Serotonin-norepinephrine reuptake inhibitor

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Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs which are used in the treatment of major depressive disorder (MDD). They are sometimes also used to treat anxiety disorders, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

SNRIs are monoamine reuptake inhibitors; specifically, they are inhibitors of the reuptake of serotonin and norepinephrine. These neurotransmitters are known to play a significant role in mood regulation. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which primarily act on serotonin.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane transport proteins that are responsible for the reuptake of serotonin and norepinephrine. Dual inhibition of serotonin and norepinephrine reuptake can offer advantages over other antidepressant drugs by treating a wider range of symptoms.[1]

SNRIs, along with selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), are second-generation antidepressants. Over the past two decades, second-generation antidepressants have gradually replaced first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) as the drugs of choice for the treatment of MDD. This is mainly because of their improved tolerability and safety profile.[2]

A closely related type of drug is a serotonin-norepinephrine releasing agent (SNRA), for instance, the withdrawn appetite suppressant fenfluramine/phentermine (Fen-Phen). SNRAs primarily induce the release of serotonin and norepinephrine rather than inhibiting their reuptake.

Types

Atomoxetine — a norepinephrine-predominant SNRI used in the treatment of ADHD and, off-label, major depression. Approved by the FDA in 2002. Originally considered to be a selective norepinephrine reuptake inhibitor, but research subsequently revealed that it significantly inhibits the reuptake of serotonin at clinical dosages as well.[3]

Desvenlafaxine[4]— the active metabolite of venlafaxine. It is believed to work similarly, though some evidence suggests lower response rates compared to venlafaxine and duloxetine. It was introduced by Wyeth in May 2008 and was then the third approved SNRI.[5]

Duloxetine[6] 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 that can lead to acute hepatitis or other diseases in certain at-risk patients. Currently, the risk of liver damage appears to be only for patients already at risk, unlike the antidepressant nefazodone, which, though rare, can spontaneously cause liver failure in healthy patients.[7] Duloxetine is also approved for major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic neuropathy, chronic musculoskeletal pain, including chronic osteoarthritis pain and chronic low back pain.[8]

Milnacipran[9] — shown to be significantly effective in the treatment of depression and fibromyalgia.[10] 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. It was first introduced in France in 1996.

Sibutramine — a SNRI, which, instead of being developed for the treatment of depression, was widely marketed as an appetite suppressant for weight loss purposes. Sibutramine was the first drug for the treatment of obesity to be approved in 30 years.[11] It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in several countries and regions including the United States in 2010.[12]

Tramadol — a dual weak opioid and SNRI. It was approved by the FDA in 1995, though it has been marketed in Germany since 1977. The drug is used to treat acute and chronic pain. It has shown effectiveness in the treatment of fibromyalgia, though it is not specifically approved for this purpose. The drug is also under investigation as an antidepressant and for the treatment of neuropathic pain. It is related in chemical structure to venlafaxine. Venlafaxine — the first and most commonly used SNRI. Wyeth introduced it in 1994. The reuptake effects of venlafaxine are dose-dependent. At low doses (<150 mg/day), it acts only on serotonergic transmission. At moderate doses (>150 mg/day), it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day), it also affects dopaminergic neurotransmission.[13]

References

  1. Cashman, JR; Ghirmai, S (2009). "Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression". Bioorganic & Medicinal Chemistry. 17 (19): 6890–7. PMID 19740668. https://doi.org/10.1016/j.bmc.2009.08.025.
  2. Spina, E; Santoro, V; d'Arrigo, C (2008). "Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: An update". Clinical therapeutics. 30 (7): 1206–27. PMID 18691982. https://doi.org/10.1016/S0149-2918(08)80047-1.
  3. Ding YS, Naganawa M, Gallezot JD, Nabulsi N, Lin SF, Ropchan J, Weinzimmer D, McCarthy TJ, Carson RE, Huang Y, Laruelle M (2014). "Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD". NeuroImage. 86: 164–71. PMID 23933039. https://doi.org/10.1016/j.neuroimage.2013.08.001.
  4. Deecher DC, Beyer CE, Johnston G, et al. (August 2006). "Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor". J. Pharmacol. Exp. Ther. 318 (2): 657–65. PMID 16675639. doi:10.1124/jpet.106.103382.
  5. Deecher DC, Beyer CE, Johnston G, et al. (August 2006). "Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor". J. Pharmacol. Exp. Ther. 318 (2): 657–65. PMID 16675639. doi:10.1124/jpet.106.103382.
  6. Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM (November 2004). "Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats". J. Pharmacol. Exp. Ther. 311 (2): 576–84. PMID 15254142. doi:10.1124/jpet.104.070656.
  7. "Nefazodone Hydrochloride Tablets. Full Prescribing Information". DailyMed. Teva Pharmaceuticals USA, Inc. North Wales, PA 19454. September 2015. Retrieved 2 September 2016.
  8. "Cymbalta (duloxetine delayed-release) Capsules for Oral Use. Full Prescribing Information" (PDF). Lilly USA, LLC, Indianapolis, IN 46285, USA. Retrieved 29 August 2016.