In a physically active adult executive (mid‑20s) with long‑standing ADHD on immediate‑release Adderall that worsens anxiety and depression, a recent major depressive episode after a breakup, minimal response to a brief fluoxetine trial, and a preference for short‑term antidepressant therapy and pharmacogenomic testing, what medication options should be trialed and in what stepwise order?

Medication Options for ADHD and Depression After Adderall-Related Worsening

Switch from immediate-release Adderall to long-acting methylphenidate (Concerta 18-36 mg once daily) as your first step, because methylphenidate causes less anxiety and depression than amphetamines, and the sustained-release formulation eliminates the peak-trough mood fluctuations that worsen depressive symptoms with immediate-release stimulants. 1, 2

Step 1: Address the Adderall Problem First

Your current immediate-release Adderall is likely causing or worsening your depression and anxiety through two mechanisms:

• Amphetamines worsen emotional lability more than methylphenidate, with meta-analysis showing amphetamines significantly increase risk of mood instability 2
• Immediate-release formulations cause peak-trough effects that produce sadness and irritability during the "crash" phase, whereas extended-release preparations eliminate this problem 1, 2
• Methylphenidate actually reduces the risk of irritability and anxiety compared to placebo, while amphetamines worsen emotional symptoms 2

Specific Switching Protocol:

1. Stop immediate-release Adderall (no taper needed for immediate-release)
2. Start Concerta 18 mg once daily in the morning (equivalent to your previous 5 mg TID methylphenidate dosing) 1
3. Titrate by 18 mg weekly up to 54-72 mg daily maximum based on ADHD response 1, 3
4. Concerta's OROS delivery system provides ascending plasma levels throughout the day, preventing the rebound depression you've experienced 3

Step 2: Optimize ADHD Treatment Before Adding Antidepressants

Wait 4-6 weeks after optimizing your stimulant to see if depression improves, because:

• Treating ADHD alone resolves comorbid depressive symptoms in many cases without additional medication 1
• Your depression started after a breakup (situational trigger) and worsens with Adderall—fixing the medication may resolve the depression 1
• Stimulants work within days for ADHD, allowing rapid assessment of whether mood improves with better ADHD control 1, 4

Monitor These Parameters Weekly:

• ADHD symptom control (concentration, task completion, organization) 1
• Mood stability throughout the day (no afternoon crashes) 1
• Anxiety levels (should improve, not worsen) 4, 2
• Blood pressure and pulse at each visit 1
• Sleep quality and appetite 1

Step 3: Add SSRI Only If Depression Persists

If depressive symptoms remain at 4-6 weeks despite optimized methylphenidate, add sertraline 25-50 mg daily (not fluoxetine, which you already tried briefly):

• SSRIs are first-line for depression and can be safely combined with stimulants with no significant drug interactions 1, 4
• Sertraline is weight-neutral long-term, addressing your concern about weight gain 1
• The combination of stimulant plus SSRI is well-established when ADHD improves but mood symptoms persist 1, 4
• Titrate sertraline to 100-150 mg daily if needed for full antidepressant effect 1

Why NOT Bupropion:

Despite your interest in alternatives, bupropion is explicitly a second-line agent for ADHD and has significant problems for your situation:

• Bupropion is inherently activating and can worsen anxiety and agitation 1
• It's only considered when two or more stimulants have failed, which hasn't happened yet 1
• No single antidepressant treats both ADHD and depression effectively—you need separate medications 1
• Bupropion causes headache, insomnia, and anxiety as common side effects 1

Step 4: Regarding Pharmacogenomic Testing

Proceed with genetic testing, but understand its limitations:

• Pharmacogenomics may help identify which antidepressants to avoid due to metabolism issues, but it does not predict efficacy for your specific symptoms 5
• The testing is most useful for avoiding adverse reactions, not for choosing the "best" medication 5
• Your clinical response (how you actually feel on the medication) remains more important than genetic predictions 5

Alternative Non-Stimulant Option (If Methylphenidate Fails)

Only if you cannot tolerate any stimulant should you consider atomoxetine 40-80 mg daily:

• Atomoxetine is the only FDA-approved non-stimulant for adult ADHD 1, 3
• It has evidence for treating ADHD with comorbid anxiety 1
• Major drawback: Requires 6-12 weeks to achieve full effect (versus days for stimulants) 1, 6
• Effect size is 0.7 compared to 1.0 for stimulants (30% less effective) 1, 7
• Carries FDA black-box warning for suicidal ideation—requires close monitoring given your depression 1

Critical Pitfalls to Avoid

• Do not assume Adderall represents all stimulants—methylphenidate has a fundamentally different side effect profile, especially for mood 2
• Do not start an antidepressant before optimizing ADHD treatment—you may not need it once the stimulant is corrected 1
• Do not use immediate-release formulations—they cause the mood crashes you're experiencing 1, 2
• Do not expect pharmacogenomic testing to tell you which medication will work best—it only identifies metabolism issues 5

Timeline Summary

Weeks 1-2: Switch to Concerta 18 mg, assess ADHD response and mood
Weeks 3-4: Titrate Concerta to 36-54 mg based on symptom control
Weeks 5-6: Evaluate depression—if improved, continue methylphenidate alone
Week 7+: If depression persists, add sertraline 25-50 mg and titrate to effect 1, 4

This stepwise approach prioritizes fixing the medication that's causing your depression (Adderall) before adding more medications, while maintaining effective ADHD treatment throughout. 1, 4, 2