Switching antidepressants

When switching antidepressants, 3 methods can be used.

A drug-free interval between antidepressants—the first antidepressant is gradually reduced and stopped, with an adequate drug-free interval before the second antidepressant is started and gradually increased to a therapeutic dose. See Recommended drug-free intervals when changing from one antidepressant to another for recommended antidepressant-free intervals.
A gradual cross-tapering process—the dose of the first antidepressant is gradually reduced and stopped; the second antidepressant is started at a low dose while the first is reduced, so the patient is taking both antidepressants simultaneously at low doses. Once the first antidepressant has been completely stopped, increase the second to a therapeutic dose.
A rapid switch—the first antidepressant is stopped abruptly, and the second antidepressant is started the next day. This method is limited to urgent clinical situations.

Note: There is limited evidence on the most appropriate method for switching between antidepressants.

There is limited evidence on the most appropriate method for switching between antidepressants. Choose the approach based on:

discussion with the patient
the patient’s capacity to manage a complex changing regimen
clinical urgency
drug pharmacokinetics¹
the dose of the antidepressant being stopped (eg high doses should generally be reduced before starting a new drug)
concurrent drugs and potential drug interactions, in particular serotonin toxicity.

Unless there is a need to stop the antidepressant urgently (eg severe adverse effect), gradually reduce the dosage of the first antidepressant to minimise the risk of discontinuation symptoms.

Discontinuation symptoms can arise when stopping an antidepressant. If switching from an antidepressant with a higher risk of discontinuation symptoms (eg paroxetine, venlafaxine), a drug-free interval may be preferable, except in urgent clinical situations (eg patients who are severely depressed, suicidal or psychotic).

Rapid switch and cross-tapering methods require an experienced clinician because drug interactions and serotonin toxicity are more likely with these methods. Keep in mind that discontinuation symptoms from the antidepressant that has been stopped may be misattributed to adverse effects of the new antidepressant. See Stopping treatment with an antidepressant for further information about discontinuation symptoms.

If using the drug-free interval method, see Recommended drug-free intervals when changing from one antidepressant to another for recommendations; these are based on the pharmacokinetics of the drug to be stopped and any active metabolites. Interpret these recommendations in the context of each patient’s situation (eg doses of the drugs, concurrent drugs, physical health).

Regardless of the method used to switch antidepressants, create a management plan that includes:

potential discontinuation symptoms and adverse effects to be alert for (eg serotonin toxicity)
switching schedule, including (as relevant) dosage reduction schedule, drug-free interval and schedule for introducing the new drug
approach to reviewing and monitoring the patient.

If significant adverse effects emerge during the changeover period, the plan may need to be adjusted.

Table 1. Recommended drug-free intervals when changing from one antidepressant to another
[NB1]
Printable table
Click on the antidepressant that is being stopped: a short-acting SSRI: citalopram, escitalopram, paroxetine, sertraline fluvoxamine long-acting SSRI: fluoxetine vortioxetine mianserin, mirtazapine moclobemide reboxetine an SNRI: desvenlafaxine, duloxetine, venlafaxine a TCA: amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, imipramine, nortriptyline an irreversible nonselective MAOI: phenelzine, tranylcypromine agomelatine
Changing from a short-acting SSRI (CITALOPRAM, ESCITALOPRAM, PAROXETINE, SERTRALINE) to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	nil
fluvoxamine	nil
fluoxetine	nil
vortioxetine	nil
mianserin, mirtazapine	2 to 4 days
moclobemide	2 to 4 days [NB4]
reboxetine	2 to 4 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	2 to 4 days
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	2 to 4 days [NB5]
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	1 week
agomelatine [NB3]	1 to 2 days
Changing from FLUVOXAMINE to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	nil
fluoxetine	2 to 4 days
vortioxetine	2 to 4 days
mianserin, mirtazapine	2 to 4 days
moclobemide	1 week
reboxetine	2 to 4 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	2 to 4 days
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	2 to 4 days [NB5]
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	1 week
agomelatine [NB3]	1 to 2 days
Changing from FLUOXETINE [NB6] to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	1 week
fluvoxamine	2 weeks
vortioxetine	1 week
mianserin, mirtazapine	1 week
moclobemide	1 week
reboxetine	2 to 4 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	1 week
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	2 weeks [NB5]
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	5 weeks
agomelatine [NB3]	2 to 4 days
Changing from VORTIOXETINE to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	nil
fluvoxamine	nil
fluoxetine	nil
mianserin, mirtazapine	nil
moclobemide	2 weeks
reboxetine	nil
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	nil
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	nil
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	3 weeks
agomelatine [NB3]	nil
Changing from MIANSERIN or MIRTAZAPINE to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	2 to 4 days
fluvoxamine	2 to 4 days
fluoxetine	2 to 4 days
vortioxetine	2 to 4 days
mianserin, mirtazapine	2 to 4 days
moclobemide	2 to 4 days
reboxetine	2 to 4 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	2 to 4 days
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	2 to 4 days
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	1 week
agomelatine [NB3]	1 to 2 days
Changing from MOCLOBEMIDE [NB7] to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	1 to 2 days
fluvoxamine	1 to 2 days
fluoxetine	1 to 2 days
vortioxetine	1 to 2 days
mianserin, mirtazapine	1 to 2 days
reboxetine	1 to 2 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	1 to 2 days
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	1 to 2 days
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	nil
agomelatine [NB3]	1 to 2 days
Changing from REBOXETINE to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	1 to 2 days
fluvoxamine	1 to 2 days
fluoxetine	1 to 2 days
vortioxetine	1 to 2 days
mianserin, mirtazapine	1 to 2 days
moclobemide	1 to 2 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	1 to 2 days
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	1 to 2 days
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	1 week
agomelatine [NB3]	1 to 2 days
Changing from an SNRI (DESVENLAFAXINE, DULOXETINE, VENLAFAXINE) to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	1 to 2 days
fluvoxamine	1 to 2 days
fluoxetine	1 to 2 days
vortioxetine	1 to 2 days
mianserin, mirtazapine	1 to 2 days
moclobemide	1 to 2 days
reboxetine	1 to 2 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	nil [NB8]
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	1 to 2 days
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	1 week
agomelatine [NB3]	1 to 2 days
Changing from a TCA (AMITRIPTYLINE, CLOMIPRAMINE, DOSULEPIN [DOTHIEPIN], DOXEPIN, IMIPRAMINE, NORTIPTYLINE) to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	2 to 4 days
fluvoxamine	2 to 4 days
fluoxetine	2 to 4 days
vortioxetine	2 to 4 days
mianserin, mirtazapine	2 to 4 days
moclobemide	clomipramine: 1 week; other TCAs: 2 to 4 days [NB9]
reboxetine	2 to 4 days
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	2 to 4 days
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	nil
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	1 week
agomelatine [NB3]	1 to 2 days
Changing from an irreversible nonselective MAOI (PHENELZINE, TRANYLCYPROMINE) to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	2 weeks
fluvoxamine	2 weeks
fluoxetine	2 weeks
vortioxetine	2 weeks
mianserin, mirtazapine	2 weeks
moclobemide	nil [NB10]
reboxetine	2 weeks
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	2 weeks
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	2 weeks
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	2 weeks
agomelatine [NB3]	1 to 2 days
Changing from AGOMELATINE [NB3] to:
a short-acting SSRI (citalopram, escitalopram, paroxetine, sertraline)	nil
fluvoxamine	nil
fluoxetine	nil
vortioxetine	nil
mianserin, mirtazapine	nil
moclobemide	nil
reboxetine	nil
an SNRI (desvenlafaxine, duloxetine, venlafaxine)	nil
a TCA (amitriptyline, clomipramine, dosulepin [dothiepin], doxepin, imipramine, nortriptyline)	nil
an irreversible nonselective MAOI [NB2] (phenelzine, tranylcypromine)	1 to 2 days
Note: nil = start the new antidepressant the next day; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin and noradrenaline reuptake inhibitor; TCA = tricyclic antidepressant NB1: Interpret these recommendations in the context of each patient’s situation (eg doses of drugs, concurrent drugs, physical health). Higher doses of antidepressant should generally be reduced before starting the new drug and the new drug should usually be started at a low dose. NB2: Exercise caution when switching to an irreversible nonselective MAOI because of the risk of severe hypertension, stroke and serotonin toxicity. If necessary, adjust the drug-free interval to accommodate individual patient differences in pharmacokinetics. NB3: Data on antidepressant-free intervals when changing to and from agomelatine are limited. NB4: If changing from a low or moderate dose of the short-acting SSRIs (citalopram, escitalopram, paroxetine or sertraline), the dose of moclobemide should not exceed 300 mg daily for the first week. The dose of moclobemide may subsequently be increased if necessary. If changing from a high dose of a short-acting SSRI, seek expert advice. NB5: The TCA concentration may be elevated for several weeks due to persisting SSRI-induced cytochrome P450 inhibition. NB6: Because of the long half-life of fluoxetine, clinically relevant concentrations persist for approximately 5 weeks after it is stopped. Exercise caution when changing to another antidepressant. NB7: The recommended drug-free intervals apply when switching from a low or moderate dose of moclobemide to a low or moderate dose of the new antidepressant—if the patient is treated with a high dose of moclobemide, gradually reduce the dose before switching. NB8: Because a drug-free interval is not needed when changing from one SNRI to another, cross-tapering or a rapid switch may be used. If switching to duloxetine using one of these methods, start at 30 mg daily and increase the duloxetine dose slowly. NB9: If changing from a low or moderate dose of a TCA (eg less than 150 mg imipramine), the dose of moclobemide should not exceed 300 mg daily for the first week. The dose of moclobemide may subsequently be increased if necessary. If changing from a high dose of a TCA, seek expert advice. NB10: This recommendation applies if moderate or low doses of both drugs are involved—if changing from a high dose of an irreversible nonselective MAOI, seek expert advice. Continue to adhere to irreversible nonselective MAOI dietary guidelines (see Irreversible nonselective monoamine oxidase inhibitor dietary guidelines) for 2 weeks after switching to moclobemide.

¹ Note there is considerable interindividual variation in antidepressant pharmacokinetics.Return