Serotonin Noradrenaline Reuptake Inhibitors (SNRIs): Mechanism, Clinical Use, and Side Effects

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.

SNRIs:

• Duloxetine
• Venlafaxine (at doses ≥ 225mg  )