Some SNRIs Useful for Depression; Avoid Others

Antidepressant drugs are not always necessary for people who feel depressed. But if feelings of depression continue for weeks, have no underlying cause (such as the death of a loved one, loss of a job, a medical condition or a drug-induced side effect) and make it difficult to function professionally or socially, it may be time to discuss antidepressant drugs with your doctor.[1]

There is no consistent evidence from high-quality studies that any particular antidepressant drug is more effective at treating depression than another.[2] Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (PROZAC, SELFEMRA) and sertraline (ZOLOFT), were for many years the most commonly prescribed depression treatments, but use of newer alternative antidepressants has been increasing in recent years.[3],[4]

This article explores one of these newer classes of drugs for depression treatment: serotonin-norepinephrine reuptake inhibitors (SNRIs), a group that includes venlafaxine (EFFEXOR XR), desvenlafaxine (KHEDEZLA, PRISTIQ), duloxetine (CYMBALTA) and levomilnacipran (FETZIMA). Milnacipran (SAVELLA) is another SNRI that is approved only for the treatment of fibromyalgia and should not be used for depression.

Public Citizen’s Health Research Group designates venlafaxine and desvenlafaxine, both available as generic drugs, as Limited Use for depression treatment. Given their higher costs, similar effectiveness and greater risk of side effects compared with SSRIs, they should be used only in patients not responding to SSRIs. We have designated all other SNRIs as Do Not Use because of either uncertainties about effectiveness and safety or known safety risks.

Venlafaxine and desvenlafaxine: Limited Use

Venlafaxine and desvenlafaxine, like all SNRI drugs, influence how the brain processes serotonin and norepinephrine, chemical messengers that help brain cells communicate.[5] By contrast, SSRIs affect primarily serotonin processing.[6]

Venlafaxine is converted into desvenlafaxine after entering the body, so the benefits and side effects of these two drugs are virtually identical.[7]

SNRIs can be effective for treating depression in patients who have not had success taking SSRIs.[8] Unfortunately, venlafaxine (and by extension desvenlafaxine) can cause higher rates of nausea and vomiting than SSRIs.[9] These two drugs also increase sweating in some patients (sweating is also common, to a lesser degree, with some SSRIs).[10],[11],[12] Such common unpleasant side effects may be the reason more patients stop taking venlafaxine due to side effects compared with SSRIs.[13] Also, venlafaxine and desvenlafaxine have been associated with rare lung problems, and the drugs’ labels therefore warn to look out for shortness of breath, cough or chest discomfort.[14],[15]

Venlafaxine and desvenlafaxine also carry risks that are common to other antidepressants, including SSRIs. All antidepressants currently carry a black-box warning that they could increase the risk of suicide in children and young adults (although the drugs do not increase suicide risk in adults over age 24).[16]

Both SSRIs and SNRIs can cause serotonin syndrome, a life-threatening condition that may involve mental changes such as agitation or hallucinations; loss of muscle coordination; seizures; or stomach-related symptoms such as nausea, vomiting and diarrhea.[17],[18] The risk of this condition increases if a patient is taking other drugs that affect serotonin, including other antidepressant drugs or the dietary supplement St. John’s wort.[19],[20]

Another risk common to both SSRIs and SNRIs is increased risk of sexual side effects, such as the inability to become aroused or achieve an orgasm.[21] Most commonly prescribed antidepressants appear to carry a risk of sexual side effects, although the risk with bupropion (APLENZIN, FORFIVO XL, WELLBUTRIN) is possibly lower.[22],[23]

Both SSRIs and SNRIs can increase the risk of certain cardiovascular problems. Venlafaxine causes elevated blood pressure, increased heart rate and possibly abnormal heart rhythms, all of which could lead to dangerous heart problems in some patients.[24],[25],[26],[27] There is some evidence that patients who overdose on venlafaxine may be more likely to die due to heart issues than those who overdose on SSRIs, but studies examining this question have shown conflicting results.[28] By contrast, SSRIs have not been shown to cause high blood pressure at normal doses, but they can cause abnormal heart rhythms, particularly the SSRI citalopram (CELEXA).[29]

Other risks that venlafaxine and desvenlafaxine share with SSRIs include increased risk of bleeding and risk of dangerously low blood sodium levels (particularly in older patients).[30],[31]

Finally, like SSRIs, venlafaxine and desvenlafaxine can cause drug withdrawal symptoms. These symptoms include dizziness, nausea, headache, sleep disturbances and mood changes, and tend to be worse when treatment is stopped abruptly.[32],[33]

Duloxetine: Do Not Use

While the Food and Drug Administration (FDA) has approved duloxetine to treat depression (as well as generalized anxiety disorder and certain types of chronic pain), it causes nearly all of the same side effects as other SNRI antidepressants, with an added risk of serious liver damage.[34],[35] Duloxetine also causes falls and fainting, a particular problem with older adults who are already at higher risk of broken bones from falls.[36] We recommend against using duloxetine for depression.

Levomilnacipran: Do Not Use for Seven Years

Levomilnacipran was approved by the FDA for depression treatment in 2013.[37] There is no evidence that the drug is any more beneficial than older antidepressants.[38]

As is often the case with anti-depressants, the clinical trials used to prove the effectiveness of levomilnacipran were short, conducted for just eight weeks, and included fewer than 2,000 patients combined across all trials.[39] As a result, any serious risks likely will become apparent only after the drug is in widespread use for a number of years. We generally recommend waiting seven years before using any new drug that shows no proven clinical benefits over existing options, because our research has shown that half of all black-box warnings and withdrawals from the market occur seven years or less after a drug is approved.[40]

What You Can Do

The SNRIs venlafaxine and desvenlafaxine are useful treatment alternatives for depression, and they may be effective in patients who fail to achieve good results with SSRIs. All antidepressant drugs, including SNRIs, carry serious risks. Be sure to read the drugs’ medication guides carefully so you can look out for dangerous drug interactions and be able to recognize the signs and symptoms of serotonin syndrome, internal bleeding, lung disease and other potentially serious drug side effects.

Do not use duloxetine, due to serious safety risks, or milnacipran, because it is not FDA-approved to treat depression. Do not use levomilnacipran until 2020, as this drug has not been on the market long enough to understand potential undiscovered rare risks and it offers no proven clinical advantages over older antidepressants.

If it is possible, drug treatment always should be combined with psychotherapy, as this combination has been shown to be more effective at treating depression symptoms than drug treatment alone.[41] Remember to take care of yourself by eating healthy, being physically active and getting enough sleep.[42]

Finally, it is important that you always consult your doctor before you decide to stop antidepressant treatment, even if you are feeling better. Your physician can help you lower your dose slowly and make adjustments to help you avoid or mitigate any withdrawal symptoms that may develop.

References

[1] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association; Arlington, VA: 2013.

[2] Gartlehner G, Hansen RA, Morgan LC, et al. Second-generation antidepressants in the pharmacologic treatment of adult depression: An update of the 2007 comparative effectiveness review [internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011. Report No.: 12-EHC012-EF. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0033744/. Accessed December 9, 2015.

[3] Marcus SC, Olfson M, National trends in the treatment for depression from 1998 to 2007. Arch Gen Psychiatry. 2010;67(12):1265-1273.

[4] Petersen T, Dording C, Neault NB, et al. A survey of prescribing practices in the treatment of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:177-187.

[5] Mayo Clinic. Depression (major depressive disorder): Serotonin and norepinephrine reuptake inhibitors (SNRIs). June 26, 2013. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20044970. Accessed December 8, 2015.

[6] Mayo Clinic. Depression (major depressive disorder): Selective serotonin reuptake inhibitors (SSRIs). July 9, 2013. http://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825. Accessed December 28, 2015.

[7] A new old drug for depression: desvenlafaxine (PRISTIQ). Worst Pills, Best Pills News. March 2010. /newsletters/view/683. Accessed December 9, 2015.

[8] Rush AJ, Trivedi MH, Wisiewski S, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163:1905-1917.

[9] Gartlehner G, Hansen RA, Morgan LC, et al. Second-generation antidepressants in the pharmacologic treatment of adult depression: An update of the 2007 comparative effectiveness review [internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011. Report No.: 12-EHC012-EF. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0033744/. Accessed December 9, 2015.

[10] Bet PM1, Hugtenburg JG, Penninx BW, Hoogendijk WJ. Side effects of antidepressants during long-term use in a naturalistic setting. Eur Neuropsychopharmacol. 2013 Nov;23(11):1443-51.

[11] DailyMed. Label: Zoloft – sertraline hydrochloride tablet, film coated. Updated August 2014. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fe9e8b7d-61ea-409d-84aa-3ebd79a046b5. Accessed January 20, 2016.

[12] DailyMed. Label: Pristiq Extended Release – desvenlafaxine succinate tablet, extended release. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Accessed January 20, 2016.

[13] Gartlehner G, Hansen RA, Morgan LC, et al. Second-generation antidepressants in the pharmacologic treatment of adult depression: An update of the 2007 comparative effectiveness review [internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011. Report No.: 12-EHC012-EF. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0033744/. Accessed December 9, 2015.

[14] DailyMed. Label: Pristiq Extended Release – desvenlafaxine succinate tablet, extended release. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Accessed December 8, 2015.

[15] DailyMed. Label: Effexor XR – venlafaxine hydrochloride capsule, extended release. Updated October 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c3e7ac-1852-4d70-d2b6-4fca819acf26. Accessed December 8, 2015.

[16] Food and Drug Administration. FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. May 2, 2007. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108905.htm. Accessed December 9, 2015.

[17] DailyMed. Label: Pristiq Extended Release – desvenlafaxine succinate tablet, extended release. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Accessed December 8, 2015.

[18] DailyMed. Label: PAXIL CR- paroxetine hydrochloride hemihydrate tablet, film coated, extended release. Updated July 2014. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=483bd97f-c4d0-4e23-aaa8-6334f4471e0c. Accessed January 7, 2016.

[19] DailyMed. Label: Pristiq Extended Release – desvenlafaxine succinate tablet, extended release. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Accessed December 8, 2015.

[20] DailyMed. Label: PAXIL CR- paroxetine hydrochloride hemihydrate tablet, film coated, extended release. Updated July 2014. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=483bd97f-c4d0-4e23-aaa8-6334f4471e0c. Accessed January 7, 2016.

[21] Serretti A, Chiesa A, Treatment-emergent sexual dysfunction related to antidepressants: A meta-analysis. J Clin Psychopharmacol. 2009;29:259-266.

[22] Gartlehner G, Hansen RA, Morgan LC, et al. Second-generation antidepressants in the pharmacologic treatment of adult depression: An update of the 2007 comparative effectiveness review [internet]. Rockville,MD: Agency for Healthcare Research and Quality (US); 2011. Report No.: 12-EHC012-EF. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0033744/. Accessed December 9, 2015.

[23] Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: A meta-analysis. J Clin Psychopharmacol. 2009;29:259-266.

[24] DailyMed. Label: Effexor XR – venlafaxine hydrochloride capsule, extended release. Updated October 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c3e7ac-1852-4d70-d2b6-4fca819acf26. Accessed December 8, 2015.

[25] DailyMed. Label: venlafaxine – venlafaxine hydrochloride tablet. Updated November 2014. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b23637e5-d37f-41b5-ba76-fc053e903bc2. Accessed December 8, 2015.

[26] DailyMed. Label: Pristiq Extended Release – desvenlafaxine succinate tablet, extended release. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Accessed December 8, 2015.

[27] Food and Drug Administration. Medical Review: Effexor ER. 1997. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020699ap_effexor_medrp2.pdf. Accessed January 8, 2016.

[28] Martinez C, Assimes TL, Mines D, et al. Use of venlafaxine compared with other antidepressants and the risk of sudden cardiac death or near death: a nested case-control study. BMJ. 2010;340:c249

[29] Beach SR, Kostis WJ, Celano CM, et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry. 2014;75(5):e441-9. http://www.ncbi.nlm.nih.gov/pubmed/24922496.

[30] DailyMed. Label: Effexor XR – venlafaxine hydrochloride capsule, extended release. Updated October 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c3e7ac-1852-4d70-d2b6-4fca819acf26. Accessed December 8, 2015.

[31] DailyMed. Label: Pristiq Extended Release – desvenlafaxine succinate tablet, extended release. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Accessed December 8, 2015.

[32] DailyMed. Label: Effexor XR – venlafaxine hydrochloride capsule, extended release. Updated October 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c3e7ac-1852-4d70-d2b6-4fca819acf26. Accessed December 8, 2015.

[33] DailyMed. Label: Pristiq Extended Release – desvenlafaxine succinate tablet, extended release. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Accessed December 8, 2015.

[34] DailyMed. Label: Cymbalta – duloxetine hydrochloride capsule, delayed release. Updated June 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba. Accessed December 9, 2015.

[35] Do not use: Duloxetine (CYMBALTA). Worst Pills, Best Pills News. June 2012. /newsletters/view/795. Accessed December 9, 2015.

[36] DailyMed. Label: Cymbalta – duloxetine hydrochloride capsule, delayed release. Updated June 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba. Accessed December 9, 2015.

[37] Food and Drug Administration. Approval letter for levomilnacipran. July 25, 2013. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba. Accessed December 29, 2015.

[38] DailyMed. Label: Fetzima – levomilnacipran hydrochloride capsule, extended release. Updated 07/14. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f371258d-91b3-4b6a-ac99-434a1964c3af. Accessed December 9, 2015.

[39] DailyMed. Label: Fetzima – levomilnacipran hydrochloride capsule, extended release. Updated 07/14. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f371258d-91b3-4b6a-ac99-434a1964c3af. Accessed December 9, 2015.

[40] Wolfe SM. The seven-year rule for safer prescribing. Aust Prescr 2012;35:138-9. http://www.australianprescriber.com/magazine/35/5/138/9. Accessed December 29, 2015.

[41] Cuijpers P, Dekker J, Hollon SD, Andersson G. Adding psychotherapy to pharmacotherapy in the treatment of depressive disorders in adults: a meta-analysis. J Clin Psychiatry. 2009;70(9):1219. http://www.ncbi.nlm.nih.gov/pubmed/19818243

[42] Mayo Clinic. Depression (major depressive disorder). July 22, 2015. http://www.mayoclinic.org/diseases-conditions/depression/basics/lifestyle-home-remedies/con-20032977. Accessed December 9, 2015.