Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Table of Contents

What are SNRIs?

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) are a class of medications used to help individuals with depression, anxiety, obsessive compulsive disorder, post traumatic stress disorder, and many other psychiatric disorders. These medications primarily work to enhance serotonin as well as norepinephrine (NE) in the brain.

Serotonin is a chemical in our brain involved in many important functions including mood regulation, circadian rhythms (sleep), memory, and more.

Norepinephrine is also a chemical in our brain involved in many important functions including mood regulation, motivation, arousal, anxiety, fear, stress responses, concentration, memory, and sleep regulation. 

There are very few studies, if any, comparing each medication with the others but we generally consider all SNRIs to be equivalent in terms of their efficacy for depression and anxiety. Clinical experience suggests that not ALL SNRIs are equal in terms of efficacy and side effect profile. 


What are Common Side Effects of SNRIs?






Emotional “Flattening”


Blood Pressure Changes

Sexual side effects: Anorgasmia, Delayed Ejaculation, Decreased libido

Bleeding Risk: All SNRIs carry a SMALL RISK for bleeding (remember that serotonin receptors are found on platelets)

Serotonin Syndrome: All SNRIs have the potential to cause serotonin syndrome but this is RARE and only occurs when taken in overdose or with other serotonin medications

How long will it take for these medications to work?

All SNRIs typically take 2-6 weeks (sometimes longer) before therapeutic effects are appreciated

Are these Medications Addictive?

NO, these medications are not addictive. Recall that addiction and dependence are different things. Addiction represents the behavioral changes in someone who begins altering their life to obtain or use something despite the negative consequences that occur when doing so (marital discord, health consequences, job loss, etc). Dependence represents the physiological changes that occur after taking a medication or drug for a long time such that when the medication/drug is stopped there are withdrawal symptoms. If you stop taking a blood pressure medication after taking it for years, your blood pressure will likely “rebound” or increase. Therefore, you are considered dependent on your medication. All SNRIs may cause a mild discontinuation (withdrawal) syndrome if stopped abruptly. However, if tapered appropriately, you are unlikely to experience a discontinuation syndrome

How long do I have to take these medications?

The recommended duration of treatment depends on the severity of your symptoms prior to starting the medication and whether you’ve experienced previous episodes of depression. However, the general recommendation is to take the medication for at least 9-12 months before beginning to taper off the medication.

Risk of Mania, Hypomania, and Rapid Cycling

All antidepressants carry a small risk of inducing a manic or hypomanic episode in patients with a preexisting diagnosis of bipolar disorder. All antidepressants carry a small risk of causing “rapid cycling” (>4 mood episodes in a year) in patients with a preexisting diagnosis of bipolar disorder

Things might get worse before they get better

It isn’t uncommon to experience initial side effects such as a small increase in anxiety, tremulousness, nausea, and indigestion for 3-4 days BUT THESE ALMOST ALWAYS GO AWAY with continued use of the medication. The therapeutic effects of these medications are thought to result from the brain slowly adapting to the presence of the medication. This can take 2-6 weeks.

Additional Comments

  • Some patients complain of an “inability to feel” or a “flatness” feeling with inability to laugh, cry, or feel joy while taking SNRIs. This usually resolves with reducing the dose or discontinuing the medication
  • In general (but not always), higher doses of SNRIs are needed to target anxiety disorder symptoms (OCD, PTSD, Generalized Anxiety) compared to doses needed for depression
  • When using SNRIs in individuals with anxiety, we generally initiate the medication at a dose lower than the recommended starting dose and increase more slowly to prevent initial side effects
  • Some experts consider SNRIs to be “better” antidepressants than SSRIs, although there is little empirical evidence to support this
  • Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) are similar to SSRIs in their ability to inhibit serotonin reuptake pumps but have the additional property of norepinephrine reuptake inhibition to varying degrees.
  • The additional norepinephrine reuptake inhibition likely accounts for their efficacy in pain disorders as well as vasomotor symptoms associated with menopause. 
  • The SNRIs, although considered to be similar in terms of efficacy, differ in their affinity for norepinephrine and serotonin transporters
  • Dosing ranges presented below are approximate. Some patients will respond to lower doses and others will require higher doses.


Antidepressants Table

Selective Serotonin Reuptake Inhibitors (SSRIs)Initial Dose (Range), mgComments
Fluoxetine (Prozac)20 (20-60)Activating. Long half-life. 2D6 Inhibitor.
Paroxetine (Paxil)20 (20-60)Anticholinergic. Sedating. 2D6 Inhibitor. Sexual side effects. D/C syndrome. Pregnancy risk.
Sertraline (Zoloft)50 (50-200)Activating. Dopaminergic. 2D6 Inhibitor at higher doses. GI side effects common early in tx.
Citalopram (Celexa)20 (20-60)Few interactions. QT prolongation (>40mg/day).
Escitalopram (Lexapro)10 (10-20)Few interactions. QT prolongation.
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Duloxetine (Cymbalta)30 (30-60)Short half life with risk of d/c symptoms. FDA approved for Diabetic neuropathy and Fibromyalgia. Morning dosing. Rarely sedating. May increase BP.
Venlafaxine XR (Effexor XR)37.5 (75-300)Nausea common. May increase BP. Once daily dosing with XR minimizes side effects (i.e., nausea). Reduce dose in renal insufficiency. May help with chronic pain.
Desvenlafaxine (Pristiq)50 (50-100)Active metabolite of venlafaxine. More noradrenergic activity than venlafaxine. Better choice for those with renal and hepatic insufficiency. May help with chronic pain. Short half-life with risk of d/c symptoms.
Atypical Antidepressants
Bupropion (Wellbutrin)100 (100-400)Noradrenergic and Dopaminergic. Minimal sexual side effects. May increase BP. Avoid in those with eating disorders or seizure hx. 2D6 inhibitor.
SR (BID dosing)150 (150-450)
XL (QAM dosing)
Trazodone (Desyrel)25 (25-400)Sedating. Commonly used for insomnia. May increase time in slow wave sleep. No anticholinergic properties. Histamine/α1 at low doses. Minimal sexual side effects. Warn about priapism. May be better for anxiety than depression.
Mirtazapine (Remeron)7.5 (7.5-45)Noradrenergic and serotonergic properties. Has actions at 5HT3 and therefore helps with nausea. Minimal sexual side effects. Sedation and weight gain common. Sedation usually limited to 7.5mg-15mg.

A Closer Look…

Duloxetine (Cymbalta)


HALF-LIFE: 12 hours
STARTING DOSE: 40mg-60mg daily
>> Initial 40mg-60mg per day (qd or BID)
>> Target dose 60mg/day
>> For doses >60mg/day increase by 30mg/d over 1 week
>> Max dose 120mg/day (Little data showing
additional benefit with doses >60mg/day
PREGNANCY: Little Safety Data Available (Not a contraindication)
BREASTFEEDING: Little Safety Data Available (Not a contraindication)
1) Major depressive disorder
2) Generalized Anxiety Disorder
3) Diabetic peripheral neuropathic pain
4) Fibromyalgia
5) Chronic musculoskeletal pain


  • Duloxetine has relatively more NET inhibition than venlafaxine and desvenlafaxine
  • Duloxetine has FDA approval for diabetic neuropathic pain, fibromyalgia, and chronic musculoskeletal pain
  • Duloxetine usually requires twice daily dosing initially, then once daily once tolerated
  • Duloxetine has a lower incidence of blood pressure elevation and milder withdrawal reactions compared to venlafaxine


Venlafaxine (Effexor)


HALF-LIFE: Venlafaxine 5 hours; O-desmethylvenlafaxine (active metabolite) 11 hours
STARTING DOSE: Use venlafaxine Extended Release (Effexor XR): Initial 37.5mg PO Daily
TARGET DOSING RANGE: 75mg-225mg daily
HOW TO DOSE (Extended Release only):
>> Initial 37.5mg PO daily for 4-7 days
>> Increase dose by 37.5mg/d every 3 days or 75mg/wk until 150mg
>> Increase dose by 75mg per week to maximum dose of 225mg/day
PREGNANCY: Minimal Data on safety (not a contraindication)
BREASTFEEDING: Minimal Data on safety (not a contraindication)
1) Major depressive disorder
2) Generalized Anxiety Disorder
3) Social Anxiety Disorder
4) Panic Disorder


  • Venlafaxine is primarily a serotonin reuptake inhibitor at lower doses, with increasing noradrenergic reuptake inhibitor actions at increasing doses
  • Venlafaxine is converted to its active metabolite, desvenlafaxine, by CYP2D6
  • Venlafaxine administration usually results in plasma levels of venlafaxine that are about half those of desvenlafaxine. This may vary depending on genetic polymorphisms of CYP2D6 and whether patients are taking drugs that are inhibitors or inducers of CYP 2D6. Therefore, this makes the degree of noradrenergic reuptake inhibitor actions of venlafaxine administration unpredictable.
  • Venlafaxine’s norepinephrine transporter (NET) inhibition contributes to the side effects of sweating and elevations in blood pressure. However, NET inhibition also contributes to the beneficial role of these medications in pain modulation and alleviation of vasomotor symptoms of perimenopause
  • Peak level nausea led to extended release formulation
  • Venlafaxine is also effective for numerous anxiety disorders and PTSD


Desvenlafaxine (Pristiq)


HALF-LIFE: 11 hours
STARTING DOSE: 50mg daily
TARGET DOSING RANGE: 50mg-100mg/day
>> Start 50mg per day for 2-4 weeks
>> If not response, increase to 100mg per day
>> No evidence that doses >100mg show additional benefit
PREGNANCY: Minimal data on safety (but not a contraindication)
BREASTFEEDING: Minimal data on safety (but not a contraindication)
1) Major depressive disorder


  • Desvenlafaxine is the active metabolite of venlafaxine (via CYP2D6)
  • Desvenlafaxine is a more potent inhibitor of serotonin transporters (SERTs) than norepinephrine transporters (NETs) but has greater NET inhibition compared to venlafaxine


Levomilnacipran (Fetzima)


HALF-LIFE: 12 hours
STARTING DOSE: 20mg daily
TARGET DOSING RANGE: 40mg-120mg/day
>> Start 20mg per day for 2-3 days
>> Increase dose to 40mg daily every 2-3 days
>> Max Dose: 120mg/day


> Taper by decreasing dose by 25% every 3-5 days

PREGNANCY: Minimal data on safety (but not a contraindication)
BREASTFEEDING: Minimal data on safety (but not a contraindication)
(1) Major depressive disorder



  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation
  • Sweating
  • Increased blood pressure
  • Urinary retention (dose-related)
  • Erectile dysfunction
  • Tachycardia
  • Weight gain is rare



  • Tramadol increases risk of seizures
  • Risk of Serotonin Syndrome with MAOIs or other serotonin agents
  • Risk of Hypertensive Crisis with MAOIs or sympathomimetics
  • Bleeding risk with NSAIDs/anticoagulants



  • Metabolized primarily by CYP3A4
  • Reduce dose to maximum of 40-80mg/day for patients with renal impairment
  • Greater potency for norepinephrine reuptake inhibition than for serotonin reuptake inhibition

Mechanism of SNRIs


  1. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  2. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  3. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  4. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  5. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  6. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  7. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  8. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  9. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.