Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

3 min read · 8 sections
Evidence-Based Care
Expert Staff

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class of drugs used primarily to treat depression, though certain SNRIs are also indicated for treatment of anxiety and chronic pain associated with diabetic neuropathy and fibromylagia.1,2

SNRIs were developed to be more effective than selective serotonin reuptake inhibitors (SSRIs), but there is not clear evidence that they are better at treating depression. Some people respond better to one than the other.3

Some studies suggest that SNRIs are as effective as tricyclic antidepressants at treating neuropathy, but with substantially fewer side effects than those older medications. However, some reports suggest that SSRIs (which are also sometimes used for certain neuropathic pain conditions—though with somewhat questionable efficacy) have even fewer side effects than SNRIs.4,5

How Do These Drugs Work?

SNRIs work by blocking the reabsorption (or reuptake) of serotonin and norepinephrine back into the nerve cells that released them, which increases the levels of active neurotransmitters in the brain.6

Both of these neurotransmitters are associated with distinct brain structures and functions and impact various processes such as mood and energy in somewhat different ways. Increasing levels of them in the brain may help improve mood and emotion.

  • Norepinephrine plays a role in attention, mental focus, and memory.7
  • Serotonin is also important for learning and memory formation, but is also instrumental in the regulation of sleep, mood, and appetite.8

Types of SNRIs

Examples of SNRIs include:6

  • Venlafaxine (Effexor).
  • Duloxetine (Cymbalta).
  • Desvenlafaxine (Pristiq, Khedezla).
  • Milnacipran (Savella).
  • Levomilnacipran (Fetzima).


Effexor was the first SNRI marketed in the United States and the first to be approved by the Food and Drug Administration (FDA). It is structurally different from several other SNRIs with its bicyclic, or two-ring, structure. Effexor and its time-released formulation Effexor XR are approved for the treatment of major depression, generalized anxiety disorder, panic disorder, and social phobia.9

Effexor has disproportionate reuptake inhibition effects. It is 30 times more selective for inhibiting the reuptake of serotonin than it is for norepinephrine. In addition, its effects on each neurotransmitter system take place sequentially—with serotonin reuptake blocking happening first, and that of norepinephrine second. Because of this, patients taking Effexor often report side effects related to serotonin (headaches, nausea, fatigue, or sexual dysfunction) first, followed by side effects related to norepinephrine (dry mouth or night sweats).9


Cymbalta first became available more than a decade after Effexor. Like Effexor, Cymbalta inhibits serotonin reuptake before norepinephrine, and results in more selective serotonin reuptake inhibition than that of norepinephrine.9

Cymbalta is approved to treat major depression, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain, and osteoarthritis. Among SNRIs, it has been approved to treat the greatest number of conditions.9


Pristiq was approved by the FDA in 2008 for the treatment of major depression. It is similar in chemical structure to Effexor. Also like Effexor, it has a greater effect on serotonin reuptake inhibition, but the difference is only 10-fold, as opposed to the 30-fold difference of Effexor.9


Savella’s approval by the FDA followed close behind that of Pristiq in 2009. Unlike the other medications in this class, Savella is only approved to treat fibromyalgia. However, it is approved in France for the treatment of depression. Savella is taken twice a day, unlike the other SNRIs, which are once a day.9

Savella’s uniqueness in this class comes from the fact that it is the “most balanced” of current SNRIs. It exhibits nearly equal inhibition of the reuptake of both serotonin and norepinephrine, but has no effect on dopamine, unlike some other SNRIs (which have small dopamine reuptake-inhibiting effects at high doses).9


Fetzima is the newest SNRI, approved in 2013. Fetzima was developed as a once-a-day, extended-release capsule in order to enhance patient adherence to a treatment regimen.9

Fetzima distinguishes itself from the other drugs in this class by showing a relatively greater effect on norepinephrine reuptake inhibition than serotonin reuptake inhibition. In fact, it has double the affinity for inhibiting norepinephrine reuptake as compared to serotonin reuptake. Fetzima is approved solely to treat major depression.9

Side Effects

If you experience serious side effects, let your doctor know right away. They may adjust the dose or put you on a different medication.

Risks of Discontinuing SNRIs

Withdrawal symptoms usually appear within 3 days of stopping the medication and last 1 to 2 weeks. Symptoms are typically mild, but if your symptoms become severe, talk to your doctor immediately.10

Consult with a doctor before stopping treatment with an SNRI. In many cases, a doctor may recommend a tapering schedule to ease withdrawal.

Is Medication Enough?

While there is much conflicting evidence about the efficacy of both SSRIs and SNRIs on their own, research done by Consumer Reports magazine indicate that patients receiving only medication (SSRIs, SNRIs, or bupropion) for depression or anxiety reported changes in their emotional state at about 70 on a scale of 100.5

Similar results were reported by patients who underwent only talk therapy. The results were somewhat higher for patients who received both talk therapy for 7 or more visits and an antidepressant medication.5

The most common talk therapy is cognitive behavioral therapy, or CBT. This is an approach in which patients learn to recognize unhealthy thoughts or behaviors that contribute to depression and anxiety and develop methods of restructuring them.11

Overall, medications are rarely recommended on their own. They are usually used as part of an overall treatment program that includes therapy and other lifestyle changes.11

Can SNRIs Be Abused?

The vast majority of people taking antidepressants do not misuse their medication. However, there have been case reports of people crushing SNRI pills to quickly consume large doses and enhance the onset of action of the drug, evidently in search of an amphetamine-like effect, which made them more sociable and euphoric. This type of abuse can place the patient at greater risk of hypertension, tremors, weight loss, dizziness, and more serious withdrawal symptoms. In both cases of abuse in the study, the patients had a history of substance abuse.12

People taking SNRIs should be careful to avoid any potential interactions with alcohol and other drugs. Alcohol can worsen depression, and though the risk of interaction with alcohol is relatively lower with SNRIs than with some other antidepressants, you should still avoid alcohol and illegal drugs while taking them.13

Other drugs that may negatively interact with SNRIs include:14

  • Central nervous system-active drugs.
  • Monoamine oxidase inhibitors (MAOIs).
  • Serotonergic drugs.
  • Nonsteroidal inflammatory drugs (e.g., ibuprofen), aspirin, and Warfarin.
  • Weight loss drugs.

Are SNRIs Right for You?

SNRIs can have tremendous benefits for people suffering from depression or other conditions. However, patients should work closely with their team of medical professionals to make sure an SNRI is the correct treatment for them and to ensure they are on the right SNRI for their symptoms.


[1]. Stahl, S., Grady, M., Moret, C., and Briley, M. (2005). SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectrums, 10(9), 732-747.

[2]. U.S. National Library of Medicine, Medline Plus. (2018). Duloxetine.

[3]. National Health Service. (2018). Antidepressants: Overview.

[4]. Baltenberger, E., Buterbaugh, W., Martin, S., and Thomas, C. (2015). Review of antidepressants in the treatment of neuropathic pain. Mental Health Clinician, 5(3),123-133.

[5]. Consumer Reports. (2010). Best antidepressant for anxiety according to our readers.

[6]. Mental Health America. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs).

[7]. University Health News Daily. (2017). Norepinephrine Deficiency: Surprising Research Challenges Our Understanding of Natural Depression Remedies.

[8]. National Eating Disorders Association. Neurotransmitters.

[9]. Sansone, R., and Sansone, L. (2014). Serotonin Norepinephrine Reuptake Inhibitors: A Pharmacological Comparison. Innovations in Clinical Neuroscience, 11(3-4), 37-42.

[10]. Warner, C., Bobo, W., Reid, S., and Rachal, J. (2006). Antidepressant Discontinuation Syndrome. American Family Physician, 74(3), 449-456.

[11]. National Alliance on Mental Illness. Psychotherapy.

[12]. Evans, E. and Sullivan, M. (2014). Abuse and misuse of antidepressants. Substance Abuse and Rehabilitation, 5, 107-120.

[13]. National Health Service. (2018). Antidepressants: Cautions.

[14]. National Library of Medicine, DailyMed. (2018). Effexor XR.

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