title: Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter--a review of current understanding of its mechanism of action.
abstract: BACKGROUND
  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.
authors: U-Pharm Laboratories LLC, 239 New Road, Suite A-107, Parsippany, NJ 07054, USA. hzhong@u-pharmlabs.com
authors: Huailing
authors: H
authors: Zhong
authors: Nasser
authors: N
authors: Haddjeri
authors: Connie
authors: C
authors: Sánchez
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism* / Q000627:therapeutic use; D015283:Citalopram / Q000378:metabolism* / Q000627:therapeutic use; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors