Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) – Mechanism of Action

Posted on: January 27, 2022
Last Updated: November 3, 2023

Serotonin-noradrenaline reuptake inhibitors (SNRIs) are evidence-based medications in treating depression and anxiety disorders. They have additional applications in pain disorders and perimenopausal depression. 

They block the reuptake of serotonin (5HT) and noradrenaline (NA) (norepinephrine) by inhibiting the serotonin and noradrenaline transporters. (SERT and NAT)

SNRIs are dual-action antidepressants as they increase NA and 5HT in the synapse.

SSRIs only increase 5HT.

Two and a half antidepressant

Although being a dual-action agent increasing 5HT & NA, they have a 3rd action on  Dopamine (DA) in the prefrontal cortex (PFC) but nowhere else in the brain.

They are not full triple-action agents (like tricyclic antidepressants or MAOIs) since they do not directly inhibit the DA transporter (DAT), but SNRIs can be considered to have 2.5 actions, rather than just two.

In the PFC, SERTs and NATs are abundant on 5HT & NA nerve terminals, but there are very few DATs on dopamine nerve terminals in this part of the brain.

NAT performs the role of DAT in the PFC.

Therefore, NAT inhibition also enhances DA levels and increases DA’s diffusion radius.


  • Duloxetine
  • Venlafaxine (at doses  225mg  ) 

The present data showed that, at its minimal effective dose in depression (75 mg/d), venlafaxine acted as a selective 5-HT reuptake inhibitor, whereas when administered at higher doses (225 and 375 mg/d), it acted as a dual 5-HT and NE reuptake inhibitor. [Debonnel et al., 2007]

  • Desvenlafaxine
  • Milnacipran

Side effects:

  • GI side effects 10%-30%
  • Weight gain- less than 10%
  • Sexual dysfunction – less than 30%
  • Anticholinergic side effects (urinary retention, dry mouth, constipation) -10%-30%
  • CNS activation – 10%-30%
  • GI bleeding risk in > 65 yrs
  • SIADH and hyponatremia in > 65 yrs

Clinical pearls: 

  1. Evidence-based in the treatment of depression and anxiety disorders 
  2. Second line in generalised anxiety disorder
  3. Efficacious in treatment of melancholic depression due to broad-spectrum effects
  4. Efficacious in treatment of psychotic depression when combined with an antipsychotic
  5. Useful in perimenopausal depression
  6. Duloxetine and milnacipran have evidence in pain disorders, e.g. fibromyalgia
  7. SNRIs are not recommended as first-line in children and adolescents


  1. Debonnel, G., Saint-André, É., Hébert, C., De Montigny, C., Lavoie, N., & Blier, P. (2007). Differential physiological effects of a low dose and high doses of venlafaxine in major depression. International Journal of Neuropsychopharmacology10(1), 51-61.