What are the pros and cons of replacing Qelbree (viloxazine) with a stimulant in a patient with Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Obsessive-Compulsive Disorder (OCD), and social anxiety disorder, who is currently experiencing significant morning fatigue on Qelbree and guanfacine?

Replacing Qelbree with a Stimulant: Recommendation for ADHD with Comorbid ASD, OCD, and Social Anxiety

Replace Qelbree with a stimulant trial to address the morning fatigue, as stimulants are first-line treatment with superior efficacy for ADHD core symptoms and do not cause sedation, while maintaining guanfacine can help manage comorbid anxiety and provide evening coverage. 1

Pros of Switching to a Stimulant

Superior Efficacy for ADHD Core Symptoms

• Stimulants demonstrate effect sizes of approximately 1.0 for ADHD symptoms, compared to viloxazine's more modest effects, making them substantially more effective for inattention, hyperactivity, and impulsivity 2, 3
• Carefully designed trials show 65-75% of patients with ADHD experience substantial improvement on stimulants 3
• Stimulants work immediately (within 30 minutes to 3 hours), unlike viloxazine which requires several weeks for full therapeutic effect 3, 4

Resolution of Morning Fatigue

• Stimulants do not cause somnolence or fatigue—in fact, they increase alertness and energy, directly addressing the current problematic morning fatigue 5
• Qelbree causes somnolence in 16% and fatigue in 6% of pediatric patients (compared to 4% and 2% with placebo respectively), making it a likely contributor to the morning fatigue 5
• The combination of Qelbree and guanfacine creates additive sedating effects, as guanfacine commonly causes fatigue (15.2% of patients) and headache (20.5%) 2

Compatibility with Comorbid Anxiety

• Early concerns about stimulants worsening anxiety in ADHD patients have been definitively refuted by large-scale trials including the MTA study, which showed that patients with comorbid ADHD and anxiety actually had greater treatment response differences favoring stimulants 1
• The guideline explicitly states: "the clinician should proceed with a stimulant trial" even when anxiety is present 1
• If anxiety symptoms remain problematic after ADHD symptoms improve on stimulants, an SSRI can be added to the stimulant for the anxiety component 1

Maintaining Guanfacine Provides Multiple Benefits

• Both extended-release guanfacine and clonidine are FDA-approved specifically for adjunctive therapy with stimulants, with demonstrated safety and efficacy in combination 2
• Guanfacine provides "around-the-clock" coverage (24 hours with once-daily dosing) that can help with evening symptom control when stimulants wear off 2
• The combination may help mitigate stimulant-related adverse effects such as sleep disturbances 2
• Guanfacine's anxiolytic properties may be particularly beneficial given the comorbid social anxiety and OCD 2

Cons of Switching to a Stimulant

Potential Cardiovascular Effects

• Stimulants increase heart rate and blood pressure, which creates opposing effects when combined with guanfacine (which decreases both parameters by 1-4 mmHg and 1-2 bpm) 2
• Monitor blood pressure and heart rate at baseline and during dose adjustments when combining medications 2, 6
• This opposing effect is generally not problematic and may actually be beneficial in offsetting stimulant cardiovascular effects 2

Anxiety Monitoring Required

• While large trials show stimulants do not worsen anxiety in most patients, individual monitoring remains important 1
• If anxiety worsens specifically with stimulant initiation (not just baseline anxiety persisting), consider adding an SSRI rather than discontinuing the stimulant 1
• Stimulants can produce dysphoria in vulnerable patients, though this is uncommon 1

Substance Abuse Considerations

• Stimulants carry controlled substance status and theoretical abuse potential, though this is primarily a concern in patients with active substance use disorders 7, 4
• Viloxazine has decreased chance of substance abuse, drug dependence, and withdrawal symptoms compared to stimulants 4
• However, in patients without substance use history, this is not a practical concern 1

Common Stimulant Side Effects

• Appetite suppression and insomnia are common with stimulants 1
• These can typically be managed with timing adjustments (earlier dosing for sleep) and nutritional counseling 3

Practical Implementation Algorithm

Step 1: Discontinue Qelbree

• Viloxazine does not require tapering and can be stopped abruptly without rebound effects 4
• The morning fatigue should begin improving within days of discontinuation 5

Step 2: Maintain Guanfacine

• Continue current guanfacine dose unchanged, as it provides anxiety management and evening ADHD coverage 2
• Evening administration of guanfacine is preferable to minimize any residual daytime somnolence 2
• Never abruptly discontinue guanfacine—it requires tapering by 1 mg every 3-7 days to avoid rebound hypertension 2

Step 3: Initiate Stimulant Trial

• Start with methylphenidate or amphetamine formulation based on duration needs 1, 3
• Begin with low dose and titrate based on response, as individual responses vary considerably 1, 3
• Assess response rapidly (within days to weeks) given immediate onset of action 3

Step 4: Monitor Cardiovascular Parameters

• Obtain baseline blood pressure and heart rate before starting stimulant 2
• Recheck at each dose adjustment, watching for the opposing effects of stimulant (increases) and guanfacine (decreases) 2
• Most patients tolerate this combination well, as the effects partially offset each other 2

Step 5: Assess Comorbid Symptoms

• If ADHD symptoms improve but anxiety/OCD remain problematic, consider adding an SSRI to the stimulant-guanfacine combination 1
• If anxiety worsens specifically with stimulant (not just persisting baseline anxiety), this represents a decision point for SSRI addition 1

Critical Pitfalls to Avoid

• Do not assume anxiety is a contraindication to stimulants—this outdated concern has been refuted by high-quality evidence 1
• Do not abruptly discontinue guanfacine if considering medication changes—always taper to avoid rebound hypertension 2
• Do not wait weeks to assess stimulant response—effects are immediate, unlike viloxazine's delayed onset 3, 4
• Do not attribute all sedation to guanfacine alone—Qelbree significantly contributes to morning fatigue and the combination creates additive sedating effects 2, 5