Is it safe to combine Doxepin (tricyclic antidepressant) and Lexapro (escitalopram) for treatment?

Combining Doxepin and Lexapro (Escitalopram): Safety Considerations

The combination of doxepin (a tricyclic antidepressant) and Lexapro (escitalopram, an SSRI) should be avoided due to the significant risk of serotonin syndrome, which can be potentially life-threatening.

Mechanism of Concern

The primary safety concern with this combination stems from their overlapping serotonergic effects:

• Escitalopram (Lexapro) is a selective serotonin reuptake inhibitor (SSRI) that increases serotonin levels by blocking its reuptake 1
• Doxepin, as a tricyclic antidepressant (TCA), has multiple mechanisms including serotonin reuptake inhibition
• When combined, these medications can cause excessive serotonin accumulation, potentially leading to serotonin syndrome

Risk of Serotonin Syndrome

The FDA drug label for escitalopram explicitly warns about this risk:

• "The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Escitalopram, alone but particularly with concomitant use of other serotonergic drugs (including tricyclic antidepressants)" 1
• Symptoms of serotonin syndrome include:
  • Mental status changes (agitation, hallucinations, delirium, coma)
  • Autonomic instability (tachycardia, labile blood pressure, hyperthermia)
  • Neuromuscular symptoms (tremor, rigidity, myoclonus)
  • Gastrointestinal symptoms (nausea, vomiting, diarrhea)

Cardiac Risks

Beyond serotonin syndrome, this combination presents additional cardiac concerns:

• Both medications can prolong the QT interval, with a potentially additive effect 2
• The European Heart Journal notes that tricyclic antidepressants like doxepin "seem to prolong the QT interval" and have been associated with cardiac arrest 2
• This combination could increase the risk of serious arrhythmias, particularly in patients with pre-existing cardiac conditions

Alternative Approaches

If treatment for both depression and insomnia is needed:

1. Monotherapy approach: Consider using escitalopram alone, as it may address both depression and anxiety symptoms 2

2. For sleep issues:

   • Low-dose doxepin (3-6mg) used alone for insomnia carries less risk than combining with an SSRI 3
   • Non-pharmacological interventions for insomnia should be considered first

3. If combination therapy is absolutely necessary:

   • Close monitoring for signs of serotonin syndrome is essential
   • Consider consulting with a psychiatrist for specialized management
   • Start with lower doses of both medications and titrate slowly

Special Considerations

• Elderly patients are at higher risk for adverse effects from both medications and their combination 2
• Patients with cardiac conditions should avoid this combination due to the increased risk of arrhythmias 2
• Discontinuation of either medication should be done gradually to prevent withdrawal symptoms 1

Conclusion

The combination of doxepin and escitalopram presents significant risks, particularly for serotonin syndrome and cardiac complications. Alternative treatment strategies should be strongly considered to optimize both safety and efficacy in managing depression and/or insomnia.