In a 24-year-old female with PHQ‑9 score 13 and GAD‑7 score 12 who is taking amphetamine salts extended‑release (Adderall XR) 10 mg, what fluoxetine starting dose should be used and how should it be titrated?

Starting Fluoxetine in a 24-Year-Old Female on Adderall XR 10 mg

Start fluoxetine at 10 mg every morning and increase to 20 mg after one week, monitoring closely for activation symptoms (anxiety, agitation, insomnia) during the first 2–4 weeks, particularly given her baseline anxiety (GAD-7 of 12). 1, 2, 3

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Initial Dosing Strategy

• Begin with fluoxetine 10 mg once daily in the morning to minimize initial activation and allow assessment of tolerability before reaching the standard therapeutic dose. 2, 3
• The 10 mg starting dose is particularly important in patients with prominent anxiety symptoms, as approximately 28% of patients cannot tolerate the full 20 mg dose when started abruptly, with panic disorder patients being especially vulnerable to activation side effects. 3
• After 7 days at 10 mg, increase to 20 mg daily if the initial dose is well tolerated. 2, 4

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Titration Beyond 20 mg (If Needed)

• Allow 6–8 weeks at 20 mg daily before concluding inadequate response, as fluoxetine's long half-life (1–3 days for parent compound, 4–16 days for norfluoxetine) means steady-state plasma concentrations are not reached until approximately 5–7 weeks. 1
• If insufficient clinical improvement occurs after 6–8 weeks at 20 mg, increase by 10–20 mg increments at 3–4 week intervals (not 1–2 weeks as with shorter half-life SSRIs), using the smallest available dose increments. 1
• The FDA-approved dose range is 20–60 mg daily for depression and anxiety disorders, with a maximum of 80 mg daily. 2, 5
• For this patient's symptom severity (PHQ-9 of 13, GAD-7 of 12), most patients achieve adequate response at 20–40 mg daily; doses above 40 mg are typically reserved for OCD or treatment-resistant cases. 1, 2

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Critical Safety Monitoring with Concurrent Adderall XR

• Monitor closely for serotonin syndrome within the first 24–48 hours after starting fluoxetine or after any dose increase, as amphetamines possess weak serotonergic activity that can augment serotonin-related risks when combined with SSRIs. 6
• Serotonin syndrome manifestations include mental status changes (confusion, agitation), neuromuscular hyperactivity (tremor, clonus, hyperreflexia), and autonomic overactivity (hypertension, tachycardia, diaphoresis). 6
• Assess for treatment-emergent suicidality weekly during the first month, especially in the first 1–2 weeks after initiation or dose changes, as SSRIs carry FDA black-box warnings for increased suicidal thinking in patients ≤24 years (absolute risk 1% vs. 0.2% placebo, NNH=143). 1, 6

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Managing Initial Activation Symptoms

• Initial adverse effects—including increased anxiety, agitation, insomnia, or restlessness—typically emerge within the first 2–4 weeks and usually resolve with continued treatment. 1, 7
• If activation symptoms appear and are intolerable, temporarily reduce the dose back to the last tolerated level (e.g., return to 10 mg if 20 mg causes problems) rather than discontinuing entirely. 1
• Starting with a subtherapeutic "test dose" of 10 mg is advisable when anxiety is a primary concern, as recommended for anxiety-prone patients. 1
• Do not add another medication to manage activation symptoms, as this creates unnecessary drug interaction risks; fluoxetine is a potent CYP2D6 inhibitor that can significantly increase levels of many medications. 1

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Drug Interaction Considerations

• Fluoxetine inhibits CYP2D6 and converts approximately 43% of extensive metabolizers to poor metabolizer phenotype during chronic use, which can affect metabolism of other medications. 1
• No significant pharmacokinetic interaction exists between fluoxetine and amphetamine salts, but the combination requires vigilant monitoring for additive CNS stimulation and cardiovascular effects. 6
• Fluoxetine's long half-life means that if switching to another antidepressant becomes necessary, a 5-week washout period is required before starting an MAOI. 2

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Expected Timeline for Response

• Initial improvement in anxiety and depressive symptoms typically appears within 2–4 weeks, with maximal therapeutic benefit achieved by 8–12 weeks at a stable dose. 1, 6
• Approximately 38% of patients do not achieve treatment response during the initial 6–12 weeks, and 54% do not achieve remission, so patience during the titration process is essential. 6

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Alternative Approach if Fluoxetine Fails

• If inadequate response after 6–8 weeks at fluoxetine 40–60 mg daily, consider switching to sertraline or an SNRI (venlafaxine) rather than continuing to escalate fluoxetine. 6
• Sertraline has a lower risk of drug interactions and may be better tolerated in patients requiring concurrent stimulant therapy. 6
• Combination treatment with cognitive-behavioral therapy (CBT) plus fluoxetine is superior to either treatment alone for anxiety disorders and should be offered preferentially if available. 1, 6

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Common Pitfalls to Avoid

• Never start at 20 mg in anxiety-prone patients—the 10 mg starting dose significantly reduces early discontinuation due to activation. 3
• Do not increase the dose more frequently than every 3–4 weeks due to fluoxetine's exceptionally long half-life; side effects may not manifest for several weeks after dose changes. 1
• Do not discontinue prematurely—full response may take 8–12 weeks, and partial response at 4–6 weeks warrants continued treatment rather than switching. 6
• Never combine with MAOIs due to serotonin syndrome risk, and allow at least 5 weeks washout when switching from fluoxetine to an MAOI. 6, 2

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Maintenance Treatment Duration

• Continue fluoxetine for a minimum of 4–9 months after achieving satisfactory response for first-episode depression or anxiety. 6
• For patients with recurrent episodes, consider longer duration (≥1 year) to reduce relapse risk. 6