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[[Image:Serotonin (5-HT).svg|thumb|right|200px|[[Serotonin]]]]
[[Image:Norepinephrine structure.png|thumb|right|200px|[[Norepinephrine]]]]
'''Serotonin–norepinephrine reuptake inhibitors''' ('''SNRIs''') are a class of [[antidepressant]] [[drug]]s used in the treatment of [[major depressive disorder|major depression]] and other [[mood disorder]]s. They are sometimes also used to treat [[anxiety disorder]]s, [[obsessive-compulsive disorder]] (OCD), [[attention deficit hyperactivity disorder]] (ADHD), chronic [[neuropathic pain]], [[fibromyalgia syndrome]] (FMS), and for the relief of [[menopause|menopausal]] symptoms.
SNRIs act upon and increase the levels of two [[neurotransmitter]]s in the [[brain]] that are known to play an important part in mood, these being [[serotonin]] and [[norepinephrine]]. This can be contrasted with the more widely-used [[selective serotonin reuptake inhibitor]]s (SSRIs) which only act on serotonin.
== Overview of SNRIs ==
* [[Venlafaxine]] (Effexor) - The first and most commonly used SNRI. It was introduced by [[Wyeth]] in 1994. The reuptake effects of venlafaxine are dose dependent. At low doses (<150&nbsp;mg/day) it acts only on serotonergic transmission. At moderate doses (>150&nbsp;mg/day) it acts on serotonergic and noradrenergic systems, whereas at high doses (>300&nbsp;mg/day) it also affects dopaminergic neurotransmission.<ref></ref>
* [[Desvenlafaxine]] (Pristiq)<ref name="pmid16675639">{{cite journal |author=Deecher DC, Beyer CE, Johnston G, ''et al.'' |title=Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor |journal=J. Pharmacol. Exp. Ther. |volume=318 |issue=2 |pages=657–65 |year=2006 |month=August |pmid=16675639 |doi=10.1124/jpet.106.103382 |url=}}</ref> - The active metabolite of venlafaxine. It is believed to work in a similar manner, though some evidence suggests lower response rates compared to venlafaxine and duloxetine. It was introduced by Wyeth in May 2008.
* [[Duloxetine]] (Cymbalta, Yentreve)<ref name="pmid15254142">{{cite journal |author=Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM |title=Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats |journal=J. Pharmacol. Exp. Ther. |volume=311 |issue=2 |pages=576–84 |year=2004 |month=November |pmid=15254142 |doi=10.1124/jpet.104.070656 |url=}}</ref> - By Eli Lilly and Company, has been approved for the treatment of depression and [[neuropathic pain]] in August 2004. Duloxetine is contraindicated in patients with heavy alcohol use or chronic liver disease, as duloxetine can increase the levels of certain liver enzymes which can lead to acute [[hepatitis]] or other diseases in certain at risk patients. Currently, the risk of liver damage appears only to be for patients already at risk, unlike the antidepressant [[nefazodone]] which, though rare, can spontaneously cause liver failure in healthy patients. {{Citation needed|date=June 2010}} Duloxetine is also approved for [[Major Depressive Disorder]] (MDD), [[Generalized Anxiety Disorder]] (GAD), chronic musculoskeletal pain, including chronic [[osteoarthritis]] pain and chronic [[low back pain]] (as of October, 2010), and is one of the only three medicines approved by the FDA for [[Fibromyalgia]] [].
* [[Milnacipran]] (Dalcipran, Ixel, Savella)<ref name="pmid17218444">{{cite journal |author=Nonogaki K, Nozue K, Kuboki T, Oka Y |title=Milnacipran, a serotonin and norepinephrine reuptake inhibitor, induces appetite-suppressing effects without inducing hypothalamic stress responses in mice |journal=Am. J. Physiol. Regul. Integr. Comp. Physiol. |volume=292 |issue=5 |pages=R1775–81 |year=2007 |month=May |pmid=17218444 |doi=10.1152/ajpregu.00527.2006 |url=}}</ref> - Shown to be significantly effective in the treatment of depression and fibromyalgia. The [[Food and Drug Administration]] (FDA) approved milnacipran for treatment of fibromyalgia in the United States of America in January 2009, however it is currently not approved for depression in that country. Milnacipran has been commercially available in Europe and Asia for several years.
* [[Levomilnacipran]] (F2695) - The levo- isomer of milnacipran. Under development for the treatment of depression in the United States and Canada.
* [[Sibutramine]] (Meridia, Reductil) - An SNRI, which, instead of being developed for the treatment of depression, was widely marketed as an [[appetite suppressant]] for [[weight loss]] purposes.
* [[Bicifadine]] (DOV-220,075) - By DOV Pharmaceutical, potently inhibits the reuptake of serotonin and norepinephrine (and dopamine to a lesser extent), but rather than being developed for the already crowded antidepressant market, it is being researched as a non-opioid, non-NSAID [[analgesic]].
* [[SEP-227162]] - An SNRI under development by Sepracor for the treatment of depression.
* [[LY 2216684]] - An SNRI under development by Eli Lilly for the treatment of depression.<ref name="pmid19909980">{{cite journal | author1 = Dubé S | author2 = Dellva MA | author3 = Jones M | author4 = Kielbasa W | author5 = Padich R | author6 = Saha A | author7 = Rao P | year = 2010 | title = A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression. | journal = J Psychiatr Res | volume = 44 | issue = 6 | pages = 356–63 | doi = 10.1016/j.jpsychires.2009.09.013 | pmid = 19909980}}</ref>
== Pharmacology ==
SNRIs work by [[Reuptake inhibitor|inhibiting]] the [[reuptake]] of the neurotransmitters serotonin and norepinephrine. This results in an increase in the [[extracellular]] concentrations of serotonin and norepinephrine and therefore an increase in [[neurotransmission]]. Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for NE than serotonin.
{{Main|Reuptake inhibitor}}
Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older [[tricyclic antidepressants]] (TCAs), but not with the SSRIs.<ref>{{cite journal |author=Sindrup SH, Otto M, Finnerup NB, Jensen TS |title=Antidepressants in the treatment of neuropathic pain. |journal=Basic Clin Pharmacol Toxicol|volume=96 |issue=6 |pages=399–409 |year=2005 |pmid=15910402 |doi=10.1111/j.1742-7843.2005.pto_96696601.x}}</ref>
== Comparison to SSRIs ==
The SNRIs were developed more recently than the SSRIs and as a result there are relatively few of them. However, the SNRIs are among the most widely used antidepressants today. In 2009 Cymbalta and Effexor were the 11th and 12th most prescribed branded drugs in the United States. This translates to the 2nd and 3rd most common antidepressants, behind Lexapro (#5).<ref>{{cite web|title=2009 Top 200 branded drugs by total prescriptions|url=|work=SDI/Verispan, VONA, full year 2009||accessdate=6 April 2011}}</ref> In some studies, SNRI's demonstrated slightly higher antidepressant efficacy than the SSRIs (response rates 63.6% versus 59.3%).<ref>{{Cite pmid|17588546}}</ref> However, in one study escitalopram had a superior efficacy profile to venlafaxine.<ref>{{Cite pmid|17394446}}</ref> It is not clear what the reasons were for this unexpected anomaly. The side effects of SNRIs are reported to be slightly less severe in comparison to the SSRIs as well.{{Citation needed|date=January 2010}}
One of the major complaints that many users of SSRIs have is the negative sexual side effects that can be very difficult to treat. []. Although SNRIs ''can'' have similar side effects, many of them can have the opposite effect of increased libido. [[Bupropion|Wellbutrin]] has had official studies done,[] and [[Strattera]] and [[Savella]] have commonly been reported as increasing libido in both men and women, even though studies have contradicted these reports.[] However, the individuals who reported increased sexual functioning also tended to report increased anxiety, heart rate, blood pressure, and other negative effects associated with [[adrenaline]] increase.
== Side effects ==
Because the SNRIs and SSRIs both act similarly to elevate serotonin levels, they subsequently share many of the same side effects, though to varying degrees. The most common include loss of appetite, weight, and sleep. There may also be drowsiness, dizziness, fatigue, headache, [[mydriasis]], nausea/vomiting, sexual dysfunction, and urinary retention. There are two common sexual side effects: diminished interest in sex (libido) and difficulty reaching climax ([[anorgasmia]]), which are usually somewhat milder with the SNRIs in comparison to the SSRIs. Nonetheless, sexual side effects account for lack of compliance with both SSRIs and SNRIs. {{Citation needed|date=October 2010}}
While [[tricyclic antidepressants]] also produce similar sexual side effects as SNRIs, discontinuation of TCAs is more often due to the other side effects (like cardiovascular effects){{Citation needed|date=October 2010}}. Also [[Amitriptyline]] (a TCAs) is more commonly associated with [[orthostatic hypotension]]{{Citation needed|date=January 2011}}.
Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. People at risk for hypertension and heart disease should have their blood pressure monitored. {{Citation needed|date=October 2010}}
== Discontinuation syndrome ==
As with SSRIs, the abrupt discontinuation of an SNRI usually leads to [[withdrawal]], or "[[SSRI discontinuation syndrome|discontinuation syndrome]]", which could include states of [[anxiety]] and other symptoms. It is therefore recommended that users seeking to discontinue an SNRI slowly taper the dose under the supervision of a professional. Discontinuation syndrome has been reported to be markedly worse for [[venlafaxine]] when compared to other SNRIs. Accordingly, as [[tramadol]] is related to venlafaxine, the same conditions apply.<ref>{{cite journal |author=Perahia DG, Pritchett YL, Kajdasz DK, Bauer M, Jain R, Russell JM, Walker DJ, Spencer KA, Froud DM, Raskin J, Thase ME. |title=A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder.|journal=J Psychiatr Res. |volume=42 |issue=1 |pages=22–34 |year=2008 |pmid=17445831 |doi=10.1016/j.jpsychires.2007.01.008}}</ref> This is likely due to venlafaxine's relatively short [[half-life]] and therefore rapid clearance upon discontinuation.
== Contraindications ==
Due to the effects of increased norepinephrine levels and therefore higher [[adrenergic]] activity, pre-existing hypertension should be controlled before treatment with SNRIs and blood pressure periodically monitored throughout treatment. Duloxetine has also been associated with cases of hepatic failure and should not be prescribed to patients with chronic alcohol use or liver disease.
SNRIs should be taken with caution when using [[St John's wort]] as the combination can lead to the potentially fatal [[serotonin syndrome]].<ref>{{cite book | title=2006 Lippincott's Nursing Drug Guide |last=Karch |first=Amy |year= 2006 |publisher=Lippincott Williams & Wilkins |location=Philadephia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo |isbn= 1-58255-436-6 }}</ref> They are contraindicated with [[dextromethorphan]], [[tramadol]], [[cyclobenzaprine]], [[meperidine|meperidine/pethidine]], and [[propoxyphene]] as well. They should also never be taken within 14 days of any other antidepressant, especially the [[monoamine oxidase inhibitor]]s (MAOIs).
==See also==
* [[Reuptake inhibitor]]
* [[Serotonin reuptake inhibitor]] (SRI)
* [[Selective serotonin reuptake inhibitor]] (SSRI)
* [[Norepinephrine reuptake inhibitor]] (NRI)
* [[Dopamine reuptake inhibitor]] (DRI)
* [[Norepinephrine-dopamine reuptake inhibitor]] (NDRI)
* [[Serotonin-norepinephrine-dopamine reuptake inhibitor]] (SNDRI)
== References ==
[[Category:Serotonin-norepinephrine reuptake inhibitors| ]]
[[es:Inhibidor de la recaptación de Serotonina-Norepinefrina]]
[[fr:Inhibiteur de la recapture de la sérotonine-noradrénaline]]
{{enWP|Serotonin–norepinephrine reuptake inhibitor}}

Latest revision as of 12:30, July 22, 2013

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