A female patient taking lamotrigine 250 mg daily, bupropion (Wellbutrin) 150 mg daily, and quetiapine (Seroquel) 150 mg daily now reports anxiety and difficulty concentrating; how should her medication regimen be adjusted?

Managing Anxiety and Difficulty Focusing in a Patient on Lamotrigine, Bupropion, and Quetiapine

Immediate Assessment and Likely Cause

The most likely culprit for new-onset anxiety and difficulty focusing in this patient is bupropion 150 mg daily, which is below the therapeutic dose for depression (300-400 mg/day) but sufficient to cause activating side effects without providing full therapeutic benefit. 1, 2, 3

• Bupropion's norepinephrine and dopamine reuptake inhibition produces stimulating properties that can provoke anxiety, particularly during initial treatment or at subtherapeutic doses 4
• The current dose of 150 mg daily is insufficient for antidepressant efficacy (therapeutic range 300-450 mg/day), creating a situation where activating effects predominate without mood stabilization 1, 3
• Behavioral activation (motor restlessness, anxiety, difficulty concentrating) is a recognized early side effect of bupropion, especially in the first weeks of treatment 2, 4

Primary Recommendation: Optimize or Discontinue Bupropion

Increase bupropion to 300 mg daily (150 mg twice daily, with second dose before 3 PM) and reassess after 2-4 weeks, OR discontinue bupropion entirely if anxiety symptoms are severe. 1, 2, 3

If Increasing Bupropion Dose:

• Titrate from 150 mg once daily to 150 mg twice daily, with the second dose administered before 3 PM to minimize insomnia risk 1
• Allow 6-8 weeks at 300 mg daily before declaring treatment failure, as full antidepressant response requires adequate trial duration 5, 1
• Monitor closely for worsening anxiety, agitation, or behavioral activation during the first 1-2 weeks after dose increase 1, 2
• If anxiety persists or worsens at 300 mg daily after 2 weeks, discontinue bupropion 2, 4

If Discontinuing Bupropion:

• Bupropion can be stopped abruptly without tapering, as it does not cause significant discontinuation syndrome 1, 3
• Symptoms of anxiety and difficulty focusing should improve within 3-7 days of discontinuation 2, 4
• Consider switching to an SSRI (sertraline 50-100 mg daily or escitalopram 10-20 mg daily) if depressive symptoms were the original indication for bupropion 5, 6

Alternative Pharmacological Interventions

Add Low-Dose Quetiapine for Anxiety:

If bupropion optimization fails and anxiety remains problematic, increase quetiapine from 150 mg to 200-300 mg at bedtime. 7, 8

• Quetiapine 200-300 mg daily provides anxiolytic effects through 5-HT2A antagonism and H1 receptor blockade 7, 8
• The current dose of 150 mg may be subtherapeutic for anxiety management in the context of bupropion-induced activation 7, 8
• Titrate quetiapine by 50 mg increments every 3-7 days to minimize sedation 7
• Monitor for excessive sedation, metabolic effects (weight gain, glucose elevation), and orthostatic hypotension 7

Consider SSRI Addition (If Bupropion Discontinued):

Add sertraline 25-50 mg daily or escitalopram 5-10 mg daily, combined with existing lamotrigine, if anxiety persists after bupropion discontinuation. 5, 6

• SSRIs are first-line pharmacotherapy for anxiety disorders with moderate-to-high strength of evidence 5, 6
• Start with a subtherapeutic "test dose" (sertraline 25 mg or escitalopram 5 mg) to assess tolerability, then increase after 3-7 days 5, 6
• Titrate sertraline by 25-50 mg increments every 1-2 weeks to target 100-150 mg daily, or escitalopram by 5 mg increments every 2-3 weeks to target 10-20 mg daily 5, 6
• Monitor for serotonin syndrome when combining with quetiapine, particularly within the first 24-48 hours after dosage changes (mental status changes, neuromuscular hyperactivity, autonomic instability) 5

Non-Pharmacological Interventions

Initiate cognitive-behavioral therapy (CBT) immediately, as combination treatment (CBT plus medication) demonstrates superior efficacy compared to medication alone for anxiety disorders. 5, 6

• CBT benefits typically emerge within 6-12 sessions when combined with pharmacotherapy 5, 6
• Individual CBT following evidence-based protocols (Clark-and-Wells or Heimberg models) is recommended first-line 6
• If face-to-face CBT is not accessible, structured self-help CBT programs with therapist support are evidence-based alternatives 6

Critical Monitoring Parameters

• Assess anxiety symptoms and concentration weekly for the first month using standardized measures (GAD-7 or similar) 5, 6
• Monitor for suicidal ideation at every visit during the first 1-2 months, as antidepressant changes increase risk 5, 1
• Evaluate for behavioral activation (agitation, restlessness, insomnia, impulsivity) at each visit, particularly in the first 2-4 weeks 5, 2
• Check blood pressure and heart rate if increasing bupropion, as it can elevate both parameters 1

Common Pitfalls to Avoid

• Do not add a benzodiazepine as first-line treatment for bupropion-induced anxiety, as this creates unnecessary polypharmacy and dependence risk when addressing the underlying cause (subtherapeutic bupropion dosing) is more appropriate 5
• Do not combine bupropion with SSRIs without extreme caution, as bupropion inhibits CYP2D6 and can increase SSRI blood levels, raising serotonin syndrome risk 9
• Do not exceed bupropion 450 mg/day (or 400 mg/day for sustained-release formulations), as seizure risk increases markedly above this threshold 1, 2, 3
• Do not discontinue lamotrigine, as it is providing mood stabilization and has no role in the current anxiety symptoms 6, 10
• Do not misinterpret early behavioral activation as worsening depression, as this can lead to inappropriate dose escalation or medication additions 5, 2

Expected Timeline for Improvement

• If bupropion is discontinued, anxiety symptoms should improve within 3-7 days 2, 4
• If bupropion is optimized to 300 mg daily, expect initial response within 2-4 weeks, with maximal benefit by 6-8 weeks 1, 3
• If an SSRI is added, expect anxiety reduction within 2-4 weeks, with maximal benefit by 8-12 weeks 5, 6
• If quetiapine is increased, anxiolytic effects should emerge within 1-2 weeks 7, 8