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New drug comment - escitalopram
Editor, – I refer to comments regarding escitalopram ('New drugs' Aust Prescr 2003;26:146-51). Only one study that investigated the efficacy of escitalopram in the treatment of major depression1 was cited in the article, when four other studies were available at the time of writing.2345 The review concludes that escitalopram is a generic strategy.
Regulatory bodies advocate that companies must recognise the existence of chirality, that they should attempt to separate enantiomers, that the contribution of individual stereoisomers to the activity of interest should be assessed and that a rational decision regarding what stereoisomer to market should be made.6
The technology to separate the enantiomers of citalopram on a commercial scale has only recently been developed.
Preclinical studies have demonstrated that the antidepressant effect of citalopram resides primarily with the S-enantiomer.7 Escitalopram alone affects serotonin levels more effectively than escitalopram in combination with the R-enantiomer.8 The R-enantiomer decreases the association of the S-enantiomer with the human serotonin transporter via an allosteric mechanism.9 The R-enantiomer thus inhibits the active S-enantiomer.
A pooled analysis4 provided a sample size adequate for statistical comparisons between escitalopram and citalopram to be made. The results suggest that escitalopram may be superior to citalopram in terms of speed of onset and magnitude of clinical effects.
A meta-analysis10 has shown that escitalopram-treated patients have significantly higher response rates and an increased mean change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) at weeks one and eight when compared with citalopram. This superiority was more apparent with severely depressed patients.
Pharmacoeconomic analyses have found escitalopram has cost-effectiveness and cost-utility advantages over some other SSRIs and venlafaxine.11
Medical Affairs Manager
Baulkham Hills, NSW
Lundbeck was invited to supply Australian Prescriber with information about escitalopram during the preparation of the new drug comment. The company informed the Editor that it would not release information because it was confidential. However, following publication of the new drug comment the company has supplied a dossier of data, including the previously confidential information. The Editorial Executive Committee welcomes the change of position by the company and hopes it will be an example other companies will follow. The additional information does not provide strong evidence that escitalopram has a clear clinical advantage over citalopram. Only two (references 3 and 5) of the four other studies included both drugs in humans. Reference 2 compares escitalopram with placebo, and reference 4 is a pooled analysis of other studies. Reference 5 was a combined study of patients and Polish rats, but it compared each drug with placebo rather than with each other. While reference 3 shows that significantly more patients were in remission after eight weeks of escitalopram than after citalopram (52% versus 43%), neither treatment was significantly better than placebo. The mean change in the 60 point Montgomery-Asberg Depression Rating Scale (MADRS) was 15 points with escitalopram, 13.6 points with citalopram and 12 points with placebo.
It is not entirely clear which three studies were included in the pooled analysis (reference 4), but they are probably included in the company-sponsored meta-analysis (reference 10). The meta-analysis includes references 1, 3, an unpublished study and a conference abstract. While the unpublished study tended to favour citalopram, the meta-analysis showed a higher response rate with escitalopram (55.5% versus 50.8%). The mean change in the MADRS after eight weeks was approximately one point greater with escitalopram than with citalopram (1.02, confidence interval 0.09-1.95). None of the studies showed that patients responded significantly faster to escitalopram although the meta-analysis found an estimated difference of 0.63 (confidence interval 0.08-1.17) in the mean change in MADRS from week one of treatment. The clinical relevance of this difference is debatable.
The Pharmaceutical Benefits Advisory Committee has also concluded that the data do not demonstrate that escitalopram has superior efficacy to citalopram.
- Wiborg O, Sanchez C. R-citalopram decreases the association of [H]-S-citalopram with the human serotonin transporter by an allosteric mechanism [poster presented at the 16th Congress of the European College of Neuropsychopharmacology; 2003 September 20-24; Prague, Czech Republic]. Eur Coll Neuropsychopharmacol 2003;13(S4) .