Everything You Need To Know About SNRIs
by Dr. Carlo Carandang, MD
What Is An SNRI?
SNRIs (serotonin norepinephrine reuptake inhibitors) were developed after the success of SSRIs (selective serotonin reuptake inhibitors). SNRIs and SSRIs are classified as second-generation antidepressants, which have largely replaced the first-generation antidepressants, TCAs (tricyclic antidepressants) and MAOIs (monoamine oxidase inhibitors), due to improved tolerability and safety.
The first SNRI to hit the market was venlafaxine (Effexor) in 1994. Other SNRIs include duloxetine (Cymbalta) and desvenlafaxine (Pristiq). Classified as antidepressants, SNRIs also treat anxiety disorders.
SNRIs are U.S. FDA (Food and Drug Administration) approved for depression (major depressive disorder) and for the major anxiety disorders, including generalized anxiety disorder (GAD), panic disorder, social phobia (also known as social anxiety disorder), post traumatic stress disorder (PTSD), and obsessive compulsive disorder (OCD)- the exception being specific phobia.1
The effect of SNRIs on anxiety can be delayed for 2 to 4 weeks, and longer in some cases. Once the anxiety symptoms are addressed, then the SNRI is usually continued for another 12 to 24 months. If there are no symptoms at that time, then the SNRI can be slowly tapered until it is discontinued.2
How do SNRI’s Work?
Like SSRIs, SNRIs work on the central nervous system (CNS) and increase the serotonin neurotransmitter in the synapse, which is the space between two neurons. In addition, SNRIs increase the norepinephrine neurotransmitter in the synapse, so it has dual actions on two neurotransmitters. To see how SNRIs increase serotonin, please click here on how SSRIs work.
Response Rate = 75%
In addition to increasing serotonin in the synapse, SNRIs increase norepinephrine. Anxiety circuits in the brain are responsible for mediating the symptoms of anxiety. These circuits in turn are made up of neurons, which connect to one another via neurotransmitters. As shown in the figure above, norepinephrine is released from the presynaptic neuron into the synapse. The norepinephrine then travels across the synaptic space and binds to postsynaptic receptors, which carries the signal downstream. Norepinephrine in the synapse is then recycled back into the presynaptic neuron via norepinephrine reuptake pumps.
SNRIs work by blocking the norepinephrine reuptake pump, thereby increasing the norepinephrine in the synapse. Exactly how SNRIs work downstream after it increases serotonin and norepinephrine in the synapse is unknown, but we do know that it affects anxiety in the following ways:
- It reduces anxiety symptoms (75% response rate).2
- Antidepressants are associated with an increased production of neurons in the hippocampus and is thought to be linked to the reduction of anxiety symptoms.3-4
- The delay in the effect of SNRIs (2 to 6 weeks) may be related to the effects downstream, where proteins are produced and the assembly of neurons are completed, and this process takes weeks, explaining the delay in the reduction of anxiety symptoms.
- For anxiety, it appears to be the serotonergic action of SNRIs that helps. The dual action effect of SNRIs on serotonin and norepinephrine appear to have slight advantages over SSRIs for the treatment of depression.5
SNRIs can be associated with agitation and anxiety when first starting it, and it can last for weeks. As such, it is recommended that SNRIs be started at the lowest dose possible, and increased to the therapeutic dose slowly. A benzodiazepine can be prescribed concurrently to help address the anxiety and agitation that can occur with the initiation of SNRIs.
The dose ranges for the SNRIs are as follows:
- Venlafaxine (Effexor) 75-375mg daily
- Duloxetine (Cymbalta) 30-60mg daily
- Desvenlafaxine (Pristiq) 50-400mg daily
- “Chapter 12 – Pharmacotherapy for Anxiety Disorders.” Anxiety Protocol. Carandang C. 2014. Healthy Mind Research Corporation.
- World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders – first revision. Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ; WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disoders, Zohar J, Hollander E, Kasper S, Möller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lépine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J. World J Biol Psychiatry. 2008;9(4):248-312.
- Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Guilloux JP, Mendez-David I, Pehrson A, Guiard BP, Repérant C, Orvoën S, Gardier AM, Hen R, Ebert B, Miller S, Sanchez C, David DJ. Neuropharmacology. 2013 Oct;73:147-59.
- Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, Spitzer G, Santarelli L, Scharf B, Hen R, Rosoklija G, Sackeim HA, Dwork AJ. J Neurosci. 2007 May 2;27(18):4894-901.
- Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Biol Psychiatry. 2007 Dec 1;62(11):1217-27.
SNRI side effects
SNRIs, similar to SSRIs, are medications that affect the entire body. The second-generation antidepressants are a significant improvement over the first-generation antidepressants, but numerous side effects can still emerge during treatment with SNRIs.1-3
With SSRIs, up to 86% of patients taking it have at least one side effect.4-5 However, it has been suggested that SNRIs may have less side effects than SSRI, but this needs to be further evaluated in larger clinical trials.6 Most of the side effects are mild to moderate, and are reversible. However, there are some side effects that can be severe or last a long time.
Also known as urticaria.
Swelling of the skin
Inflammation can occur in the face, throat, tongue, lips, eyes, hands, feet, ankles, and lower legs.
Bleeding & bruising
Yellowing of the skin/eyes
Peeling/blistering of skin
Pain, burning, numbness, or tingling in the hands or feet
Difficulty breathing; shortness of breath.
Difficult, frequent, or painful urination
Dark colored urine
Change in taste of food
Ringing in the ears
Eye pain, redness
Sexual side effects
SSRIs can cause reduced sexual desire and anorgasmia (or delayed orgasms).
Muscle pain, cramps
Also known as myalgia.
Numbness, tingling in the hands, feet, arms, or legs
Stiff or twitching muscles
Loss of consciousness
Loss of coordination
Change in taste
Loss of appetite
Swelling of the abdomen
Rapid, pounding, irregular heartbeat
- “Venlafaxine.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- “Duloxetine.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015.
- “Desvenlafaxine.” MedlinePlus. 2014. American Society of Health System Pharmacists, Inc. 2015
- Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. Hu XH, Bull SA, Hunkeler EM, Ming E, Lee JY, Fireman B, Markson LE. J Clin Psychiatry. 2004 Jul;65(7):959-65.
- Real-World Data on SSRI Antidepressant Side Effects. Cascade E, Kalali AH, Kennedy SH. Psychiatry (Edgmont). 2009 Feb;6(2):16-8.
- A double-blind, placebo-controlled comparison of venlafaxine and fluoxetine treatment in depressed outpatients. Nemeroff CB, Thase ME; EPIC 014 Study Group. J Psychiatr Res. 2007 Apr-Jun;41(3-4):351-9.
Sexual Side Effects and SNRIs
SNRIs, along with SSRIs, have significant sexual side effects, and is a common reason for discontinuing these second-generation antidepressants.1 The sexual side effects include decreased libido (reduced sexual desire), erectile dysfunction, difficulty with arousal, delayed ejaculation (or suppressed ejaculation), problems with orgasm, and painful intercourse (also known as dyspareunia).
And even when you discontinue your SNRI, you still may have persistent and lingering problems with sexual side effects. A study showed that a significant portion of people who previously took an SNRI still had persistent sexual side effects.2 The term for this persistent sexual side effect after the discontinuance of an SNRI is Post SSRI (SNRI) Sexual Dysfunction (PSSD). It is important to discuss with your doctor the potential for sexual side effects both during active treatment and after discontinuing it.
- Antidepressants and sexual dysfunction: mechanisms and clinical implications. Clayton AH, Croft HA, Handiwala L. Postgrad Med. 2014 Mar;126(2):91-9. doi: 10.3810/pgm.2014.03.2744.
- Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship. Ben-Sheetrit J, Aizenberg D, Csoka AB, Weizman A, Hermesh H. J Clin Psychopharmacol. 2015 Jun;35(3):273-8.
Discontinuation Syndrome and SNRIs
SNRIs, like SSRIs, can be associated with withdrawal symptoms when the dose is lowered, doses are missed, or when it is abruptly discontinued. These withdrawal symptoms, more commonly known as discontinuation syndrome, can last a few weeks, and in some cases longer. Discontinuation syndrome is characterized by anxiety, irritability, sleep disturbance, shock-like sensations, dizziness, sensation of ‘pins and needles’, nausea, headache, fatigue, diarrhea, visual disturbances, and tremor.1
Indeed, SNRIs may have more severe withdrawal symptoms when compared to SSRIs, with venlafaxine (Effexor) showing the worst withdrawal symptoms of all the second generation antidepressants.2-4
To alleviate the severe withdrawal symptoms associated with SNRIs, restarting it leads to resolution within a couple of days. It is important to discuss the possibility of discontinuation syndrome with your doctor, BEFORE considering an SNRI for treatment. If you already have discontinuation syndrome and are trying to discontinue an SNRI, then you should talk to your doctor about ways to reduce the withdrawal symptoms, such as slowly tapering the dose over a period of months- a very slow taper. You can also talk with your doctor about prescribing benzodiazepines temporarily until you have successfully discontinued the SNRI.
- Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. Black K, Shea C, Dursun S, Kutcher S. J Psychiatry Neurosci. 2000 May;25(3):255-61.
- Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. Fava M, Mulroy R, Alpert J, Nierenberg AA, Rosenbaum JF. Am J Psychiatry. 1997 Dec;154(12):1760-2.
- Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. Sir A, D’Souza RF, Uguz S, George T, Vahip S, Hopwood M, Martin AJ, Lam W, Burt T. J Clin Psychiatry. 2005 Oct;66(10):1312-20.
- SSRIs and SNRIs: A review of the Discontinuation Syndrome in Children and Adolescents. Hosenbocus S, Chahal R. J Can Acad Child Adolesc Psychiatry. 2011 Feb;20(1):60-7.
Suicide and SNRIs
There is an FDA Black Box Warning regarding the use of SNRIs in children and adults under the age of 25. In this population, there is an increased risk of suicide when taking an SNRI, compared to placebo.1 However, for other age groups, there is no increased risk of suicide when taking an SNRI. For adults aged 25 to 64, the risk for suicide on SNRIs was neutral. For adults aged 65 and older, there was a decreased risk of suicide when taking an SNRI.2
If you are under the age of 25, use extreme caution when taking SNRIs, given the increased risk of suicide. Please click here for a more detailed discussion on antidepressants, SNRIs, and the risk for suicide.
- Relationship between psychotropic drugs and pediatric suicidality: review and evaluation of clinical data. Silver Spring, MD: Food and Drug Administration. Hamad T (2004). (http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf).
- Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, Hammad TA, Temple R, Rochester G. BMJ. 2009 Aug 11;339:b2880.
Violence and SNRIs
Controversy exists over the association between violence and second-generation antidepressants, such as SNRIs. This controversy has been fueled by conflicting studies. One study showed that antidepressants which affect serotonin, such as SNRIs, are associated with an increased risk for violence.1 However, another group found that there was a decrease in the risk for violence when there was an increase in exposure to antidepressants.2
For more information on the association between violence and SNRIs, please click here.
- Prescription drugs associated with reports of violence towards others. Moore TJ, Glenmullen J, Furberg CD. PLoS One. 2010 Dec 15;5(12):e15337.
- Antidepressants and lethal violence in the Netherlands 1994-2008.
Bouvy PF, Liem M. Psychopharmacology (Berl). 2012 Aug;222(3):499-506.
History of SNRIs
Venlafaxine (Effexor) was the first SNRI to hit the market in 1994, manufactured by Wyeth. Like the SSRIs, SNRIs were introduced as a more tolerable and safer alternative to the first-generation antidepressants, which includes TCAs (tricyclic antidepressants) and MAOIs (monoamine oxidase inhibitors). Other SNRIs followed, including duloxetine (Cymbalta) in 2004 and desvenlafaxine (Pristiq) in 2008.
Presentation of bias
I’m a psychiatrist, and I must inform and educate people for their treatment options. It is impossible for me to be completely objective, and thus it’s important for me to clarify my bias.
My bias: I’ve suffered from anxiety nearly my entire life, from childhood until adulthood. The only solution most doctors have prescribed left me worse off than not taking any medications. I’ve always looked for natural ways to combat my anxiety without side effects. When I eventually became a psychiatrist, I found techniques that helped my patients with anxiety, and then began to apply those same techniques to help for my own anxiety. I am now able to control my anxiety symptoms with The Anxiety Protocol. Also, instead of taking prescription medications with multiple side effects, I use KalmPro, a natural anxiety supplement I formulated from research studies, to help quell my anxiety symptoms. Taking KalmPro augments the techniques I use in The Anxiety Protocol.