Thursday, October 8, 2009

Is Seroquel XR better than generic quetiapine?

A supplement written by Christoph Correll for The Canadian Journal of Diagnosis (September 2009) was delivered--free--into my office mailbox the other day.

It starts off describing the receptor-binding profiles of different atypical antipsychotic drugs. A table is presented early on.

First of all, the table as presented is almost meaningless: it merely shows the concentrations of the different drugs required to block 50% of the given receptors. These so-called "Ki" concentrations have little meaning, particularly for comparing between one drug and another, UNLESS one has a clear idea of what concentrations the given drugs actually reach when administered at typical doses.

So, of course, quetiapine has much higher Ki concentrations for most receptors, compared to risperidone -- this is related to the fact that quetiapine doses are in the hundreds of milligrams, whereas risperidone doses are less than ten milligrams (these dose differences are not reflective of anything clinically relevant, and only pertain to the size of the tablet needed).

A much more meaningful chart would show one of the following:

1) the receptor blockades for each drug when the drug is administered at typical doses

2) the relative receptor blockade compared to a common receptor (so, for example, the ratio between receptor blockades of H1 or M1 or 5-HT2 compared to D2, for each drug).

The article goes on to explore a variety of other interesting differences between antipsychotics. Many of the statements made were theoretical propositions, not necessarily well-proven empirically. But in general I found this discussion valuable.

Despite apparent efforts for the author to be fair and balanced regarding the different antipsychotics, I note a few things:

1) there are two charts in this article showing symptom improvements in bipolar disorder among patients taking quetiapine extended-release (Seroquel XR).

2) one large figure appears to show that quetiapine has superior efficacy in treating schizophrenia, compared to olanzapine and risperidone (the only "p<.05 asterisk" was for quetiapine!) -- this figure was based on a single 2005 meta-analysis, published in a minor journal, before the CATIE results were published. No other figures were shown based on more recent results, nor was clozapine included in any figure.

I think quetiapine is a good drug. BUT -- I don't see any evidence that quetiapine extended release is actually any better, in any regard, than regular quetiapine. In fact, I have seen several patients for whom regular quetiapine suited them better than extended-release, and for whom a smaller total daily dose was needed.

Here is a reference to one study, done by Astra-Zeneca, comparing Seroquel with Seroquel XR, in healthy subjects: It shows that subjects given regular quetiapine were much more sedated 1 hour after dosing, compared to those given the same dose of Seroquel XR. It implies that the extended release drug was superior in terms of side-effects. Here is my critique of this study: first of all, sedation is often a goal in giving quetiapine, particularly in the treatment of psychosis or mania. Secondly, problematic sedation is usually the type that persists 12 hours or more after the dose, as opposed to one hour after the dose. In this study, the two different formulations did not differ in a statistically significant way with respect to sedation 7, 8 or 14 hours after dosing. In fact, if you look closely at the tables presented within the article, you can see that the Seroquel XR group actually had slightly higher sedation scores 14 hours after dosing. Thirdly, dosing of any drug can be titrated to optimal effect. Regular quetiapine need not be given at exactly the same dose as quetiapine XR--to give both drugs at the same dose, rather than at the optimally effective dose for each, is likely to bias the results greatly. Fourth, this study lasted only 5 days for each drug ! In order to meaningfully compare effectiveness or side-effects between two different drugs, it is necessary to look at differences after a month, or after a year, of continuous treatment. For most sedating drugs, problematic sedation diminishes after a period of weeks or months. Once again, if immediate sedation is the measure of side-effect adversity, then this study is biased in favour of Seroquel XR. Fifth, the study was done in healthy subjects who did not have active symptoms to treat. This reminds me of giving insulin to non-diabetic subjects, and comparing the side-effects of the different insulin preparations: the choice of population is an obvious strong bias!

Regular quetiapine has gone generic.

Quetiapine extended-release (Seroquel XR) has not.

I am bothered by the possibility of bias in Correll's article.

It is noted, in small print at the very end of this article, that Dr. Correll is "an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Organon, Ortho McNeill-Janssen, Otsuka, Pfizer, Solvay, Supernus, and Vanda." AstraZeneca is the company which manufactures Seroquel XR.

In conlusion, I agree that there are obviously differences in receptor binding profiles between these different drugs. There are some side-effect differences.

Differences in actual effectiveness, as shown in comparative studies, are minimal. But probably olanzapine, and especially clozapine, are slightly better than the others, in terms of symptom control.

Quetiapine can be an excellent drug. Seroquel XR can be an excellent formulation of quetiapine, and might suit some people better.

BUT -- there is no evidence that brand-name Seroquel XR is superior to generic regular quetiapine.

One individual might respond better to one drug, compared to another.

The author, despite including 40 references, seems to have left out many important research studies on differences between antipsychotics, such as from CATIE and SOHO.

(see my previous post on antipsychotics: )

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