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Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter—a review of current understanding of its mechanism of action

Abstract

Rationale

Escitalopram is a widely used antidepressant for the treatment of patients with major depression. It is the pure S-enantiomer of racemic citalopram. Several clinical trials and meta-analyses indicate that escitalopram is quantitatively more efficacious than many other antidepressants with a faster onset of action.

Objective

This paper reviews current knowledge about the mechanism of action of escitalopram.

Results

The primary target for escitalopram is the serotonin transporter (SERT), which is responsible for serotonin (or 5-hydroxytryptamine [5-HT]) reuptake at the terminals and cell bodies of serotonergic neurons. Escitalopram and selective serotonin reuptake inhibitors bind with high affinity to the 5-HT binding site (orthosteric site) on the transporter. This leads to antidepressant effects by increasing extracellular 5-HT levels which enhance 5-HT neurotransmission. SERT also has one or more allosteric sites, binding to which modulates activity at the orthosteric binding site but does not directly affect 5-HT reuptake by the transporter. In vitro studies have shown that through allosteric binding, escitalopram decreases its own dissociation rate from the orthosteric site on the SERT. R-citalopram, the nontherapeutic enantiomer in citalopram, is also an allosteric modulator of SERT but can inhibit the actions of escitalopram by interfering negatively with its binding. Both nonclinical studies and some clinical investigations have demonstrated the cellular, neurochemical, neuroadaptive, and neuroplastic changes induced by escitalopram with acute and chronic administration.

Conclusions

The findings from binding, neurochemical, and neurophysiological studies may provide a mechanistic rationale for the clinical difference observed with escitalopram compared to other antidepressant therapies.

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Acknowledgments

The authors thank Drs. David Simpson, Anna-Greta Nylander, and Simon Graham for helpful insights and comments.

Financial interests/disclosure

The work by HZ was performed during previous employment and as current consultancy with Lundbeck; NH is a full-time employee of INSERM (Institut National de la Santé Et de la Recherche Médicale) and has provided consultancy to Lundbeck and Solvay companies; CS is a full-time employee of Lundbeck.

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Correspondence to Huailing Zhong.

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Zhong, H., Haddjeri, N. & Sánchez, C. Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter—a review of current understanding of its mechanism of action. Psychopharmacology 219, 1–13 (2012). https://doi.org/10.1007/s00213-011-2463-5

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Keywords

  • Escitalopram (S-citalopram)
  • Allosteric
  • Serotonin (5-HT)
  • Serotonin transporter (SERT)
  • Selective serotonin reuptake inhibitor (SSRI)