Forest Laboratories, Inc. announced the results of a pre-clinical study that may provide a potential explanation why the investigational selective serotonin reuptake inhibitor (SSRI) Lexapro (escitalopram oxalate) has been shown in clinical trials to be more than twice as potent as the widely prescribed antidepressant Celexa (citalopram HBr).

The microdialysis study results were presented at the 23rd Collegium Internationale Neuro-Psychopharmacologium (CINP) Congress in Montreal.

Lexapro is the single-active isomer of Celexa, a racemic mixture with two mirror-image halves called the S- and R-enantiomers.

The new study shows that Lexapro (the S-enantiomer of citalopram), when given at 2 mg/kg subcutaneously (s.c.), was more than twice as potent as Celexa at 4 mg/kg s.c. (2.0 mg/kg S-enantiomer + 2.0 mg/kg R-enantiomer) in increasing brain serotonin levels (about 300 percent vs. 200 percent, respectively). In contrast to Lexapro, the R-enantiomer of citalopram, when given at 2.5 mg/kg s.c., did not increase brain serotonin levels.

"The results suggest that the R-enantiomer, when given as part of racemic Celexa, decreases the ability of the S-enantiomer to increase serotonin levels in the brain," said Jack Gorman, M.D., Lieber Professor and Vice Chair for Research at the College of Physicians and Surgeons, Columbia University. "This is significant because the data demonstrate that Lexapro when given alone is more than twice as potent as when an equal amount of the S-enantiomer is given in combination with the same amount of the R-enantiomer, as is the case for Celexa."

The mechanism by which the R-enantiomer affects the ability of the S-enantiomer to increase brain serotonin levels is still unknown. It is possible that the R-enantiomer might interfere with the well-known feedback inhibition seen in the serotonin system.

The microdialysis technique allows sampling of small quantities of biological fluids from discrete, closed compartments in the body, such as the brain. The samples can then be subjected to analysis for the determination of concentrations of various drugs, chemicals and/or neurotransmitters. A major advantage of the technique is that it can be performed in the conscious animal. The procedure involves implantation of a microdialysis probe in the desired specific location, in this case the frontal cortex of rat brain.

An added advantage of this technique is that it also permits application of drugs through the microdialysis probe to the area of interest. Thus, one can determine how a particular drug or treatment changes the neurochemistry in a particular brain region without the interference/modulation of the other brain regions or pharmacokinetic considerations.