Choosing and Switching Antidepressants
(Modified April 2024)
Less than one-third of patients achieve remission with the first antidepressant tried.23 Switching is a common strategy if there is no response four to six weeks after dose optimization, or the patient cannot tolerate an adequate dose.1,5 There is no robust evidence for switching to a drug in a different class.1,3,5,31 Other options include switching to or adding cognitive behavioral therapy, or pharmacologic combination treatment.5,34 A pharmacologic combination treatment strategy should be considered after two antidepressant trials.1 The chart below provides practical considerations for choosing and switching antidepressants. Consult product labeling regarding switching to/from MAOIs.
Choice of Agent (Agents not typically used as initial therapy [e.g., MAOIs, trazodone, TCAs, gepironee] not included below.) |
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Choose an agent based on side effects, personal or family response history, drug interactions, comorbidities, and cost.1,36 Some clinicians target specific depression symptoms (e.g., pain, fatigue, insomnia, anxiety).17 Non-MAOIs with the highest risk of drug interactions include fluoxetine, fluvoxamine, and paroxetine.1 Those with the lowest risk of drug interactions include citalopram, escitalopram, mirtazapine, venlafaxine, and desvenlafaxine.1 Dose antidepressants cautiously in elderly (e.g., half the usual starting dose).5 |
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Drug/Class |
Consider for… |
Avoid or use particular caution in… |
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SSRI |
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SNRI |
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Mirtazapine |
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Bupropionb |
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Vilazodonea |
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Vortioxetine |
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Brexanolone (Zulresso) (US) |
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Zuranolone (Zurzuvae) |
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Switching. Evidence-based options for a second agent, due to evidence of superiority, include sertraline, escitalopram, venlafaxine, mirtazapine,1 vortioxetine,24 or bupropion.3 For general information of switching strategies (i.e., abruptly switching vs tapering/cross-tapering) is available in footnote d. |
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Switching Scenario |
Suggested Approach |
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SSRI (other than fluoxetine) to another SSRI |
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SSRI (other than fluoxetine) to duloxetine |
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Switching Scenario |
Suggested Approach |
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SSRI (other than fluoxetine) to venlafaxine |
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SSRI (other than fluoxetine) to mirtazapine |
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Venlafaxine to an SSRI |
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Venlafaxine to duloxetine |
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Venlafaxine or duloxetine to mirtazapine |
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Switching Scenario |
Suggested Approach |
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Duloxetine to an SSRI |
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Duloxetine to venlafaxine |
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Fluoxetine to another SSRI |
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Fluoxetine to mirtazapine |
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Fluoxetine to venlafaxine or duloxetine |
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Bupropion to/from another agent |
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Mirtazapine to an SSRI or SNRI |
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Switching Scenario |
Suggested Approach |
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Switching to/from vortioxetine |
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Switching to/from vilazodone (Viibryd) |
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Switching to/from desvenlafaxine (e.g., Pristiq). |
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Switching to/from levomilnacipran (Fetzima) |
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- Vilazodone is not a first-line agent per Canadian guidelines due to lack of head-to-head or relapse data and need to titrate and take with food.1
- Auvelity (US) contains bupropion and dextromethorphan. Dextromethorphan is an NMDA (N-methyl-D-aspartate) receptor antagonist, but its mechanism in depression is unclear.32 Bupropion boosts dextromethorphan levels via CYP2D6 inhibition.32 There is no proof that dextromethorphan alone is effective for depression. There is no proof that Auvelity is better than standard-dose bupropion (e.g., bupropion 150 mg twice or 300 mg once daily). Auvelity use with other dextromethorphan-containing products (e.g., cough or cold medicine) could cause neuropsychiatric adverse effects (e.g., psychosis, stupor, seizures).32 Serotonin syndrome could result from extra dextromethorphan use, or Auvelity use with serotonergic drugs (e.g., linezolid, serotonergic antidepressants).32,33
- Wholesale Acquisition Cost (WAC).Medication pricing by Elsevier, accessed January 2024.
- Limited available evidence suggests that abruptly switching (i.e., direct switch) from one short-acting SSRI or SNRI to another SSRI or SNRI is generally well-tolerated.3,7,10Transient serotonergic side effects (e.g., anxiety) may occur early in the switch, but this is not usually a safety issue, and a direct switch is usually better tolerated than a washout if the first agent is short-acting.TAPERING/CROSS-TAPERING (i.e., gradually increasing the new agent [often starting with a lower dose than usual] while decreasing the first agent):22Tapering may be more appropriate in some cases due to two concerns when switching:symptom recurrence and discontinuation syndromes.12,30Discontinuation syndromes are of most concern when switching from a serotonergic agent to a nonserotonergic agent, particularly when switching from venlafaxine or paroxetine.2,7Consider tapering any antidepressant taken for more than one week.27 Fluoxetine and bupropion may not need tapering.6,26,27For others, consider tapering over several weeks unless there is a clinical reason not to.30Monitor patient and adjust switching strategy (e.g., speed of taper) based on symptoms of withdrawal, side effects, or return of depressive symptoms.2,10Consider increasing the dose of the serotonergic agent if withdrawal symptoms emerge (e.g., “GI flu”-like symptoms, paresthesias, irritability, insomnia, dizziness, vivid dreams).10Individual symptoms could also be treated (e.g., meclizine for dizziness).27A resource for switching is https://switchrx.com/antidepressants.php/switch.
- Gepirone [Exxua, US] is a selective serotonin 5HT1A receptor agonist.44 It has not been shown to be more effective than other antidepressants, and is more expensive than generic first-line agents. Long-term data is limited. Common adverse effects include dizziness, nausea, and headache.44 It requires baseline and periodic electrocardiographic monitoring due to risk of QT prolongation, and has significant interactions with CYP3A4 inhibitors.44 Additionally, dose adjustments are required for older adults and for patients with kidney or liver impairment.44
Abbreviations: CHF = congestive heart failure; GI = gastrointestinal; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant.
Levels of Evidence
In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.
Level |
Definition |
Study Quality |
A |
Good-quality patient-oriented evidence.* |
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B |
Inconsistent or limited-quality patient-oriented evidence.* |
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C |
Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. |
*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).
[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]
References
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- Glassman AH, O'Connor CM, Califf RM, et al. Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002 Aug 14;288(6):701-9. Erratum in: JAMA 2002 Oct 9;288(14):1720.
- O'Connor CM, Jiang W, Kuchibhatla M, et al. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol. 2010 Aug 24;56(9):692-9.
- Zerumsky K, Maxwell RA, Ansani NT. To abruptly cross over or not: that is the question in SSRI conversion. P&T 2005;30:740-4.
- Perahia DG, Quail D, Desaiah D, et al. Switching to duloxetine from selective serotonin reuptake inhibitor antidepressants: a multicenter trial comparing 2 switching techniques. J Clin Psychiatry. 2008 Jan;69(1):95-105.
- Fava M. Management of nonresponse and intolerance: switching strategies. J Clin Psychiatry. 2000;61 Suppl 2:10-2.
- Product information for Trintellix. Takeda Pharmaceuticals America. Lexington, MA 02421. September 2021.
- Product information for Cymbalta. Lilly USA. Indianapolis, IN 46285. September 2021.
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- Product monograph for Trintellix. Lundbeck Canada. St-Laurent, QC H4S 0A9. August 2021.
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- Fava M, Dunner DL, Greist JH, et al. Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label trial. J Clin Psychiatry. 2001 Jun;62(6):413-20.
- Wiese BS. Geriatric depression: the use of antidepressants in the elderly. B C Med J 2011;53:341-7.
- Jefferson JW. Strategies for switching antidepressants to achieve maximum efficacy adolescents. J Clin Psychiatry. 2008;69 Suppl E1:14-8.
- Mohamed S, Johnson GR, Chen P, et al. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial. JAMA. 2017 Jul 11;318(2):132-145.
- Alvarez E, Perez V, Artigas F. Pharmacology and clinical potential of vortioxetine in the treatment of major depressive disorder. Neuropsychiatr Dis Treat. 2014 Jul 15;10:1297-307.
- Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018 Apr 7;391(10128):1357-1366.
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- Anon. Pharmacy Life. Antidepressants. MIMS guidance on switching and withdrawing antidepressants updated. February 17, 2016. http://pharmacy-life.co.uk/mims-guidance-on-switching-and-withdrawing-antidepressants-updated/. (Accessed March 14, 2023).
- Keks N, Hope J, Keogh S. Switching and stopping antidepressants. Aust Prescr 2016;39:76-83.
- Santaguida P, MacQueen G, Keshavarz H, et al. Treatment for depression after unsatisfactory response to SSRIs. Comparative effectiveness review No. 62. (Prepared by McMaster University Evidence-based Practice Center under Contract No. HHSA 290 2007 10060 I.). AHRQ publication No. 12-EHC050-EF. Rockville, MD: Agency for Healthcare Research and Quality; April 2012. https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/depression-treatment-ssri_research.pdf. (Accessed March 14, 2023).
- Product information for Auvelity. Axsome Therapeutics. New York, NY 10007. December 2022.
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- Product information for Zurzuvae. Biogen. Cambridge, MA 02142. November 2023.
- Product information for gepirone. Mission Pharmacal Company. San Antonio, TX 78230. September 2023.
Cite this document as follows: Clinical Resource, Choosing and Switching Antidepressants. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber’s Letter. April 2023. [390432]