Thursday, October 05, 2006

Second generation antipsychotics-efficacy versus effectiveness

In the 1960s, the phenothiazines changed the face of psychiatry when chlorpromazine was shown to be effective treatment for schizophrenia. These first generation antipsychotics (FGAs) are associated with major side effects-namely acute extrapyramidal symptoms and tardive dyskinesia. So when the first of the second generation antipsychotics(SGAs),clozapine,was approved by the FDA and it seemed to be less likely to cause these very troublesome side effects another new era in psychiatric therapeutics seemed to be launched. Other SGAs were developed and approved and were widely accepted and generally believed to not only be more efficacious regarding the so-called negative symptoms of schizophrenia but safer and capable of inducing a better quality of life.The evidence that clozapine did in fact produce superior results in symptom reduction in patients resistant to other drugs is convincing: the question seems to be are the other drugs (five have been approved in the last ten years) in the second generation category also superior.

In 2005 and 2006, two clinical trials (CATIE and CUtLASS1) were published which have raised considerable doubt about the alleged superiority of these SGAs. (Thanks to PHARMAGOSSIP for the reference.)

Dr. Jeffery Lieberman from Columbia Psychiatry Department published an excellent commentary on this issue and his article is available on line full text from the AMA site (go to "Newsroom" and then to "Publications" for the comments found in the October 2006 issue of the Archives of General Psychiatry.Also full text free links to the Studies are found in his reference list)

The issue of the relative value of the FGAs and the SGAs is important per se.Dr. Lieberman's comments not only address that but also the broader issue which can be stated as follows:

How can the following happen-A medication is approved by the FDA based on Phase 2 and Phase 3 RCTs, becomes widely accepted largely replacing the older drugs with that application and then following more Scrutiny and analysis is found to not be any better than the drug(s) it replaced?

He suggests two reasons"

1.The traditional efficacy-effectiveness gap. Things do not always work out the same in the helter-skelter world of clinical medicine as they do in the sometimes cherry picked world of randomized clinical trials. The second Gaultian axiom of evidence based medicine is that "Treatments do not work as well in the clinical practice as they do in randomized trials and they cause more problems".(The first axiom is "The basic fact of clinical trials is that everyone does not respond the same to a particular treatment and almost no one has the average effect")

2.Claims of a drug's superiority were "greatly exaggerated". Drug company hype and overt and sometimes covert promotional activities certainly play a role as does (and this is my contribution to that reason) the sincere desire of physicians to be able to have better tools and be better able to treat their patients. In other words, docs yearn for better drugs and sometimes overlook the weakness of the evidence that is presented.

There will be much more written about whether FGA or SGA are better or safer and neither Dr. Lieberman nor I claim to have the final word.But if there is a lesson here I think it is that because of the efficacy-effectiveness gap a RCT (or even several RCTs) is/are just the beginning of the process of deciding what to do for a given patient; it is not the determining factor and we often cannot really judge the value of a given treatment until there is enough real world clinical experience to see how it really works.


Anonymous said...

"No one has the average effect" reminds me of a prof telling me "the normal pancreas is firmer than normal." Meanwhile, whereas I think most clinical trials are surely based in good intentions, it seems that the not-rare disconnect from office practice reflects inherant and nearly unavoidable biases of investigators.

Michael Rack, MD said...

My opinion on atypicals vs 1st generation antipsychotics is:
1. Clozaril has clearly superior efficacy, Zyprexa is moderately more effective, and the rest of the atypicals are marginally more effective than the 1st generation.
2. Although ALL antipsychotics(old and new) can cause weight gain and diabetes and hypercholesterolemia, the risk is clearly greater with zyprexa and clozaril.
3. Risperidone frequently causes hyperprolactinemia. This commonly causes sexual side effects, including breast enlargement in men. Whether this hyperprolactinemia causes osteoporosis in the long term is unknown.
4. Seroquel, Geodon, and Abilify are reasonable initial choices when an antipsychotic is indicated. Like all of the atypicals, the risk of tardive dyskinesia is lower than the 1st generation drugs. In my opinion, their side effect profile is better than zyprexa/risperidone.
5. Clozaril remains the drug of choice in treatment resistant patients, but because of the risk of agranulocytosis, should not be used initially.