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.
  • Similar to SSRIs, these medications work to enhance serotonin in the brain. However, unlike SSRIs, they have the additional property of enhancing norepinephrine. 
  • Serotonin and norepinephrine are chemicals (neurotransmitters) in our brain involved in many important functions including mood regulation, circadian rhythms (sleep), memory, arousal, anxiety, fear, stress responses, and more.
  • 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
    • My clinical experience has been that not ALL are equal

What are common side effects of these medications?

  • Most Common Side Effects:
    • Nausea
    • Indigestion
    • Headache
    • Tremulousness
    • 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 does it take for these medications to work?

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

Will I become dependent or addicted to these medications?

  • 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 discontinuation (withdrawal) syndrome if stopped abruptly. However, if tapered appropriately, you are unlikely to experience a discontinuation syndrome

How long do I have to be on these medications?

  • It 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

  • 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

It may get a little worse before it gets 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.

Final Points

  • 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
  • Duloxetine (Cymbalta)
  • Venlafaxine (Effexor)
  • Desvenlafaxine (Pristiq)
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 norepinephrine reuptake inhibition than venlafaxine (Effexor) and desvenlafaxine (Pristiq)
  • 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 (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
  • At higher doses, there is increasing  norepinephrine actions
  • Venlafaxine (Effexor) is converted to its active metabolite, desvenlafaxine (Pristiq), by enzymes in your liver and GI tract
  • Venlafaxine (Effexor) alters norepinephrine and serotonin systems which partially explains common side effects like increased sweating, increased blood pressure, nausea, and indigestion
  • However, the additional norepinephrine properties of SNRIs partially explains their role in relieving neuropathic pain as well as the vasomotor symptoms of perimenopause (i.e., hot flashes)
  • Venlafaxine is also effective for numerous anxiety disorders, Obsessive Compulsive Disorder, and PTSD
  • The nausea associated with venlafaxine can be reduced with the extended release formulation


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 (Pristiq) is the active metabolite of venlafaxine (Effexor)
  • Desvenlafaxine’s has greater norepinephrine inhibition properties than venlafaxine


  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.