Neuropsychiatric and Cognitive Safety of Subcutaneous Foslevodopa/Foscarbidopa in Advanced Parkinson’s Disease: Insights From a Real-World Cohort

Background Continuous subcutaneous foslevodopa/foscarbidopa infusion (CSFLI) represents a transformative therapy for advanced Parkinson's disease (aPD), but real-world neuropsychiatric safety data remain limited, particularly in populations typically excluded from trials. Objective: To assess the frequency, clinical patterns, and predictors of neuropsychiatric and/or cognitive worsening in a real-world CSFLI-treated cohort.

Methods We performed a retrospective observational study of 36 consecutive aPD patients initiating CSFLI with six-month follow-up. Neuropsychiatric/cognitive worsening was defined as any clinically meaningful increase in MDS-UPDRS Part I or PDQ-8 cognitive/psychiatric subscores. Patients were classified as "worsening" versus "no worsening" and compared for baseline characteristics. Predictors were identified using univariable and exploratory multivariable analyses.

Results Seventeen patients (47.2%) experienced neuropsychiatric/cognitive worsening within six months. Critically, patients with prior confusion or hallucinations who were managed with baseline clozapine had significantly better outcomes: confusion history 57.9% in stable group versus 11.8% in worsening group (p=0.006); clozapine use 63.2% versus 23.5% (p=0.023). Conversely, COMT inhibitor (COMT-I) use was more frequent in the worsening group (70.6% vs 21.1%, p=0.006). Motor outcomes remained stable at 6 months regardless of neuropsychiatric status.

Conclusions In a vulnerable real-world aPD population, neuropsychiatric/cognitive worsening under CSFLI was more frequent than in pivotal trials (47% vs 7-17%) but generally mild and without motor deterioration. Importantly, proactive clozapine use enabled safe CSFLI treatment in patients with psychiatric histories traditionally considered high-risk. COMT-I emerged as a modifiable risk factor. Findings support broader CSFLI use with structured neuropsychiatric monitoring and proactive clozapine in selected patients.