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Interaction of the week: Fluoxetine (Prozac) + Amitriptyline

Fluoxetine (Prozac) and amitriptyline (Elavil) are both serotonin reuptake inhibitors.

More importantly, fluoxetine appears to increase steady state serum levels of amitriptyline 2-fold and the nortriptyline metabolite 9-fold (el-Yazigi et al, 1995).

Interaction between fluoxetine (Prozac) and Amitriptyline Stahl

Fluoxetine is a "fluffer" inHibitor of both enzymes that metabolize tricyclic antidepressants, CYP2D6 and CYP2C19

Combining two SRIs (like fluoxetine + amitriptyline) will not cause a life-threatening serotonin syndrome, but mild serotonin toxicity symptoms could present such as twitching, sweating, nausea, and tremor.

If amitriptyline is being taken at a substantial dose, cardiac arrhythmias may result from toxic amitriptyline levels. A fatality was attributed to a combination of fluoxetine 40 mg/day and amitriptyline 150 mg/day (Preskorn & Baker, 1997).

If a combination of fluoxetine and amitriptyline is used, the amitriptyline dose should be kept low (probably not exceeding 25 mg) and serum amitriptyline/nortriptyline levels should be monitored.

Serotonin Syndrome

SRIs, even in over-dose, are insufficient to cause fatalities related to serotonin toxicity in healthy adults (Isbister et al, 2004). Perhaps the only combination of antidepressants likely to elevate serotonin to a life-threatening extent is the combination of a monoamine oxidase inhibitor (MAOI) and a serotonin reuptake inhibitor (Gillman, 2014). Serotonin releasers like amphetamine and MDMA (ecstasy) could be fatal if mixed with a MAOI.

If the combination of fluoxetine plus a TCA proves fatal, it would be due to pharmacokinetic interaction, not to serotonin toxicity.

Interaction of fluoxetine with other TCAs

Fluoxetine reduces clearance of both imipramine and desipramine as much as 10-fold  (Bergstrom et al, 1992). This is particularly dangerous because desipramine has more arrhythmogenic potential than other TCAs.

Due to the long half-life of fluoxetine and its active metabolite, this interaction may persist for 5 weeks after fluoxetine discontinuation. However the CYP-inHibitory effect of the norfluoxetine metabolite is weaker than that of the parent drug.


Fluoxetine (Prozac) mechanism of action Stahl

Amitriptyline mechanism of action Stahl

Amitriptyline and nortriptyline


Mnemonics for fluoxetine (Prozac) with interaction avatars / mascot  / Jason Cafer MD

Amitriptyline mnemonics and interactions by Jason Cafer MD

nortriptyline Pamelor mnemonics TCA interactions Jason Cafer MD

Copyright 2024, CaferMed. Intended for prescribers.

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