What are the potential interactions between sertraline (Zoloft) and nortriptyline?

Sertraline and Nortriptyline Interactions

When combining sertraline (Zoloft) and nortriptyline, monitor plasma nortriptyline levels closely as sertraline can increase nortriptyline concentrations by up to 40% at higher doses (100-150 mg/day), potentially causing toxicity.

Mechanism of Interaction

Sertraline inhibits cytochrome P450 2D6 (CYP2D6), the enzyme primarily responsible for nortriptyline metabolism. This interaction has several important clinical implications:

• At standard sertraline doses (50 mg/day), the median increase in nortriptyline levels is minimal (2%), but can range widely (-26% to 117%) 1
• At higher sertraline doses (100-150 mg/day), the median increase in nortriptyline levels is more significant (40%), with some patients experiencing increases up to 239% 1
• Approximately 14% of elderly patients experience clinically significant increases (≥50%) in nortriptyline levels even at lower sertraline doses 1

Clinical Implications and Monitoring

1. Plasma Level Monitoring

   • Check nortriptyline plasma levels before adding sertraline
   • Recheck levels 1-2 weeks after adding sertraline or changing doses
   • Target therapeutic nortriptyline level window: 50-150 ng/mL (190-570 nmol/L) 2

2. Signs of Tricyclic Toxicity to Monitor

   • Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision)
   • Cardiac effects (tachycardia, arrhythmias)
   • CNS effects (confusion, agitation, seizures)
   • Serotonin syndrome (see below)

3. Risk of Serotonin Syndrome

   • Both medications affect serotonergic neurotransmission
   • Monitor for mental status changes, neuromuscular hyperactivity, and autonomic instability 3
   • Symptoms can range from mild (tremor, diarrhea) to severe (hyperthermia, seizures, unconsciousness)

Dosing Considerations

• Start with the lowest effective doses of both medications

• When adding sertraline to established nortriptyline therapy:

  • Begin with 25 mg/day of sertraline
  • Increase sertraline gradually while monitoring nortriptyline levels
  • Adjust nortriptyline dose downward if levels exceed therapeutic range

• When adding nortriptyline to established sertraline therapy:

  • Begin with lower nortriptyline doses (10 mg at bedtime)
  • Titrate slowly based on plasma levels and clinical response
  • Consider that higher sertraline doses will require more conservative nortriptyline dosing

Special Populations

• Elderly patients require extra caution due to:

  • Altered drug metabolism
  • Increased sensitivity to side effects
  • Higher risk of drug interactions
  • More pronounced pharmacokinetic interaction between these medications 1

• Patients with hepatic impairment may experience more pronounced interactions due to reduced drug metabolism

Alternatives to Consider

If the interaction proves problematic, consider alternative strategies:

• Switch to an SSRI with less CYP2D6 inhibition (e.g., citalopram)
• Use a non-tricyclic antidepressant in combination with sertraline
• Consider monotherapy with a different class of antidepressant

Conclusion

While sertraline and nortriptyline can be used together, this combination requires careful monitoring of nortriptyline plasma levels and vigilance for signs of toxicity. The interaction is dose-dependent, with higher sertraline doses causing more significant increases in nortriptyline levels. Individual patient variability is substantial, making laboratory monitoring essential for safe co-administration.