Maddie is a 23 yo woman with generalized anxiety disorder. She started escitalopram 5mg daily 4 months ago, titrated to 20mg at bedtime over 2 months with a significant improvement in her anxiety. However, the escitalopram also caused significant daytime sedation, even when taken at night. A dose reduction to escitalopram 15mg at bedtime helped slightly with the sedation, but led to an increase in anxiety symptoms. You decide to switch escitalopram to sertraline, which is less sedating than escitalopram on average. How do you make the switch?
How do you switch from one antidepressant medication to another?
In this PsychSnap, I describe 3 switch strategies. I do not review when it is clinically indicated to switch antidepressants, or what antidepressant should be chosen next if one decides to switch.
There are several factors to consider when switching antidepressants.
- What is the risk of withdrawal symptoms from stopping the first antidepressant?
- What is the risk of side effects when starting the second antidepressant?
- Is there any cross-tolerance (ie pharmacologic similarity between the medications) that could mitigate withdrawal or early side effects if the drugs are overlapped?
- Are there any pertinent drug-drug interactions (CYP450, risk of serotonin syndrome) to consider?
When we start or stop an individual antidepressant, we mitigate side effects by starting at a low-dose and titrating slowly. We mitigate withdrawal symptoms by tapering the antidepressant before stopping. This gives the brain time to adapt to the medication changes.
This table reviews the most common symptoms of antidepressant withdrawal and the early side effects of the SSRIs, SNRIs, bupropion, and mirtazapine. Both withdrawal symptoms and early side effects can range from absent to very severe.
There are 3 strategies one can reasonably choose when switching between antidepressants: sequential titration, cross-titration, or direct switch.
The most conservative option, called sequential titration, involves tapering the first antidepressant before stopping it, a drug-free washout period (usually 5 half lives), and then starting the new antidepressant at a low dose and increasing the dose slowly to a therapeutic dose. I choose this strategy for patients who are likely to stop a new medication if they experience any side effects, because it prevents drug withdrawal symptoms from the 1st medication from being erroneously identified as side effects from the 2nd medication. Otherwise, I rarely use this strategy.
Factors that support particular switch strategies between antidepressants (ADs)
| Sequential titration | Cross-titration | Direct switch |
| If a patient is very sensitive to side effects and you don’t want their experience with a new antidepressant to be complicated by withdrawal symptoms from stopping the previous med. If a patient has a severe side effect (new suicidality, significant hyponatremia), the first med should be stopped abruptly. Monitor the patient, and start the new med only after the side effect has fully resolved. Required if switching to or from an MAOi | If there is a higher risk for antidepressant withdrawal due to: -High dose antidepressant -Antidepressant with a higher rate of withdrawal (e.g. paroxetine, venlafaxine, desvenlafaxine, duloxetine) -Patient with a personal history of antidepressant withdrawal If there is a higher risk of start-up side effects due to patient history *patient must be able to manage the complexity of cross-titration | If there is a lower risk for antidepressant withdrawal due to: -Low-dose antidepressant -Short exposure to drug (weeks) -Drugs are very similar (ex citalopram/escitalopram; some authors also include all SSRIs and SNRIs) If cross-titration would be too complicated for the patient |
With cross-titration, the dose of one antidepressant is tapered while the other one is started and titrated up. Cross-titration is faster than sequential titration, eliminating the drug washout period and completing the down titration of the first antidepressant (AD1) and the uptitration of the second antidepressant (AD2) simultaneously. It can usually be completed in 1-2 weeks, though it may take longer if a high dose medication is involved. If the medications are pharmacologically similar, the presence of AD2 may help prevent withdrawal from AD1, and the presence of AD1 may help reduce early side effects from AD2 (Wohlreich, 2005). If a patient has been taking a moderate or high dose AD for at least a month, cross-titration is my usual method for switching ADs.
Sometimes there is concern about the safety of taking two antidepressants at the same time. Is there a risk of serotonin syndrome with cross-titration? In brief, as long as one of the ADs is not an MAOi, and the patient has a functioning liver, don’t worry about serotonin syndrome when cross-titrating between antidepressants.
CYP450 interactions may be relevant if one of the antidepressants is a strong CYPD26 inhibitor, specifically paroxetine, bupropion, or fluoxetine (which also inhibits CYP2C19). When these antidepressants overlap with other medications, including another antidepressant, one should always use a drug-interaction checker.
The main downside of cross-titrations is the complexity for the patient. In addition, when a new side effect emerges during a cross-titration, it can be unclear if the symptom is due to withdrawal from AD1 or early side effects from AD2, as the doses of both medications are changed at the same time.
To design a cross-titration:
- Choose a target dose for AD2, often the equivalent dose to AD1, though it may be lower.
This table lists the estimated dose equivalence of commonly used antidepressants, rounded to the nearest available pill size. - Start a low dose of AD2, as when starting any antidepressant.
- Stop slow as you go low with AD1, as with any taper.
- Complete the cross-titration within 2 weeks, 3-4 weeks at most. I generally change doses once a week to make it easier for the patient, but changing doses every 3-4 days is often tolerated.
- Write down the taper for the patient.
For Maddie, the dose of escitalopram that was helpful for anxiety was escitalopram 20mg daily. She is currently taking escitalopram 15mg daily. In switching to sertraline in this situation, I’m going to aim for the “dose equivalent” of escitalopram 20mg, the effective dose, which is sertraline 100mg daily.
Maddie’s cross-titration
Week 0: escitalopram 15 mg
Week 1: escitalopram 7.5mg (1 ½ of a 5mg tab) + sertraline 25mg (½ of 50mg tab)
(this should be the smallest step in titrating AD2)
Week 2: escitalopram 2.5mg (½ of 5mg tab) + sertraline 50mg
Week 3: stop escitalopram (this should be the smallest step in stopping AD1).
sertraline 100mg daily
Notice that the milligram decrements in dose for AD1 (i.e. the size of the “steps”) gets smaller as they go down. The escitalopram taper goes 15mg – 7.5mg – 2.5mg – stop, with decrements of 7.5mg – 5mg – 2.5mg.
Finally, a direct switch between two antidepressants (ADs) means stopping the first antidepressant and starting the “equivalent dose” of the second antidepressant the next day. Sometimes the second antidepressant is started at a lower dose to minimize early side effects. Patients are generally more able to adhere to a plan for direct switching than for cross-titrations. Direct switching may be preferable when there is a low risk of withdrawal from AD1 such as when AD1 has been recently introduced, is a low dose, or is pharmacologically very similar to AD2. For example, a patient who benefitted from citalopram 40mg daily but developed QTc prolongation could be switched directly to escitalopram 20mg daily. Citalopram, as a racemic mixture of 50% S-citalopram and 50% R-citalopram, is pharmacologically very similar to escitalopram.
If Maddie were to switch directly from escitalopram 15mg to sertraline 100mg, she would stop escitalopram 15mg at bedtime one day and start sertraline 100mg daily the next day.
Key Points
- There are three strategies for switching between antidepressant medications: sequential titration, cross-titration, and direct switch.
- In most situations, I use the cross-titration strategy. I use a direct switch strategy if the first antidepressant is low dose or if a cross-titration is too complicated for the patient.
- For a cross-titrations – choose the target dose for AD2, start low with AD2 to avoid start up side effects, stop slow as you go low with AD1 to avoid withdrawal symptoms, try to get it done within 1-2 weeks, and write the taper down for the patient.
Related PsychSnaps:
“How do you stop an SSRI?” Emma Samelson-Jones, November 2023.
“How do you manage the side effects of SSRIs?” Zoë Kopp, January 2024.
References:
Keks, Nicholas, Judy Hope, and Simone Keogh. “Switching and stopping antidepressants.” Australian Prescriber 39.3 (2016): 76.
Mills, Natalie T., et al. “Clinical switching strategies of various antidepressants to vortioxetine in the PREDDICT trial.” International Journal of Neuropsychopharmacology 24.4 (2021): 314-321.
Ogle, Nikki R., and Shawn R. Akkerman. “Guidance for the discontinuation or switching of antidepressant therapies in adults.” Journal of pharmacy practice 26.4 (2013): 389-396.
Perahia, David GS, et al. “Switching to duloxetine from selective serotonin reuptake inhibitor antidepressants: a multicenter trial comparing 2 switching techniques.” Journal of Clinical Psychiatry 69.1 (2008): 95.
Wohlreich, Madelaine M., et al. “An open-label study of duloxetine for the treatment of major depressive disorder: comparison of switching versus initiating treatment approaches.” Journal of clinical psychopharmacology 25.6 (2005): 552-560.
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