Serotonin-norepinephrine reuptake inhibitors

SNRI stands for serotonin-norepinephrine reuptake Inhibitor. These may also be called selective serotonin-norepinephrine reuptake Inhibitors (SSNRIs). SNRIs increase levels of serotonin and norepinephrine in the brain by blocking or delaying their reuptake by nerves.

Serotonin is a neurotransmitter that is often referred to as the “feel good hormone”. It carries messages between brain cells and contributes to well-being, good mood, appetite, social behavior, as well as helping to regulate the body’s sleep-wake cycle and internal clock.

Norepinephrine is another neurotransmitter that is also thought to be important in the regulation of emotions and thought processes. It works closely with dopamine and serotonin systems and is thought to help mobilize the brain for action, increasing alertness, focus and the retrieval of memory.

Having more serotonin and norepinephrine available in the nerve synapse means that information can be transmitted easier from one nerve to another. All SNRIs are thought to work in this way.

What are SNRIs used for?

SNRIs help to relieve the symptoms of depression in major depressive disorder (MDD) such as low mood, irritability, feelings of worthlessness, restlessness, anxiety, and difficulty in sleeping.
In addition to depression, some SNRIs may be used to treat other conditions, such as:

• Anxiety
• Bipolar depression
• Chronic muscle or joint pain
• Diabetic neuropathy
• Fibromyalgia
• Low back pain or osteoarthritis pain
• Panic disorder
• Social phobia.

Some reduction in symptoms may be noticed within one to two weeks; however, it may take six to eight weeks of treatment before the full effects are seen.

What are the differences between SNRI antidepressants?

Although all SNRI antidepressants are thought to act in the same way, each has a different effect on reuptake inhibition. Venlafaxine inhibits serotonin reuptake more than norepinephrine reuptake. Although the difference is less with duloxetine and desvenlafaxine, the effect on serotonin remains greater with these two SNRIs. Milnacipran exerts a relatively equal influence on serotonin and norepinephrine whereas levomilnacipran affects norepinephrine more than serotonin. Depending on the SNRI, serotonin side effects may be seen before norepinephrine side effects.

Venlafaxine was the first SNRI marketed in the United States. Only venlafaxine immediate release and milnacipran are dosed twice a day, all the rest are dose once a day. Both venlafaxine and duloxetine are available in generic formulations.

Duloxetine has the most approved indications followed by venlafaxine. Desvenlafaxine (depression), levomilnacipran (depression) and milnacipran (fibromyalgia) have only one indication each.

Compared to other antidepressants, such as SSRIs or TCADs the SNRIs have relatively short half-lives and only venlafaxine has an active metabolite (desvenlafaxine).

Venlafaxine and duloxetine are more likely than other SNRIs to interact.

Are SNRI antidepressants safe?

When taken at the recommended dosage, SNRI antidepressants are considered safe. However, they have been associated with a few serious, potentially fatal, severe side effects such as:

• An increase in suicidal thoughts and behaviors, particularly in children and young adults under the age of 25 years. This is most likely to occur when starting therapy
• Serotonin syndrome – this is caused by excessive levels of serotonin in the body and is more likely to occur with higher dosages of SNRIs or when SNRIs are administered with other medications that also release serotonin (such as dextromethorphan, tramadol, and St. John's Wort). Symptoms include agitation, confusion, sweating, tremors, and a rapid heart rate
• Most SNRIs have been associated with a discontinuation syndrome if stopped abruptly or even when tapered. Symptoms may include anxiety, headache, dizziness, diarrhea, abnormal sensations such as pins and needles, irritability, insomnia, increased sweating, and tiredness. Discontinue slowly on a doctor's advice.
• Interaction or overdosage may cause serotonin syndrome (symptoms include mental status changes [such as agitation, hallucinations, coma, delirium), fast heart rate, dizziness, flushing, muscle tremor or rigidity and stomach symptoms (including nausea, vomiting, and diarrhea).
• May precipitate a manic episode in people with undiagnosed bipolar disorder, although reportedly less likely to do so than SSRIs.
• May cause a lowering of blood pressure - this may be particularly noticeable when going from a sitting to a standing position. Some SNRIs (such as venlafaxine) may be associated with a sustained moderate increase in blood pressure (about 10-15mm Hg) in some people; regular monitoring of blood pressure may be required.
• May increase the risk of bleeding; caution when using with other drugs that increase bleeding risk (such as aspirin and NSAIDs).
• May cause a lowering of total body sodium (called hyponatremia); elderly people or people taking diuretics or already dehydrated may be more at-risk.
• The dosage of some SNRIs may need reducing in people with mild to moderate kidney or liver disease. Avoid in severe kidney and liver disease and may not be suitable for people who are susceptible to glaucoma. Not generally recommended for people under the age of 18.
• May impair judgment or cause drowsiness and affect a person's ability to drive or operate machinery. Avoid alcohol.
• May cause a lowering of sodium levels in the body (this is called hyponatremia). Elderly people or people taking diuretics or who are already dehydrated may be more at risk.
• Rarely causes seizures.
• May interact with some other medications, including other antidepressants and those metabolized through CYP3A4 or CYP2D6 enzymes, although the degree of interaction appears smaller than with some other antidepressants.
• May worsen blood sugar control in people with diabetes.

What are the side effects of SNRI antidepressants?

Some of the more commonly reported side effects of SNRIs include:

• Constipation
• Dizziness
• Drowsiness
• Dry mouth
• Gastrointestinal upset (such as constipation, diarrhea, or nausea)
• A Headache
• Hot flushes
• Insomnia
• Nausea
• Sexual dysfunction (such as reduced desire or erectile dysfunction).

Some SNRIs have been associated with a discontinuation syndrome when they have been stopped suddenly. For this reason, it is best to withdraw all antidepressants slowly.

For a complete list of side effects, please refer to the individual drug monographs.

Additional references:
Sansone RA, Sansone LA. Serotonin Norepinephrine Reuptake Inhibitors: A Pharmacological Comparison. Innovations in Clinical Neuroscience. 2014;11(3-4):37-42.