ADHD Treatment Failure: Switch to Stimulant Medications
You should discontinue the current non-stimulant regimen and initiate a trial of stimulant medication, as stimulants demonstrate 70-80% response rates with the largest effect sizes (1.0) compared to atomoxetine and bupropion, which have significantly smaller effect sizes (0.7) and are explicitly positioned as second-line agents. 1
Why Your Current Regimen Is Failing
Your combination of Strattera (atomoxetine) 100mg and Wellbutrin XL (bupropion) 300mg represents a second-line approach that bypassed first-line treatment entirely. The American Academy of Child and Adolescent Psychiatry explicitly states that no single antidepressant is proven to effectively treat both ADHD and depression, and bupropion is a second-line agent for ADHD treatment compared to stimulants 1. While bupropion shows low-quality evidence for decreasing ADHD symptom severity (standardized mean difference -0.50), this effect is substantially weaker than stimulants 2.
Atomoxetine requires 6-12 weeks to achieve full therapeutic effect and has medium-range effect sizes of approximately 0.7, compared to stimulants which work within days and have effect sizes of 1.0 3, 1. You've essentially been treated with medications that have 30-50% less efficacy than first-line options.
Primary Recommendation: Initiate Stimulant Therapy
First-Line Stimulant Options
Start with either methylphenidate or lisdexamfetamine (Vyvanse) as your first stimulant trial. 1 The choice between these two classes is idiosyncratic—approximately 40% of patients respond to both, 40% respond to only one, and 20% respond to neither 1. This means you need to trial both classes before concluding stimulants don't work.
For methylphenidate: Start with long-acting formulations like Concerta (OROS-methylphenidate) 18-36mg once daily in the morning, titrating by 18mg weekly up to a maximum of 72mg daily 1, 4. Long-acting formulations provide 8-12 hour coverage, improve adherence, reduce rebound effects, and have lower diversion potential 3, 1.
For amphetamines: Start with lisdexamfetamine (Vyvanse) 20-30mg once daily, titrating by 10-20mg weekly up to 70mg daily maximum, or mixed amphetamine salts (Adderall XR) 10mg once daily, titrating by 5-10mg weekly up to 40-50mg daily 1, 5.
Monitoring During Stimulant Initiation
Monitor these parameters at baseline and regularly during treatment 3, 1:
- Blood pressure and pulse (stimulants can elevate both)
- Height and weight (particularly if you're younger, though less critical in adults)
- Sleep quality and appetite changes
- ADHD symptom improvement using standardized rating scales
You should see response within days to weeks with stimulants, unlike the 6-12 weeks required for atomoxetine 3, 1.
What to Do With Your Current Medications
Continue the Wellbutrin XL 300mg during stimulant initiation if you have comorbid depression. 1 There are no significant pharmacokinetic interactions between stimulants and bupropion 1. The American Academy of Child and Adolescent Psychiatry recommends treating ADHD first with stimulants, then adding an SSRI if mood symptoms persist after ADHD improves 1. However, bupropion can remain as your antidepressant while you address the ADHD with appropriate first-line treatment.
Discontinue the Strattera (atomoxetine). There's no evidence supporting the combination of atomoxetine with stimulants as initial therapy, and you're already on a suboptimal regimen 1. Atomoxetine is reserved for patients who fail stimulants or have contraindications to stimulant use 3, 1.
If Stimulants Fail or Are Not Tolerated
Only after adequate trials of both methylphenidate AND amphetamine classes should you consider returning to non-stimulants 1. "Adequate trial" means:
- Proper dose titration to maximum tolerated dose or maximum recommended dose
- Sufficient duration (at least 4-6 weeks at optimal dose)
- Good medication adherence
Non-Stimulant Options After Stimulant Failure
Atomoxetine 60-100mg daily remains an option if both stimulant classes fail, particularly if you have comorbid substance use disorder, anxiety, or tics 3, 1. Target dose is 60-100mg daily for adults, with median time to response of 3.7 weeks 1.
Extended-release guanfacine (1-4mg daily) or extended-release clonidine (0.1-0.4mg daily) are additional options with effect sizes around 0.7, particularly useful if you have comorbid sleep disturbances, tics, or disruptive behavior 3, 1. These require 2-4 weeks for full effect and are best dosed in the evening due to sedation 3.
Critical Safety Considerations
Avoid stimulants if you have: 1, 5
- Uncontrolled hypertension
- Symptomatic cardiovascular disease
- Active substance abuse (though long-acting formulations may still be considered)
- Uncontrolled hyperthyroidism
- Glaucoma
Never combine stimulants or bupropion with MAO inhibitors due to risk of hypertensive crisis—at least 14 days must elapse between discontinuation of an MAOI and initiation of these medications 1.
Common Pitfalls to Avoid
Don't assume your current regimen just needs "optimization." You're on second-line agents that have been proven inferior to stimulants in over 161 randomized controlled trials 1. The American Academy of Child and Adolescent Psychiatry explicitly recommends trying all three stimulant classes (methylphenidate, dextroamphetamine, and mixed amphetamine salts) before turning to antidepressants like bupropion 1.
Don't accept "partial response" to non-stimulants when you haven't tried first-line treatment. Stimulants achieve 70-80% response rates when properly titrated 3, 1. You deserve an adequate trial of medications with the strongest evidence base.
Don't worry about tolerance development. There is little evidence of tolerance to stimulant effects on ADHD symptoms, and little evidence of needing to increase doses to maintain response over prolonged treatment periods 1.