SNRIs: How These Popular Antidepressants Work

Major depressive disorder, or depression, is one of the most common mental disorders. It can occur in people of all ages and backgrounds, with an estimated 21 million US adults affected by some form of depression in 2020. And if you’re experiencing depression or anxiety — chances are high you’ve heard of SSRIs and SNRIs.

If you’ve been diagnosed with depression, your healthcare provider may recommend taking an antidepressant to make your symptoms less severe and help you recover.

Serotonin-norepinephrine reuptake inhibitors (SNRIs), are a class of antidepressants commonly used to treat depression and anxiety disorders. They’re similar to SSRIs, but have a few key differences it’s helpful to know about before using this type of medication. 

Read on to learn more about SNRIs, including how they work as treatments for depression, anxiety and other forms of mental illness, potential side effects, and other treatment options you may want to consider — either in combination with SNRIs or on their own. 

Serotonin-norepinephrine reuptake inhibitors (SNRIs), are a class of antidepressants. They’re used to treat major depressive disorder (typically known as clinical depression), as well as anxiety disorders such as generalized anxiety disorder (GAD), social anxiety disorder (SAD) and panic disorder (PD).

The first SNRIs were introduced in the mid-1990s, with venlafaxine (sold as Effexor®) approved by the FDA in 1993. 

Like other antidepressants, SNRIs work by increasing the levels of neurotransmitters, which are chemicals related to your thoughts, feelings and moods.

More specifically, SNRIs work by preventing the reuptake of the neurotransmitters serotonin and norepinephrine.

Serotonin is a neurotransmitter that has a range of functions within your brain and body. It’s best known for its effects on mood and behavior. Serotonin helps manage your moods and certain feelings, such as anxiety and happiness.

In addition to affecting the way you think and feel, serotonin plays an important role in regulating your sleep-wake cycle (the process responsible for making you feel tired at night and alert in the morning), your digestive function and some aspects of the wound healing process. 

Normal serotonin levels are associated with focus, calmness and emotional stability. Low levels of serotonin are associated with the symptoms of depression.

Norepinephrine, or noradrenaline, is a neurotransmitter that’s also responsible for controlling the way you think, feel and behave.

Within your body, norepinephrine is involved in stimulating your cardiovascular system, breaking down fat and providing your body with energy. Within your brain, it’s involved in managing your sleep-wake cycle, providing mental focus and in functions such as memory storage.

Norepinephrine plays a major role in both mental and physical alertness. It’s part of your body’s natural fight or flight response, which helps mobilize your brain and body in situations that are stressful or dangerous.

Like serotonin, low levels of norepinephrine are linked with depression, anxiety and other mental health issues, as well as physical symptoms such as lethargy. 

By preventing the reuptake of the two neurotransmitters, SNRIs help increase the amounts of serotonin and norepinephrine that remain active in your brain and body.

In contrast, selective serotonin reuptake inhibitors (SSRIs) — another popular class of medications used to treat depression — only prevent the reuptake of serotonin.

Because they work by targeting two neurotransmitters, SNRIs are sometimes referred to as dual-reuptake inhibitors, or dual-action antidepressants.

SNRIs differ in their level of selectivity for serotonin and norepinephrine. Some SNRIs increase levels of one neurotransmitter more than the other, while others work more evenly to increase levels of both neurotransmitters.

By increasing serotonin and norepinephrine levels, SNRIs typically help to treat depression and certain forms of anxiety. 

Their effects aren’t immediate: Like other antidepressants, most take two to four weeks to start working — but for many people, they make the symptoms of depression or anxiety easier to manage.

Some SNRI drugs may also be used to treat obsessive-compulsive disorder (OCD), although research on the effectiveness is limited.

An SNRI may also be used to treat attention deficit hyperactivity disorder (ADHD) in adults who do not respond well to other ADHD medications.

SNRIs are commonly prescribed to treat depression and anxiety, either as first-line treatments (the first type of medication prescribed by a healthcare provider), or as second-line treatments when other medications aren’t effective. 

Currently, several SNRIs are prescribed by healthcare providers in the United States. You can find more information about each medication below.

Venlafaxine (sold as Effexor XR®)

Venlafaxine was the first SNRI approved by the FDA for use in the United States. It comes as a capsule and is generally used once per day. 

Venlafaxine is prescribed to treat major depression and anxiety disorders, including generalized anxiety disorder, social anxiety disorder and panic disorder. It’s also used off-label for migraine prevention, hot flashes, fibromyalgia and other conditions.

In addition to targeting serotonin and norepinephrine, venlafaxine also increases the amount of dopamine (a neurotransmitter that’s involved in recognizing and pursuing goals) that’s active in the brain and body.

Venlafaxine was originally sold as Effexor, which is now discontinued. Today, it’s available as a generic medication and in extended-release form under the brand name Effexor XR.

Desvenlafaxine (sold as Pristiq®)

Desvenlafaxine is an SNRI that’s used to treat major depressive disorder. It was first approved by the FDA in 2008 and comes as a capsule for use one time per day.

Like other SNRIs, desvenlafaxine works by increasing serotonin and norepinephrine levels. It has a mild effect on dopamine. Research shows that desvenlafaxine is selective for serotonin, meaning it has a greater effect on serotonin levels then on levels of norepinephrine.

In addition to its approved use as a treatment for depression, desvenlafaxine is used off-label to hot flashes in women going through menopause.

Desvenlafaxine was originally approved as Pristiq and is still sold under this name. It’s also sold as a generic medication.

Duloxetine (sold as Cymbalta®)

Duloxetine is a common SNRI that’s available as Cymbalta. It was approved by the FDA in 2004 and comes as a capsule for use once per day.

Duloxetine is approved by the FDA to treat major depressive disorder, fibromyalgia, generalized anxiety disorder, diabetic peripheral neuropathic pain and chronic musculoskeletal pain. 

In some cases, duloxetine may be prescribed off-label to treat stress urinary incontinence (SUI, or leakage of urine during moments of physical activity) and nerve damage that develops due to chemotherapy.

Like other SNRIs, duloxetine also increases dopamine levels, specifically in the prefrontal cortex area of the brain.

Duloxetine was originally approved under the brand name Cymbalta. It’s currently available as a brand name medication and as a generic.

Milnacipran (sold as Savella®)

Milnacipran is an SNRI that’s sold under the brand name Savella. It was approved by the FDA in 2009.

Unlike other SNRIs, milnacipran isn’t approved by the FDA to treat depression. Instead, it’s used as a treatment for fibromyalgia, a chronic condition that involves pain in muscle and other tissue throughout the body. 

Milnacipran comes in tablet form and is typically used twice a day. Although this SNRI isn’t approved to treat depression in the United States, it may be prescribed for this purpose in other countries.

Levomilnacipran (sold as Fetzima®)

Levomilnacipran is a newer SNRI that’s sold under the brand name Fetzima. It was approved by the FDA in 2013 as a treatment for major depressive disorder.

Levomilnacipran is chemically similar to milnacipran. It comes as an extended-release capsule and is designed for use once per day. Research suggests that levomilnacipran has greater effects on norepinephrine than serotonin within the body.

Research shows that SNRIs are effective at reducing the severity of depression and anxiety for most people. 

For example, clinical trials of the SNRI duloxetine revealed that people with depression were more likely to experience improvements after taking the medication over a period of eight weeks than after using a non-therapeutic placebo for the same period of time.

Other research has showed that many SNRIs are also effective at reducing the severity of anxiety symptoms.

In general, research shows that SNRIs are roughly as effective as SSRIs for treating depression, albeit with slightly higher rates of remission. Other studies have found that SNRIs offer greater benefits than SSRIs for the relief of chronic pain.

Because the precise causes and symptoms of depression can vary from person to person, there isn’t a “perfect” antidepressant for everyone.

Your healthcare provider may suggest using an SNRI as a first-line treatment if you have clinical depression or an anxiety disorder. Alternatively, they may suggest switching to an SNRI if you’ve used another type of antidepressant without seeing results.

Like with other types of antidepressants, you might need to try several SNRIs before finding the right one for your symptoms, lifestyle and mental health needs.

Like other antidepressants, serotonin-norepinephrine reuptake inhibitors can potentially cause side effects. 

Most side effects of SNRIs are mild and gradually pass as your body gets used to the medication. Common SNRI side effects include:

• Nausea

• Drowsiness

• Dry mouth

• Insomnia

• Difficulty urinating

• Excessive sweating

• Abnormal ejaculation

• Change in appetite

• Muscle weakness

• Constipation

• Decreased libido

• Erectile dysfunction (ED)

• Increased blood pressure

Some SNRIs may cause more serious or persistent side effects. Our full guide to antidepressant side effects provides more information on common issues that you may experience while taking an SNRI or similar medication for depression or anxiety.

As with other types of antidepressants, SNRIs can potentially cause sexual side effects. If you’re prescribed an SNRI for depression or anxiety, you may find that it’s difficult to reach orgasm and ejaculate during sex or masturbation, or that you have difficulty maintaining an erection.

You may also notice a general reduction in your level of interest in sex. These side effects vary between specific SNRIs and can also be caused by depression and anxiety disorders, meaning your medication may not be solely responsible for changes in your sexual health and function.

Our guide to antidepressants and sexual side effects provides more information about how your sex drive and sexual function may change while using antidepressants. 

For most people, SNRIs are safe and effective medications that help to treat depression, anxiety and other conditions with few issues. 

However, like other medications, SNRIs may interact with other drugs. They also have risks that may affect your health and wellbeing in certain situations, or if you have existing conditions. You can find more information about these interactions and safety issues below.

Interactions with Other Antidepressants

SNRIs should not be used with other antidepressants, or with non-antidepressant medications that can increase serotonin levels.

When taken with other medications that increase serotonin levels, SNRIs can potentially result in a life-threatening condition called serotonin syndrome.

Serotonin syndrome occurs when serotonin levels become dangerously high. Symptoms may include hypertension (high blood pressure), tachycardia (increased heart rate), mydriasis (pupil dilation), sweating, shivering, tremor, involuntary muscle jerking and overactive reflexes.

When severe, symptoms of serotonin syndrome can include fever, rigid muscles and significant increases in body temperature.

To reduce your risk of experiencing interactions, make sure to inform your healthcare provider about all medications you currently use or have recently used before taking any SNRI or other type of antidepressant. 

It’s also important to tell your healthcare provider about any herbs or supplements you use to be sure to check for contraindications. (Even ‘natural’ supplements can sometimes cause negative interactions with medications, and your healthcare provider can best advise you.)

Antidepressant Discontinuation Syndrome

SNRIs and other antidepressant drugs can take several weeks to start working. You may only begin to notice the effects of an SNRI after two to four weeks of daily use, and symptoms (that related to depression and anxiety) such as your appetite, sleep habits and mental focus may improve before your mood.

If you don’t think your SNRI is working after several weeks of treatment, it’s important to talk to your healthcare provider before making any changes to your use of your medication.

Do not abruptly stop using your SNRI. Suddenly stopping treatment can cause antidepressant discontinuation syndrome: a dangerous range of withdrawal symptoms that can develop two to four days after drug cessation.

Stopping your medication early may also affect your treatment of depression and increase your risk of relapse.

If you wish to stop taking your SNRI, your healthcare provider can help you safely taper your dosage over the course of several weeks.

Increased Suicide Risk in Teens and Young Adults

All antidepressants, including SNRIs, include a “black box” warning from the FDA to notify users of an increased risk of suicidal thoughts and behavior in children, teenagers and young adults.

Research has found that antidepressants may increase the risk of suicidal thinking and behavior in people aged 24 and under. This increased suicide risks does not appear in people above 24 years of age; in this group, antidepressants are associated with a reduced rate of suicide.

If you develop suicidal thoughts while using any type of antidepressant, contact your healthcare provider as soon as you can.

If you’re going through a mental health crisis, you can get help right now by calling emergency medical services on 911, contacting the National Suicide Prevention Lifeline (1-800-273-8255) or using the resources in our list of crisis and mental health hotlines.

SNRI Use in People with Hypertension or Liver Damage

Large-scale research suggests that SNRIs can cause a modest increase in systolic and diastolic blood pressure. This may be an issue if you have hypertension (clinically high blood pressure), especially if you are prescribed medication to manage your blood pressure levels. 

Most SNRIs are metabolized through the liver. Although research does not show any increase in liver injury amongst people treated with SNRIs, existing liver problems may increase your risk of adverse effects from SNRIs or slow the processing of these medications by your body.

If you have high blood pressure, liver damage or other existing medical conditions, make sure to talk to your healthcare provider before using any SNRI medication. 

Alcohol and SNRIs

Consuming alcohol while taking SNRIs and other antidepressants can lead to:

• Worsened symptoms of depression, including suicidal thoughts and behaviors

• Increased risk of antidepressant side effects

• Worsened antidepressant side effects

• Increased risk of overdose

• Risk of liver problems

The National Alliance on Mental Illness recommends that those who want to continue drinking alcohol while taking antidepressants do so in the safest way possible, in moderation.

SNRI Use During Pregnancy or Breastfeeding

SNRIs and other antidepressants may cause side effects and safety issues during pregnancy and breastfeeding. Research has found that newborn babies exposed to SNRIs and/or SSRIs during pregnancy often require longer hospitalization, tube feeding and breathing support.

Exposure to SNRIs and SSRIs is also linked to decreased birth weight, neurobehavioral issues, decreased heart rate and cognitive issues in young children.

If your partner is reading this and she’s currently pregnant, breastfeeding or planning to become pregnant, make sure to talk to a healthcare provider about safely treating her depression during this period. 

In addition to SNRIs, numerous other types of antidepressants are used to treat depression and anxiety. Other common medications for depression include:

• Selective serotonin reuptake inhibitors (SSRIs). SSRIs work by inhibiting serotonin reuptake and increasing serotonin levels. Medications of this type are commonly used as first-line treatments for depression and anxiety.
  
  

• Tricyclic antidepressants (TCAs). TCAs are older antidepressants that are sometimes used when newer medications aren’t effective. They’re more likely to cause side effects and health issues than newer antidepressants.
  
  

• Monoamine oxidase inhibitors (MAOIs). MAOIs are another class of older medications for depression. They can cause significant side effects and interactions, meaning they’re generally only used when all other antidepressants are unsuccessful.
  
  

• Atypical antidepressants. Some medications, such as bupropion and trazodone, are referred to as atypical antidepressants. Your healthcare provider may suggest using an atypical antidepressant if other medications are ineffective or unsuitable for you.  

Beyond medication, depression and anxiety often improve with psychotherapy, including options such as cognitive behavioral therapy (CBT). 

Making certain changes to your lifestyle, such as exercising regularly and practicing techniques to promote relaxation, may also help improve some depression and anxiety symptoms.

Our list of ways to help depression shares science-based techniques you can use with your medication to improve your symptoms and overcome clinical depression. 

SNRIs such as venlafaxine, duloxetine and others can make the symptoms of depression and anxiety less severe, helping you improve your quality of life and gain more control over your mental health and wellbeing. 

We offer several SNRIs online through our online psychiatry service, following an evaluation by a licensed psychiatry provider who will determine if a prescription is appropriate. 

Interested in learning more about taking control of your mental health? Our online mental health resources offer effective strategies from licensed professionals to help you successfully deal with depression, anxiety, chronic stress and other common issues.