What antidepressant can be safely prescribed to a patient taking oral linezolid (Zyvox) who is currently on escitalopram (Lexapro)?

Antidepressant Selection During Linezolid Therapy

Switch from escitalopram to mirtazapine immediately, as mirtazapine is not a serotonergic antidepressant and does not carry the risk of serotonin syndrome when combined with linezolid.

Understanding the Drug Interaction

Linezolid is a reversible, nonselective monoamine oxidase inhibitor (MAOI), and combining it with serotonergic antidepressants like escitalopram creates a risk of serotonin syndrome—a potentially fatal condition characterized by mental status changes, neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic instability (hypertension, tachycardia, diaphoresis). 1

• All SSRIs and SNRIs are contraindicated with MAOIs, including linezolid, due to this serotonin syndrome risk. 1
• Escitalopram specifically has been documented to cause serotonin syndrome with linezolid, including one case resulting in tonic-clonic seizure. 2

Recommended Antidepressant: Mirtazapine

Mirtazapine is the safest antidepressant choice during linezolid therapy because it works through alpha-2 adrenergic antagonism and histamine receptor blockade rather than serotonin reuptake inhibition. 1

Switching Protocol

• Day 1: Discontinue escitalopram and start mirtazapine 15 mg at bedtime. 1
• Week 2-4: Increase mirtazapine to 30 mg at bedtime if tolerated and clinically indicated. 1
• No washout period is required when switching from escitalopram to mirtazapine, unlike switching between serotonergic agents. 1

Advantages of Mirtazapine

• Faster onset of action than SSRIs—mirtazapine shows statistically significant improvement within 1-2 weeks, though response rates equalize with SSRIs by week 4. 1
• Sedating properties help with anxiety and insomnia, which are common in patients requiring antibiotics for serious infections. 1
• No serotonin syndrome risk with linezolid because it does not increase synaptic serotonin through reuptake inhibition. 1

Alternative Option: Bupropion

Bupropion is another safe alternative as it works through norepinephrine and dopamine reuptake inhibition without serotonergic activity. 1

• Start bupropion SR 150 mg once daily, increase to 150 mg twice daily after 3-4 days if tolerated. 1
• Caution: Bupropion lowers seizure threshold and should be avoided in patients with seizure disorders, eating disorders, or abrupt alcohol/benzodiazepine withdrawal. 1

What NOT to Do

Never continue escitalopram or any SSRI/SNRI during linezolid therapy. The following antidepressants are absolutely contraindicated with linezolid: 1, 3

• All SSRIs: escitalopram, citalopram, sertraline, fluoxetine, paroxetine, fluvoxamine
• All SNRIs: venlafaxine, desvenlafaxine, duloxetine
• Tricyclic antidepressants (TCAs) with serotonergic activity

Do not rely on a 14-day washout period as a safety measure—while guidelines traditionally recommend waiting 14 days after stopping an MAOI before starting an SSRI, this patient needs antidepressant coverage during linezolid therapy, not after. 1, 3

Addressing the Controversy: Can SSRIs Ever Be Used With Linezolid?

There is conflicting evidence in the literature about concurrent use:

• Conservative approach (recommended): One retrospective study found serotonin syndrome occurred in only 2 of 72 patients (3%) receiving linezolid with SSRIs, and a 2022 population study of 1,134 older patients found serotonin syndrome in fewer than 6 patients (<0.5%). 4, 5
• However, case reports document severe outcomes: including cardiopulmonary arrest, coma, seizures, and death when linezolid was combined with sertraline, citalopram, and escitalopram. 2, 3, 6

The risk-benefit analysis favors switching to a non-serotonergic antidepressant rather than gambling on the 1-3% risk of a potentially fatal drug interaction, especially when safe alternatives like mirtazapine exist. 4, 2, 3, 5

Monitoring During Transition

• Watch for serotonin syndrome symptoms in the first 24-48 hours after any medication change: confusion, agitation, tremors, muscle rigidity, hypertension, tachycardia, diaphoresis, diarrhea. 1
• Monitor for worsening depression or suicidality during the antidepressant switch, particularly in patients under age 24. 1, 7
• Symptoms can appear up to 10 days after linezolid discontinuation if the SSRI is continued, so maintain vigilance throughout the entire linezolid course and for 2 weeks after completion. 2, 3

Duration of Mirtazapine Therapy

• Continue mirtazapine for the entire duration of linezolid therapy plus 2 weeks after linezolid completion to ensure complete MAOI washout. 1
• After linezolid is discontinued and 2 weeks have passed, you may consider switching back to escitalopram if mirtazapine is not well-tolerated, though many patients do well on mirtazapine long-term. 1
• If continuing mirtazapine long-term for depression/anxiety, maintain therapy for minimum 4-9 months after satisfactory response. 1, 7