SNRIs: what are they, uses, side effects, and risks

If you’ve been considering starting an antidepressant and have tried doing some research, you may quickly find yourself bombarded with endless initials: SSRIs, SNRIs, TCAs, MAOIs. All these letters may leave you feeling more confused than ever. Not to worry—these simply refer to the different types of antidepressants.

Here, we’ll look at one of these types, SNRIs, and discuss the benefits and risks of starting treatment.

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Serotonin-norepinephrine reuptake inhibitors, or SNRIs, are antidepressants used to treat depression, other mental health conditions, and certain chronic pain disorders. SNRIs are a newer type of antidepressant and are safer and better tolerated than older classes of antidepressants (Zajecka, 2004). 

SNRIs work by increasing levels of serotonin and norepinephrine in the brain. Serotonin and norepinephrine are neurotransmitters—chemical messengers that send signals from one part of the body to another. Typically, after neurotransmitters have sent their signal, cells in the brain take up these chemicals and store them for later use. SNRIs prevent this reuptake, which increases serotonin and norepinephrine levels (Faquih, 2019). 

Serotonin and norepinephrine help regulate many functions, including mood, emotion, fear, sleep, appetite, sexual behavior, pain response, and attention. Researchers believe low levels of serotonin and norepinephrine (along with other neurotransmitters) contribute to depression. SNRIs help correct this imbalance (Moret, 2011; Sahli, 2016).

When used to treat depression, SNRIs take several weeks to become effective. Some people may see improvement in their symptoms within the first two weeks, but it can take six weeks or longer (Machado-Vieira, 2010). Keep this in mind if you don’t see any benefit right away, and continue to take your SNRI each day as prescribed. 

SNRIs were originally developed to treat depression, but today they are used for much more. Currently, the U.S. Food and Drug Administration (FDA) approves SNRIs to treat the following conditions (Dhaliwal, 2020; Singh, 2020): 

• Chronic muscle pain 

• Diabetic peripheral neuropathy (nerve pain associated with diabetes)

• Fibromyalgia 

• Generalized anxiety disorder

• Major depressive disorder 

• Panic disorder 

• Social anxiety disorder 

SNRIs can also be used “off-label” to treat other conditions, meaning the FDA didn’t explicitly approve them for those uses. Healthcare providers can prescribe drugs for an unapproved use if they decide that it’s the correct treatment for their patients.

Off-label uses for SNRIs include (Dhaliwal, 2020; Singh, 2020):

• Hot flashes and night sweats associated with menopause  

• Migraine prevention 

• Narcolepsy with cataplexy (sudden muscle weakness) 

• Nerve pain caused by chemotherapy 

• Obsessive-compulsive disorder (OCD)

• Post-traumatic stress disorder (PTSD) 

• Premenstrual dysphoric disorder (a severe form of premenstrual syndrome, or PMS) 

• Urinary incontinence 

There are currently five FDA-approved SNRIs available in the United States: 

• Desvenlafaxine (brand name Pristiq) 

• Duloxetine (brand name Cymbalta) 

• Levomilnacipran (brand name Fetzima) 

• Milnacipran (brand name Savella) 

• Venlafaxine (brand name Effexor XR)

SNRIs are generally well tolerated and considered safer than older antidepressant medications. However, all drugs have the potential for side effects, and SNRIs are no exception. 

Nausea is the most common adverse effect reported in studies. Gastrointestinal side effects typically occur within the first few days to weeks after starting an SNRI. They tend to go away with time (Carvalho, 2016). If nausea becomes bothersome, taking your SNRI with food may help. 

Unlike many other antidepressants, SNRIs don’t usually cause significant weight gain. While some people may gain weight, weight loss is actually more common (Dhaliwal, 2020; Singh, 2020). 

Several other side effects may occur while taking SNRIs. Be on the lookout for the following (Dhaliwal, 2020; Singh, 2020):

• Abdominal pain 

• Constipation 

• Decreased appetite

• Dizziness 

• Drowsiness 

• Dry mouth 

• Fatigue 

• Headache

• Nausea 

• Sexual dysfunction 

• Sweating 

• Trouble sleeping

• Weakness

Be sure to speak with your healthcare professional if any side effects start to impact your quality of life. They may be able to adjust your dose or switch to another medication.  

If you’re starting an SNRI, it’s important to be aware of some of the warnings and risks of these medications. Don’t hesitate to contact your healthcare provider if you experience any symptoms related to these risks.

Suicidal thoughts and behaviors 

All antidepressants, including SNRIs, carry a boxed warning from the FDA—their strongest warning for serious risks—regarding the increased risk of suicidal thoughts and behaviors in children and young adults. People over the age of 24 do not experience increased risk. Adults 65 and older actually show a decrease in suicidal thoughts and behaviors (Friedman, 2014).

The FDA notes that untreated depression can also increase these behaviors, so you and your provider will need to weigh the risks of starting or withholding treatment. Nevertheless, all people starting an antidepressant should be monitored for any worsening of symptoms or signs of suicidality (Friedman, 2014).

Serotonin syndrome 

Serotonin syndrome is a condition that occurs when there is too much serotonin in the body. This can happen with any drug that increases serotonin levels but more commonly occurs when two or more medications that affect serotonin are taken together.

The symptoms of serotonin syndrome can be mild; however, severe toxicity requiring hospitalization can occur. Mild symptoms include nausea, diarrhea, nervousness, tremor, and insomnia. As the syndrome progresses, you can develop sweating, agitation, muscle spasms, and side-to-side eye movements. Severe serotonin syndrome involves fever, stiff muscles, muscle breakdown, and confusion. If you notice any of these symptoms, it is important to seek medical advice right away since the condition can quickly become dangerous (Foong, 2018). 

Some medications should never be taken with SNRIs since they increase the risk of developing serotonin syndrome. These include a group of antidepressants called monoamine oxidase inhibitors (MAOIs) and an antibiotic called linezolid (brand name Zyvox) (Foong, 2018). 

Many other medications can interact with SNRIs, so always check with your healthcare provider before starting anything new. Other medications that can increase the risk of serotonin syndrome, especially if taken with SNRIs, include (Foong, 2018):

• Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac) or sertraline (Zoloft) 

• Tricyclic antidepressants (TCAs), like clomipramine (brand name Anafranil) or imipramine 

• Pain medications, including tramadol (brand name Ultram), methadone (brand name Dolophine), and fentanyl (brand name Duragesic) 

• Over-the-counter cough and cold products that include dextromethorphan or chlorpheniramine 

• Natural products, such as St. John's wort, l-tryptophan, or diet pills 

• Drugs of abuse, including cocaine, amphetamine, and ecstasy (MDMA)

Bleeding risks 

SNRIs can increase the risk of bleeding, including bruising, nose bleeds, and bleeding in the stomach. People taking non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, or naproxen, or blood thinners may be at increased risk for bleeding. Let your healthcare provider know about all medications you take, including over-the-counter, nonprescription products (Dhaliwal, 2020).

Blood pressure and heart rate effects 

SNRIs can increase blood pressure and heart rate in some people (Carvalho, 2016). The effect is typically small, but it may be more of a concern if you have high blood pressure or heart problems. Your healthcare provider will check your blood pressure and heart rate before starting you on an SNRI. They’ll periodically re-check these numbers to make sure everything remains in check (Dhaliwal, 2020). 

Discontinuation syndrome 

You may experience withdrawal symptoms if you stop taking your SNRI. This is more likely to occur if you stop the medication abruptly or if there is a large decrease in the dose. Withdrawal symptoms can happen with any SNRI but are more common with venlafaxine (brand name Effexor XR) or desvenlafaxine (brand name Pristiq) (Faquih, 2019; Fava, 2018). 

Symptoms typically occur within a few days of stopping the medication and can last for several weeks. You may experience flu-like symptoms, dizziness, trouble sleeping, anxiety, or a tingling or burning sensation (Fava, 2018). 

If you’re interested in stopping your SNRI, be sure to speak with your healthcare provider first. Together, you can develop a plan to decrease your dose slowly and minimize any side effects. 

Pregnancy and breastfeeding 

Finding out you’re pregnant can be an exciting and emotional time. Unfortunately, pregnancy is also a risk factor for depression. Some estimates show depression rates as high as 20% during and after pregnancy (postpartum depression). Managing your depression symptoms is vital since studies have shown that untreated depression can lead to poor outcomes for both the mother and the baby (Dubovicky, 2017). 

SNRIs have not been as extensively studied in pregnancy as SSRIs; however, they are used during pregnancy. Most of the research has involved venlafaxine (brand name Effexor XR) or duloxetine (brand name Cymbalta). The risk of birth defects appears to be low, but some pregnancy complications can occur. SNRIs can increase the risk of excessive blood loss after giving birth. High blood pressure during pregnancy may also occur, especially with venlafaxine (Carvalho, 2016).

Newborns whose mothers took SNRIs during the third trimester of pregnancy can develop withdrawal-type reactions after delivery. These include excessive crying, irritability, difficulty sleeping, and trouble feeding (Dubovicky, 2017).

If you wish to breastfeed your baby, other antidepressants are generally preferred. However, you may be able to continue your SNRI if it has helped with your depression symptoms. Venlafaxine and desvenlafaxine appear safe, although you should monitor your baby for excessive drowsiness, difficulty eating, and proper weight gain (Drugs and Lactation Database, 2021-a; Drugs and Lactation Database, 2021-c).

Duloxetine, levomilnacipran, and milnacipran are present in low levels in breastmilk, but the information regarding the use of these drugs during breastfeeding is limited (Drugs and Lactation Database, 2021-b; Drugs and Lactation Database, 2020-a; Drugs and Lactation Database, 2020-b). 

SNRIs have helped many people struggling with the symptoms of depression, anxiety, and other conditions regain control of their lives. Speak with your healthcare provider to see if these medications could be an option for you. 

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Current version

July 02, 2021

Written by

Christina Varvatsis, PharmD

Fact checked by

Steve Silvestro, MD

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About the medical reviewer

Steve Silvestro, MD, Ro

Dr. Steve Silvestro is a board-certified pediatrician and Associate Director, Clinical Content & Education at Ro.