History 

Introduction 

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant. They work by blocking the reuptake of two key neurotransmitters in the brain—serotonin and norepinephrine—thereby increasing their availability in the synaptic cleft to help improve mood and relieve symptoms of depression.

SNRIs are used primarily to treat major depressive disorder but are also effective for anxiety disorders, chronic neuropathic pain, fibromyalgia, and menopausal symptoms. Compared to selective serotonin reuptake inhibitors (SSRIs), which affect only serotonin, SNRIs target both serotonin and norepinephrine, potentially offering broader symptom relief.

 SNRIs are FDA-approved, including venlafaxine, duloxetine, desvenlafaxine, levomilnacipran, and milnacipran.

Mechanism of action 

Medication Brand Names

Indication

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are 

primarily indicated for:

• Major depressive disorder (MDD)

• Generalized anxiety disorder (GAD)

• Panic disorder

• Social anxiety disorder

• Posttraumatic stress disorder (PTSD)

• Obsessive-compulsive disorder (OCD)

• Neuropathic pain, including diabetic peripheral neuropathy

• Fibromyalgia

• Chronic musculoskeletal pain and osteoarthritis pain

• Menopausal symptoms such as hot flashes and night sweats

Side Effects 

Precautions 

• Blood pressure monitoring: SNRIs can slightly raise blood pressure; patients, especially those with hypertension, should have their blood pressure monitored regularly.

• Liver and kidney function: Use caution in patients with hepatic or renal impairment, as SNRIs (notably duloxetine) can worsen liver conditions and may require dose adjustment or avoidance.

• Bleeding risk: SNRIs may impair platelet aggregation by depleting platelet serotonin, increasing bleeding risk. Caution is advised when combined with anticoagulants, antiplatelet drugs (e.g., aspirin), or NSAIDs.

• Serotonin syndrome risk: Combining SNRIs with other serotonergic agents (e.g., SSRIs, triptans, tramadol, St. John’s wort, lithium) increases the risk of serotonin syndrome, a potentially life-threatening condition.

• Discontinuation syndrome: Abrupt cessation can cause withdrawal symptoms such as dizziness, nausea, headache, anxiety, and sensory disturbances,Gradual tapering is recommended, especially with short-acting agents like venlafaxine.

• Pregnancy and breastfeeding: There is an increased risk of postpartum hemorrhage and possible adverse effects on the infant exposed via breast milk,Benefits must be weighed against risks.

• Angle-closure glaucoma: SNRIs can increase intraocular pressure and may precipitate acute angle-closure glaucoma in susceptible individuals.

• Bipolar disorder: SNRIs are generally contraindicated in bipolar I disorder due to risk of manic episodes and should be used cautiously in bipolar II disorder.

Contraindications

• Concurrent or recent use of MAO inhibitors (MAOIs)

• Drugs with MAOI activity (e.g., linezolid, intravenous methylene blue) are also contraindicated.

• Known hypersensitivity: Allergy or hypersensitivity to the SNRI or related compounds contraindicates use.

• Uncontrolled narrow-angle glaucoma: Due to risk of increased intraocular pressure.

• Severe hepatic impairment: Particularly with duloxetine, which is contraindicated in patients with significant liver dysfunction.

• Pregnancy (relative contraindication): Especially during the first trimester, unless benefits outweigh risks.

Monographs

Reference

https://www.mayoclinic.org/diseases-conditions/depression/in-depth/snris/art-20044970

https://my.clevelandclinic.org/health/treatments/24797-snri?utm_source=perplexity

https://pmc.ncbi.nlm.nih.gov/articles/PMC4008300/

https://www.perplexity.ai/search/history-of-snris-yZ6O8tAYQWeemQi5YBz92Q