View source for Chemistry:Serotonin reuptake inhibitor

{{Short description|Class of drug}}
[[Image:Serotonin (5-HT).svg|thumb|right|200px|[[Chemistry:Serotonin|Serotonin]]]]

A '''serotonin reuptake inhibitor''' ('''SRI''') is a type of drug which acts as a [[Chemistry:Reuptake inhibitor|reuptake inhibitor]] of the [[Biology:Neurotransmitter|neurotransmitter]] [[Chemistry:Serotonin|serotonin]] (5-hydroxytryptamine, or 5-HT) by blocking the [[Chemistry:Drug action|action]] of the [[Biology:Serotonin transporter|serotonin transporter]] (SERT). This in turn leads to increased [[Biology:Extracellular|extracellular]] [[Chemistry:Concentration|concentration]]s of serotonin and, therefore, an increase in [[Chemistry:Serotonin|serotonergic]] [[Biology:Neurotransmission|neurotransmission]]. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include [[Chemistry:Dopamine reuptake inhibitor|dopamine reuptake inhibitor]]s and [[Chemistry:Norepinephrine reuptake inhibitor|norepinephrine reuptake inhibitor]]s.

SRIs are not synonymous with [[Chemistry:Selective serotonin reuptake inhibitor|selective serotonin reuptake inhibitor]]s (SSRIs), as the latter term is usually used to describe the [[Chemistry:Chemical class|class]] of [[Chemistry:Antidepressant|antidepressant]]s of the same name, and because SRIs, unlike SSRIs, can either be [[Chemistry:Binding selectivity|selective]] or non-selective in their [[Chemistry:Drug action|action]]. For example, [[Biology:Cocaine|cocaine]], which non-selectively inhibits the reuptake of [[Chemistry:Serotonin|serotonin]], [[Biology:Norepinephrine|norepinephrine]], and [[Biology:Dopamine|dopamine]], is an SRI but not an SSRI.

SRIs are used predominantly as [[Chemistry:Antidepressant|antidepressant]]s (e.g., SSRIs, SNRIs, and [[Chemistry:Tricyclic antidepressant|TCA]]s), though they are also commonly used in the treatment of other psychological conditions such as [[Medicine:Anxiety disorder|anxiety disorder]]s and [[Medicine:Eating disorder|eating disorder]]s. Less often, SRIs are also used to treat a variety of other medical conditions including neuropathic pain and [[Medicine:Fibromyalgia|fibromyalgia]] (e.g., [[Chemistry:Duloxetine|duloxetine]], [[Chemistry:Milnacipran|milnacipran]]), and [[Medicine:Premature ejaculation|premature ejaculation]] (e.g., [[Chemistry:Dapoxetine|dapoxetine]]) as well as for dieting (e.g., [[Chemistry:Sibutramine|sibutramine]]). Additionally, some clinically used drugs such as chlorpheniramine, [[Chemistry:Dextromethorphan|dextromethorphan]], and [[Chemistry:Methadone|methadone]] possess SRI properties secondarily to their primary [[Chemistry:Mechanism of action|mechanism of action]](s) and this contributes to their [[Medicine:Side effect|side effect]] and [[Medicine:Drug interaction|drug interaction]] profiles.

A closely related type of drug is a [[Chemistry:Serotonin releasing agent|serotonin releasing agent]] (SRA), an example of which is [[Chemistry:Fenfluramine|fenfluramine]].


==Comparison of SRIs==

===Binding profiles===
{| class="wikitable"
|+ Binding affinities of SRIs at {{abbr|MATs|monoamine transporters}}<ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = Eur. J. Pharmacol. | volume = 340 | issue = 2–3 | pages = 249–58 | year = 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9}}</ref><ref name="pmid11543737">{{cite journal | vauthors = Owens MJ, Knight DL, Nemeroff CB | title = Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine | journal = Biol Psychiatry | volume = 50 | issue = 5 | pages = 345–50 | year = 2001 | pmid = 11543737 | doi = 10.1016/s0006-3223(01)01145-3}}</ref>
|-
! Medication !! {{abbrlink|SERT|Serotonin transporter}} !! {{abbrlink|NET|Norepinephrine transporter}} !! {{abbrlink|DAT|Dopamine transporter}}
|-
| [[Chemistry:Citalopram|Citalopram]] || 1.16 || 4070 || 28100
|-
| [[Chemistry:Desmethylcitalopram|Desmethylcitalopram]] || 3.6 || 1820 || 18300
|-
| [[Chemistry:Escitalopram|Escitalopram]] || 1.1 || 7841 || 27410
|-
| [[Chemistry:Femoxetine|Femoxetine]] || 11.0 || 760 || 2050
|-
| [[Chemistry:Fluoxetine|Fluoxetine]] || 0.81 || 240 || 3600
|-
| [[Chemistry:Fluvoxamine|Fluvoxamine]] || 2.2 || 1300 || 9200
|-
| Norfluoxetine || 1.47 || 1426 || 420
|-
| [[Chemistry:Paroxetine|Paroxetine]] || 0.13 || 40 || 490
|-
| [[Chemistry:Sertraline|Sertraline]] || 0.29 || 420 || 25
|-
| [[Chemistry:Desmethylsertraline|Desmethylsertraline]] || 3.0 || 390 || 129
|-
| [[Chemistry:Zimelidine|Zimelidine]] || 152 || 9400 || 11700
|-
| [[Chemistry:Levomilnacipran|Levomilnacipran]]<ref name="pmid25224953">{{cite journal | vauthors = Deardorff WJ, Grossberg GT | title = A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine | journal = Expert Opin Pharmacother | volume = 15 | issue = 17 | pages = 2525–42 | year = 2014 | pmid = 25224953 | doi = 10.1517/14656566.2014.960842 }}</ref> || 19.0 || 10.5 || {{abbr|ND|No data}}
|-
| [[Chemistry:Venlafaxine|Venlafaxine]] || 8.9 || 1060 || 9300
|-
| [[Chemistry:Vilazodone|Vilazodone]]<ref name="pmid25224953" /> || 1.6 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Chemistry:Vortioxetine|Vortioxetine]]<ref name="pmid25224953" /> || 5.4 || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Chemistry:Amitriptyline|Amitriptyline]] || 4.30 || 35 || 3250
|-
| [[Chemistry:Clomipramine|Clomipramine]] || 0.28 || 38 || 2190
|-
| [[Chemistry:Imipramine|Imipramine]] || 1.40 || 37 || 8500
|}

===SERT occupancy===
{| class="wikitable"
|+ {{abbr|SERT|Serotonin transporter}} occupancy by SRIs at clinically approved dosages
|-
! Medication !! Dosage range<br />(mg/day)<ref name="KoocherNorcross2013">{{cite book|author1=Gerald P. Koocher|author2=John C. Norcross|author3=Beverly A. Greene|title=Psychologists' Desk Reference|url=https://books.google.com/books?id=Ox1wAgAAQBAJ&pg=PA442|date=2013|publisher=Oxford University Press|isbn=978-0-19-984550-7|pages=442–}}</ref> !! ~80% {{abbr|SERT|Serotonin transporter}}<br />occupancy<br />(mg/day)<ref name="pmid21959785">{{cite journal | vauthors = Gründer G, Hiemke C, Paulzen M, Veselinovic T, Vernaleken I | title = Therapeutic plasma concentrations of antidepressants and antipsychotics: lessons from PET imaging | journal = Pharmacopsychiatry | volume = 44 | issue = 6 | pages = 236–48 | year = 2011 | pmid = 21959785 | doi = 10.1055/s-0031-1286282 }}</ref><ref name="pmid19367152">{{cite journal | vauthors = Kasper S, Sacher J, Klein N, Mossaheb N, Attarbaschi-Steiner T, Lanzenberger R, Spindelegger C, Asenbaum S, Holik A, Dudczak R | title = Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram | journal = Int Clin Psychopharmacol | volume = 24 | issue = 3 | pages = 119–25 | year = 2009 | pmid = 19367152 | doi = 10.1097/YIC.0b013e32832a8ec8 }}</ref> !! Ratio (dosage /<br />80% occupancy)
|-
| [[Chemistry:Citalopram|Citalopram]] || 20–40 || 40 || 0.5–1
|-
| [[Chemistry:Escitalopram|Escitalopram]] || 10–20 || 10 || 1–2
|-
| [[Chemistry:Fluoxetine|Fluoxetine]] || 20–80 || 20 || 1–4
|-
| [[Chemistry:Fluvoxamine|Fluvoxamine]] || 50–350 || 70 || 0.71–5
|-
| [[Chemistry:Paroxetine|Paroxetine]] || 10–60 || 20 || 0.5–3
|-
| [[Chemistry:Sertraline|Sertraline]] || 25–200 || 50 || 0.5–4
|-
| [[Chemistry:Duloxetine|Duloxetine]] || 20–120 || 30 || 0.67–2
|-
| [[Chemistry:Venlafaxine|Venlafaxine]] || 75–375 || 75 || 1–5
|-
| [[Chemistry:Clomipramine|Clomipramine]] || 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 [[Biology:Monoamine transporter|monoamine transporter]]s (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====
* [[Chemistry:Citalopram|Citalopram]] (Celexa)
* [[Chemistry:Dapoxetine|Dapoxetine]] (Priligy)
* [[Chemistry:Escitalopram|Escitalopram]] (Lexapro, Cipralex)
* [[Chemistry:Fluoxetine|Fluoxetine]] (Prozac)
* [[Chemistry:Fluvoxamine|Fluvoxamine]] (Luvox)
* [[Chemistry:Paroxetine|Paroxetine]] (Paxil, Seroxat)
* [[Chemistry:Sertraline|Sertraline]] (Zoloft, Lustral)

====Discontinued====
* [[Chemistry:Indalpine|Indalpine]] (Upstene)
* [[Chemistry:Zimelidine|Zimelidine]] (Normud, Zelmid)

====Never marketed====
* [[Chemistry:Alaproclate|Alaproclate]] (GEA-654)
* [[Chemistry:Cericlamine|Cericlamine]] (JO-1017)
* [[Chemistry:Desmethylcitalopram|Desmethylcitalopram]]
* [[Chemistry:Didesmethylcitalopram|Didesmethylcitalopram]]
* [[Chemistry:Femoxetine|Femoxetine]] (FG-4963; Malexil)
* [[Chemistry:Ifoxetine|Ifoxetine]] (CGP-15,210-G)
* [[Chemistry:Omiloxetine|Omiloxetine]]
* [[Chemistry:Panuramine|Panuramine]] (WY-26,002)
* [[Chemistry:Pirandamine|Pirandamine]] (AY-23,713)
* [[Chemistry:RTI-353|RTI-353]]
* [[Chemistry:Seproxetine|Seproxetine]] ((''S'')-norfluoxetine)

===Dual serotonin reuptake inhibitors and serotonin receptor modulators===

====Marketed====
* [[Chemistry:Trazodone|Trazodone]] (Desyrel)
* [[Chemistry:Vilazodone|Vilazodone]] (Viibryd)
* [[Chemistry:Vortioxetine|Vortioxetine]] (Trintellix)

====Never marketed====
* [[Chemistry:Cianopramine|Cianopramine]] (Ro 11-2465)
* [[Chemistry:Litoxetine|Litoxetine]] (SL-810,385)
* [[Chemistry:Lubazodone|Lubazodone]] (YM-992, YM-35,995)
* [[Chemistry:SB-649,915|SB-649,915]]

===Serotonin reuptake inhibition as a weaker/unintended secondary effect===

====Marketed====
* [[Chemistry:Dextromethorphan|Dextromethorphan]] (DXM; Robitussin)<ref name="pmid17689532">{{cite journal |author1=Werling LL |author2=Keller A |author3=Frank JG |author4=Nuwayhid SJ | title = A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder | journal = Exp. Neurol. | volume = 207 | issue = 2 | pages = 248–57 | year = 2007 | pmid = 17689532 | doi = 10.1016/j.expneurol.2007.06.013 }}</ref>
* [[Chemistry:Dextropropoxyphene|Dextropropoxyphene]] (Darvon)<ref name="pmid16051647">{{cite journal | vauthors = Gillman PK | title = Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity | journal = Br J Anaesth | volume = 95 | issue = 4 | pages = 434–41 | year = 2005 | pmid = 16051647 | doi = 10.1093/bja/aei210 | doi-access = free }}</ref>
* [[Chemistry:Dimenhydrinate|Dimenhydrinate]] (Dramamine)
* [[Chemistry:Diphenhydramine|Diphenhydramine]] (Benadryl)<ref name="pmid10420168">{{cite journal |author1=Yeh SY |author2=Dersch C |author3=Rothman R |author4=Cadet JL | title =  Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats| journal = Synapse | volume = 33 | issue = 3 | pages = 207–17 |date=September 1999 | pmid = 10420168 | doi = 10.1002/(SICI)1098-2396(19990901)33:3<207::AID-SYN5>3.0.CO;2-8 | url = https://zenodo.org/record/1235502}}</ref>
* [[Chemistry:Mepyramine|Mepyramine (pyrilamine)]] (Anthisan)<ref name="pmid10420168" />
* [[Biology:Mifepristone|Mifepristone]] (Korlym, Mifeprex)<ref name="pmid25206868">{{cite journal | vauthors = Li C, Shan L, Li X, Wei L, Li D | title = Mifepristone modulates serotonin transporter function | journal = Neural Regen Res | volume = 9 | issue = 6 | pages = 646–52 | year = 2014 | pmid = 25206868 | pmc = 4146234 | doi = 10.4103/1673-5374.130112 | doi-access = free }}</ref>

====Never marketed====
* [[Chemistry:Delucemine|Delucemine]] (also an NMDA antagonist)
* [[Chemistry:Mesembrenone|Mesembrenone]] (also a weak PDE4 inhibitor (found in ''[[Biology:Sceletium tortuosum|Sceletium tortuosum]]'' (kanna))
* [[Chemistry:Mesembrine|Mesembrine]] (also a weak PDE4 inhibitor (found in ''[[Biology:Sceletium tortuosum|Sceletium tortuosum]]'' (kanna))<ref name="mesembrine-ssri_patent">Pharmaceutical compositions containing mesembrine and related compounds. [http://patft.uspto.gov/netacgi/nph-Parser?patentnumber=6,288,104 U.S. Patent 6,288,104] [http://www.pat2pdf.org/pat2pdf/foo.pl?number=6,288,104 (PDF)]</ref>
* [[Chemistry:Roxindole|Roxindole]] (EMD-49,980) (also a [[Biology:5-HT1A receptor|5-HT<sub>1A</sub>]] and [[Biology:D2-like receptor|D<sub>2</sub>-like receptor]] [[Biology:Agonist|agonist]])

==See also==
* Monoamine reuptake inhibitor

==References==
{{Reflist|2}}

{{Antidepressants}}
{{Anxiolytics}}
{{OCD pharmacotherapies}}
{{Monoamine reuptake inhibitors}}

{{DEFAULTSORT:Serotonin Reuptake Inhibitor}}
[[Category:Serotonin reuptake inhibitors| ]]

{{Sourceattribution|Serotonin reuptake inhibitor}}