What are alternative treatments for ADHD and depression in patients who cannot tolerate Selective Serotonin Reuptake Inhibitors (SSRIs) or stimulants?

Alternative Treatments for ADHD and Depression in Patients Intolerant to SSRIs and Stimulants

Start with atomoxetine as your first-line non-stimulant medication for ADHD, titrating to 80-100 mg/day over 6-12 weeks, while addressing depression separately with non-SSRI antidepressants such as bupropion or tricyclics if needed. 1

Primary ADHD Treatment: Atomoxetine

Atomoxetine is the recommended first-line non-stimulant for patients who cannot tolerate stimulants, offering proven efficacy with 28-30% reduction in ADHD symptom scores versus 18-20% with placebo. 1

Dosing Protocol

• Start at 40 mg/day, then titrate to target dose of 80-100 mg/day (maximum 100 mg/day or 1.4 mg/kg/day, whichever is lower). 1, 2
• Allow 6-12 weeks for full therapeutic effects to manifest, as atomoxetine has a slower onset compared to stimulants. 3, 1
• Administer as single morning dose or split into morning and evening doses to reduce adverse effects. 3

Key Advantages Over Stimulants

• Non-controlled substance status eliminates abuse potential, making it particularly appropriate for patients with substance use history. 1
• Provides continuous 24-hour symptom coverage without peaks and valleys. 1
• Lower risk of exacerbating anxiety symptoms compared to stimulants. 1
• Fewer effects on appetite and growth with long-term use. 3, 1

Critical Safety Monitoring

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during the first few weeks of treatment. 1, 2
• Assess blood pressure and heart rate at baseline and with dose increases. 1
• Common adverse effects include somnolence, fatigue, irritability, insomnia, and nightmares. 1
• Discontinuation rate is approximately 3.5%, often dose-dependent at doses >1.5 mg/kg/day. 4

Second-Line ADHD Option: Guanfacine Extended-Release

Switch to guanfacine if atomoxetine is ineffective after 12 weeks at therapeutic dose, causes intolerable side effects, or if comorbid anxiety or sleep disturbances are present. 1, 5

Dosing and Administration

• Weight-based dosing at approximately 0.1 mg/kg once daily. 1
• Available in 1,2,3, and 4 mg tablets. 1
• Administer in the evening due to sedation risk. 3, 1

Specific Indications

• Particularly useful for comorbid tics, Tourette's syndrome, anxiety, or sleep disturbances. 3, 1, 5
• May reduce tics, though evidence remains inconclusive. 3

Third-Line ADHD Option: Bupropion

Consider bupropion if both atomoxetine and guanfacine have failed, or when comorbid depression requires treatment. 3, 1, 5

Important Considerations

• Not FDA-approved for ADHD but has demonstrated efficacy in adults. 3, 1
• Particularly beneficial when comorbid depression is present, as it addresses both conditions. 5
• Lowers seizure threshold, requiring caution with other medications that affect seizure risk. 6
• Contraindicated with MAOIs (requires 14-day washout period). 6

Addressing Comorbid Depression Without SSRIs

Treatment Algorithm for Depression

• If depression is primary or severe (with psychosis, suicidality, or severe neurovegetative signs), treat depression first before addressing ADHD. 3
• If depression is less severe or secondary, initiate ADHD treatment first and reassess depressive symptoms after ADHD symptom control. 3
• Bupropion serves dual purpose for both ADHD and depression, though its antidepressant efficacy in pediatric populations is not well-established. 3, 1
• Tricyclic antidepressants (TCAs) are second-line agents with proven antidepressant activity in adults but limited pediatric depression data. 3, 7

Critical Pitfall to Avoid

Do not assume atomoxetine will treat comorbid depression—despite being initially developed as an antidepressant, evidence does not support efficacy in this symptom domain. 3

Monitoring Timeline

Baseline Assessment

• Blood pressure, heart rate, weight, and suicidality assessment. 1

Early Follow-up (2-4 weeks)

• Vital signs, side effects, and early response evaluation. 1

Therapeutic Assessment

• 6-12 weeks for atomoxetine, 2-4 weeks for guanfacine: ADHD symptom scales, functional impairment, and quality of life. 1

Ongoing Monitoring

• Quarterly vital signs, annual growth parameters if applicable, and continuous suicidality monitoring. 1

Clinical Pearls

Approximately 50% of methylphenidate non-responders will respond to atomoxetine, and 75% of methylphenidate responders will also respond to atomoxetine. 8

Atomoxetine can be discontinued abruptly without rebound effects or discontinuation syndrome, unlike stimulants. 8

For patients with complex psychiatric comorbidities (psychosis, schizoaffective disorder), atomoxetine carries lower risk of exacerbating psychotic symptoms compared to stimulants. 5