Is it safe to use Cymbalta (duloxetine) and Strattera (atomoxetine) together in a patient with depression or anxiety and ADHD?

Combining Cymbalta (Duloxetine) and Strattera (Atomoxetine): Safety and Efficacy

Yes, combining duloxetine and atomoxetine is generally safe and can be effective for patients with comorbid ADHD and depression/anxiety, but requires careful monitoring for serotonin syndrome, cardiovascular effects (particularly blood pressure and heart rate elevations), and suicidal ideation, especially during the first 1-2 weeks of treatment. 1, 2

Evidence Supporting Combination Use

Direct Clinical Evidence

• A randomized controlled trial demonstrated that atomoxetine combined with fluoxetine (another SSRI/SNRI like duloxetine) was well tolerated in children and adolescents with ADHD and comorbid depression/anxiety symptoms, with marked reductions in ADHD, depressive, and anxiety symptoms (p < .001 for all symptom clusters). 2
• The combination group showed similar completion rates and discontinuation rates for adverse events compared to atomoxetine monotherapy, indicating acceptable tolerability. 2
• Atomoxetine is particularly useful for patients with comorbid anxiety disorders, as it does not exacerbate anxiety symptoms and may improve them. 1, 3

Mechanism and Rationale

• Atomoxetine selectively inhibits norepinephrine reuptake in the prefrontal cortex, while duloxetine inhibits both serotonin and norepinephrine reuptake, providing complementary mechanisms for treating both ADHD and mood/anxiety symptoms. 3, 1
• This combination addresses different neurotransmitter systems without the abuse potential of stimulants, making it appropriate for patients with substance use concerns. 1, 3

Critical Safety Monitoring Requirements

Serotonin Syndrome Risk

• Exercise caution when combining two serotonergic drugs (duloxetine is an SNRI with serotonergic activity). Start at low doses, increase slowly, and monitor intensively for symptoms in the first 24-48 hours after initiation or dose changes. 1
• Serotonin syndrome symptoms include mental status changes (confusion, agitation, anxiety), neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis). 1
• While the risk is lower than with MAOIs, vigilance is essential when combining any two non-MAOI serotonergic medications. 1

Cardiovascular Monitoring

• Monitor blood pressure and heart rate at baseline and regularly during treatment, as both medications can increase these parameters. 1, 2
• The combination group in clinical trials showed greater increases in blood pressure and pulse than atomoxetine monotherapy alone. 2
• Duloxetine has been associated with sustained clinical hypertension and increased blood pressure/pulse. 1
• Atomoxetine causes statistically (but not clinically) significant increases in heart rate and blood pressure. 3

Suicidal Ideation Monitoring

• Monitor closely for treatment-emergent suicidality, especially in patients under age 24, during the first 1-2 weeks after initiation or dose changes. 1
• Both duloxetine (as an SNRI) and atomoxetine carry FDA black box warnings for increased suicidal thinking and behavior in young patients. 1, 3
• Atomoxetine has been associated with significantly higher incidence of suicidal ideation than placebo in meta-analyses. 3

Hepatic Function Monitoring

• Discontinue duloxetine immediately if jaundice or clinically significant liver dysfunction develops, as duloxetine has been associated with hepatic failure presenting as abdominal pain, hepatomegaly, and elevated transaminases. 1
• Atomoxetine has rarely been associated with serious liver injury in postmarketing data. 3
• Monitor for signs of liver dysfunction, particularly abdominal pain or jaundice. 1

Practical Prescribing Strategy

Starting the Combination

• Begin with atomoxetine monotherapy first if the patient is treatment-naive, as it addresses ADHD symptoms and may improve comorbid anxiety/depression without adding serotonergic risk. 2
• If inadequate response to atomoxetine alone after 6-8 weeks at therapeutic doses, add duloxetine at a low starting dose (30 mg daily). 1, 2
• Alternatively, if the patient is already on duloxetine for depression/anxiety, add atomoxetine cautiously with close monitoring. 2

Dose Titration

• Increase duloxetine slowly (at 1-2 week intervals for shorter half-life SNRIs) to minimize adverse effects and allow monitoring for serotonin syndrome. 1
• Atomoxetine can be dosed once or twice daily; once-daily dosing in the morning provides symptom control into the evening. 3
• Maximum duloxetine dose is typically 60-120 mg daily for depression/anxiety. 1

Drug Interaction Considerations

• Duloxetine may interact with drugs metabolized by CYP1A2 and CYP2D6, which could affect atomoxetine metabolism since atomoxetine is extensively metabolized by CYP2D6. 1, 3
• Patients who are CYP2D6 poor metabolizers (or those taking CYP2D6 inhibitors) have greater atomoxetine exposure and slower elimination, potentially increasing side effects when combined with duloxetine. 3
• This interaction is less concerning than with strong CYP2D6 inhibitors like paroxetine, but warrants awareness. 3

Common Pitfalls to Avoid

• Don't abruptly discontinue either medication, as both duloxetine and atomoxetine can cause discontinuation syndromes with symptoms including dizziness, nausea, fatigue, and sensory disturbances. 1
• Don't combine with MAOIs or other strongly serotonergic medications (tramadol, triptans, St. John's wort) due to dramatically increased serotonin syndrome risk. 1
• Don't ignore initial adverse effects like nausea, dry mouth, or increased blood pressure—these may indicate need for dose adjustment rather than discontinuation. 1, 2
• Don't prescribe this combination without establishing a monitoring plan for cardiovascular parameters, suicidality, and hepatic function. 1, 2

When This Combination is Particularly Appropriate

• Patients with ADHD and comorbid depression or anxiety who have not responded adequately to monotherapy with either agent. 2, 4
• Patients with substance use concerns where stimulants are contraindicated, as atomoxetine has negligible abuse potential. 1, 3
• Patients with ADHD and comorbid tic disorders or Tourette's syndrome, where atomoxetine does not worsen tics. 1
• Patients requiring extended symptom coverage throughout the day and evening. 3

Alternative Strategies if Combination Fails

• If inadequate response after 8 weeks of combination therapy at therapeutic doses, consider switching to a stimulant medication (methylphenidate or amphetamine) combined with duloxetine, as stimulants have larger effect sizes for ADHD than atomoxetine. 1, 3
• Extended-release guanfacine or clonidine can be used as adjunctive therapy with either medication if cardiovascular effects are manageable. 1
• Combination therapy with stimulants and atomoxetine has limited evidence but may benefit some treatment-resistant patients. 4, 5