Celexa (Citalopram) has been used in Europe since the late 1980s, and since its introduction in the U.S. market in 1998 it has made steady inroads into the SSRI market, largely because it has the reputation of being unusually well tolerated.

Now we have the newest antidepressant to be approved in the U.S.: Lexapro, which is the purified S-isomer of Celexa.

Like many other antidepressants, the mother compound Celexa is a racemic mixture of two different isomers: R-Celexa and S-Celexa. These two isomers share the same components and configuration, but are non-superimposable mirror images of one another. Early studies by Forest indicated that the effectiveness of Celexa is due largely to the S-isomer, while many of the side effects are caused by the R-isomer. Hence, separating out the S-isomer appeared to make good sense.

Incidentally, the isolation of desirable isomers is the latest rage in pharmaceutical drug development. Isomer purification often leads to advantages such as fewer side effects, better selectivity for their molecular target, higher potency, and cleaner drug-drug interaction profiles. In 1998, fully 69% of newly licensed drugs were single isomers, vs. only 21% in 1991, and 3% in 1983.

Eli Lilly tried this strategy with prozac in the late 1990s, and hoped to market “R-Prozac” as an antidepressant with a shorter half-life and fewer side effects. However, its development was halted because of cardiac side effects at higher doses. Both Paxil and Zoloft already are purified isomers, and were initially introduced to the market as such.

Forest Laboratories appears to have lucked out in its own foray in the enantiomer business. TCR has reviewed two of the pivotal Lexapro studies, and they are intriguing. A fixed dose study (1) randomly assigned 491 depressed outpatients to placebo, Lexapro 10 mg/day, Lexapro 20 mg/day, and Celexa 40 mg/day. Response rates for both Lexapro groups were similar to the Celexa response rate, and all active treatments were superior to placebo. With regard to the important issue of side effects, only the Lexapro 10 mg/day group reported no more adverse events than placebo.

So far so good. We have a “cleaner”, more potent SSRI. But what Forest will really try to push is a more controversial claim: that Lexapro may have a faster onset of action than other SSRIs. This possibility is based on results from three studies comparing Lexapro with Celexa and Placebo, all of which were pooled into one analysis (2). This pooled analysis included 1,321 outpatients with depression, assigned randomly to three groups: Lexapro (n = 520), Celexa (n = 403) and placebo (n = 398). The results showed that Lexapro separated from placebo on the MADRS depression scale by week 1, whereas Celexa didn’t separate until week 6. This trend was even more pronounced in the subgroup of patients who had more severe depression.

Given this pooled analysis data, I predict that Forest reps will rankly speculate that, since Lexapro seems to work a bit faster than Celexa, maybe it works faster than all the other SSRIs. One problem with these results involves dosing. The average comparator dose of Celexa was only 28.9 mg., a dose that many clinicians would consider sub-optimal.

Nonetheless, it is hard to criticize an SSRI that is as well tolerated as placebo at effective antidepressant doses, and which causes essentially no drug-drug interactions.

TCR VERDICT: Big bucks for Forest.

<sub>1. Burke WJ, Gergel I, Bose A. Fixed-Dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002;63:331-336.
2. Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: Pooled analysis of placebo-controlled trials. CNS Spectrums 2002;7 (suppl 1).</sub>