From the Guidelines
Fluoxetine (Prozac) requires the longest washout period when switching from a MAO inhibitor to avoid serotonin syndrome. While most antidepressants require a 2-week washout period, fluoxetine needs 5 weeks due to its long half-life and active metabolite norfluoxetine 1. Fluoxetine and its metabolite remain in the body much longer than paroxetine, amitriptyline, or citalopram, increasing the risk of dangerous drug interactions if a MAO inhibitor is introduced too soon.
Key Considerations
- Serotonin syndrome occurs when excessive serotonin accumulates in the body, causing symptoms ranging from mild (agitation, tremor) to severe (hyperthermia, muscle rigidity, and potentially death) 1.
- The extended elimination time of fluoxetine means patients must wait longer before safely starting MAO inhibitor therapy to ensure complete clearance of the medication from their system.
- Monoamine oxidase inhibitors (MAOIs) should be avoided in combination with any other serotonergic drug, including another MAOI, to prevent serotonin syndrome 1.
Comparison of Agents
- Paroxetine, amitriptyline, and citalopram have shorter half-lives compared to fluoxetine, reducing the required washout period 1.
- Fluoxetine's active metabolite norfluoxetine contributes to its longer half-life, making it the agent that requires the longest time of separation from a MAO inhibitor 1.
From the FDA Drug Label
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Prozac before starting an MAOI Since fluoxetine and its major metabolite have very long elimination half–lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY)] should be allowed after stopping Prozac before starting an MAOI
The agent that would need the longest time of separation from a MAO inhibitor to avoid serotonin syndrome is Fluoxetine (Prozac), with a recommended separation time of at least 5 weeks 2.
From the Research
Serotonin Syndrome and MAO Inhibitors
To avoid serotonin syndrome when switching from a MAO inhibitor to an antidepressant, a washout period is necessary. The length of this period depends on the half-life of the antidepressant and its active metabolites.
Half-Lives of Antidepressants
- Fluoxetine (Prozac) has a half-life of 1-3 days, but its active metabolite norfluoxetine has a half-life of 7-10 days 3
- Paroxetine (Paxil) has a half-life of 21 hours, but it is a potent inhibitor of CYP2D6, which can affect the metabolism of other drugs 3
- Citalopram (Celexa) has a half-life of 35 hours 4
- Amitriptyline (Elavil) is a tricyclic antidepressant with a half-life of 10-50 hours, but it is not an SSRI 3
Washout Period
The washout period is necessary to allow the antidepressant and its active metabolites to be eliminated from the body before starting a MAO inhibitor. Based on the half-lives of the antidepressants, the longest time of separation from a MAO inhibitor would be needed for:
- Fluoxetine (Prozac), due to its active metabolite norfluoxetine, which has a long half-life 3
Comparison of Antidepressants
- Fluoxetine (Prozac) would require the longest washout period due to its long-acting metabolite norfluoxetine 3
- Paroxetine (Paxil) and citalopram (Celexa) have shorter half-lives, but paroxetine is a potent inhibitor of CYP2D6, which can affect the metabolism of other drugs 3
- Amitriptyline (Elavil) is not an SSRI, but it can still interact with MAO inhibitors and cause serotonin syndrome 5