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

OBJECTIVE: 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 clinical trials. This study aimed 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 involving 36 consecutive aPD patients who underwent CSFLI with a six-month follow-up. Neuropsychiatric/cognitive worsening was defined as any clinically meaningful increase in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I or the Parkinson's Disease Questionnaire-8 (PDQ-8) cognitive/psychiatric subscores. Patients were classified as "worsening" versus "no worsening" and compared with respect to 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 was common in 57.9% of the patients in the stable group versus 11.8% in the worsening group (p=0.006), with clozapine use corresponding to 63.2% of the patients versus 23.5% (p=0.023). Conversely, catechol-O-methyltransferase 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 the patient's neuropsychiatric status. CONCLUSION: In a vulnerable real-world aPD population, neuropsychiatric/cognitive worsening under CSFLI was more frequent than it was in pivotal trials (47% vs. 7%-17%) but was generally mild and not associated with 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. These findings support broader CSFLI use with structured neuropsychiatric monitoring and proactive clozapine in selected patients.