amitriptyline and fluoxetine

Pharmacokinetic: fluoxetine is a potent inhibitor of CYP2D6, the enzyme that metabolises amitriptyline. This increases amitriptyline plasma concentrations. Pharmacodynamic: both drugs have serotonergic activity. Amitriptyline inhibits serotonin reuptake, and fluoxetine is an SSRI. Their combined action can cause excessive serotonergic stimulation, leading to serotonin syndrome. Additive anticholinergic and cardiac effects also contribute to toxicity.

Increased risk of amitriptyline toxicity, including anticholinergic effects such as dry mouth, constipation, urinary retention and blurred vision. CNS effects may include sedation, confusion and delirium. Cardiovascular effects include QT prolongation, arrhythmias and orthostatic hypotension. There is also a risk of serotonin syndrome, presenting with agitation, hyperthermia, myoclonus, diaphoresis and diarrhoea. Symptoms can occur within days of starting the combination.

Avoid the combination if possible. If co-prescription is deemed necessary, use extreme caution. Consider an alternative antidepressant that does not inhibit CYP2D6. If used, reduce the amitriptyline dose and monitor for signs of toxicity and serotonin syndrome. Monitor ECG, blood pressure and heart rate. Advise the patient to report any symptoms such as palpitations, syncope or serotonin syndrome features. Monitoring should continue for several weeks after stopping fluoxetine due to its long half-life.

Well documented in pharmacokinetic studies and case reports. Fluoxetine is known to increase tricyclic antidepressant levels significantly. The active metabolite norfluoxetine has a long half-life, prolonging the interaction after fluoxetine is stopped. Evidence is strong, but clinical guidance varies by region and formulary, and cautious use is occasionally accepted under specialist supervision.