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to the other Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary) Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug.
The risks and precautions when using Amitriptyline (tricyclic antidepressant) and Selective Serotonin Reuptake Inhibitors (SSRIs) together include:
- Increased risk of adverse interactions due to the inhibition of cytochrome P450 2D6 by SSRIs
- Potential for increased plasma concentrations of tricyclic antidepressants, which may lead to toxicity
- Need for cautious dose adjustment when coadministering TCAs with SSRIs
- Importance of allowing sufficient time (at least 5 weeks) to elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine
- Requirement for close monitoring of patients when switching from one class to the other 1
From the Research
Using amitriptyline (a tricyclic antidepressant) together with SSRIs is generally not recommended due to significant risks of serotonin syndrome, a potentially life-threatening condition. This combination should only be used under careful medical supervision with close monitoring, as highlighted in a recent study on serotonin syndrome 2. Specific SSRIs that pose particular concern include fluoxetine, paroxetine, and fluvoxamine, as they can increase amitriptyline blood levels through enzyme inhibition.
The risks associated with this combination are significant and include:
- Serotonin syndrome, characterized by neuromuscular excitation, autonomic dysfunction, and altered mental status 3, 2
- QT interval prolongation, a heart rhythm abnormality, especially in patients with pre-existing cardiac conditions or electrolyte abnormalities
- Increased risk of adverse effects due to the synergistic increase in serotonin levels in the brain
If this combination is deemed necessary by a healthcare provider, they will typically start with lower doses of both medications and gradually increase while monitoring for adverse effects. Warning signs of serotonin syndrome that require immediate medical attention include:
- Agitation
- Confusion
- Rapid heart rate
- Dilated pupils
- Muscle rigidity
- Tremor
- Excessive sweating
- High fever
- Seizures
The most recent and highest quality study on serotonin syndrome 2 emphasizes the importance of careful diagnosis and management of this condition, which can be life-threatening. Therefore, the use of amitriptyline and SSRIs together should be approached with caution and only under close medical supervision. Regular ECG monitoring may be required for patients on this combination therapy, especially those with pre-existing cardiac conditions or electrolyte abnormalities.