Does atomoxetine (a norepinephrine reuptake inhibitor) have an impact on anxiety and depression in patients with Attention Deficit Hyperactivity Disorder (ADHD)?

Atomoxetine's Impact on Anxiety and Depression in ADHD

Atomoxetine effectively treats ADHD symptoms without worsening anxiety or depression, and may actually improve these comorbid mood symptoms, though it should not be relied upon as monotherapy for treating depression or anxiety disorders. 1, 2, 3

Evidence for Safety in Comorbid Anxiety and Depression

Atomoxetine does not exacerbate anxiety or depressive symptoms in patients with ADHD and these comorbidities, based on controlled trials:

• In a 12-week trial of 176 pediatric patients (ages 8-17) with ADHD and comorbid anxiety disorders (separation anxiety, generalized anxiety, or social phobia), atomoxetine at 1.2 mg/kg/day did not worsen anxiety as measured by the Pediatric Anxiety Rating Scale 3

• In a 16-week trial of 442 adults with ADHD and social anxiety disorder, atomoxetine (mean dose 83 mg/day) did not worsen anxiety symptoms on the Liebowitz Social Anxiety Scale 3

• A comprehensive review of 50 clinical studies (37 in children, 13 in adults) found that comorbid anxiety, depression, or substance use disorder did not adversely impact atomoxetine's efficacy for ADHD symptoms, and atomoxetine did not exacerbate any comorbid conditions 4

Potential Benefits for Mood Symptoms

Atomoxetine may provide modest improvement in depressive and anxiety symptoms, though this should be considered a secondary benefit rather than the primary indication:

• In Egyptian children with ADHD and comorbid mood disorders, atomoxetine monotherapy showed improvement in depressive symptoms after 1 month of treatment, though ADHD symptom improvement occurred more slowly than in children without mood comorbidity 5

• When combined with SSRIs/SNRIs in adults with ADHD and partially responsive generalized anxiety (HAM-A >7), adjunctive atomoxetine produced significant resolution of anxiety symptoms at 12 weeks (P<.001), with 93% study completion 6

• In pediatric patients receiving atomoxetine with or without fluoxetine, both groups showed marked reductions in ADHD, depressive, and anxiety symptoms (p<.001), though the absence of a placebo-only arm limits conclusions about atomoxetine's specific contribution to mood improvement 7

Critical Treatment Algorithm Considerations

Position atomoxetine as second-line to stimulants for ADHD, but consider it first-line in specific scenarios:

• Stimulants remain first-line with 70-80% response rates and larger effect sizes than atomoxetine 1, 2
• Atomoxetine is particularly appropriate for patients with comorbid anxiety disorders, substance use history, or tic disorders 1, 8
• The American Academy of Child and Adolescent Psychiatry warns against assuming any single antidepressant (including atomoxetine) will effectively treat both ADHD and depression 1

If ADHD improves but mood symptoms persist on atomoxetine monotherapy, add an SSRI rather than switching medications 1

Important Monitoring Requirements

The FDA Black Box Warning mandates close monitoring for suicidal ideation, especially during the first few months of treatment or with dose changes, which is particularly critical in patients with comorbid depression 2, 3

Additional monitoring parameters include:

• Blood pressure and pulse at baseline and regularly during treatment 1, 2
• When combining atomoxetine with SSRIs, be aware that SSRIs can elevate atomoxetine levels through CYP2D6 inhibition, requiring dose adjustment 1
• Common side effects include somnolence, fatigue, decreased appetite, nausea, and gastrointestinal symptoms 2, 3

Dosing Considerations

Target dose is 1.2 mg/kg/day (maximum 1.4 mg/kg/day or 100 mg/day, whichever is lower) for optimal efficacy:

• Start at 0.5 mg/kg/day for children/adolescents up to 70 kg, or 40 mg/day for those over 70 kg and adults 2
• Titrate every 7-14 days to target dose 2
• Full therapeutic effects require 6-12 weeks, unlike stimulants which work within days 1, 2
• Can be administered as single daily dose or split into two divided doses to reduce side effects 2

Common Pitfalls to Avoid

• Do not prescribe atomoxetine first-line when fatigue is a chief complaint, as somnolence and fatigue are the most common adverse effects, which would directly worsen this symptom 1
• Do not rely on atomoxetine monotherapy to treat moderate-to-severe depression—address the mood disorder with appropriate antidepressant therapy 1
• Do not expect rapid response—the 6-12 week onset requires patient counseling about realistic expectations to prevent premature discontinuation 2