What is the preferred treatment between Xcopri (cenobamate) and Lamotrigine for Hallucinogen Persisting Perception Disorder (HPPD)?

Lamotrigine is Preferred Over Cenobamate (Xcopri) for Hallucinogen Persisting Perception Disorder (HPPD)

Lamotrigine is the preferred treatment for Hallucinogen Persisting Perception Disorder (HPPD) over cenobamate (Xcopri) based on clinical evidence and established treatment protocols. While neither medication has FDA approval specifically for HPPD, lamotrigine has demonstrated efficacy in treating perceptual disturbances that characterize this condition.

Evidence-Based Rationale

Efficacy for HPPD

• Lamotrigine is considered the gold standard for treating perceptual disturbances in time and space that characterize HPPD 1
• Clinical case reports have shown improvement in HPPD symptoms with lamotrigine treatment 1
• Lamotrigine has good antiseizure activity and is recommended by the European Association of Neuro-Oncology (EANO) as a preferred option for seizure control 2

Safety Considerations

• Cenobamate (Xcopri) has significant adverse effects including somnolence (11-37%), dizziness (15-33%), fatigue (7-24%), and diplopia (6-17%) 3
• Cenobamate carries a risk of drug-drug interactions with multiple medication classes 3
• Cenobamate can cause serious adverse effects including drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening 3
• Lamotrigine requires slow titration to reduce the risk of serious rash (0.1% in studies), but this risk can be managed with proper dosing protocols 4

Treatment Approach for HPPD

First-Line Treatment

1. Start with lamotrigine:
   • Initial dosage: 25 mg daily
   • Titrate slowly over 6 weeks to target dose (typically 100-200 mg daily)
   • Monitor for rash, particularly during the first 8 weeks of treatment
   • Discontinue immediately if rash appears with fever or flu-like symptoms

Alternative Options if Lamotrigine is Ineffective or Not Tolerated

1. Benzodiazepines (particularly clonazepam) 5
2. Alpha-2 adrenergic agonists such as clonidine 1
3. Consider atypical antipsychotics in select cases (risperidone has shown efficacy in some case reports) 6

Clinical Monitoring

For Lamotrigine

• Baseline evaluation: Complete blood count, liver function tests
• Monitor for emergence of rash, especially during titration period
• Assess visual symptoms at each follow-up visit using standardized assessment
• Evaluate for psychiatric comorbidities that may complicate treatment

Important Considerations

• HPPD symptoms often include visual snow, floaters, palinopsia, photophobia, and nyctalopia 5
• Psychiatric comorbidities are common and should be addressed concurrently
• Avoid substances that may exacerbate symptoms, particularly cannabis and other hallucinogens

Cautions and Contraindications

For Lamotrigine

• Risk of serious rash including Stevens-Johnson syndrome (0.1% in studies)
• Requires slow titration to minimize risk
• Interactions with valproate (increases lamotrigine levels) and carbamazepine (decreases lamotrigine levels)

For Cenobamate

• Not studied specifically for HPPD
• High rate of adverse events (21% discontinuation rate at 400 mg/day dose) 3
• Multiple drug interactions with antiepileptic drugs and other medications 3
• Can shorten QT interval, requiring caution with other medications affecting cardiac conduction 3

Conclusion

Based on the available evidence, lamotrigine should be preferred over cenobamate for HPPD treatment due to its demonstrated efficacy in perceptual disturbances, more favorable side effect profile, and clinical experience in treating this condition. Cenobamate lacks specific evidence for HPPD treatment and carries significant risks of adverse effects and drug interactions.