Lexapro, Celexa, and the difference between red and green jelly beans

If you request Lexapro (escitalopram) for your patient, the PHC formulary requires a trial and failure or a contraindication to two formulary agents, one of which must be citalopram . Why?  Is it just to make things difficult, or is there an actual sensible reason?  The answer has to do with ISOMERS.  Bear with me for a few minutes while I explain what I mean.  Isomers are molecules that have the same atomic structure but are mirror images of each other.  Imagine a 50:50 mixture of red and green jelly beans.  The green jelly beans taste like mint, while the red jelly beans have no taste at all. The red jelly beans won’t hurt you, but they don’t do anything to satisfy your need for jelly beans.  Citalopram can be thought of as a red-green jelly bean mixture.  Lexapro consists of exclusively green jelly beans.  Citalopram is a racemic mixture of the levo isomer – the green jelly beans – and an inactive mirror-image dextro isomer – the red jelly beans.  Half of citalopram is Lexapro (the “L” in Lexapro stands for left).  Chemical mixtures containing both isomers are referred to as RACEMIC mixtures.  About half of all drugs in current use have this handedness property and nearly 90% of recently approved drugs are racemic mixtures.

Many if not most drugs originate as racemic mixtures.  Usually, one of the isomers is active (the EUTOMER) with the other isomer (the DISTOMER) being much less so or inactive.  The distomer usually contributes little to the activity of the drug but can sometimes contribute to toxicity, side effects, or changes in metabolism.  As drugs are usually developed and undergo trials in their racemic forms, those drugs with toxic or interfering distomers are weeded out.

The list of drugs where activity resides in a single isomer is long and includes beta blockers, ACE inhibitors, calcium channel antagonists, and beta agonist bronchodilators.  Other drugs with single active isomers include ethosuximide, propafenone, ofloxacin, moxalactam, warfarin, terfenadine, loratadine, atorvastatin, amphetamine, omeprazole, pantoprazole, and lansoprazole.   In none of these cases is the distomer harmful.  A few drugs have equally active isomers: cyclophosphamide, flecainide, and fluoxetine.  Some drugs metabolically move between isomers.

Isomers may undergo differences in metabolism based upon protein binding, genetics or selectivity of the metabolic pathways.  This is the case with many antiarrhythmic medications and occasionally beta blockers.

Advances in the ability to produce only the eutomer (active isomer) of a current racemic drug has introduced three factors:

  • If produced from a pre-existing racemic drug, a new patent is issued for the pure eutomer drug, lengthening the brand name product life of the original molecule.
  • As the racemic mixtures have previous FDA approval, the pathway to approval of the eutomer is easier.
  • The possibility of improved efficacy.

Pharma’s motivation for the first two is obvious.  Was the timing of the marketing of the eutomer for Pristiq (desvenlafaxine) purely a coincidence of discovery or was it linked to when the patent of Effexor (venlafaxine) ran out?   

The evidence for improved efficacy is less clear.  Examples:  a.) Racemic citalopram (Celexa) showed no clinical benefit in a randomized controlled trial over its more expensive eutomer escitalopram (Lexapro).  b.) The branded eutomer esomeprazole (Nexium) has not shown clinical benefit over pharmacokinetically equally dosed racemic generic omeprazole (Prilosec). c.) Studies comparing generic racemic cetirizine (Zyrtec) to the eutomer levocetirizine (Xyzal ) have not been carried out. d.) The FDA approved the levo isomer of albuterol, levalbuterol, presumably to reduce the side effects of its dextro isomer but studies have failed to support this claim.

The reasoning for the non-formulary status of the costly brand-name-only eutomer form of a medication available in its less-costly generic racemic form is clear.  There is no therapeutic benefit.  The green jelly beans can be enjoyed, while the red ones do no harm, so why pay extra for someone to separate the green from the red?  If Celexa has been used and proven ineffective, there is no reason Lexapro would work, since they both contain the same green jelly beans.

“The concept that a single (isomer) of a chiral drug may be preferable to a racemic mixture is intellectually appealing.  However, in most instances this strategy has not been demonstrated to confer any clinical advantage.”3

Marshall Kubota, MD

  1. Chiral Drugs.  An Overview, Nguyen, L.A., Hue, H., Phan-Huy, Chuong.   International Journal of Biomedical Sciences 2(2), 85-100, Jun 15, 2006
  2. Information Packages on Drugs n. 3-November 2006, Servizio Sanitario Regionale Emilia-Romaga and Centro per La Valutazione dell’Efficacia dell’Assistenza Sanitaria
  3. Therapeutics Letter, June-September 2002.

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