Choosing and Switching Antidepressants

Full update July 2020

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 not robust evidence for switching to a drug in a different class.1,3,5,31 Patients who fail two antidepressants in the same class should try a different class (consider venlafaxine), or combination treatement.5 The chart below provides practical considerations for choosing and switching antidepressants. Consult product labeling regarding switching to/from MAOIs.

Abbreviations: CV – cardiovascular GAD – generalized anxiety disorder; MAOI – monoamine oxidase inhibitor; OCD – obsessive compulsive disorder; SSRI – selective serotonin reuptake inhibitor SNRI – serotonin norepinephrine reuptake inhibitor

Choice of Agent (Agents not typically used as initial therapy [e.g., MAOIs, trazodone, TCAs] not included below)

Choose an agent based on side effects, personal or family response history, drug interactions, comorbidities, and cost.2 Some clinicians target specific depression symptoms (e.g., pain, fatigue, insomnia, anxiety).17 Non-MAOI agents with the highest risk of drug interactions include fluoxetine, fluvoxamine, and paroxetine.1 Those with the lowest include citalopram, escitalopram, mirtazapine, venlafaxine, and desvenlafaxine.1 Fluoxetine is well-tolerated.25 Dose antidepressants cautiously in elderly (e.g., half the usual starting dose).5

Drug/Class

Consider for…

Avoid or use particular caution in…

SSRI

anxiety disorders (start with low dose;2 indications vary)

CV disease (sertraline)8,9

adolescents (fluoxetine, sertraline, escitalopram)25,28

underweight (paroxetine)17

psychomotor slowing (fluoxetine)17

insomnia (paroxetine)17

overweight or obese patients (fluoxetine)2

overweight or obese patients (paroxetine)2

QT prolongation or torsades risk

agitation or insomnia (fluoxetine)1,17

pregnancy

elderly (paroxetine)21

SNRI

psychomotor slowing (duloxetine)1

pain related to depression, fibromyalgia, or neuropathy.1

anxiety disorders (start with low dose;2 indications vary)

hypertension2

agitation or insomnia2

Mirtazapine

agitation4

insomnia5

sexual dysfunction concern5

underweight patients5

overweight or obese patients5

hyperlipidemia2

Bupropion

sexual dysfunction concern5

smokers5

psychomotor slowing/fatigue1

overweight or obese patients5

seizure disorders5

hypertension5

anxiety or insomnia17

Vilazodonea or
Vortioxetine

sexual dysfunction concern15,24

overweight or obese patients15,24

cognitive dysfunction1,15

if nausea is a particular concern1

Switching

Evidence-based options for a second agent, due to evidence of superiority, include sertraline, escitalopram, venlafaxine, mirtazapine,1 vortioxetine,24 or bupropion.3 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.3,7,10 Transient serotonergic side effects 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.7

TAPERING/CROSS-TAPERING (i.e., gradually increasing the new agent [often starting with a lower dose than usual] while decreasing the first agent):22 Tapering may be more appropriate in some cases due to two concerns when switching: symptom recurrence and discontinuation syndromes.2,12 Discontinuation syndromes are of most concern when switching from a serotonergic agent to a nonserotonergic agent, particularly when switching from venlafaxine or paroxetine.2,7 Consider tapering any antidepressant taken for more than one week.27 Fluoxetine and bupropion may not need tapering.6,26,27 Vortioxetine can be tapered by 10 mg/day over seven days.29 For others, consider tapering over several weeks unless there is a clinical reason not to.1,2 A conservative taper for paroxetine or venlafaxine is 25% every four to six weeks,6 or for venlafaxine ER 37.5 to 75 mg weekly or paroxetine CR 12.5 mg weekly.27 Monitor patient and adjust switching strategy (e.g., speed of taper) based on symptoms of withdrawal, side effects, or return of depressive symptoms.2,10 Consider increasing the dose of the serotonergic agent if withdrawal symptoms emerge (e.g., “GI flu”-like symptoms, paresthesias, irritability, insomnia, dizziness, vivid dreams).10 Could also treat individual symptoms (e.g., meclizine for dizziness).27

Switching Scenario

Suggested Approach
Note: keep drug interactions, side effects, and illness severity in mind when choosing method/dose.30

SSRI (other than fluoxetine) to another SSRI

Stop SSRI.7,10 Start new SSRI at a low dose (e.g., citalopram, escitalopram, or paroxetine10 mg/day; sertraline 25 mg/day; or fluoxetine 20 mg every-other-day).3,27,30 If the patient was taking a high dose of the first agent, consider tapering to a lower dose before starting the new agent.10 Or, stop the first agent and start a dose of the new agent that is in the same range as the first agent (i.e., low, moderate, high).7 Or, cross-taper.30 If switching to/from fluvoxamine, cross-tapering is not recommended; taper and stop SSRI before starting new agent at a low dose (e.g., fluvoxamine 50 mg/day).30

SSRI (other than fluoxetine) to duloxetine

Stop SSRI and start duloxetine 60 mg once daily [Evidence level B-1].11,18 Or, start duloxetine 60 mg once daily and taper SSRI over two weeks.11 Keep in mind some antidepressants could inhibit duloxetine metabolism through CYP2D6 (e.g., fluoxetine, paroxetine) or CYP1A2 (e.g., fluvoxamine) inhibition until the SSRI is cleared.14 If switching from fluvoxamine, cross-tapering is not recommended; taper and stop fluvoxamine before starting duloxetine, at a low dose.30

SSRI (other than fluoxetine) to venlafaxine

Stop SSRI and start venlafaxine at a low dose (e.g., 37.5 mg to 75 mg total daily dose).3,7,18,19 If the patient was taking a high dose of an SSRI, consider tapering to a lower dose before stopping it and starting venlafaxine.10 Cautious cross-taper, starting with low dose of venlafaxine, is another option.30 Some antidepressants (e.g., paroxetine) could inhibit venlafaxine metabolism through CYP2D6 inhibition until the SSRI is cleared.7 If switching from fluvoxamine, cross-tapering is not recommended; taper and stop fluvoxamine before starting venlafaxine, at a low dose (e.g., 37.5 mg to 75 mg total daily dose).19,30

SSRI (other than fluoxetine) to mirtazapine

Cross-taper.27 Or, taper SSRI to the minimum therapeutic dose (e.g., paroxetine 20 mg once daily, sertraline 50 mg once daily), then switch to mirtazapine 15 mg once daily [Evidence level B-1].20 If switching from fluvoxamine, cross-tapering is not recommended; taper and stop fluvoxamine before starting mirtazapine, at a low dose (e.g., mirtazapine 15 mg at bedtime).19,30

Venlafaxine to an SSRI

Stop venlafaxine and start the SSRI at a therapeutic dose.7,18 Or, cross-taper, starting the new SSRI at a low dose (e.g., citalopram, escitalopram, or paroxetine 10 mg/day; sertraline 25 mg/day).27,30 If the patient was taking a high dose of venlafaxine, consider tapering to a lower dose before stopping it and starting the new agent.10 If switching to fluoxetine or fluvoxamine, cross-tapering is not recommended taper and stop venlafaxine and start fluoxetine at 10 mg/day or fluvoxamine at 50 mg/day.30

Venlafaxine to duloxetine

Stop venlafaxine and start duloxetine 60 mg once daily [Evidence level B; nonrandomized clinical trial]18 if venlafaxine dose is <150 mg/day.27 If the patient was taking a high dose of venlafaxine (e.g., ≥150 mg per day), consider tapering over four weeks before stopping it and starting duloxetine 60 mg every-other-day.10,27 Or, cross-taper over two to three weeks.27,30

Venlafaxine or duloxetine to mirtazapine

Taper and stop SNRI, then start mirtazapine at a low dose (e.g., 15 mg at bedtime).19,30 Or, cross-taper, starting mirtazapine at a low dose (e.g., 15 mg at bedtime).19,30

Duloxetine to an SSRI

Stop duloxetine (if <60 mg/day) and start SSRI at a therapeutic dose.7,18,27 If the patient was taking a higher dose of duloxetine, consider tapering to a lower dose before stopping it and starting the new agent.10 Or, cross-taper, starting SSRI at a low dose (e.g., citalopram, escitalopram, or paroxetine 10 mg/day; sertraline 25 mg/day).27,30 If switching to fluoxetine or fluvoxamine, cross-tapering is not recommended; taper and stop duloxetine and start fluoxetine at 10 mg/day or fluvoxamine at 50 mg/day.30

Duloxetine to venlafaxine

Stop duloxetine and start venlafaxine at a therapeutic dose (e.g., 75 mg total daily dose)7,18,19 If the patient was taking a high dose of duloxetine (e.g., 60 mg/day), consider tapering to a lower dose before stopping it and starting venlafaxine.10 Or, cross-taper, starting venlafaxine at a low dose (e.g., 37.5 mg to 75 mg total daily dose).19,30

Fluoxetine to another SSRI

Stop fluoxetine (taper if dose >40 mg/day).30 Start new SSRI after a seven-day washout.30 Start new agent at a low dose (e.g., citalopram, escitalopram, or paroxetine 10 mg/day; sertraline 25 mg/day).27 If switching to fluvoxamine, start at a dose of 50 mg/day after a 14-day washout.30 Cross-tapering not recommended.30

Fluoxetine to mirtazapine

Stop fluoxetine (taper if dose >40 mg/day). Start mirtazapine at a low dose (e.g., 15 mg at bedtime).19,30 Or, taper fluoxetine to 20 mg once daily, then switch to mirtazapine 15 mg once daily [Evidence level B-1].20

Fluoxetine to venlafaxine or duloxetine

Taper and stop fluoxetine.30 After a four- to seven-day washout, start SNRI at a low dose (duloxetine 60 mg/day or venlafaxine 37.5 mg/day).11,27,30 Cross-tapering not recommended.30

Bupropion to/from another agent

Cross-taper.7 Consider reducing bupropion dose over one week, although withdrawal is not common.27

Mirtazapine to an SSRI or SNRI

Cross-taper.27,29 Consider reducing mirtazapine over four weeks, although withdrawal is rare.27 If switching to duloxetine, start with 60 mg every-other day or 30 mg once daily.27,29 Or, switch abruptly to an approximately equivalent dose of an SSRI.27 Or, taper mirtazapine, then switch to an SSRI.27

Switching to/from vortioxetine
(Trintellix)

Data limited; use extra caution.30

Note that strong CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine) can increase vortioxetine levels. Consider starting with vortioxetine 5 mg once daily (i.e., half of the usual starting dose) when cross-tapering or switching abruptly from one of these agents, other SSRIs, venlafaxine, or duloxetine, or in patient taking a strong CYP2D6 inhibitor.13,16,23,30

When switching from vortioxetine to fluoxetine or fluvoxamine, taper vortioxetine over seven days to 10 mg/day, then stop and add new agent at a low dose (fluoxetine 10 mg/day or fluvoxamine 50 mg/day).29,30 When switching to other SSRIs, SNRIs, or mirtazapine, first taper and stop vortioxetine, or cross-taper, starting SSRI or SNRI at a low dose (e.g., duloxetine 60 mg/day).29,30 Can switch abruptly to duloxetine 60 mg/day.29

Cautious cross-tapering is recommended when switching to mirtazapine.29

Switching to/from vilazodone (Viibryd)

Follow manufacturer’s recommended titration schedule when starting vilazodone (Viibryd).

Switching to/from desvenlafaxine (e.g., Pristiq) or levomilnacipran (Fetzima)

Information limited.27 Consider managing as for venlafaxine due to similar mechanism of action.30

  1. 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

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.*

  1. High-quality RCT
  2. SR/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

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).

RCT = randomized controlled trial; SR = systematic review [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. http://www.aafp.org/afp/2004/0201/p548.pdf.]

Project Leader in preparation of this clinical resource (360730): Melanie Cupp, Pharm.D., BCPS

References

  1. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder. Section 3. Pharmacological treatments. Can J Psychiatry 2016;61:540-60.
  2. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (3rd Edition). October 2010. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. (Accessed June 25, 2020).
  3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006;354:1231-42.
  4. Mann JJ. The medical management of depression. N Engl J Med 2005;353:1819-34.
  5. U.S. Department of Defense. Department of Veterans Affairs. VA/DoD clinical practice guideline or the management of major depressive disorder. April 2016. https://www.healthquality.va.gov/guidelines/MH/mdd/VADoDMDDCPGFINAL82916.pdf. (Accessed June 25, 2020).
  6. Haddad PM. Antidepressant discontinuation syndromes. Drug Saf 2001;24:183-97.
  7. Marangell LB. Switching antidepressants for treatment-resistant major depression. J Clin Psychiatry 2001;62(Suppl 18):12-7.
  8. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288:701-9.
  9. 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;56:692-9.
  10. 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.
  11. 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;69:95-105.
  12. Fava M. Management of nonresponse and intolerance: switching strategies. J Clin Psychiatry 2000;61(Suppl 2):10-2.
  13. Product information for Trintellix. Takeda Pharmaceuticals America. Deerfield, IL 60015. July 2019.
  14. Product information for Cymbalta. Lilly USA. Indianapolis, IN 46285. May 2020.
  15. Hellerstein DJ, Flaxer J. Vilazodone for the treatment of major depressive disorder: an evidence-based review of its place in therapy. Core Evid 2015;10:49-62.
  16. Product monograph for Trintellix. Lundbeck Canada. St-Laurent, QC H4S 0A9. April 2019.
  17. Lin SY, Stevens MB. The symptom cluster-based approach to individualize patient-centered treatment for major depression. J AM Board of Fam Med 2014;27:151-9.
  18. Wohlreich MM, Mallinckrodt CH, Watkin JG, et al. Immediate switching of antidepressant therapy: results from a clinical trial of duloxetine. Ann Clin Psychiatry 2005;17:259-68.
  19. Clinical Pharmacology powered by ClinicalKey. Tampa, FL: Elsevier. 2020. http://clinicalkey.com. (Accessed July 27, 2020).
  20. 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;62:413-20.
  21. Wiese BS. Geriatric depression: the use of antidepressants in the elderly. B C Med J 2011;53:341-7.
  22. Jefferson JW. Strategies for switching antidepressants to achieve maximum efficacy adolescents. J Clin Psychiatry 2008;69(Suppl E1):14-8.
  23. 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;318:132-45.
  24. Alvarez E, Perez V, Artigas F. Pharmacology and clinical potential of vortioxetine in the treatment of major depressive disorder. Neuropsychiatr Dis Treat 2014;10:1297-307.
  25. 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;391:1357-66.
  26. Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry 2006;67(Suppl 4):27-30.
  27. Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. J Pharm Pract 2013;26:389-96.
  28. Cheung AH, Zuckerbrot RA, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD-PC): part II. Treatment and ongoing management. Pediatrics 2018;141:e20174082.
  29. 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 June 25, 2020).
  30. Keks N, Hope J, Keogh S. Switching and stopping antidepressants. Aust Prescr 2016;39:76-83.
  31. 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 June 25, 2020).

Cite this document as follows: Clinical Resource, Choosing and Switching Antidepressants. Pharmacist’s Letter/Prescriber’s Letter. July 2020.

Related Articles