Switching antidepressants: cross-taper and washout matrix

The three switch patterns

Direct switch

Stop the first drug at its current dose, start the second drug the next day at a standard starting dose. Works when both drugs are in the same class, half-lives are similar, and there's no serotonin syndrome or discontinuation risk from doing it fast.

Reasonable direct switches:

• SSRI to another SSRI at roughly equivalent dose (sertraline 50 to escitalopram 10, citalopram 20 to sertraline 50).
• SSRI to SNRI at starting dose (paroxetine 20 to venlafaxine 75 XR, sertraline 100 to duloxetine 30).
• SNRI to SNRI (venlafaxine 150 to duloxetine 60).
• Anything to bupropion (low serotonergic risk from bupropion, so overlap isn't needed, though tapering off the first drug still matters for its own discontinuation risk).
• Anything to mirtazapine (mirtazapine's mechanism doesn't create interaction risk with SSRIs/SNRIs at typical doses).

Cross-taper

Overlap for 1 to 2 weeks. Reduce the first drug in scheduled steps while starting the second at a low dose and titrating up. By end of the overlap, the first drug is off and the second is at target.

Example: escitalopram 20 to sertraline 100, over 2 weeks:

• Days 1 to 7: escitalopram 10 mg + sertraline 25 mg.
• Days 8 to 14: escitalopram 5 mg + sertraline 50 mg.
• Day 15 onward: sertraline 50 mg, titrate to 100 mg over next 1 to 2 weeks.

Cross-taper is the default for most SSRI/SNRI switches when you want to protect against both discontinuation symptoms and loss of therapeutic effect. It's especially useful when switching away from paroxetine or venlafaxine, which have serious discontinuation profiles.

Wash and switch

Fully discontinue the first drug (with taper as needed), wait for washout, then start the second. Required when starting or stopping an MAOI, and often preferable when the incoming drug is fluoxetine after a difficult discontinuer.

MAOI washout rules

MAOIs deserve their own section because getting this wrong causes serotonin syndrome or hypertensive crisis.

Before starting an MAOI (phenelzine, tranylcypromine, isocarboxazid, selegiline):

• 14 days after stopping most SSRIs, SNRIs, TCAs, mirtazapine.
• 5 weeks after stopping fluoxetine (long half-life; the active metabolite norfluoxetine has a half-life of 7 to 15 days).
• 14 days after stopping other MAOIs (allows enzyme regeneration).
• 24 hours after stopping bupropion (cautious; some sources say 14 days).
• Meperidine, tramadol, dextromethorphan, linezolid, methylene blue: same 14-day rule going into an MAOI, and never combine with an active MAOI.

Before starting a serotonergic drug after an MAOI:

• 14 days after the last MAOI dose (allows MAO enzyme regeneration).
• Same rule for switching between MAOIs.

Selegiline transdermal at 6 mg/24 hr has no dietary restrictions and doesn't fully inhibit gut MAO, but it still requires the same 14-day washouts. Higher-dose selegiline patches (9 and 12 mg) do carry dietary restrictions.

The matrix

Special cases worth calling out

Fluoxetine to anything. Fluoxetine's active metabolite norfluoxetine has a half-life of 7 to 15 days. So when you stop fluoxetine 20 mg, the patient has meaningful drug in their system for 4 to 6 weeks. This is usually a feature (self-tapering, no discontinuation syndrome) but becomes a problem when: (1) the next drug is an MAOI (5-week wait), (2) the next drug is a 2D6 substrate whose levels will be raised (aripiprazole, atomoxetine, TCAs, risperidone, some opioids), or (3) you need to clear the drug quickly for another reason. In cases 1 and 2, you may need to plan for the residual fluoxetine effect.

Paroxetine to anything. Paroxetine has a short half-life (21 hours) plus significant anticholinergic activity and non-linear kinetics at higher doses. Discontinuation syndrome is intense: nausea, dizziness, brain zaps, flu-like symptoms, sometimes irritability that gets misread as relapse. Cross-taper slowly, ideally over 2 to 4 weeks, using liquid formulation for finer control at the low end. If the incoming drug is an SSRI, overlapping can prevent discontinuation. If it's bupropion, expect the paroxetine discontinuation to happen even during the overlap because bupropion doesn't cover the serotonergic withdrawal.

Venlafaxine to duloxetine. Usually a direct switch works: venlafaxine 150 XR to duloxetine 60, next day. Both are SNRIs. Watch blood pressure. If you want to be conservative, cross-taper for 4 to 7 days.

TCA to SSRI (especially fluoxetine or paroxetine). Fluoxetine and paroxetine are potent 2D6 inhibitors. If the patient is on a 2D6-metabolized TCA (nortriptyline, desipramine, amitriptyline, imipramine, clomipramine), starting the SSRI can raise TCA levels 2 to 4 fold. Check a level before starting the SSRI, or better, reduce the TCA meaningfully first, or pick a non-2D6-inhibiting SSRI (sertraline, citalopram, escitalopram).

Bupropion to anything. Usually direct. Bupropion has minimal discontinuation syndrome. Watch for anxiety that bupropion was covering to re-emerge.

Mirtazapine to anything. Overlap is safe with SSRIs and SNRIs (that combination is the "California rocket fuel" adjunct). Don't stop mirtazapine abruptly if the patient's been on it a while: some patients get flu-like or GI symptoms.

Serotonin syndrome risk during overlap

Cross-tapers involving two serotonergic drugs create a window of dual serotonin activity. In practice, at typical doses this is well-tolerated. Serotonin syndrome usually requires either an MAOI plus serotonergic agent, or supratherapeutic doses, or a serotonergic agent plus an unexpected inhibitor (linezolid, methylene blue, high-dose tramadol, MDMA).

Warning signs during overlap: agitation, diaphoresis, hyperreflexia, clonus (especially lower extremity), tremor, tachycardia, GI symptoms. Mild features can look like SSRI initiation side effects, so context matters. If you see clonus, temperature over 38C, or altered mental status, stop both drugs and manage as serotonin syndrome.

Common questions

Do I really need to wait 5 weeks after fluoxetine before starting an MAOI? Yes. Norfluoxetine (the active metabolite) has a half-life of 7 to 15 days. Five half-lives puts you at 35 to 75 days of meaningful residual activity. The 5-week rule is a compromise. Under 5 weeks and you're gambling with serotonin syndrome; the syndrome from MAOI + SSRI combinations is often severe (hyperthermia, rigidity, cardiovascular instability). The waiting period is uncomfortable, but the risk isn't theoretical.

Can I go straight from Effexor to Cymbalta? Usually yes. Both are SNRIs. Common practice: venlafaxine 150 XR yesterday, duloxetine 60 today. Watch blood pressure and expect the first week to feel slightly different (duloxetine has more NE activity at 60 mg than venlafaxine at 150, and some GI effects differ). If you want to be conservative, do a 4 to 7 day cross-taper. Direct is fine for most patients.

How do I cross-taper someone off Paxil onto Lexapro? Reduce paroxetine slowly, overlap with escitalopram. Example over 2 to 3 weeks:

• Days 1 to 7: paroxetine 20 + escitalopram 5.
• Days 8 to 14: paroxetine 10 + escitalopram 10.
• Days 15 to 21: paroxetine 5 + escitalopram 10.
• Day 22 onward: escitalopram 10, titrate as needed.

If the patient has had discontinuation trouble before, extend the paroxetine taper further and use liquid paroxetine for micro-doses at the low end. Some patients need 4 to 6 weeks. The escitalopram overlap helps a lot but doesn't fully prevent paroxetine discontinuation because paroxetine's anticholinergic and 5-HT reuptake profile isn't fully replaced by other SSRIs.

When is direct switch actually safe? When both drugs are in the same class, the doses are equipotent, the outgoing drug has a manageable discontinuation profile (or a long half-life like fluoxetine), and the patient doesn't have a history of dramatic response to changes. Same-class SSRI switches, SNRI to SNRI, and any switch involving bupropion or mirtazapine as the incoming drug generally tolerate direct approaches. When in doubt, cross-taper: it costs you nothing except a bit of patient education.

What if the patient can't tolerate a cross-taper? Some patients get side effect additivity during overlap (nausea, dizziness, sleep disruption). Options: shorten the overlap (3 to 4 days instead of 1 to 2 weeks), use lower doses of both drugs during overlap, or do a brief wash-and-switch if the outgoing drug has a benign discontinuation profile. If the patient is on paroxetine or venlafaxine, wash-and-switch usually isn't kind. Slow the taper instead.

Sources

• Maudsley Prescribing Guidelines in Psychiatry, 14th edition (Taylor, Barnes, Young).
• NICE NG222: Depression in adults: treatment and management. Updated 2022.
• American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd edition.
• CANMAT 2016 Clinical Guidelines for the Management of Adults with MDD.
• Package inserts for phenelzine, tranylcypromine, selegiline transdermal, fluoxetine, paroxetine, venlafaxine, duloxetine, vortioxetine, vilazodone.
• Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.

Reviewed against current guidelines as of June 8, 2026. This is not medical advice.