Serotonin Norepinephrine Reuptake Inhibitors (SNRI)

Serotonin Norepinephrine Reuptake Inhibitors (SNRI)

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.

Resources

Sansone, R. A., & Sansone, L. A. (2014). Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innovations in clinical neuroscience, 11(3-4), 37.

antidepressants

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