What are the treatment options for a 56-year-old female with Attention Deficit Hyperactivity Disorder (ADHD) who couldn't tolerate Atomoxetine (Strattera) and Adderall (amphetamine and dextroamphetamine) due to activation and is now on Guanfacine (Intuniv) 1mg Extended Release (ER)?

Treatment Options for ADHD in a 56-Year-Old Female Currently on Guanfacine 1mg ER

Given your patient's intolerance to both stimulants and atomoxetine due to activation, the most appropriate next step is to optimize her current guanfacine dose by titrating upward to 2-4 mg daily, as she is currently on a subtherapeutic starting dose. 1

Optimizing Current Guanfacine Therapy

Your patient is on guanfacine 1 mg ER, which is merely the starting dose, not a therapeutic dose. The evidence strongly supports further titration:

• Target dosing for guanfacine is 0.05-0.12 mg/kg/day or 1-7 mg/day, with typical therapeutic range of 2-4 mg daily for adults 1
• Titrate by 1 mg per week based on response and tolerability 1
• Evening administration is strongly preferred to minimize daytime somnolence and fatigue, which are the most common adverse effects 1
• Expect 2-4 weeks before observing clinical benefits at each optimized dose, unlike stimulants which work immediately 1
• Monitor blood pressure and heart rate at baseline and during each dose adjustment 1

Critical Safety Monitoring During Titration

• Check blood pressure and heart rate before each dose increase 1
• Watch for hypotension/bradycardia, somnolence/sedation, and headache (occurs in 20.5% of patients) 1
• Never abruptly discontinue guanfacine—it must be tapered by 1 mg every 3-7 days to avoid rebound hypertension 1, 2

Alternative Non-Stimulant Options If Guanfacine Optimization Fails

If titrating guanfacine to therapeutic doses (3-4 mg) over 6-8 weeks fails to adequately control symptoms, consider these alternatives:

Bupropion (Off-Label but Evidence-Based)

• Bupropion is a noradrenergic and dopaminergic antidepressant that has demonstrated efficacy for adult ADHD and would be particularly appropriate given her activation intolerance to other agents 3
• Start with bupropion SR 150 mg daily, then increase to 150 mg twice daily or bupropion XL 300 mg daily 3
• This option provides a different mechanism of action than what she has already failed 3
• Particularly useful if comorbid depression or anxiety is present 3

Viloxazine ER (Newer Non-Stimulant)

• Viloxazine is a selective norepinephrine reuptake inhibitor with serotonergic effects, recently approved for ADHD 3
• May be better tolerated than atomoxetine in patients sensitive to activation 3
• Dosing typically starts at 200 mg daily and can be titrated to 400-600 mg daily 3

Tricyclic Antidepressants (Off-Label)

• Desipramine or nortriptyline have noradrenergic activity and demonstrated efficacy for adult ADHD 3
• These may be particularly appropriate given her intolerance to activation, as they tend to be more sedating 3
• Requires baseline ECG and monitoring for cardiac conduction effects 3

What NOT to Do

• Do not add clonidine to guanfacine—both work through the same alpha-2A adrenergic receptor mechanism, which would increase sedation and cardiovascular effects without clear evidence of superior efficacy 1
• Do not retry atomoxetine at lower doses, as she has already demonstrated intolerance 4
• Do not consider stimulant rechallenge given her clear activation intolerance to Adderall 4

Clinical Algorithm for This Patient

1. First: Optimize guanfacine to 3-4 mg ER taken in the evening 1

   • Increase by 1 mg weekly 1
   • Monitor BP/HR at each increase 1
   • Allow 2-4 weeks at target dose before assessing efficacy 1

2. If inadequate response after 6-8 weeks at therapeutic guanfacine dose:

   • Add bupropion XL 300 mg daily (combination therapy is safe) 3
   • OR switch to bupropion monotherapy if guanfacine causes excessive sedation 3

3. If bupropion causes activation (unlikely but possible):

   • Consider viloxazine ER or tricyclic antidepressants 3

4. Monitor for treatment response using standardized ADHD rating scales at each medication adjustment 1

Important Caveats

• Guanfacine has an effect size of approximately 0.7 compared to placebo, which is lower than stimulants but clinically meaningful 1, 4
• The delayed onset of action (2-4 weeks) requires patience and consistent dosing before determining treatment response 1
• Combination therapy with behavioral interventions should be considered to maximize functional outcomes 4
• If substance use disorder is a concern, guanfacine's non-controlled status makes it particularly appropriate 1