Which SNRI is most appropriate to add for anxiety in a patient already taking atomoxetine (Strattera)?

Do Not Add an SNRI to Atomoxetine for Anxiety

Adding an SNRI to atomoxetine (Strattera) is not recommended due to significant safety concerns, including serotonin syndrome risk, cardiovascular complications from dual noradrenergic effects, and lack of evidence supporting this combination. 1

Why This Combination Is Problematic

Overlapping Mechanisms Create Risk

• Atomoxetine is itself a selective norepinephrine reuptake inhibitor that increases noradrenergic transmission in the prefrontal cortex 2
• Adding an SNRI creates dual norepinephrine reuptake inhibition plus serotonergic effects, substantially increasing the risk of serotonin syndrome when combining two serotonergic agents 3, 1
• Both drug classes cause sustained hypertension and increased pulse, requiring blood pressure and heart rate monitoring at every visit when used together 3, 1

Serotonin Syndrome Warning Signs

• Early symptoms include mental status changes (agitation, confusion), neuromuscular abnormalities (tremors, clonus, hyperreflexia, muscle rigidity), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis, vomiting) 3
• Advanced symptoms can progress to fever, seizures, arrhythmias, unconsciousness, and fatalities 3
• Patients must be educated specifically about these symptoms and instructed to seek immediate medical attention if they develop 1

Safer Alternative Approaches

SNRI Monotherapy (Preferred First-Line)

• If anxiety is the primary concern, consider switching from atomoxetine to SNRI monotherapy rather than combining them 4, 5
• SNRIs demonstrate significant efficacy for anxiety disorders compared to placebo (high strength of evidence based on 4 RCTs with 911 patients ages 6-18 years) 4
• SNRIs show comparable efficacy to SSRIs for anxiety (NNT = 4.94 for SNRIs vs 4.70 for SSRIs) 4

Specific SNRI Options If Switching

• Venlafaxine extended-release allows once-daily dosing with sufficiently long elimination half-life 3, 4
• Duloxetine permits single daily dosing (60 mg once daily as effective as 60 mg twice daily) and shows efficacy in generalized anxiety disorder 3, 4
• Desvenlafaxine has a 9-15 hour half-life allowing once-daily dosing 6
• Venlafaxine may have the least effect on CYP450 enzymes compared to other SNRIs, reducing drug interaction potential 3

Combination CBT Plus Medication

• Combination CBT plus SSRI/SNRI shows superior outcomes to medication alone for anxiety disorders in patients 6-18 years old 3, 1
• This approach is preferable to polypharmacy with two noradrenergic agents 1

Augmentation for Treatment-Resistant Cases

• Atypical antipsychotics (e.g., risperidone) have stronger evidence for treatment-resistant anxiety than adding a second antidepressant 1
• This is a safer augmentation strategy than combining atomoxetine with an SNRI 1

Critical Monitoring If Combination Is Unavoidable

Cardiovascular Surveillance

• Monitor blood pressure and pulse at every visit, as both atomoxetine and SNRIs cause sustained hypertension and tachycardia 3, 1, 2
• SNRIs (particularly venlafaxine) demonstrate dose-dependent cardiovascular effects, principally hypertension 7

Starting and Titrating Safely

• Start with the lowest possible doses of both agents 1
• Increase doses slowly with monitoring for serotonin syndrome symptoms, especially in the first 24-48 hours after dosage changes 3
• Document clear rationale for choosing this high-risk combination over safer alternatives 1

Discontinuation Precautions

• Never discontinue either medication abruptly due to severe discontinuation syndrome risk, particularly with SNRIs 1, 4
• Venlafaxine is particularly associated with discontinuation symptoms and has been associated with overdose fatalities 3, 4
• Both venlafaxine and desvenlafaxine are associated with overdose fatalities 4

Common Pitfalls to Avoid

• Do not assume atomoxetine lacks serotonergic effects - while primarily noradrenergic, combining it with SNRIs still creates serotonin syndrome risk 3, 1
• Do not overlook cardiovascular monitoring - dual noradrenergic effects substantially increase hypertension and tachycardia risk 3, 1
• Do not use this combination as first-line - SNRI monotherapy or CBT plus single medication are evidence-based alternatives with better safety profiles 1, 4