Switching antidepressants isn’t hard.

Unless you rush it—or forget the exceptions.

This is Part 2 in my A to Z mini-series from the upcoming 8th edition of the Med Fact Book.

Today: Antidepressants.There are two basic ways to switch antidepressants (or any class of meds):

Direct switch and cross taper.

▸ Direct switch means stopping one medication and starting the next the very next day. 

→ Day 1: Drug A. Day 2: Stop Drug A, start Drug B. 

→ Example: sertraline to citalopram.

▸ Cross taper means gradually lowering the dose of one while slowly introducing the other. 

→ Day 1: Drug A. Day 2: Lower Drug A, add low dose of Drug B. Continue overlap with dose adjustments over 2–4 weeks, until you end up with Drug B only. 

→ Example: paroxetine to vortioxetine.

Here’s how I think about it:

▸ Direct switch (no overlap or taper) Use when meds have similar mechanisms and low interaction risk.

→ Sertraline to citalopram — fine to switch overnight.

→ Venlafaxine to duloxetine — usually okay directly, especially at moderate doses (e.g., venlafaxine 75–150 mg).

→ Sertraline to duloxetine or venlafaxine — often safe as a direct switch; start low and monitor closely.

→ SSRI to mirtazapine — generally safe to stop one and start the other the next day. May even help with sleep and appetite during the transition.

▸ Cross taper (gradual overlap) Use when switching drug classes or when interaction risks are higher.

→ Paroxetine to vortioxetine — taper paroxetine over 2–4 weeks while building vortioxetine.

→ Fluoxetine to bupropion — taper fluoxetine first to avoid higher bupropion levels and seizure risk.

→ Fluoxetine to nortriptyline — cross taper to avoid metabolic inhibition.

→ Sertraline to MAOI — stop sertraline, wait 2 weeks (5 weeks for fluoxetine), then start MAOI.

→ MAOI to new antidepressant — same: 2-week washout before switching.

▸ Discontinuation risk

→ Paroxetine, venlafaxine— high risk of withdrawal; taper slowly.

→ Bupropion, mirtazapine — lower risk; faster taper is usually fine.

→ Fluoxetine — long half-life; often no taper needed.These aren’t comprehensive rules—just reliable shortcuts for the most common situations.Adjust to the patient, not the protocol.

Next up: Antipsychotics—and when not to cross taper.

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▸ What’s the antidepressant switch that still gives you pause?

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