What antidepressant is best to start with Strattera (atomoxetine)?

Antidepressant Selection with Strattera (Atomoxetine)

Direct Recommendation

When combining an antidepressant with Strattera (atomoxetine), avoid fluoxetine and paroxetine as first-line choices due to significant drug-drug interactions; instead, select sertraline, citalopram, or escitalopram as safer SSRI options, or consider bupropion if sexual side effects are a concern. 1

Critical Drug Interaction Considerations

Strong CYP2D6 Inhibitors Require Dose Adjustment

The FDA label for atomoxetine explicitly warns that strong CYP2D6 inhibitors (paroxetine, fluoxetine, and quinidine) significantly increase atomoxetine plasma concentrations 1:

• In extensive metabolizers, these inhibitors increase atomoxetine steady-state plasma concentrations 6- to 8-fold for AUC and 3- to 4-fold for peak concentrations 1
• When combining atomoxetine with paroxetine or fluoxetine, atomoxetine must be initiated at 0.5 mg/kg/day (rather than the standard dose) and only increased to 1.2 mg/kg/day if symptoms fail to improve after 4 weeks 1
• For adults, atomoxetine should be initiated at 40 mg/day (not 80 mg) when combined with these inhibitors 1

Serotonin Syndrome Risk

Combining multiple serotonergic agents increases the risk of serotonin syndrome, which can be life-threatening 2:

• Symptoms include mental status changes, neuromuscular hyperactivity (tremors, clonus), and autonomic instability (hypertension, tachycardia) 2
• While atomoxetine is primarily a norepinephrine reuptake inhibitor, caution is warranted when combining with SSRIs 2
• MAOIs are absolutely contraindicated with atomoxetine 1

Preferred Antidepressant Options

First-Line Choices

Sertraline, citalopram, or escitalopram are preferred SSRIs when combining with atomoxetine 2:

• Citalopram/escitalopram have the least effect on CYP450 isoenzymes compared with other SSRIs and thus have lower propensity for drug interactions 2
• These agents are effective for depression with numbers needed to treat of 7-8 2
• Starting doses: citalopram 10 mg daily, escitalopram 10 mg daily, sertraline 25 mg daily 2

Alternative: Bupropion

Bupropion is an excellent alternative that avoids CYP2D6 interactions entirely 2:

• Bupropion is associated with lower rates of sexual adverse events than fluoxetine or sertraline 2
• Does not significantly interact with atomoxetine's metabolism 2
• Starting dose: 100-150 mg daily (SR formulation) or 150 mg daily (XL formulation) 2
• Maximum dose: 450 mg per day 2

Monitoring Requirements

Initial Monitoring (First 1-2 Weeks)

Close monitoring is essential when initiating combination therapy 2, 1:

• Monitor for suicidal ideation, particularly in children and adolescents—atomoxetine carries a black-box warning for increased suicidal thoughts 1, 3
• Watch for behavioral activation: agitation, irritability, anxiety, restlessness, mania 1
• Monitor blood pressure and heart rate regularly, as both atomoxetine and some antidepressants can affect cardiovascular parameters 1

Ongoing Assessment

• Reassess therapeutic response at 6-8 weeks; modify treatment if inadequate response 2
• Continue monitoring for adverse effects throughout treatment 2
• Telephone contact may be as effective as face-to-face visits for monitoring adverse events 2

Antidepressants to Avoid

Do Not Use as First-Line

Paroxetine and fluoxetine should be avoided unless atomoxetine dosing is appropriately reduced 1:

• Paroxetine has higher rates of sexual dysfunction than other SSRIs 2
• Paroxetine has been associated with increased risk of suicidal thinking compared to other SSRIs 2
• Both require complex dose adjustments of atomoxetine that increase treatment complexity 1
• Paroxetine is associated with discontinuation syndrome 2
• In older adults, paroxetine and fluoxetine should generally be avoided due to higher rates of adverse effects 2

Absolute Contraindications

MAOIs are absolutely contraindicated with atomoxetine 1:

• Risk of serious, potentially fatal reactions including hyperthermia, rigidity, and autonomic instability 1
• Must wait 14 days after discontinuing an MAOI before starting atomoxetine 1

Special Populations

Adolescents

• Fluoxetine is the only FDA-approved antidepressant for children and adolescents with depression 2
• Escitalopram is approved for adolescents aged 12 years and older 2
• However, given the CYP2D6 interaction, sertraline, citalopram, or escitalopram are preferable when combined with atomoxetine 2

Older Adults

Preferred agents include citalopram, escitalopram, sertraline, mirtazapine, venlafaxine, and bupropion 2:

• Use a "start low, go slow" approach 2
• Avoid paroxetine and fluoxetine due to higher adverse effect rates 2

Clinical Pearls

• All second-generation antidepressants are equally effective for treatment-naive patients; selection should be based on adverse effect profiles, drug interactions, and cost 2
• Atomoxetine can be discontinued without tapering, but SSRIs should be slowly tapered to avoid withdrawal effects 2
• Treatment duration for first episode of major depression should be at least 4 months; longer for recurrent depression 2
• Atomoxetine has negligible abuse potential and is not a controlled substance, making it particularly useful for patients at risk of substance abuse 3, 4