- Last edited on March 6, 2021
Serotonin Norepinephrine Reuptake Inhibitors (SNRI)
Primer
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.
Mechanism of Action
- 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.
Pain
- 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
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) |
Clinical Pearls
- 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.
Common Side Effects
- GI upset, headaches, dry mouth, increased suicidal ideation drug, hypomania/mania, sexual dysfunction, bleeding, hyponatremia, and weight gain.
Adverse Events
Withdrawal
See main article: Antidepressant Withdrawal (Discontinuation) Syndrome
Bleeding Risks
See main article: SSRI and SNRI Bleeding Risks
- 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.
Suicidal Behaviours
See main article: Introduction to Antidepressants: Suicidal Ideation
- There is a risk for increased suicidal behaviour and ideation for youths on antidepressants.