Can paroxetine and Elavil (amitriptyline) be taken together?

Can Paroxetine and Elavil (Amitriptyline) Be Taken Together?

Yes, paroxetine and amitriptyline can be taken together, but this combination requires careful dose adjustment, close monitoring, and awareness of significant drug interactions—specifically, paroxetine will substantially increase amitriptyline blood levels, necessitating lower starting doses than typical monotherapy.

Critical Drug Interaction: CYP2D6 Inhibition

• Paroxetine is a potent inhibitor of the CYP2D6 enzyme, which metabolizes amitriptyline and its active metabolite nortriptyline 1
• When paroxetine is added to amitriptyline therapy, nortriptyline levels increase dramatically (approximately doubling from 88 to 176 ng/ml), while amitriptyline itself increases more modestly 1
• This interaction occurs because paroxetine blocks the second step of tricyclic metabolism—the hydroxylation of nortriptyline—causing metabolite accumulation 1
• Blood level monitoring is essential when combining these medications to prevent toxicity 1

Primary Safety Concerns

Serotonin Syndrome Risk

• The combination increases risk of serotonin syndrome due to overlapping serotonergic effects, with symptoms developing within 24-48 hours including mental status changes, neuromuscular hyperactivity (myoclonus, hyperreflexia), and autonomic instability (diaphoresis, shivering, hypertension) 2
• Advanced symptoms can progress to fever, seizures, arrhythmias, and unconsciousness 2
• Monitor especially closely during the first 24-48 hours after initiating combination therapy or after any dose changes 2

Cardiac Considerations

• Avoid this combination in patients with cardiac conduction abnormalities or QT prolongation, as amitriptyline prolongs QT interval and delays AV-node conduction 2
• Tricyclic antidepressants are associated with increased cardiac arrest risk (OR = 1.69), particularly in older patients 2
• Obtain a baseline ECG before starting the combination, especially in patients over 60 years or with cardiac risk factors 2

Dosing Strategy

• Start with lower doses than used in monotherapy when combining these agents 2
• If adding paroxetine to existing amitriptyline therapy, consider reducing the amitriptyline dose by 25-50% initially to account for the anticipated increase in blood levels 1
• Increase doses slowly while monitoring for adverse effects 2
• The therapeutic range for combined amitriptyline plus nortriptyline is approximately 80-200 ng/mL 2

Monitoring Requirements

• Consider therapeutic drug monitoring of amitriptyline and nortriptyline plasma levels, particularly if side effects emerge or therapeutic response is inadequate 2
• Schedule more frequent follow-up visits during the initial combination period and after any dose adjustments 2
• Watch for anticholinergic effects (dry mouth, constipation, urinary retention, confusion), which are characteristic of tricyclics and may be intensified by elevated drug levels 1

Absolute Contraindications

• This combination is contraindicated in patients taking MAOIs or within 14 days of stopping an MAOI 2
• Avoid in patients with cardiac conduction abnormalities or QT prolongation 2

Clinical Tolerability Data

• Despite significant increases in tricyclic blood levels when paroxetine is added, the combination is generally well tolerated with appropriate monitoring—in one study, only one case of incipient delirium occurred despite high TCA level rises 1
• Paroxetine causes fewer anticholinergic side effects than amitriptyline (anticholinergic events were six times more frequent with amitriptyline alone) 3
• Overall adverse event rates favor paroxetine over amitriptyline in monotherapy (44% vs 62%) 4

Common Pitfalls to Avoid

• Do not use standard monotherapy doses when combining—this will lead to toxic tricyclic levels 1
• Do not assume the combination is safe without baseline cardiac assessment in at-risk patients 2
• Do not discontinue paroxetine abruptly, as it is strongly associated with discontinuation syndrome 5
• Do not fail to educate patients about early signs of serotonin syndrome before discharge 2