous individual trial (p. 1069).”

Next: “The second reason for the disparity in results between CUtLASS 1/CATIE and previous studies is that the claims of superiority for the SGAs were greatly exaggerated… the aggressive marketing of these drugs may have contributed to this enhanced perception of their effectiveness in the absence of empirical evidence (p. 1070).”

Lieberman also points out that many prior FGA-SGA comparison studies failed to allow concomitant anticholinergic medications for the FGA group and administered the FGAs at doses where side effects at moderate to high doses. This, of course, maximized FGA dropout and side effect rates while likely reducing efficacy.

One more eminent quote from Lieberman: “...any reasoned and objective view of the evidence in light of CUtLASS 1 and CATIE must lead to the conclusion that with the possible exception of clozapine, the SGAs are not the great breakthrough in therapeutics they were once thought to be; rather, they represent an incremental advance at best (p. 1071).”

My View: SGA = FGA. We’ll see how it pans out on the EPS issue, since SGAs were pimped heavily as being much less likely to induce movement disorders. The jury is still out on this issue, but more recent research seems to favor equivalence between classes. Crazy idea: Why not make a new class of antipsychotics rather than making a bunch of me-too’s in the SGA class? That would require a real investment in R & D, so don’t bet on it.

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