Switching from Fluoxetine to an MAOI
STOP fluoxetine and wait 5 weeks prior to starting a MAOI 1.
Rationale for the 5-Week Washout Period
The extended washout period is mandated by fluoxetine's pharmacokinetic profile:
Fluoxetine has an extremely long elimination half-life, and its active metabolite norfluoxetine has an even longer half-life, requiring at least 5 weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) after stopping fluoxetine before starting an MAOI 1.
Complete clearance of both fluoxetine and norfluoxetine is essential to prevent life-threatening serotonin syndrome when initiating MAOI therapy 2.
Why Other Options Are Incorrect and Dangerous
5-7 Days Is Inadequate
A 5-7 day washout is appropriate for most antidepressants (those with shorter half-lives like sertraline, paroxetine, or citalopram), but fluoxetine is the critical exception due to its uniquely long half-life 3.
Starting an MAOI within 10 days of stopping fluoxetine resulted in a very high incidence of adverse effects, especially serotonin syndrome characterized by mental status changes (hypomania, confusion), myoclonus, hypertension, tremor, and diarrhea 4.
Starting MAOI First Is Contraindicated
Fluoxetine should never be used in combination with an MAOI, as there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations of vital signs, and mental status changes progressing to delirium and coma 1.
Seven of eight clinical cases reviewed where an MAOI was initiated shortly after discontinuing fluoxetine resulted in fatal outcomes, with only one patient surviving after cyproheptadine therapy 5.
Cross-Tapering Is Absolutely Contraindicated
Cross-tapering involves overlapping administration of both medications, which creates the exact scenario that causes serotonin syndrome and is explicitly contraindicated by FDA labeling 1.
The combination of fluoxetine and MAOIs presents features resembling neuroleptic malignant syndrome and can result in hypermetabolic states involving serotonin and serotonin-dopamine interactions 5.
Clinical Monitoring During the Washout Period
Monitor for depressive symptom exacerbation during the 5-week medication-free period, as this represents a significant clinical challenge requiring close observation 3.
Educate patients about the rationale for the extended washout to ensure adherence, as premature MAOI initiation carries mortality risk 5.
Consider bridging strategies such as supportive psychotherapy or non-pharmacologic interventions during the washout period, though no serotonergic medications can be added 2.
Common Pitfalls to Avoid
Never assume fluoxetine behaves like other SSRIs when calculating washout periods—it is pharmacokinetically distinct and requires special consideration 1, 3.
Do not rely on symptom resolution as an indicator that fluoxetine has cleared; the 5-week period is based on pharmacokinetics, not clinical response 1.
Avoid any serotonergic medications during the washout, including tramadol, meperidine, dextromethorphan, St. John's Wort, or triptans, as these can precipitate serotonin syndrome even without an MAOI present 6, 2.