Serotonin-norepinephrine reuptake inhibitors are a class of drugs used for the treatment of depression in patients in whom SSRIs are ineffective. Since they have little activity on  histaminic, muscarinic and alpha 1postsynaptic receptors; they lack of most of tricyclic antidepressants (TCAs) side effects .

Note: the terms Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and Selective Serotonin-Norepinephrine Reuptake Inhibitors (SSNRIs) are used interchangeably in this text.

Serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants share aspects of their mechanism of action

5- HT (serotonin) and norepinephrine (noradrenaline) are released from the nerve terminal to the synaptic cleft and bind to post-synaptic receptors. Drugs like venlafaxine, duloxetine, and the newer desvenlafaxine – all of them Serotonin-Norepinephrine Reuptake Inhibitors– block proteins in the pre-synaptic neuron that act as re-uptakers. This increases the concentration of both neurotransmitters at the synaptic cleft.


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Tricyclic antidepressants (TCAs) are an important group of antidepressants in clinical practice; this drug class includes imipramine, amitriptyline, clomipramine, and desipramine. The main pharmacological effect on presynaptic 5-HT and norepinephrine receptors is the same that SNRIs. This is, they block the reuptake protein that acts as transporter in the nerve terminal. TCAs have very little effect on dopamine reuptake.

Drug Uptake inhibition
Norepinephrine Serotonin
Selective serotonin re-uptake inhibitor
Fluoxetine none ++++
Selective serotonin/norepinephrine re-uptake inhibitor:
Venlafaxine ++ ++++
Duloxetine ++++ ++++
Tricyclic antidepressant
Imipramine ++++ +++

From: Lippincott Illustrated reviews: Pharmacology, 4ed. Lippincott Williams and Wilkins.

TCAs adverse effects are determined by they blockade on cholinergic, adrenergic and histamine transmission

What gives TCAs a different adverse effects profile is their ability to block muscarinic, alpha 1 adrenergic and histamine H1 receptors. The blockade of these receptors gives as a result:

Anticholinergic (atropine-like) effects: blurred vision, xerostomia, urinary retention, constipation and narrow angle glaucoma.

Sympatholytic effects (alpha 1 blockade): postural hypotension, dizziness and reflex tachicardia.

Histamine (H1) antagonism: sedation.

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Mechanism in pain modulation

As the title of the image below explains, multiple neurotransmitters modulate pain processing in the spinal cord. Pain is only in part modulated by 5-HT (serotonin) and norepinephrine (NE). In adition, there are higher centers involved in pain processing ( periaqueductal grey matter, nucleus raphe magnus, thalamus and the brain cortex itself) that are not shown in the picture.


List of drugs included in the TCAs class

Tertiary Amines

Amitriptyline (Elavil, Endep, Vanatrip)
Imipramine (Tofranil)
Clomipramine (Anafranil)
Doxepin (Adapin)
Butriptyline (Evadene, Evadyne)
Dosulepin (Prothiade)
Lofepramine (Feprapax, Gamanil, Lomont)
Trimipramine (Surmontil)

Secondary Amines

Desipramine (Norpramin, Pertofrane)
Nortriptyline (Aventyl, Nortrilen, Pamelor)
Protriptyline (Vivactil)

List of SNRIs

Venlafaxine (Effexor XR, Effexor)
Desvenlafaxine (Pristiq)

Mind map of TCAs and SNRI pharmacological properties


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