How to use stimulant and non-stimulant medications, such as methylphenidate (Ritalin) and atomoxetine (Strattera), together in patients with Attention Deficit Hyperactivity Disorder (ADHD)?

Combined Use of Stimulant and Non-Stimulant Medications for ADHD

Stimulant and non-stimulant medications can be safely combined in ADHD treatment, with extended-release guanfacine and extended-release clonidine being the only FDA-approved adjunctive therapies to stimulants, though atomoxetine can also be used in combination with careful monitoring. 1

Approved Combinations and Evidence

• Extended-release guanfacine and extended-release clonidine are specifically FDA-approved "as adjunctive therapy to stimulant medications" to enhance treatment effects and/or decrease stimulant adverse effects 1, 2
• Atomoxetine can be safely used with stimulants as part of a combination approach, though this is considered off-label use 2, 3
• Combination therapy has shown significant improvement in ADHD symptoms compared to monotherapy in clinical studies 3

Benefits of Combination Therapy

• Stimulants provide rapid symptom control with large effect sizes, while non-stimulants offer complementary benefits 2, 4
• Non-stimulants can provide continuous 24-hour coverage, including morning and evening symptom control 2, 5
• Alpha-agonists (clonidine/guanfacine) can counteract stimulant-induced insomnia when given at bedtime 1
• Combination therapy may help reduce stimulant-related side effects such as sleep disturbances and cardiovascular effects 1

Specific Combination Strategies

Methylphenidate + Alpha-Agonists

• Start with a half clonidine tablet (0.05 mg) at bedtime and increase slowly, never exceeding 0.3 mg/day 1
• Clonidine can be given at bedtime for sleep or 4 times daily for aggressive behavior control 1
• Before starting clonidine, obtain a full medical history of the patient and first-degree family members 1
• A history of sudden death, repeated fainting, or arrhythmias in family members would contraindicate alpha-agonist use 1

Methylphenidate + Atomoxetine

• Atomoxetine can be administered once daily or split into two doses to reduce side effects 1, 5
• Monitor for additive cardiovascular effects, though these are typically minimal 1, 2
• This combination has shown enhanced effectiveness over monotherapy in clinical studies 3

Safety Considerations

• Routine ECG monitoring during treatment with stimulant and alpha-agonist combinations is not advised based on largely negative findings 1
• The rate of side effects such as bradycardia, hypotension, and hypertension with alpha-agonist combinations appears to be rare (less than 1/100) 1
• Common side effects of combined therapy include irritability (41.6%), appetite reduction (25%), palpitations (16.7%), and headache (8.3%) 3
• Atomoxetine has fewer and less pronounced adverse effects compared to alpha-agonists, making it better tolerated in most patients 2

Contraindications and Cautions

• Patients on MAO inhibitors should not be given stimulants due to risk of hypertensive crisis 1
• A case report of a child who died of cardiac arrhythmia while being treated with dextroamphetamine and high-dose imipramine (6.9 mg/kg/day) suggests caution with tricyclic antidepressant combinations 1
• SSRIs may be added to methylphenidate for treating comorbid depression, with no significant interactions reported 1
• There are no studies of the combination of bupropion and stimulants; proceed with caution until further studies are available 1

Monitoring Recommendations

• Once a child with ADHD is stabilized on medication, schedule visits once a month 1
• Use standardized rating scales to assess symptoms before initiating treatment and after each major dose adjustment 1
• Monitor vital signs in patients receiving stimulant treatment, as they can increase heart rate and blood pressure 1
• For combination therapy, more frequent monitoring may be necessary initially to assess for additive side effects 3