What adjustments should be made to the treatment regimen for a patient with a history of pulmonary embolism, seizures, asthma, depression, anxiety, and PTSD, taking Buspirone, Fluoxetine, Gabapentin, Lamotrigine, and Topiramate, with increased depression and anxiety symptoms?

Management of Worsening Depression and Anxiety in a Complex Psychiatric Patient

Primary Recommendation

Increase fluoxetine from 80 mg to the maximum FDA-approved dose of 80 mg daily (already at maximum) and add evidence-based psychotherapy, while carefully monitoring for drug interactions and seizure risk given the complex polypharmacy regimen. 1

Immediate Assessment Priorities

Evaluate Current Medication Efficacy and Safety

• Fluoxetine 80 mg daily is already at the maximum FDA-approved dose for depression/anxiety/OCD, so further dose escalation is not an option 1
• The combination of buspirone 30 mg twice daily (60 mg total) with fluoxetine carries risk of serotonin syndrome, particularly with confusion, diaphoresis, incoordination, diarrhea, and myoclonus as warning signs 2
• Buspirone maximum recommended dose is 60 mg/day (20 mg three times daily), and this patient is already at that threshold 3, 4
• Gabapentin, lamotrigine, and topiramate are all appropriate for seizure management, though topiramate has emerging evidence for mood stabilization 3, 5

Critical Drug Interaction Concerns

The current regimen poses several interaction risks:

• Fluoxetine is a potent CYP3A4 inhibitor which can increase buspirone levels 5-6 fold, necessitating lower buspirone doses (typically 2.5 mg twice daily when combined) 4
• This patient's buspirone dose of 30 mg twice daily is inappropriately high when combined with fluoxetine and may be contributing to treatment failure or adverse effects 4
• Buspirone overdose can cause seizures (reported 36 hours post-ingestion in overdose cases), which is particularly concerning given this patient's seizure history 6

Recommended Treatment Algorithm

Step 1: Optimize Current Pharmacotherapy (Weeks 1-4)

Reduce buspirone to 2.5-5 mg twice daily due to the significant CYP3A4 inhibition by fluoxetine, which increases buspirone concentrations 5-6 fold 4

• The current dose of 60 mg/day total is likely causing excessive buspirone levels and potential toxicity
• Monitor for improvement in anxiety symptoms at the lower, more appropriate dose
• Watch for serotonin syndrome symptoms (confusion, diaphoresis, myoclonus, diarrhea) 2

Maintain fluoxetine at 80 mg daily as this is the maximum FDA-approved dose and changing it would require 10-14 day taper to avoid withdrawal 3, 1

Continue current anticonvulsant regimen (gabapentin 600 mg twice daily, lamotrigine 150 mg twice daily, topiramate 50 mg twice daily) as these are appropriate for seizure control 5

Step 2: Add Evidence-Based Psychotherapy (Weeks 1-8)

Initiate manualized cognitive behavioral therapy (CBT) or unified protocol addressing both depression and anxiety, as psychological interventions are first-line adjuncts 3

• Prioritize treatment of depressive symptoms as recommended by ASCO guidelines, since treating depression often improves comorbid anxiety 3
• CBT should be delivered by a mental health practitioner using empirically supported, manualized treatments 3
• Assess treatment response at 4 and 8 weeks using standardized validated instruments (PHQ-9 for depression, GAD-7 for anxiety) 3

Step 3: Reassess at 8 Weeks

If inadequate response after 8 weeks despite good adherence:

• Consider switching from fluoxetine to an SNRI (duloxetine or venlafaxine) which may provide superior efficacy for comorbid depression, anxiety, and pain (given gabapentin use suggests pain component) 3
• Alternative: Augment with low-dose quetiapine (25-50 mg at bedtime), which showed odds ratio of 6.75 for abstinence in alcohol studies but may help treatment-resistant depression/anxiety 3
• Do NOT add benzodiazepines despite anxiety symptoms, as they increase respiratory depression risk with opioids and complicate seizure management 3

Step 4: Consider Topiramate Optimization

Topiramate has emerging evidence for mood disorders:

• Current dose of 50 mg twice daily (100 mg total) is relatively low
• Topiramate showed odds ratio of 1.88 for improved outcomes in alcohol abstinence studies and may help mood/anxiety 3
• Could consider increasing to 100 mg twice daily (200 mg total) for enhanced mood stabilization effects, though this is off-label for depression/anxiety
• Monitor for cognitive side effects and word-finding difficulties

Critical Safety Monitoring

Seizure Risk Management

Multiple medications in this regimen can lower seizure threshold:

• Fluoxetine can induce seizures, particularly at high doses or in overdose situations 7
• Buspirone overdose causes seizures in animal models and human case reports 6
• The excessive buspirone dosing (given fluoxetine interaction) may be approaching toxic levels

Maintain therapeutic anticonvulsant levels and avoid abrupt discontinuation of any seizure medications 5

Pulmonary Embolism Considerations

Ensure appropriate anticoagulation management:

• Patient should be on therapeutic anticoagulation (warfarin with INR 2-3, or LMWH, or NOAC) for at least 3 months post-PE 3
• If first PE with identifiable risk factor, can discontinue after 3 months 3
• If unprovoked PE, consider indefinite anticoagulation 3
• Monitor for drug interactions between anticoagulants and psychiatric medications

Depression and Suicide Risk

Patients with depression, anxiety, and PTSD require enhanced monitoring:

• Assess suicide risk at every visit, particularly during medication changes 3
• Optimize treatment for depression as this can reduce overdose risk 3
• Consider that treatment-resistant depression may require psychiatric specialist consultation 3

Common Pitfalls to Avoid

1. Do not continue buspirone at 60 mg/day with fluoxetine - this combination creates dangerously high buspirone levels due to CYP3A4 inhibition 4

2. Do not add benzodiazepines despite anxiety symptoms - they increase respiratory depression risk and complicate management in patients with substance use risk factors 3

3. Do not assume maximum-dose fluoxetine failure means SSRI class failure - consider switching to SNRI rather than adding more medications 3

4. Do not neglect psychotherapy - medication alone is insufficient; manualized CBT or unified protocol is essential 3

5. Do not forget to reassess at 4 and 8 weeks using validated instruments (PHQ-9, GAD-7) rather than subjective assessment alone 3