Serotonin

A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.

SRIs are not synonymous with selective serotonin reuptake inhibitors (SSRIs), as the latter term is usually used to describe the class of antidepressants of the same name, and because SRIs, unlike SSRIs, can either be selective or non-selective in their action. For example, cocaine, which non-selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine, is an SRI but not an SSRI.

SRIs are used predominantly as antidepressants (e.g., SSRIs, SNRIs, and TCAs), though they are also commonly used in the treatment of other psychological conditions such as anxiety disorders and eating disorders. Less often, SRIs are also used to treat a variety of other medical conditions including neuropathic pain and fibromyalgia (e.g., duloxetine, milnacipran), and premature ejaculation (e.g., dapoxetine) as well as for dieting (e.g., sibutramine). Additionally, some clinically used drugs such as chlorpheniramine, dextromethorphan, and methadone possess SRI properties secondarily to their primary mechanism of action(s) and this contributes to their side effect and drug interaction profiles.

A closely related type of drug is a serotonin releasing agent (SRA), an example of which is fenfluramine.

Comparison of SRIs

Binding profiles

Binding affinities of SRIs at MATs[1][2]
MedicationSERTNETDAT
Citalopram1.16407028100
Desmethylcitalopram3.6182018300
Escitalopram1.1784127410
Femoxetine11.07602050
Fluoxetine0.812403600
Fluvoxamine2.213009200
Norfluoxetine1.471426420
Paroxetine0.1340490
Sertraline0.2942025
Desmethylsertraline3.0390129
Zimelidine152940011700
Levomilnacipran[3]19.010.5ND
Venlafaxine8.910609300
Vilazodone[3]1.6NDND
Vortioxetine[3]5.4NDND
Amitriptyline4.30353250
Clomipramine0.28382190
Imipramine1.40378500

SERT occupancy

SERT occupancy by SRIs at clinically approved dosages
MedicationDosage range
(mg/day)[4]		~80% SERT
occupancy
(mg/day)[5][6]		Ratio (dosage /
80% occupancy)
Citalopram20–40400.5–1
Escitalopram10–20101–2
Fluoxetine20–80201–4
Fluvoxamine50–350700.71–5
Paroxetine10–60200.5–3
Sertraline25–200500.5–4
Duloxetine20–120300.67–2
Venlafaxine75–375751–5
Clomipramine50–250105–25

List of SERT-selective SRIs

Many SRIs exist, an assortment of which are listed below. Note that only SRIs selective for the SERT over the other monoamine transporters (MATs) are listed below. For a list of SRIs that act at multiple MATs, see other monoamine reuptake inhibitor pages such as SNRI and SNDRI.

Selective serotonin reuptake inhibitors (SSRIs)

Marketed

Discontinued

Never marketed

Dual serotonin reuptake inhibitors and serotonin receptor modulators

Marketed

Never marketed

Serotonin reuptake inhibition as a weaker/unintended secondary effect

Marketed

Never marketed

See also

References

  1. ↑ Tatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur. J. Pharmacol. 340 (2–3): 249–58. doi:10.1016/s0014-2999(97)01393-9. PMID 9537821.
  2. ↑ Owens MJ, Knight DL, Nemeroff CB (2001). "Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine". Biol Psychiatry. 50 (5): 345–50. doi:10.1016/s0006-3223(01)01145-3. PMID 11543737.
  3. 1 2 3 Deardorff WJ, Grossberg GT (2014). "A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine". Expert Opin Pharmacother. 15 (17): 2525–42. doi:10.1517/14656566.2014.960842. PMID 25224953.
  4. ↑ Gerald P. Koocher; John C. Norcross; Beverly A. Greene (2013). Psychologists' Desk Reference. Oxford University Press. pp. 442–. ISBN 978-0-19-984550-7.
  5. ↑ Gründer G, Hiemke C, Paulzen M, Veselinovic T, Vernaleken I (2011). "Therapeutic plasma concentrations of antidepressants and antipsychotics: lessons from PET imaging". Pharmacopsychiatry. 44 (6): 236–48. doi:10.1055/s-0031-1286282. PMID 21959785.
  6. ↑ Kasper S, Sacher J, Klein N, Mossaheb N, Attarbaschi-Steiner T, Lanzenberger R, Spindelegger C, Asenbaum S, Holik A, Dudczak R (2009). "Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram". Int Clin Psychopharmacol. 24 (3): 119–25. doi:10.1097/YIC.0b013e32832a8ec8. PMID 19367152.
  7. ↑ Werling LL; Keller A; Frank JG; Nuwayhid SJ (2007). "A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder". Exp. Neurol. 207 (2): 248–57. doi:10.1016/j.expneurol.2007.06.013. PMID 17689532.
  8. ↑ Gillman PK (2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". Br J Anaesth. 95 (4): 434–41. doi:10.1093/bja/aei210. PMID 16051647.
  9. 1 2 Yeh SY; Dersch C; Rothman R; Cadet JL (September 1999). "Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats". Synapse. 33 (3): 207–17. doi:10.1002/(SICI)1098-2396(19990901)33:3<207::AID-SYN5>3.0.CO;2-8. PMID 10420168.
  10. ↑ Li C, Shan L, Li X, Wei L, Li D (2014). "Mifepristone modulates serotonin transporter function". Neural Regen Res. 9 (6): 646–52. doi:10.4103/1673-5374.130112. PMC 4146234. PMID 25206868.
  11. ↑ Pharmaceutical compositions containing mesembrine and related compounds. U.S. Patent 6,288,104 (PDF)
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