Combining Lexapro (Escitalopram) with Cymbalta (Duloxetine)
You should not routinely combine Lexapro with Cymbalta, as there is limited evidence supporting the use of two antidepressants from different classes as an initial or endpoint treatment strategy, and this combination significantly increases the risk of serotonin syndrome. 1
Critical Safety Concerns
Serotonin Syndrome Risk
- Combining escitalopram (an SSRI) with duloxetine (an SNRI) creates additive serotonergic effects that substantially increase the risk of serotonin syndrome, a potentially life-threatening condition characterized by mental status changes, neuromuscular hyperactivity (tremor, rigidity, myoclonus), and autonomic instability (hyperthermia, tachycardia, labile blood pressure). 1, 2
- The American Academy of Child and Adolescent Psychiatry explicitly advises avoiding combining multiple serotonergic agents due to this risk. 1, 2
Limited Evidence Base
- There is limited evidence in both children and adults for using two antidepressants as an initial treatment approach or as a specific endpoint for treatment. 1
- The guideline states that "evidence supporting medication combinations based on matching medication mechanism of action with a hypothesized underlying central nervous system abnormality is rudimentary at best." 1
Evidence-Based Alternative Strategies
If Lexapro Monotherapy Has Failed
- Switch to duloxetine rather than combining them. Switching to an SNRI like duloxetine demonstrates statistically significantly better response and remission rates than continuing SSRI therapy in treatment-resistant cases. 1, 2
- Allow 6-8 weeks at an adequate dose (escitalopram 20 mg daily) before declaring treatment failure. 1
If Augmentation Is Necessary
- Add bupropion SR (150-400 mg daily) to escitalopram instead of duloxetine. This combination achieves remission rates of approximately 50% with significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone augmentation (20.6%). 1, 2
- Add cognitive-behavioral therapy (CBT) to escitalopram, which has demonstrated superior efficacy compared to medication alone for anxiety disorders. 1, 2
Acceptable Combination Scenarios
- The only scenario where combining medications from similar classes might be temporarily acceptable is during cross-titration when transitioning from one medication to another—not as a long-term treatment strategy. 1
Clinical Decision Algorithm
Verify adequate trial of current medication: Ensure escitalopram has been used at 20 mg daily for at least 8-12 weeks before considering any change. 1, 2
Assess adherence and comorbidities: Rule out medication non-adherence, substance use, thyroid dysfunction, or bipolar disorder before adding medications. 1, 2
Choose switching over combining:
If augmentation is preferred over switching:
Common Pitfalls to Avoid
- Do not combine escitalopram with duloxetine based on theories about "covering neurotransmitter bases"—this approach lacks empirical support and increases risk. 1
- Do not add duloxetine before ensuring adequate dose and duration of escitalopram monotherapy (minimum 8 weeks at 20 mg daily). 1, 2
- Do not exceed escitalopram 20 mg daily when combining with other medications, as higher doses increase QT prolongation risk. 2
Monitoring Requirements If Combination Is Unavoidable
If clinical circumstances absolutely require this combination despite the risks:
- Monitor closely for serotonin syndrome symptoms within the first 24-48 hours: confusion, agitation, tremor, muscle rigidity, fever, tachycardia. 1, 2
- Assess for suicidal ideation during the first 1-2 months, as risk is greatest during treatment changes. 1, 2
- Obtain baseline and follow-up ECG monitoring for QT prolongation, especially with escitalopram doses at 20 mg. 2
- Monitor blood pressure regularly, as duloxetine can cause sustained hypertension. 1