Serotonin Norepinephrine Reuptake Inhibitors (SNRI)

Serotonin Norepinephrine Reuptake Inhibitor (SNRIs) are first-line agents for treatment of mood disorders and anxiety disorders. The exact agent chosen will vary depending on prescriber comfort and specific patient factors including gender, diagnosis, symptoms, and patient preference.

  • SNRIs have a similar mechanism of action as SSRIs
  • In addition to increasing serotonin (5-HT) by inhibiting the serotonin transporter (SERT) (and thus decreasing reuptake into cells), SNRIs also inhibit norepinephrine (NE) reuptake via the norepinephrine transporter (NET)
  • Mild dopamine reuptake inhibition via the dopamine transporter (DAT) may also exist.
  • The reason that some SNRIs (e.g. - duloxetine) are also indicated in treatment of pain syndromes (e.g. - neuropathic pain) is that norepinephrine as a main neurotransmitter that modulate pain pathways. This is also why some tricyclic antidepressants (TCAs) with norepinephrine action such as amitriptyline are also used in pain syndromes.

Comparison of SNRIs

Adapted from: Sansone, R. A. et al. (2014). Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innovations in clinical neuroscience, 11(3-4), 37.
Year of FDA Approval Half-life (hours) Metabolism Metabolites Dosing Serotonin:Noradrenergic Effects Ratio
Venlafaxine 1993 (IR), 1997 (XR) IR = 5, XR = 11 Hepatic, Phase I (CYP450) Desvenlafaxine IR = BID, XR = once daily 30:1 (least noradrenergic)
Duloxetine 2004 12 Hepatic, Phase I (CYP450) Multiple temporary/inactive Once daily 10:1
Desvenlafaxine 2008 11 Partially hepatic, mostly Phase II None Once daily 10:1
Milacipran 2009 8 Minimal hepatic, mostly Phase II None BID 1:1
Levomilnacipran 2013 12 Minimal hepatic, some Phase I (CYP450) None Once daily 1:2 (most noradrenergic)
  • Similar to SSRIs, SNRIs are generally safer in overdose than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)
  • However, SNRIs may exhibit greater toxicity than SSRIs in the case of overdoses.
  • GI upset, headaches, dry mouth, increased suicidal ideation drug, hypomania/mania, sexual dysfunction, bleeding, hyponatremia, and weight gain.
  • SNRIs can inhibit platelet aggregation via altering platelet serotonin receptors.
  • This can increase the risk for gastrointestinal bleeding, and the risk may be doubled with concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Use of acid-suppressing drugs such as proton pump inhibitors (PPIs) can reduce the risk of gastrointestinal (GI) bleeding.
  • There is a risk for increased suicidal behaviour and ideation for youths on antidepressants.