What is the next best step for a patient with a history of anxiety, depression, and Attention Deficit Hyperactivity Disorder (ADHD) who has failed to improve on Prozac (fluoxetine) and is now experiencing increased anxiety and nausea on Wellbutrin (bupropion) 300 mg once a day?

Next Best Step: Switch to Sertraline

For a patient with anxiety, depression, and ADHD who failed fluoxetine and is now experiencing worsened anxiety and nausea on bupropion 300 mg, the next best step is to switch to sertraline 50 mg daily, as it is the preferred first-line SSRI for treating comorbid anxiety and depression, with superior tolerability and specific efficacy for anxiety disorders. 1

Why Bupropion is Problematic in This Case

• Bupropion is inherently activating and commonly causes anxiety and nausea as side effects, making it particularly problematic for patients with prominent anxiety symptoms 2, 3
• The FDA label explicitly warns that bupropion should not be used in agitated patients, and this patient's increased anxiety represents treatment-emergent agitation 2
• Bupropion's mechanism as a norepinephrine-dopamine reuptake inhibitor can exacerbate anxiety rather than relieve it, which is the opposite of what this patient needs 4

Why Sertraline is the Optimal Choice

• Sertraline is specifically recommended as the first-line SSRI for patients with both depression and anxiety due to its optimal balance of efficacy, safety, and tolerability 1
• Sertraline is FDA-approved for major depressive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and PTSD—making it ideal for this patient's anxiety-predominant presentation 1
• Sertraline has the lowest risk of drug interactions among SSRIs and does not require dose adjustment based on age, providing a favorable safety profile 1
• In patients with mixed anxiety-depression disorder, sertraline reduces anxiety by 55% and depression by 60%, with a mean effective dose of 83.4 mg/day 1

Practical Implementation Strategy

• Start sertraline 50 mg daily in the morning (or 25 mg daily as a "test dose" if the patient is particularly anxious about medication side effects) 1
• Taper bupropion to 150 mg daily for 3-7 days before discontinuing to minimize withdrawal symptoms 3
• Increase sertraline in 50 mg increments at 1-2 week intervals if response is inadequate, up to a maximum of 200 mg daily 1
• Allow 6-8 weeks for an adequate trial, including at least 2 weeks at the maximum tolerated dose 1

Critical Monitoring Parameters

• Monitor for treatment-emergent suicidality closely during the first 1-2 weeks after initiation or dose changes, as all SSRIs carry FDA black box warnings for suicidal thinking in young adults 1
• Assess treatment response at 4 weeks and 8 weeks using standardized symptom rating scales 1
• Monitor for common SSRI side effects including nausea (which typically resolves within 1-2 weeks), sexual dysfunction, and initial anxiety or agitation 1
• Never combine sertraline with MAOIs due to serotonin syndrome risk—allow at least 2 weeks washout when switching 1

Addressing the ADHD Component

• Once anxiety and depression are stabilized on sertraline (typically after 6-8 weeks), reassess ADHD symptoms to determine if stimulant medication is needed 5
• Stimulants can be safely combined with SSRIs, as there are no significant drug-drug interactions between sertraline and stimulants like methylphenidate or amphetamines 5
• Treatment of depression and anxiety often improves ADHD-related functional impairment indirectly, so the full extent of ADHD symptoms may not be apparent until mood symptoms are controlled 1
• If ADHD symptoms remain significantly impairing after mood stabilization, add a long-acting stimulant (methylphenidate or lisdexamfetamine) to the sertraline regimen 5

Common Pitfalls to Avoid

• Do not continue bupropion hoping the anxiety will resolve—the activating properties are intrinsic to the medication and unlikely to improve with time in an already anxious patient 2
• Do not switch to paroxetine despite its FDA approval for multiple anxiety disorders, as it has significantly higher risk of discontinuation syndrome and increased suicidal thinking compared to sertraline 1
• Do not discontinue sertraline prematurely if there is partial response at 4 weeks—full response may take 6-8 weeks, and approximately 38% of patients do not achieve response during initial treatment at suboptimal doses 1
• Do not assume a single medication will adequately treat all three conditions (anxiety, depression, ADHD)—sequential treatment addressing mood symptoms first, then ADHD if needed, is the evidence-based approach 1, 5

If Sertraline Fails After Adequate Trial

• Switch to venlafaxine extended-release 75-225 mg daily, which demonstrated statistically significantly better response rates than fluoxetine specifically for depression with prominent anxiety symptoms 1
• Consider adding cognitive behavioral therapy (CBT), as combination treatment (CBT + SSRI) is superior to either alone for anxiety disorders 1
• Continue sertraline for a minimum of 4-9 months after satisfactory response for first-episode depression, and longer duration (≥1 year) for recurrent episodes 1