Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

This article provides a comprehensive overview of SNRIs, including their mechanism of action, the specific types, side effects, and how they fit into a professional mental health treatment plan.

Key Takeaways:

• SNRIs are the second most common type of antidepressant, right behind SSRIs. They mainly work by increasing the effects of serotonin and norepinephrine in the brain.

• SNRIs are used for depression, especially more severe or treatment-resistant forms. They are also often used for chronic pain and some anxiety disorders.

• There are several possible side effects of SNRIs, some of which are severe. Individualized treatment plans are essential with SNRIs since they affect everyone differently.

Understanding SNRIs

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a type of prescription antidepressant medication. They are very commonly used in the treatment of depression, and may be particularly effective for more severe forms. ^[1]

Note that SNRIs should not be confused with selective serotonin reuptake inhibitors (SSRIs). They do have similar effects, but also key differences in the way they affect neurotransmitters in the brain.

How do SNRIs Work?

SNRIs work by altering the levels of certain neurotransmitters in your brain, mainly serotonin and norepinephrine. These drugs block or delay the reuptake of serotonin and norepinephrine by nerves, which allows more of these chemicals to be available. ^{[1] [2]}

Serotonin is involved in mood, sleep, appetite, sexual function, and other important functions. Norepinephrine is important for energy, motivation, focus, and attention. Therefore, increasing the availability of these neurotransmitters offers several potential benefits. ^{[1] [2]}

SNRIs to Treat Depression

SNRIs are one of the most common medications used to treat depression, falling right behind SSRIs, which are the most common. There are four SNRIs approved for the treatment of major depressive disorder (MDD) and other forms of depression: ^{[1] [2] [3]}

• Venlafaxine (Effexor®, Effexor XR®)

• Duloxetine (Cymbalta®, Drizalma®, Irenka®)

• Desvenlafaxine (Khedezla®, Pristiq®)

• Levomilnacipran (Fetzima®)

A fifth SNRI known as Milnaciparan® also exists, but it is only approved for fibromyalgia and not depression.

Venlafaxine

Venlafaxine was the first SNRI marketed for use in the USA. The instant-release form was approved in 1993, and the extended release form was approved in 1997. It is 30 times more selective for inhibiting the reuptake of serotonin compared to norepinephrine, and it also inhibits serotonin reuptake first before inhibiting the reuptake of norepinephrine. ^[4]

Duloxetine

Duloxetine was approved for use in 2004. It is 10 times more selective for inhibiting the reuptake of serotonin versus norepinephrine, and it also exerts its effects on serotonin before norepinephrine. Duloxetine also mildly inhibits the reuptake of dopamine. ^[4]

Desvenlafaxine

Desvenlafaxine was approved for use in 2008. It is 10 times more selective for inhibiting the reuptake of serotonin compared to norepinephrine, just like duloxetine. And desvenlafaxine also mildly inhibits the reuptake of dopamine. ^[4]

Levomilnacipran

Levomilnacipran is the latest SNRI approved for use in 2013. It is unique compared to the other forms because it is 2 times more selective for inhibiting the reuptake of norepinephrine compared to serotonin, and because it affects these two neurotransmitters simultaneously. ^[4]

Most of these medications are taken once per day, although venlafaxine instant-release is taken twice daily.

Other Conditions Treated by SNRIs

SNRIs have several other indications besides MDD and other forms of depression. For example:

• Venlafaxine is used for generalized anxiety disorder (GAD), panic disorder, and social anxiety disorder (SAD). ^{[2] [4]}

• Duloxetine is approved for use in GAD, diabetic peripheral neuropathy, fibromyalgia, musculoskeletal pain, and osteoarthritis. It has the most approved indications.

• Milnacipran is approved for use with fibromyalgia.

Thus, common conditions treated by SNRIs besides depression mainly include anxiety disorders and chronic pain. They may also be used off-label for hot flashes and night sweats associated with menopause, urinary incontinence, attention-deficit hyperactivity disorder (ADHD), migraine prevention, and obsessive-compulsive disorder (OCD). ^[3]

Common Side Effects of SNRIs

There are several common side effects of SNRIs, including: ^{[1] [2] [3]}

• Nausea

• Headache

• Dry mouth

• Dizziness

• Vomiting

• Constipation

• Diarrhea

• Hot flushes

• Insomnia

• Reduced libido

• Erectile dysfunction

• Weight gain

Of these, nausea, dizziness, dry mouth, headache, and sweating are the most common. ^[1]

Rare and Severe Side Effects

SNRIs also have several less common side effects, some of which may be severe. This includes: ^{[2] [3] [5]}

• Serotonin syndrome

• Increase in suicidal thoughts

• Bleeding

• Low blood pressure

• Hyponatremia (low sodium in the blood)

Serotonin Syndrome

Serotonin syndrome occurs when there is too much serotonin in the body. Initial symptoms are often milder and include nervousness, dilated pupils, muscle twitching, and nausea, among others. Severe cases can lead to rapid heart rate, delirium, seizures, high blood pressure, and loss of consciousness. ^{[3] [5]}

Suicide Risk

SNRIs can sometimes increase the risk of suicidal ideation, especially in children and adults under 25. The risk is greatest when someone initially starts taking an SNRI or if they switch medications. ^{[2] [3]}

Therefore, it’s essential to watch out for suicide warning signs, such as:

• Abrupt mood changes

• Severe mood swings

• Thoughts about harming oneself or others

• Thinking or talking about wanting to die

• Excessive guilt or worthlessness

Getting a Prescription for SNRIs

To get a prescription for an SNRI, you’ll need to schedule an appointment with your primary care doctor. They’ll review your history, ask about your symptoms, and conduct any necessary assessments. In some cases, referral to a psychiatrist or other mental health professional may be needed, particularly for additional mental health testing and to ensure you’re given the most effective and appropriate medication.

When to Seek a Diagnosis for Depression

You should seek a diagnosis for depression if you’re experiencing frequent and moderate to severe symptoms that interfere with your mental well-being and ability to function in everyday life. Notable symptoms that may warrant a mental health evaluation for depression include:

• Trouble sleeping or sleeping too much

• Persistent sadness or low mood

• Feelings of hopelessness

• Eating too much or not enough/skipping meals

• Significant weight loss or weight gain

• Thoughts of harming yourself or wanting to die

• Agitation and mood swings

SNRI Treatment Plan

If you are prescribed an SNRI, your doctor will go over a specific treatment plan. SNRIs are taken every day. Some improvements may occur within 1 to 2 weeks, but the greatest effects often don’t appear until 6 to 8 weeks. ^[2]

Within this timeframe, it’s important to let your doctor know of any side effects you’re experiencing. You’ll often have a scheduled follow-up several weeks from the time you started taking the medication, but it’s important to notify your doctor sooner than this if you’re experiencing any side effects or concerns.

You and your doctor will stay in close communication, with regular check-ups. At each appointment, they’ll evaluate your symptoms and side effects. If you’re not responding as desired, they may change the dose of your medication, switch medications, or add another medication. Open and honest communication with your doctor and all other involved healthcare providers is essential to ensure the most appropriate and effective treatment plan.

How Long Does it Last?

The length of treatment with SNRIs depends on a variety of factors, such as symptom severity, treatment response, and age. Most individuals are typically prescribed SNRIs for at least 6 months to not only reduce symptoms, but also to help reduce the likelihood of returning symptoms.

Some individuals may only require SNRI treatment for a few months, especially for milder cases. Others with more severe and/or chronic depression and greater risk of relapse may use SNRIs for several years or indefinitely.

Safely Stopping SNRI Medication Treatment

Suddenly stopping SNRIs can lead to antidepressant discontinuation syndrome (sometimes referred to as SNRI “withdrawal”). This can lead to several troubling symptoms, such as: ^{[2] [3] [5]}

• Insomnia

• Nausea

• Dizziness

• Agitation

• Anxiety

• Worsening depression

• Burning, tingling, or shock-like sensations

If you want to stop taking your SNRI, it’s important to do so under the guidance of your healthcare provider. Your doctor will set up a tapering plan, which involves gradually lowering the dose of the medication over time. Typically, this is most effective when it is reduced by a specific percentage (e.g. 25%). ^[1]

Final Thoughts

SNRIs can be a valuable part of your treatment plan, especially for more severe forms of depression, as well as anxiety and chronic pain. Like any prescription medication, there are possible side effects. And the most effective treatments vary from person to person. Always talk with your doctor to see what medication and treatment plan is best for you.

Commonly Asked Questions About SNRIs

What substances react badly with SNRIs?

SNRIs have several important possible interactions with other substances. This includes: ^{[2] [3] [5]}

• Increased risk of bleeding when combined with NSAIDs and aspirin

• Increased risk of hyponatremia when used with diuretics

• Increased risk of serotonin syndrome when combined with other medications or substances that increase serotonin, such as:

• St. John’s wort

• Dextromethorphan

• Tramadol

• Other antidepressants (e.g. SSRIs, MAOIs)

• Illicit drugs (e.g. cocaine, ecstasy)

Can I take SNRIs without a prescription?

No, a prescription is required to take SNRIs. This is to ensure safety and effectiveness.

Are there any effective alternatives to SNRIs?

There are other possible options to SNRIs, which vary depending on your symptoms, health status, goals, and other individual factors.

For example, depression and anxiety can also be treated with SSRIs, other antidepressants, and/or psychotherapy, such as cognitive behavioral therapy (CBT).

If you’re taking SNRIs for pain, possible effective alternatives include other forms of antidepressants, anti-inflammatory drugs, topical analgesics, anticonvulsants, muscle relaxants, and physical therapy. Talk to your healthcare provider to see what treatment plan is best for you.