Shannon Williams is a Research Associate who holds a Bachelor of Science degree in chemistry with a minor in English and creative writing from Sweet Briar College. Her research has focused on synthesizing and determining the photochemistry of a novel furanone compound for use as an anti-tumor agent. She also has three years of quality control experience in the printed circuit board industry. At Valisure, Shannon conducts testing of medications on High Performance Liquid Chromatography (HPLC) and DXR.

Citalopram and escitalopram are both active ingredients in medications used to treat depression and other mental health conditions. You may be more familiar with them as Celexa and Lexapro.1 According to GoodRx, the average retail price of a month’s supply of the most popular form of generic citalopram is $162 while the average price of a month’s supply of generic escitalopram is $69.3 You might think that these molecules must be very distinct to have such a difference in cost, but they only differ in one tiny way.

These two molecules have the same chemical formula (C20H21FN2O), but their structures are non-superimposable mirror images of each other. Molecules like these are called stereoisomers. Stereoisomers are molecules that have the same molecular formula and differ only in how their atoms are positioned. Stereoisomers are identified with the designation R or S depending on the arrangement of the atoms bonded to a specific carbon atom. This difference in this arrangement is referred to as chirality or handedness.4 Like your left and right hands, there is no way to align S-citalopram and R-citalopram so that they are identical. The carbon bond highlighted in blue in the image below points out toward your screen in S-citalopram (escitalopram) and points away from you in R-citalopram. The orientation of this bond is like how the position of your thumbs differentiates your left and right hands.

Although this difference in configuration may seem small, the amount of either stereoisomer in a medication can drastically alter its effectiveness. A medication labeled as citalopram is mixture of both stereoisomers while a medication labeled as escitalopram should contain only the S-stereoisomer. Many studies suggest that the escitalopram molecule is better at targeting the specific neuron receptors necessary to prevent the absorption of serotonin, giving patients faster relief from depressive symptoms at a lower dosage and potentially without an increase in side effects.5 Healthcare professionals prescribe 10mg tablets of escitalopram as an equivalent strength alternative to a 20mg citalopram tablet.6 Furthermore, several studies have suggested that R-citalopram may interfere with the effectiveness of escitalopram, although exactly how the molecules clash is not currently well understood. It is possible that when R-citalopram attaches to a serotonin receptor the shape of a nearby serotonin receptor on the same nerve is altered enough to prevent the S-citalopram from attaching to the second receptor7 or shortens the time it can be attached.8  When two S-citaloprams attach to receptors on the same nerve, they may not cause that change in shape, letting them work longer and more effectively.

To obtain pure escitalopram, a separate synthesis process must be used. This separate synthesis must be carefully controlled to prevent the formation of R-citalopram.7 Considering the cost and dosage differences between these two drugs, it is important to have confidence in exactly which compound is in your medication.9

At Valisure, we can determine the composition of citalopram and escitalopram tablets using high performance liquid chromatography (HPLC). This technique injects the dissolved powder of a crushed tablet into a solvent stream leading to a specialized column which separates the compounds in the sample by size, polarity, and in this case, chirality. As the solvent and sample flow through the column, the compounds in the sample are separated according to their chemical properties. Once out of the column, the compounds in the solvent stream are exposed to ultraviolet light and the absorbance of each of those compounds is recorded. Compounds in a sample are identified by comparing them to reference standard material, the purest form of a particular compound. For HPLC, we compare the retention times of the sample compounds with the reference standard’s retention time and quantify the amount of that compound based on the intensity of the signals they produce relative to reference standards of known concentration. With the appropriate column, we can distinguish the two stereoisomers and ensure that the proper compound, or active ingredient, is in the tablets we dispense to our patients.

Figure 1: Spectrum of escitalopram reference standard analyzed with a chiral column. Escitalopram exits the column 7.1 minutes after injection.

Figure 2: Spectrum of citalopram reference standard analyzed with a chiral column. It is clear there are 2 compounds present in approximately equal amounts. The peak that occurs 6.5 minutes after injection is R-citalopram and the peak that occurs 7.1 minutes after injection is S-citalopram.

References

  1. Fookes, C. (Aug 25, 2019). What is the difference between Celexa and Lexapro? https://www.drugs.com/medical-answers/difference-between-celexa-lexapro-3508736/
  2. Generic Citalopram Cost
    https://www.goodrx.com/citalopram
  3. Generic Escitalopram Cost
    https://www.goodrx.com/escitalopram
  4. Explanation of Isomers
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC314378/
    Burke WJ, Kratochvil CJ. Stereoisomers in Psychiatry: The Case of Escitalopram. Prim Care Companion J Clin Psychiatry. 2002;4(1):20–24. doi:10.4088/pcc.v04n0107
  5. Comparison Review
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413963/
    Kennedy SH, Andersen HF, Lam RW. Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis [published correction appears in J Psychiatry Neurosci. 2006 Jul;31(4):228]. J Psychiatry Neurosci. 2006;31(2):122–131.
  6. General Overview Escitalopram vs Citalopram
    Citalopram and Escitalopram – Same But Different. Waitemata District Health Board. http://www.saferx.co.nz/assets/Documents/full/61270f4b03/citalopram_escitalopram.pdf Published June 2016. Accessed March 2020.
  7. Detailed Overview of Discovery and Synthesis of Both Isomers
    https://www.researchgate.net/publication/256067218_The_Discovery_of_Citalopram_and_Its_Refinement_to_Escitalopram
    Bøgesø, Klaus & Sánchez, Connie. (2012). The Discovery of Citalopram and Its Refinement to Escitalopram. 10.1002/9783527651085.ch11.
  8. Citalopram interference with Escitalopram
    https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-7843.2006.pto_295.x
    Sánchez, C. (2006), The Pharmacology of Citalopram Enantiomers: The Antagonism by R‐Citalopram on the Effect of S‐Citalopram*. Basic & Clinical Pharmacology & Toxicology, 99: 91-95. doi:1111/j.1742-7843.2006.pto_295.x
  9. Cost Effectiveness and Remission Analysis
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410906/
    Ramsberg J, Asseburg C, Henriksson M. Effectiveness and cost-effectiveness of antidepressants in primary care: a multiple treatment comparison meta-analysis and cost-effectiveness model. PLoS One. 2012;7(8):e42003. doi:10.1371/journal.pone.0042003.

 

Further Reading

General Overview Escitalopram
https://www.drugbank.ca/drugs/DB01175

Labeling Text Escitalopram (Lexapro)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021323s032,021365s023lbl.pdf

Expert Opinion on Escitalopram
https://www.ncbi.nlm.nih.gov/pubmed/24289655
Pastoor D, Gobburu J: Clinical pharmacology review of escitalopram for the treatment of depression. Expert Opin Drug Metab Toxicol. 2014 Jan;10(1):121-8. doi: 10.1517/17425255.2014.863873. Epub 2013 Nov 30.

Comparison of Several Anti-Depressants
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204633/
Cipriani A, Purgato  M, Furukawa  TA, Trespidi  C, Imperadore  G, Signoretti  A, Churchill  R, Watanabe  N, Barbui  C. Citalopram versus other anti‐depressive agents for depression. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD006534. DOI: 10.1002/14651858.CD006534.pub2.

Review of Effectiveness
https://academic.oup.com/ijnp/article/14/2/261/696727
Stuart Montgomery, Thomas Hansen, Siegfried Kasper, Efficacy of escitalopram compared to citalopram: a meta-analysis, International Journal of Neuropsychopharmacology, Volume 14, Issue 2, March 2011, Pages 261–268, https://doi.org/10.1017/S146114571000115X

Comparison of Effectiveness in Spain
https://www.tandfonline.com/doi/abs/10.1185/03007995.2010.529430?journalCode=icmo20
Antoni Sicras-Mainar, Ruth Navarro-Artieda, Milagrosa Blanca-Tamayo, Victoria Gimeno-de la Fuente & Jordi Salvatella-Pasant (2010) Comparison of escitalopram vs. citalopram and venlafaxine in the treatment of major depression in Spain: clinical and economic consequences, Current Medical Research and Opinion, 26:12, 2757-2764, DOI: 10.1185/03007995.2010.529430

Clinical Study of Effectiveness (French)
https://www.sciencedirect.com/science/article/abs/pii/S0013700611001965?via%3Dihub
Favré P (February 2012). “[Clinical efficacy and achievement of a complete remission in depression: increasing interest in treatment with escitalopram]” [Clinical efficacy and achievement of a complete remission in depression: Increasing interest in treatment with escitalopram]. L’Encephale (in French). 38 (1): 86–96. doi:10.1016/j.encep.2011.11.003. PMID 22381728

Study of R-Citalopram Interference in Humanized Mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346315/
Jacobsen JP, Plenge P, Sachs BD, et al. The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse. Psychopharmacology (Berl). 2014;231(23):4527–4540. doi:10.1007/s00213-014-3595-1

Study of Effects on Blood Platelets
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823918/
Roweth HG, Yan R, Bedwani NH, et al. Citalopram inhibits platelet function independently of SERT-mediated 5-HT transport. Sci Rep. 2018;8(1):3494. Published 2018 Feb 22. doi:10.1038/s41598-018-21348-3