What is the interaction between Amitriptyline (a tricyclic antidepressant) and Linezolid (an antibiotic), specifically regarding their potential pharmacodynamic and pharmacokinetic effects?

From the Guidelines

Amitriptyline and linezolid should not be used together due to the risk of serotonin syndrome, a potentially life-threatening condition. This interaction is supported by the most recent and highest quality study, which highlights the risk of serious CNS reactions, such as serotonin syndrome, when linezolid is administered concurrently with serotonergic agents, including tricyclic antidepressants like amitriptyline 1. The study emphasizes the importance of strict clinical monitoring for potential toxicity, particularly when using linezolid for extended periods.

Key Considerations

• Linezolid is a monoamine oxidase inhibitor (MAOI), which can increase the risk of serotonin syndrome when combined with serotonergic agents like amitriptyline.
• Amitriptyline, a tricyclic antidepressant, increases serotonin levels, which can lead to dangerous serotonin accumulation in the brain when combined with linezolid.
• The risk of serotonin syndrome is potentially life-threatening, and patients should be closely monitored for signs of this condition, including agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and hyperthermia.

Recommendations

• If a patient requires linezolid, amitriptyline should be discontinued at least 2 weeks before starting linezolid therapy.
• In urgent situations where linezolid must be given, amitriptyline should be stopped immediately, and the patient should be closely monitored for signs of serotonin syndrome for at least 2 weeks.
• Alternative antibiotics to linezolid or non-serotonergic antidepressants may be considered if clinically appropriate, as supported by other studies 1.

From the FDA Drug Label

Monoamine Oxidase Inhibition Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents Serotonergic Agents: Co-administration of linezolid and serotonergic agents was not associated with serotonin syndrome in Phase 1,2 or 3 studies Spontaneous reports of serotonin syndrome associated with co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Patients who are treated with ZYVOX and concomitant serotonergic agents should be closely observed as described in the PRECAUTIONS, General Section They should inform their physician if taking serotonin re-uptake inhibitors or other antidepressants.

The interaction between Amitriptyline (a tricyclic antidepressant) and Linezolid (an antibiotic) is a potential pharmacodynamic interaction, as Linezolid is a reversible, nonselective inhibitor of monoamine oxidase and may interact with serotonergic agents, including antidepressants like Amitriptyline. Serotonin syndrome is a potential risk, although it was not associated with co-administration in Phase 1,2, or 3 studies. However, spontaneous reports have been made, and patients taking both medications should be closely observed 2.

From the Research

Pharmacodynamic Effects

• The combination of Amitriptyline (a tricyclic antidepressant) and Linezolid (an antibiotic) may increase the risk of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonin release 3, 4, 5, 6, 7.
• Serotonin syndrome can cause symptoms such as agitation, confusion, tremors, tachycardia, hyperthermia, mental status changes, autonomic hyperactivity, and neuromuscular abnormalities 3, 4, 5, 6, 7.
• The risk of serotonin syndrome is higher when Linezolid is used in combination with other serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) 4, 6, 7.

Pharmacokinetic Effects

• Linezolid is a mild monoamine oxidase inhibitor, which can increase the levels of serotonin and other biogenic amines in the body 3, 4, 7.
• The concomitant use of Linezolid and Amitriptyline may lead to increased levels of serotonin, increasing the risk of serotonin syndrome 4, 6, 7.
• The incidence of serotonin syndrome with the combined use of Linezolid and SSRIs or SNRIs is low, but caution should still be exercised when using these medications together 6.

Clinical Implications

• Clinicians should obtain complete drug histories to identify patients at risk of serotonin syndrome when using Linezolid and Amitriptyline together 7.
• Patients should be strictly monitored for symptoms of serotonin syndrome, such as agitation, confusion, and tremors, when using these medications together 3, 4, 5, 6, 7.
• Alternative antibiotic options should be considered for patients taking Amitriptyline or other serotonergic agents, and Linezolid should be reserved as a last resort if possible 4.