From the FDA Drug Label
While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary)
The use of amitriptyline with fluoxetine is not recommended without caution. Caution is advised when coadministering these medications due to the potential for increased plasma concentrations of amitriptyline and the risk of adverse effects.
- The concomitant use of tricyclic antidepressants with SSRIs may require lower doses than usually prescribed for either medication.
- It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6, such as fluoxetine 1.
- At least 5 weeks should elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, due to the long half-life of fluoxetine and its active metabolite 1.
From the Research
Combining amitriptyline with fluoxetine is not considered safe without close medical supervision due to the risk of serotonin syndrome. This potentially life-threatening drug interaction occurs because both medications increase serotonin levels in the brain through different mechanisms - fluoxetine blocks serotonin reuptake while amitriptyline affects multiple neurotransmitters including serotonin. Symptoms of serotonin syndrome include confusion, agitation, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremors, excessive sweating, diarrhea, and in severe cases, seizures or loss of consciousness. Additionally, this combination can increase the risk of QT interval prolongation (a heart rhythm abnormality) and may enhance side effects like drowsiness, dry mouth, blurred vision, and constipation. According to a recent study 2, the combination of SSRIs with other drugs, including antidepressants, can increase the risk of serotonin syndrome, highlighting the need for caution when combining these medications. If you're currently taking one of these medications and your doctor is considering adding the other, they would need to carefully evaluate your specific situation, possibly start with very low doses, monitor you closely, and potentially check blood levels of the medications. Some key points to consider when evaluating the safety of combining amitriptyline and fluoxetine include:
- The risk of serotonin syndrome, which can be life-threatening
- The potential for increased side effects, such as drowsiness and dry mouth
- The need for close medical supervision and monitoring
- The importance of carefully evaluating the patient's specific situation and medical history before combining these medications. It's also worth noting that while older studies 3, 4, 5, 6 provide some insight into the risks of combining serotonergic medications, the most recent and highest-quality study 2 should be prioritized when making decisions about patient care.