Serotonin reuptake inhibitor explained

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 [1] [2]
Medication
1.16 4070 28100
3.6 1820 18300
1.1 7841 27410
11.0 760 2050
0.81 240 3600
2.2 1300 9200
1.47 1426 420
0.13 40 490
0.29 420 25
3.0 390 129
152 9400 11700
Levomilnacipran[3] 19.0 10.5
8.9 1060 9300
1.6
5.4
4.30 35 3250
0.28 38 2190
1.40 37 8500

SERT occupancy

occupancy by SRIs at clinically approved dosages
Medication Dosage range
(mg/day)[4] 		~80%
occupancy
(mg/day)[5] [6] 		Ratio (dosage /
80% occupancy)
20–40 40 0.5–1
10–20 10 1–2
20–80 20 1–4
50–350 70 0.71–5
10–60 20 0.5–3
25–200 50 0.5–4
20–120 30 0.67–2
75–375 75 1–5
50–250 10 5–25

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

Notes and References

  1. Tatsumi M, Groshan K, Blakely RD, Richelson E . Pharmacological profile of antidepressants and related compounds at human monoamine transporters . Eur. J. Pharmacol. . 340 . 2–3 . 249–58 . 1997 . 9537821 . 10.1016/s0014-2999(97)01393-9.
  2. Owens MJ, Knight DL, Nemeroff CB . Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine . Biol Psychiatry . 50 . 5 . 345–50 . 2001 . 11543737 . 10.1016/s0006-3223(01)01145-3. 11247427 .
  3. Deardorff WJ, Grossberg GT . A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine . Expert Opin Pharmacother . 15 . 17 . 2525–42 . 2014 . 25224953 . 10.1517/14656566.2014.960842 . 12581442 .
  4. Book: Gerald P. Koocher. John C. Norcross. Beverly A. Greene. Psychologists' Desk Reference. 2013. Oxford University Press. 978-0-19-984550-7. 442–.
  5. Gründer G, Hiemke C, Paulzen M, Veselinovic T, Vernaleken I . Therapeutic plasma concentrations of antidepressants and antipsychotics: lessons from PET imaging . Pharmacopsychiatry . 44 . 6 . 236–48 . 2011 . 21959785 . 10.1055/s-0031-1286282 . 30691618 .
  6. Kasper S, Sacher J, Klein N, Mossaheb N, Attarbaschi-Steiner T, Lanzenberger R, Spindelegger C, Asenbaum S, Holik A, Dudczak R . 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 . 2009 . 19367152 . 10.1097/YIC.0b013e32832a8ec8 . 17470375 .
  7. Werling LL . Keller A . Frank JG . Nuwayhid SJ . A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder . Exp. Neurol. . 207 . 2 . 248–57 . 2007 . 17689532 . 10.1016/j.expneurol.2007.06.013 . 38476281 .
  8. Gillman PK . Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity . Br J Anaesth . 95 . 4 . 434–41 . 2005 . 16051647 . 10.1093/bja/aei210 . free .
  9. Yeh SY . Dersch C . Rothman R . Cadet JL . Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats. Synapse . 33 . 3 . 207–17 . September 1999 . 10420168 . 10.1002/(SICI)1098-2396(19990901)33:3<207::AID-SYN5>3.0.CO;2-8 . 16399789 .
  10. Li C, Shan L, Li X, Wei L, Li D . Mifepristone modulates serotonin transporter function . Neural Regen Res . 9 . 6 . 646–52 . 2014 . 25206868 . 4146234 . 10.4103/1673-5374.130112 . free .
  11. Pharmaceutical compositions containing mesembrine and related compounds. U.S. Patent 6,288,104 (PDF)

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