Serotonin and norepinephrine reuptake inhibitors

Serotonin and norepinephrine reuptake inhibitors also known as SNRIs are a class of antidepressant medications that block the reabsorption of serotonin and norepinephrine (noradrenaline) neurotransmitters or chemical messengers in your brain, increasing their availability and potentially improving mood and relieving depression, anxiety, and chronic pain ¹, ², ³. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are effective in treating depression. Serotonin and norepinephrine reuptake inhibitors (SNRIs) also are sometimes used to treat other conditions, such as anxiety disorders and long-term pain (chronic pain), especially nerve pain (neuropathic pain). SNRIs may be helpful if you have both long-term pain and depression.

Serotonin norepinephrine reuptake inhibitors (SNRIs) differ from selective serotonin reuptake inhibitors (SSRIs) in that they also inhibit the reuptake of norepinephrine (noradrenaline), as the class name indicates, but their potency with regard to serotonin reuptake inhibition is comparable to that of the SSRIs. Despite the expectation that dual receptor activity might provide greater clinical efficacy, SNRIs as a class appear to provide similar response rates to SSRIs in the treatment of major depression in adults ⁴.

SNRIs and their brand names that doctors currently prescribe in the United States include:

• Desvenlafaxine (Khedezla®, Pristiq®) is FDA-approved to treat symptoms of major depressive disorder ⁵
• Duloxetine (Cymbalta®, Drizalma®, Irenka®). Duloxetine is also approved to treat generalized anxiety disorder (GAD) and certain types of pain, such as fibromyalgia pain and pain from diabetic neuropathy ⁶
• Levomilnacipran (Fetzima®) ⁷
• Venlafaxine (Effexor®). Venlafaxine is also approved to treat generalized anxiety disorder (GAD), social anxiety disorder (social phobia) and panic disorder ⁸, ⁹
• Milnacipran (Savella) is the only SNRI not approved in the U.S. for the treatment of major depressive disorder, but the drug is effective for depression and is approved in some other countries for major depressive disorder. In the U.S., Milnacipran is used to treat fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ¹⁰, ¹¹.

SNRIs can interact with other medications, so it’s important to inform your doctor about all the medications you are taking.

SNRIs can cause side effects, which may include nausea, dry mouth, constipation, and dizziness.

SNRIs can cause withdrawal symptoms if stopped abruptly, so it’s important to discuss tapering the medication with your doctor.

What is anxiety?

Anxiety is a common mental health condition characterized by excessive worry, fear, and apprehension that can significantly impact your daily life, often accompanied by physical symptoms like rapid heartbeat and sweating. Anxiety is a natural human emotion that can be a normal response to stress or perceived threats.  However, when anxiety becomes persistent, intense, and difficult to control, it can indicate an anxiety disorder. Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear that impair a person’s social, occupational, and personal functions.

Symptoms of Anxiety:

• Emotional or Psychological: Excessive worry, fear, restlessness, difficulty concentrating, feeling on edge, and a sense of impending doom.
• Physical: Rapid heartbeat, sweating, trembling, shortness of breath, stomach problems, and difficulty sleeping

What types of antidepressants might I be prescribed?

There are many different types of antidepressants. They are grouped according to how they work in the body. Within each group, there are several different medicines that work in a similar way ¹².

• Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant class. While they are not necessarily more effective than others, they are usually well-tolerated by most people, which means that most people find that side effects are not too troublesome. Examples of this class of antidepressants include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline.
• Serotonin and noradrenaline reuptake inhibitors (SNRIs) have fewer side effects than SSRIs and may be used for more severe depression. They include duloxetine, venlafaxine, desvenlafaxine and levomilnacipran. Serotonin and noradrenaline reuptake inhibitors (SNRIs) are similar to selective serotonin reuptake inhibitors (SSRIs). They were designed to be a more effective antidepressant than SSRIs. However, the evidence that SNRIs are more effective in treating depression is uncertain. It seems that some people respond better to SSRIs, while others respond better to SNRIs.
• Norepinephrine reuptake inhibitors (NRIs) also called noradrenaline reuptake inhibitors (NARIs) work on norepinephrine (noradrenaline) and are less likely to cause drowsiness than other classes. This class includes reboxetine.
• Tricyclic antidepressants (TCAs) are an older type of antidepressant. Tricyclic antidepressants (TCAs) are no longer usually recommended as the first-line treatment for depression because they can be more dangerous if an overdose is taken. Tricyclic antidepressants (TCAs) also cause more unpleasant side effects than SSRIs and SNRIs. Tricyclic antidepressants (TCAs) include amitriptyline, nortriptyline, clomipramine, dothiepin, doxepin, imipramine and trimipramine.
• Reversible inhibitors of monoamine oxidase A (RIMAs) are more commonly used to treat anxiety than depression. They include moclobemide.
• Noradrenergic and specific serotonergic antidepressants (NaSSAs) are a relatively new antidepressant class with fewer sexual side effects but can cause weight gain. Noradrenergic and specific serotonergic antidepressant (NaSSA) includes mirtazapine. NASSAs may be effective for some people who are unable to take SSRIs. The side effects of NASSAs are similar to those of SSRIs, but they’re thought to cause fewer sexual problems. However, they may also cause more drowsiness at first.
• Serotonin antagonists and reuptake inhibitors (SARIs). Serotonin antagonist and reuptake inhibitors (SARIs) are a class of antidepressants that work by both blocking serotonin receptors and inhibiting the reuptake of serotonin, potentially leading to increased serotonin levels in the brain. Serotonin antagonists and reuptake inhibitors (SARIs) are not usually the first choice of antidepressant, but they may be prescribed if other antidepressants have not worked or have caused side effects. SARIs are known to have fewer sexual side effects compared to some other antidepressants.
• Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants that work by blocking the enzyme monoamine oxidase (MAO), which breaks down neurotransmitters like serotonin, norepinephrine, and dopamine, thus increasing their levels in the brain and potentially improving mood. Monoamine oxidase inhibitors (MAOIs) are rarely prescribed today for depression as they can have more side effects and interactions than other types of antidepressants. MAOIs can cause side effects, such as dizziness, insomnia, and dry mouth. Monoamine oxidase inhibitors (MAOIs) include phenelzine, tranylcypromine, selegiline, isocarboxazid and moclobemide.
• ‘Atypical’ antidepressants that don’t easily fit into the classes above, and include agomelatine, vortioxetine and lithium. Agomelatine stimulate melatonin receptors to affect mood. Vortioxetine works on serotonin receptors, but in a different way to SSRIs and SNRIs. If you’ve tried several different antidepressants and seen no improvement, your doctor may offer you a medicine called lithium, in addition to your current treatment. If the level of lithium in your blood becomes too high, it can become toxic. So, you’ll need blood tests every few months to check your lithium levels while you’re taking it. You’ll also need to avoid eating a low-salt diet because this can also cause the lithium to become toxic. Ask your doctor for advice about your diet. Side effects of lithium include:
  • dry mouth
  • a metallic taste in your mouth
  • some mild shaking of your hands
  • diarrhea
  • These side effects usually pass with time once your body gets used to the medicine.

What’s the difference between SNRIs and SSRIs?

Serotonin and noradrenaline reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) are both classes of antidepressants, but they work in different ways.

Selective serotonin reuptake inhibitors (SSRIs) work by blocking only serotonin reuptake, which increases serotonin levels in your brain.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) on the other hand increase both serotonin and norepinephrine levels.

Because SNRIs and SSRIs medications work differently, they have different side effects.

Researchers originally designed SNRIs to be more effective in treating depression symptoms than SSRIs. But studies haven’t conclusively confirmed that they are, in fact, more effective.

Finding the right antidepressant

Your doctor will take into account a range of factors when deciding which antidepressant to prescribe, including:

• Your age
• Your sex
• Your main symptoms or symptoms that bother you most. Some antidepressants may do a better job helping specific symptoms, such as trouble sleeping.
• Potential side effects
• Potential interactions with any other medicines you are taking. Some antidepressants can cause problems if you take them with certain medicines and herbs.
• Are you pregnant, planning for pregnancy, or breastfeeding? If so, your doctor will help you find a way to treat your depression that’s safe for you and your baby.
• Other health conditions. Certain antidepressants can make some other conditions better or worse. Any other conditions that you have will be part of choosing your depression treatment.
• Your preferences.

You may find that one type of antidepressant is more effective than others at relieving your symptoms. It can take some time to identify which antidepressant is right for you, so it’s important to keep in touch with your doctor, especially when you first start taking an antidepressant. If the medicine is causing side effects, or isn’t working, your doctor can advise whether another type of antidepressant might be more suitable.

Each person reacts differently to a particular antidepressant. Some people may be more likely to have certain side effects. Because of this, one antidepressant may work better for you than another. When choosing an antidepressant, your doctor considers your symptoms, any health issues you have, other medicines you take, drug interactions, drug-specific precautions (e.g., kidney disease, liver disease), and what has worked for you in the past.

Genes passed down in families may play a role in how antidepressants affect you. For some people, blood tests, where available, may offer clues about how their bodies may respond to a particular antidepressant. But other things besides genetics can affect your response to medicine.

It may take several weeks or longer before an antidepressant has a full effect. It also may take several weeks or longer for initial side effects to ease up. Your doctor may recommend dose changes or a different antidepressant. With patience, you and your doctor can find a medicine that works well for you.

How long does it take SNRIs to work?

It usually takes 6 to 8 weeks to feel the full effect of SNRIs and notice an improvement in your symptoms. Talk to your doctor if you don’t feel better after this time.

How do serotonin and norepinephrine reuptake inhibitors work?

Normally serotonin and norepinephrine (noradrenaline) neurotransmitters (chemical messengers) in your brain, that play a role in mood, alertness, and other bodily functions, after their release, they’re typically reabsorbed by the sending neuron in a process called reuptake. SNRIs work by blocking the reuptake of both serotonin and norepinephrine, which increases their levels in the brain neurons ⁴, ². By blocking (inhibiting) reabsorption or reuptake of both serotonin and norepinephrine neurotransmitters (chemical messengers) in your brain, more serotonin and norepinephrine are active in your brain contributing to the therapeutic effects of SNRIs in depression and anxiety, however, the exact mechanism is not known.

The members of the serotonin norepinephrine reuptake inhibitors (SNRIs) class differ in their relative potency at serotonin and norepinephrine auto-receptors; duloxetine and desvenlafaxine demonstrate a 10-fold higher selectivity for serotonin reuptake inhibition than norepinephrine reuptake inhibition and venlafaxine has a 30-fold higher affinity for the reuptake inhibition of serotonin compared to norepinephrine. Conversely, levomilnacipran and milnacipran demonstrate a 2-fold and 3-fold greater potency for norepinephrine reuptake inhibition than serotonin reuptake inhibition, respectively ¹³, ¹⁴. Norepinephrine receptor blockade is considered important in the treatment of pain, as selective serotonin reuptake inhibitors (SSRIs) have not been proven efficacious for pain disorders. Therefore, some SNRIs, including milnacipran and duloxetine, have FDA-approved indications in the treatment of some pain disorders.

All SNRIs inhibit serotonin uptake in human platelets, which has been associated with an increased risk of bleeding adverse events. SNRIs do not have a significant affinity for histaminergic, muscarinic, alpha1-adrenergic, postsynaptic serotonin or dopamine, gamma-aminobutyric acid (GABA), or glutamate receptors in test tube study, nor do they inhibit monoamine oxidase (MAO). Duloxetine and venlafaxine at high doses weakly inhibit the reuptake of dopamine, which may contribute to effects on blood pressure

Serotonin and norepinephrine reuptake inhibitors examples

The U.S. Food and Drug Administration (FDA), has approved these SNRIs to treat depression:

• Desvenlafaxine (Khedezla®, Pristiq®) is FDA-approved to treat symptoms of major depressive disorder ⁵
• Duloxetine (Cymbalta®, Drizalma®, Irenka®). Duloxetine is also approved to treat generalized anxiety disorder (GAD) and certain types of pain, such as fibromyalgia pain and pain from diabetic neuropathy ⁶
• Levomilnacipran (Fetzima®) ⁷
• Venlafaxine (Effexor®). Venlafaxine is also approved to treat generalized anxiety disorder (GAD), social anxiety disorder (social phobia) and panic disorder ⁸, ⁹
• Milnacipran (Savella®) is the only SNRI not approved in the U.S. for the treatment of major depressive disorder, but the drug is effective for depression and is approved in some other countries for major depressive disorder. In the U.S., Milnacipran is used to treat fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ¹⁰, ¹¹.

Serotonin and norepinephrine reuptake inhibitors uses

The U.S. Food and Drug Administration (FDA), has approved these SNRIs to treat depression:

• Desvenlafaxine (Pristiq) ⁵
• Duloxetine (Cymbalta, Drizalma Sprinkle). Duloxetine is also approved to treat generalized anxiety disorder (GAD) and certain types of pain, such as fibromyalgia pain and pain from diabetic neuropathy ⁶
• Levomilnacipran (Fetzima) ⁷
• Venlafaxine (Effexor XR). Venlafaxine is also approved to treat generalized anxiety disorder (GAD), social anxiety disorder (social phobia) and panic disorder ⁸, ⁹
• Milnacipran (Savella) is the only SNRI not approved in the U.S. for the treatment of major depressive disorder, but the drug is effective for depression and is approved in some other countries for major depressive disorder. In the U.S., Milnacipran is used to treat fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) ¹⁰, ¹¹.

Drug interactions may occur with duloxetine, desvenlafaxine, and venlafaxine due to metabolism by CYP isoenzymes. Milnacipran and levomilnacipran have minimal CYP450 metabolism, and clinically relevant interactions related to CYP metabolism are not expected.

Duloxetine should not be used in patients with liver impairment or risk factors for liver impairment (e.g., alcoholism). Milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine can be used in patients with hepatic impairment; however, dosage adjustments for venlafaxine and desvenlafaxine are required.

Drug-specific dosage adjustments are required for desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine in the presence of renal dysfunction and are based upon the severity of the kidney impairment.

Major depressive disorder

Given the absence of differences in efficacy or tolerability between drug classes, the SNRIs are not preferentially recommended over SSRIs in the treatment of major depressive disorder (clinical depression) ¹⁵, ¹⁶, ¹⁷.

Choice of antidepressant for each patient is based on several factors such as tolerability, drug interactions, prior history of response, and efficacy in the selected indication ¹⁸, ¹⁹, ¹⁷.

SNRIs have not been approved for use in pediatric populations for the treatment of depression; however, guidelines from the American Academy of Child and Adolescent Psychiatry (AACAP) recommend the use of antidepressants when nonpharmacologic treatment is insufficient or illness severity is high. Data specific to SNRIs in the treatment of pediatric depression are limited. Therefore, SNRIs are generally reserved for use in pediatric patients with documented antidepressant treatment failure or intolerability to an SSRI ²⁰, ²¹.

According to the manufacturer of duloxetine, efficacy was not established in two 10-week controlled trials with 800 pediatric patients 7 years and older with major depressive disorder ⁶.

Fibromyalgia

Duloxetine and milnacipran have proven efficacy and safety in the treatment of fibromyalgia in adults. Duloxetine is the only SNRI approved for the treatment of fibromyalgia in adolescents 13 years and older ⁶.

In adults, the overall benefit is modest (i.e., benefit for pain, sleep, fatigue, depression, and health-related quality of life in randomized controlled trials was significant, but the effect size was small for pain and not substantial for the other efficacy parameters) ²².

Duloxetine and milnacipran are similar in efficacy to pregabalin, an anticonvulsant with FDA approval for the treatment of fibromyalgia; however, pregabalin is superior to milnacipran for sleep outcomes ²³.

Off-label uses

Doctors sometimes prescribe SNRIs for other conditions. This is considered an off-label, or non-FDA-approved, use of the medication. Examples of off-label uses include:

• Anxiety disorders.
• Hot flashes and night sweats associated with menopause.
• Peripheral neuropathy due to chemotherapy.
• Urinary incontinence.
• Attention-deficit and hyperactivity disorder (ADHD).
• Obsessive-compulsive disorder (OCD).
• Migraine prevention.

Anxiety disorder

Due to their efficacy and safety profile, venlafaxine and duloxetine are considered first-line treatment options for generalized anxiety disorder (GAD) in adults ²⁴.

Duloxetine is approved for generalized anxiety disorder (GAD) in children 7 years and older ⁶, ²⁵.

Other uses

Duloxetine has shown effectiveness in treating pain associated with diabetic peripheral neuropathy and was the first drug specifically approved for diabetic peripheral neuropathy in adults.

Duloxetine is beneficial for treating chronic musculoskeletal pain in adults. Efficacy was established in patients with chronic low back pain and chronic pain due to osteoarthritis.

Duloxetine is recommended for the off-label treatment of stress urinary incontinence in women because it increases detrusor muscle tone.

Venlafaxine and desvenlafaxine are used off-label in the treatment of vasomotor symptoms (hot flushes) associated with menopause or breast cancer; these drugs are effective alternatives for women who cannot use, or do not wish to use, hormonal therapy for vasomotor symptom control.

What to know before taking SNRI

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are safe for most people. But sometimes SNRI can slightly raise your blood pressure, lower electrolyte levels such as sodium (hyponatremia) and worsen liver conditions. You should know that SNRIs may cause angle-closure glaucoma, a form of glaucoma that happens when the iris bulges blocking the fluid outflow inside your eye and causing a quick, severe increase in eye pressure which may lead to a loss of vision. Talk to your doctor about having an eye examination before you start taking SNRI. If you have nausea, eye pain, changes in vision, such as seeing colored rings around lights, and swelling or redness in or around the eye, call your doctor or get emergency medical treatment right away. Most of these safety issues can be monitored by your doctor while you’re taking SNRI.

Talk with your doctor about safety issues before you take an SNRI, including:

• Medicine interactions. Tell your doctor about any other prescription or nonprescription medicines, herbs or other supplements you’re taking. Some antidepressants can cause dangerous reactions when taken with certain medicines or herbal products. For example, SNRIs may slightly raise your risk of bleeding, especially when you’re taking other medicines that also raise the risk of bleeding. These other medicines can include ibuprofen (Advil, Motrin IB, others), aspirin, warfarin (Jantoven) and other blood thinners.
• Serotonin syndrome (serotonin toxicity). Rarely, antidepressants can cause dangerously high levels of serotonin in the body. This is called serotonin syndrome or serotonin toxicity. Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonin activity in your brain, often triggered by drug interactions or overdose, and characterized by a combination of mental, autonomic, and neuromuscular symptoms. Symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, lack of coordination, major changes in blood pressure and rapid heart rate. Get medical help right away if you have any of these symptoms. Severe serotonin syndrome can be life-threatening due to complications like seizures, hyperthermia (high body temperature), and organ damage. Serotonin syndrome happens most often when you take two medicines that both raise serotonin levels. This includes taking an SNRI with other antidepressants (selective serotonin reuptake inhibitors (SSRIs) + SNRIs), migraine medications (triptans), certain pain or headache medicines, the herbal supplement St. John’s wort or even some illicit drugs.
• Antidepressants and pregnancy. Some antidepressants may harm your baby if you take them during pregnancy or while you’re breastfeeding. If you are pregnant, are thinking about getting pregnant or are breastfeeding, talk to your doctor about the benefits and possible risks of antidepressants. Don’t stop taking your medicine without talking with your doctor first.

Increased risk of suicide

Most antidepressants are generally safe, but the U.S. Food and Drug Administration (FDA) says that all antidepressants must carry boxed warnings, the strictest warnings for prescriptions. In some cases, children, teenagers and young adults under age 25 may have an increase in suicidal thoughts or behavior when taking antidepressants. This may be more likely in the first few weeks after starting the medicine or when the dose is changed. There has been no evidence that this increase in suicidal thoughts or behaviors has resulted in completed suicides. In 2004, the U.S. Food and Drug Administration (FDA) issued a “black-box” warning regarding a potential increase in suicidality in adolescents receiving antidepressant treatment for depression that was later expanded to include both young adults and a broader range of antidepressants.

Anyone taking an antidepressant should be watched closely for worsening depression or unusual behavior. If you or someone you know has suicidal thoughts when taking an antidepressant, call your doctor right away or get emergency help. Keep in mind that depression that’s not treated is a more concerning risk factor for suicide. And antidepressants may lessen suicide risk in the long run by improving mood for many people ²⁶.

Bipolar disorder

The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, the antidepressant should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Hypersensitivity and cross-sensitivity issues

Allergic reactions may occur with the use of any SNRI. Because some SNRIs are available as both a racemic compound (e.g., milnacipran) and a single enantiomer of the racemic compound (e.g., levomilnacipran), cross-sensitivity should be expected. Similarly, cross-sensitivity is possible between desvenlafaxine and venlafaxine, since venlafaxine is the parent compound of desvenlafaxine. Levomilnacipran and milnacipran are contraindicated in patients exhibiting hypersensitivity to the related drug; desvenlafaxine and venlafaxine are contraindicated in patients who have demonstrated a hypersensitivity to the related drug.

Breastfeeding

Small concentrations of SNRIs have been measured in breast milk, with uncertain consequences for the infant. The benefits of drug treatment to the mother need to be weighed against the potential risk of infant drug exposure. There are reports of agitation, irritability, poor feeding, and poor weight gain following exposure to serotonergic antidepressants through breast milk. Any infant exposed to an SNRI through breast-feeding should be monitored for these adverse effects.

Pregnancy

The American Psychiatric Association guidelines state that treatment of depression during early pregnancy requires careful risk-benefit assessment, in collaboration with the patient and potentially a neonatal specialist. Use of serotonergic antidepressants, including SNRIs, during the third trimester has been associated with neonatal complications, including prolonged hospitalization, respiratory support, and tube feeding. In addition, exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia; this potential has been reported for venlafaxine. Data indicate exposure to SNRIs, particularly in the month before obstetric delivery, may be associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Treatment with any SNRI during pregnancy should be individualized.

Alcohol and antidepressants

Talk to your doctor about drinking alcohol while taking an antidepressant. You should be careful about drinking until you know how the medicine affects you. The effects of alcohol can combine with the effects of the antidepressant and cause problems. Regular heavy drinking can make it harder to treat depression. Certain kinds of medicine can lead to seizures for heavy drinkers.

Liver impairment

SNRI use has been associated with elevated hepatic enzymes. Duloxetine is not recommended in patients with any degree of hepatic impairment. Avoidance of duloxetine is recommended in patients with substantial alcohol use, alcoholism, hepatic necrosis, and/or chronic liver disease. Dosage adjustments of venlafaxine and desvenlafaxine are recommended in patients with hepatic impairment. Milnacipran can be used cautiously in patients with hepatic impairment. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative option in patients with hepatic disease.

Stopping treatment with SNRIs

Talk with your doctor before you stop taking an SNRI. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are not considered habit-forming. But stopping antidepressant treatment suddenly or missing several doses may cause some symptoms. This is sometimes called discontinuation syndrome or antidepressant discontinuation syndrome. A discontinuation syndrome can occur when SNRIs are abruptly halted. This syndrome is characterized by dizziness, weakness, nausea, headache, lethargy, insomnia, anxiety, poor concentration, paresthesias (tactile sensations), and increased gastrointestinal motility. Symptoms occur most frequently and severely with shorter-acting agents (e.g., immediate-release venlafaxine). A slow, individualized taper is advisable, particularly after chronic use, to minimize discontinuation symptoms. If your doctor recommended you take a lower dosage of your medicine and you’re experiencing symptoms of antidepressant discontinuation syndrome, talk with your doctor. You may need to take a higher dosage before weaning your body from the medicine completely.

If you decided to stop taking your antidepressant medicine on your own, talk to your doctor about why you stopped. For example, was the medicine causing an unpleasant side effect? Did it cost too much? Your doctor can help by altering your dosage or suggesting another antidepressant.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) discontinuation symptoms can include:

• Dizziness.
• Headache.
• Flu-like symptoms, such as tiredness, chills and muscle aches.
• Irritability and restlessness.
• Upset stomach.
• Insomnia or sleep disturbances, such as nightmares.
• Diarrhea.

These symptoms may be more likely to happen with venlafaxine or desvenlafaxine, though they can happen when any SNRI is stopped suddenly. Work with your doctor to slowly and safely lower your dose over time so you can stop the medicine safely.

Drug Interactions

Monoamine oxidase inhibitors (MAOIs)

SNRIs are contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) or within 2 weeks of their discontinuation due to the risk of serotonin syndrome. Medications with monoamine oxidase inhibitors (MAOIs) activity, such as linezolid or intravenous methylene blue, are also contraindicated for use with SNRIs because of an increased risk of serotonin syndrome or serotonin toxicity. Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonin activity in your central nervous system (brain and spinal cord), often triggered by combining medications that increase serotonin levels, such as certain antidepressants (SSRIs, SNRIs), migraine medications (triptans), or even some illicit drugs or supplements or overdose. Serotonin syndrome causes signs and symptoms that can range from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures). Severe serotonin syndrome can cause death if not treated.

Serotonin syndrome symptoms usually occur within several hours of taking a new drug or increasing the dose of a drug you’re already taking.

Serotonin syndrome signs and symptoms include:

• Agitation or restlessness
• Insomnia
• Confusion
• Rapid heart rate and high blood pressure
• Dilated pupils
• Loss of muscle coordination or twitching muscles
• High blood pressure
• Muscle rigidity
• Heavy sweating
• Diarrhea
• Headache
• Shivering
• Goose bumps

Severe serotonin syndrome can be life-threatening. Signs include:

• High fever
• Tremor
• Seizures
• Irregular heartbeat
• Unconsciousness.

If you suspect you might have serotonin syndrome after starting a new drug or increasing the dose of a drug you’re already taking, call your doctor right away or go to the emergency room. If you have severe or rapidly worsening symptoms, seek emergency treatment immediately.

SSRIs, SNRIs and other serotonergic drugs

Any use of an SNRI with other serotonergic agents increases the likelihood of serotonergic adverse effects and should be monitored closely. Drugs that have serotonergic properties include opiates, triptans, most antidepressants, amphetamines, St. John’s wort, tramadol, lithium, buspirone, and others.

Antithrombotic drugs (antiplatelet and anticoagulant therapies)

Anticoagulants (blood thinners), antiplatelet drugs (e.g., aspirin), and nonsteroidal anti-inflammatory drugs (NSAIDs) should be administered with caution to any patient taking an SNRI. Platelet aggregation may be impaired by SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.

Drugs that inhibit CYP2D6 or CYP1A2

Levomilnacipran and milnacipran are not metabolized to any significant extent by CYP450 isoenzymes and are not inducers or inhibitors of any of these isoenzymes. Venlafaxine is metabolized by CYP2D6, and CYP2D6 inhibitors may increase venlafaxine concentrations. A dose-related CYP2D6 inhibitory effect has been observed with desvenlafaxine; therefore, the dose of primary CYP2D6 substrates should be reduced by up to one-half if coadministered with desvenlafaxine 400 mg/day. Duloxetine is metabolized by CYP1A2 and CYP2D6; inhibitors of CYP1A2 and CYP2D6 may increase duloxetine concentrations.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) Dosage

Dosages fluctuated depending on the SNRI used due to varying potencies of the drug in question as well as multiple strengths for each drug.

• Venlafaxine: The starting dose is 75 mg daily, and the usual maintenance dose is 225 to 375 mg daily.
• Desvenlafaxine: The starting dose is 25 to 50 mg daily; the usual maintenance dose is 50 mg daily.
• Duloxetine: The starting dose is 30 mg daily, and the usual maintenance dose is 60 mg daily.
• Milnacipran: The starting dose is 12.5 mg daily, and the usual maintenance dose is 100 mg daily.
• Levomilnacipran: The starting dose is 20 mg daily, and the usual maintenance dose is 40 to 120 mg daily.

Serotonin and norepinephrine reuptake inhibitors side effects

All serotonin and norepinephrine reuptake inhibitors (SNRIs) work in much the same way and generally can cause the same kinds of side effects. Some people may not have any side effects. Side effects that do occur are usually mild and go away after the first few weeks of treatment. Taking medicine with food may lessen upset stomach, a common side effect. If you can’t handle the side effects of one SNRI, you may have fewer side effects with a different one, as each SNRI has a different chemical makeup.

The most common possible side effects of serotonin and norepinephrine reuptake inhibitors (SNRIs) include:

• Upset stomach.
• Dry mouth.
• Dizziness.
• Headache.
• Sweating.

Other possible side effects of serotonin and norepinephrine reuptake inhibitors (SNRIs) may include:

• Tiredness.
• Constipation.
• Trouble sleeping.
• Less sexual desire or trouble reaching orgasm.
• Loss of appetite.

The benefits of antidepressants typically outweigh the possible side effects when depression is severe. Which antidepressant is best for you depends on several factors, such as your symptoms and any other health conditions you may have.

Ask your doctor or pharmacist about the most common possible side effects for your specific medicine. Read the patient medication guide that comes with the prescription.

Gastrointestinal adverse reactions

Gastrointestinal (GI) side effects are the most common adverse reactions in patients receiving SNRI treatment. Nausea is the most common adverse reaction with any SNRI. It is most often transient and of mild to moderate intensity. Other less frequently reported gastrointestinal effects include dry mouth (xerostomia), constipation, and vomiting. One review noted that venlafaxine, one of the SNRIs, was associated with a higher risk for nausea when compared to agents in the SSRI class ⁶, ¹⁰, ⁸, ⁹, ⁵, ¹⁹, ⁷.

Central nervous system adverse reactions

Headache, dizziness, drowsiness, and insomnia are the most common centrally-mediated adverse reactions, but are rarely severe and usually do not lead to treatment discontinuation.

Bleeding disorder

Monitor patients taking an SNRI for signs and symptoms of bleeding. Impaired platelet aggregation may occur during treatment with SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. In published observational studies, pregnant patients taking SSRIs, particularly in the month prior to obstetric delivery, were at an increased risk of postpartum hemorrhage; this effect is also possible with the SNRIs. A postmarketing study showed a higher incidence of postpartum hemorrhage in mothers taking the SNRI duloxetine. Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase the risk of these bleeding complications. Patients should be instructed to promptly report any bleeding events to their health care provider.

Blood pressure changes

All SNRIs have been associated with sustained elevation of blood pressure, most notably venlafaxine. Blood pressure should be monitored closely when initiating therapy or increasing SNRI dosages, and routinely thereafter. Orthostatic hypotension has also been reported, particularly in the elderly.

Low blood sodium (hyponatremia)

SNRIs may cause hyponatremia (low blood sodium level) as a result of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion; serum sodium levels less than 110 mmol/L have been reported. Elderly patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume-depleted (e.g., hypovolemia) appear to be at greatest risk. The syndrome of inappropriate antidiuretic hormone (SIADH) is reversible upon discontinuation of the causative SNRI.

Skin and hypersensitivity reactions

Hyperhidrosis (increased sweating) is the most common adverse dermatologic effect associated with SNRIs. Severe reactions, including anaphylactoid reactions, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have been reported rarely with the various SNRIs. The SNRI should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other cause can be identified.

Sexual dysfunction

Sexual dysfunction is commonly reported with the use of serotonergic agents such as SNRIs and may result in treatment discontinuation in some patients. In men, these symptoms may include ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Women may experience decreased libido and delayed or absent orgasm. Clinicians should discuss sexual function with patients prior to initiating treatment and throughout treatment to identify any changes in sexual function and determine if they are medication-related or attributed to the underlying psychiatric disorder. Patients should also be provided with management strategies and treatment options for symptoms of sexual dysfunction.

Angle-closure glaucoma

Closed-angle glaucoma has occurred in patients with untreated anatomically narrow angles during treatment with antidepressants. Duloxetine is contraindicated in patients with uncontrolled angle-closure glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

Liver toxicity

Elevated liver function tests (LFTs) have been reported with all SNRIs and appear to be dose-related. Hepatitis and hepatic failure have occurred during administration of some SNRIs; fatalities have been reported. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative to consider in patients with hepatic disease.

Neonatal abstinence syndrome

Symptoms consistent with a neonatal discontinuation syndrome (e.g., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting) have been reported in infants exposed to SNRIs in utero, particularly during the third trimester. SNRIs should be used in pregnancy only where the benefit to the mother clearly outweighs any potential risk to the fetus. Consider the risks of untreated depression during pregnancy as well as the potential risks to the fetus from exposure to the drug. If clinically feasible, and taking the drug half-life into consideration, tapering of the antidepressant prior to delivery may be considered.

SNRI Poisoning

Clinical features include:

• Tachycardia
• Hypertension
• Electrocardiogram (ECG) changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia
• Changes in the level of consciousness (ranging from somnolence to coma)
• Mydriasis
• Serotonin syndrome
• Rhabdomyolysis
• Liver necrosis
• Death

SNRI Poisoning management:

• In case of acute overdose with SNRI, the clinician should ensure an adequate airway, breathing, and circulation.
• For serotonin syndrome, specific treatment such as with cyproheptadine may be considered.
• Treat prolonged QRS intervals with sodium bicarbonate
• Prolonged QTc leading to Torsades de pointes: Administer magnesium sulfate 2 g IV.
• Consider extracorporeal life support in severe poisoning with venlafaxine ²⁷.

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