What non-stimulant medications can be used to treat a patient with comorbid Attention Deficit Hyperactivity Disorder (ADHD) and depression?

Non-Stimulant Medications for Comorbid ADHD and Depression

Atomoxetine is the first-line non-stimulant medication for patients with comorbid ADHD and depression, with bupropion serving as a valuable second-line option particularly when depressive symptoms are prominent. 1, 2

Primary Recommendation: Atomoxetine

Start with atomoxetine 40 mg/day, then titrate to a target dose of 80-100 mg/day (maximum 100 mg/day or 1.4 mg/kg/day, whichever is lower). 1 This is the only FDA-approved non-stimulant for adult ADHD and has been extensively studied with demonstrated efficacy in treating ADHD symptoms while having a lower risk of exacerbating anxiety compared to stimulants. 1, 3

Key Advantages of Atomoxetine:

• Provides continuous 24-hour symptom coverage without peaks and valleys 1
• Non-controlled substance status eliminates abuse potential, making it particularly indicated for patients with comorbid substance use disorders 1
• Lower risk of worsening anxiety or mood symptoms compared to stimulants 1
• May improve comorbid anxiety symptoms that often accompany depression 4

Critical Safety Monitoring for Atomoxetine:

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during the first few weeks of treatment 1, 5
• Assess blood pressure and heart rate at baseline and with dose increases 1
• Common adverse effects include somnolence, fatigue, irritability, insomnia, and nightmares 1
• Full therapeutic effects require 6-12 weeks, substantially longer than stimulants 1

Second-Line Option: Bupropion

Consider bupropion if atomoxetine is ineffective after 12 weeks at therapeutic dose, or if comorbid depression requires specific treatment. 1, 2 Bupropion is not FDA-approved for ADHD but may be particularly useful when both conditions need addressing. 1

Dosing for Bupropion:

• Start with 100-150 mg daily (SR) or 150 mg daily (XL) 2
• Titrate to maintenance doses of 100-150 mg twice daily (SR) or 150-300 mg daily (XL) 2
• Maximum dose is 450 mg per day 2

Important Cautions with Bupropion:

• Can cause headache, insomnia, and anxiety as side effects, which may worsen hyperactivity or agitation 2
• Increased seizure risk, particularly at higher doses 2
• Contraindicated with MAO inhibitors due to risk of hypertensive crisis - at least 14 days must elapse between discontinuation of an MAOI and initiation of bupropion 2, 6
• Bupropion alone should not be assumed to effectively treat both ADHD and depression - no single antidepressant is proven for this dual purpose 2

Third-Line Option: Guanfacine Extended-Release

Switch to guanfacine if both atomoxetine and bupropion have failed, or if comorbid anxiety, tics, or sleep disturbances are present. 1 Weight-based dosing is approximately 0.1 mg/kg once daily, with available strengths of 1,2,3, and 4 mg tablets. 1

Advantages of Guanfacine:

• Should be administered in the evening due to sedation risk 1
• Particularly useful for patients with comorbid anxiety or sleep disturbances 1
• Requires 2-4 weeks for full therapeutic effect 4

Treatment Algorithm for Comorbid ADHD and Depression

1. Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma) 1

2. If depressive symptoms are severe, address the mood disorder first with an SSRI, then add atomoxetine for ADHD symptoms 2

3. If ADHD symptoms improve on atomoxetine but depression persists, add an SSRI to the regimen 2

4. Switch to bupropion if atomoxetine is ineffective after 12 weeks at therapeutic dose, or if intolerable side effects occur, or if comorbid depression requires specific treatment 1, 2

5. Consider guanfacine if both atomoxetine and bupropion have failed, or if comorbid tics, anxiety, or sleep disturbances are present 1

Monitoring Parameters

Baseline Assessment:

• Blood pressure and heart rate 1
• Weight 1
• Suicidality assessment 1

Follow-up Monitoring (2-4 weeks):

• Vital signs 1
• Side effects 1
• Early response 1
• Suicidal ideation, especially with atomoxetine 1, 5

Therapeutic Assessment (6-12 weeks for atomoxetine):

• ADHD symptom scales 1
• Functional impairment 1
• Quality of life 1
• Depression symptom severity 2

Ongoing Monitoring:

• Quarterly vital signs 1
• Continuous suicidality monitoring 1

Common Pitfalls to Avoid

• Do not assume a single antidepressant will effectively treat both ADHD and depression - evidence specifically states no single antidepressant is proven for this dual purpose 2
• Do not use MAO inhibitors concurrently with bupropion due to risk of severe hypertension and potential cerebrovascular accidents 2, 6
• Do not discontinue atomoxetine prematurely - full therapeutic effects require 6-12 weeks 1
• Do not overlook the FDA Black Box Warning for atomoxetine regarding suicidal ideation, particularly critical in patients with comorbid depression 1, 5
• Be cautious with bupropion in patients with prominent hyperactivity or anxiety, as its activating properties can worsen these symptoms 2

Alternative Consideration: Viloxazine

Viloxazine (Qelbree) is FDA-approved for adults with ADHD, offering another non-stimulant option with a starting dose of 200 mg once daily and a maximum dose of 600 mg once daily. 1 This represents a newer alternative when traditional non-stimulants have failed. 3