What is the best selective serotonin reuptake inhibitor (SSRI) to add to atomoxetine (Stratterra)?

SSRI Selection with Atomoxetine

When combining an SSRI with atomoxetine, fluoxetine or sertraline are the preferred choices due to their well-established safety profiles, favorable pharmacokinetics, and lower risk of severe drug interactions, though all SSRIs carry risk of serotonin syndrome when combined with atomoxetine and require careful monitoring. 1, 2

Critical Safety Consideration: Serotonin Syndrome Risk

Atomoxetine can cause serotonin syndrome even when used alone in overdose, and this risk increases substantially when combined with any SSRI. 2

• Atomoxetine, while primarily a norepinephrine reuptake inhibitor, has demonstrated serotonergic effects sufficient to cause serotonin syndrome 2, 3
• Serotonin syndrome can develop within 24-48 hours of combining serotonergic medications 1
• Clinical presentation includes mental status changes (confusion, agitation, anxiety), neuromuscular hyperactivity (tremor, myoclonus, hyperreflexia), and autonomic hyperactivity (diaphoresis, tachycardia, fever) 1, 2
• Advanced symptoms can progress to seizures, arrhythmias, and unconsciousness, which can be fatal 1

Preferred SSRI Options

First Choice: Fluoxetine or Sertraline

Fluoxetine and sertraline represent the most evidence-based SSRI choices for combination with atomoxetine based on their extensive safety data and clinical experience. 4

• Both fluoxetine and sertraline had sufficient data in systematic reviews to support their use as part of the SSRI class recommendation 4
• Fluoxetine has a long half-life (1-3 days acute, 4-6 days chronic) with active metabolite norfluoxetine (4-16 days), allowing for steady plasma levels and reduced risk of withdrawal 5
• Sertraline demonstrates linear, dose-proportional pharmacokinetics with a terminal half-life of approximately 26 hours, achieving steady state after one week 6
• Both medications are potent and selective serotonin reuptake inhibitors with minimal effects on other neurotransmitter systems 6, 5

Alternative Options: Escitalopram, Citalopram

• Escitalopram is highly selective for serotonin reuptake with minimal effects on norepinephrine and dopamine, achieving steady state within approximately one week 7
• These agents may be considered if fluoxetine or sertraline are not tolerated 4

Avoid: Paroxetine

Paroxetine should be avoided when combining with atomoxetine due to significant CYP2D6 inhibition. 3

• Paroxetine is a potent CYP2D6 inhibitor that significantly alters atomoxetine pharmacokinetics 3
• This interaction increases atomoxetine exposure and slows elimination, mimicking poor metabolizer status and substantially increasing adverse effect risk 3

Initiation and Monitoring Protocol

Starting the Combination

When combination therapy is necessary, start the SSRI at a low dose and increase slowly with intensive monitoring. 1

• Begin with subtherapeutic "test" doses to assess tolerance 1
• If atomoxetine is already established, start SSRI at 50% of usual starting dose
• Increase doses gradually over weeks, not days 1

Monitoring Requirements

Monitor for serotonin syndrome symptoms at every visit, particularly in the first 24-48 hours after any dose change. 1

• Assess mental status (confusion, agitation, anxiety)
• Check for neuromuscular signs (tremor, myoclonus, hyperreflexia, rigidity)
• Monitor autonomic symptoms (diaphoresis, tachycardia, blood pressure changes, fever) 1, 2
• Evaluate for other adverse effects including appetite/weight changes, sleep disturbances, and sexual dysfunction 4, 1

Absolute Contraindications

• Concurrent or recent (within 14 days) MAOI use 1
• History of severe adverse reactions to either medication 1
• Uncontrolled seizure disorders 1
• Previous serotonin syndrome with either agent 1

Emergency Management

If serotonin syndrome is suspected, immediately discontinue both atomoxetine and the SSRI, provide supportive care, and arrange continuous cardiac monitoring. 1

• This is a medical emergency requiring immediate intervention 1
• Supportive measures include cooling for hyperthermia, benzodiazepines for agitation, and fluid resuscitation 1

Clinical Pearls

• The combination of atomoxetine with SSRIs is not FDA-approved but may be clinically necessary for comorbid ADHD and anxiety/depression 4, 3
• SSRIs as a class improve anxiety symptoms with moderate to high strength of evidence in pediatric populations 4
• Atomoxetine is particularly useful for patients with ADHD who have comorbid anxiety or tics, or who are at risk for substance abuse 3
• Most SSRI adverse effects emerge within the first few weeks and are generally mild to moderate 4
• Clinical improvement with SSRIs typically occurs by week 6, with maximal benefit by week 12 or later 4