The therapy, known as foslevodopa/foscarbidopa or LDp/CDp, is a soluble prodrug formulation of levodopa and carbidopa delivered through a small pump via continuous subcutaneous infusion. Unlike oral tablets, whose absorption in the gut is erratic and easily disrupted by meals and gastrointestinal slowdown, the infusion maintains a steady level of dopamine stimulation throughout the day and night. For patients with advanced disease whose brains can no longer buffer the peaks and troughs of oral medication, that steadiness translates into smoother motor control. But the same continuous dopaminergic stimulation can, in susceptible patients, tip the mesolimbic system toward hallucinations, psychosis, and compulsive behaviors.

Because pivotal trials excluded patients with significant cognitive impairment or severe psychiatric comorbidity, clinicians have lacked solid data on who is truly at risk. To fill that gap, a team of Italian researchers from two tertiary referral centers, the Parkinson Institute of Milan and the IRCCS Mondino Foundation in Pavia, retrospectively analyzed 77 consecutive patients with advanced Parkinson’s disease who had started LDp/CDp infusion, each followed for at least six months. The results, published in the Journal of Neurology, offer one of the clearest portraits yet of the therapy’s neuropsychiatric safety in everyday clinical care.

The cohort was typical of advanced Parkinson’s patients seen in specialist centers: a mean disease duration of nearly 14 years, moderate-to-severe motor burden on the MDS-UPDRS scale, and a substantial load of pre-existing vulnerabilities. Almost half of the patients met criteria for cognitive decline, with mild cognitive impairment in 41.6 percent and Parkinson’s disease dementia in 7.8 percent. A quarter had a history of hallucinations or psychosis, and roughly 27 percent had experienced impulse control disorders, the gambling, shopping, and hypersexual behaviors that can emerge with dopaminergic drugs. Notably, eight patients were already experiencing active but well-controlled neuropsychiatric symptoms when they began the infusion.

Over six months of treatment, the therapy delivered on its motor promise. Total levodopa equivalent daily dose rose by roughly 300 milligrams, and motor scores improved significantly: MDS-UPDRS III fell from 34.4 to 27.0, while Part IV scores, which capture fluctuations and dyskinesia, dropped from 8.3 to 5.25. At the same time, clinicians simplified the medication regimen, tapering dopamine agonists, COMT inhibitors, and MAO-B inhibitors, a move supported by recent analyses suggesting that infusion monotherapy can be as effective as polytherapy.

The psychiatric picture was more nuanced. New-onset neuropsychiatric adverse events emerged in 17 patients, or 22.1 percent of the cohort, at a median of 30 days after starting the pump. Hallucinations, mostly distressing visual phenomena occurring at night, accounted for about 41 percent of these events, followed by psychosis or delusional ideas at nearly 30 percent. Isolated cases of punding, aggression, and acute psychomotor agitation also appeared. This rate is higher than the 15 to 17 percent reported in the pivotal phase III trials, but the researchers attribute that gap to their deliberately unselected population, which included many patients that regulatory studies would have screened out.

Crucially, the story does not end with the adverse events themselves. Most episodes were managed successfully through straightforward measures: lowering the infusion rate, particularly at night, reducing or withdrawing dopamine agonists, and, when needed, adding low-dose atypical antipsychotics such as quetiapine or clozapine. Overall, 82 percent of events resolved or improved. Only three patients, just under 18 percent of those affected, had to abandon the therapy because of severe psychiatric complications. Across the entire cohort, the six-month dropout rate was 16.9 percent, with adverse events, bridging to deep brain stimulation, and device intolerance listed as the leading causes. One patient also developed a length-dependent lower-limb polyneuropathy detected on nerve conduction studies, prompting discontinuation as a precaution.

Perhaps the most clinically valuable finding came from the search for risk factors. Among all demographic, pharmacological, and cognitive variables tested, the baseline score on the Frontal Assessment Battery, or FAB, a short bedside test of executive function, stood out as the strongest independent predictor of neuropsychiatric adverse events, with lower scores roughly doubling the risk in the multivariable models. Daytime and nighttime infusion rates and total daily dose also contributed to risk, but FAB retained its predictive power across every regression model tested, outperforming the widely used MMSE global cognitive screen. Kaplan-Meier curves confirmed that patients below accepted FAB and MoCA thresholds accumulated new-onset events far faster than cognitively preserved peers.

The findings carry practical weight for dosing strategy. The Italian team maintained deliberately conservative flow rates, averaging 0.33 milliliters per hour during the day and 0.20 at night, which is well below the aggressive rates of roughly 0.60 milliliters per hour reported in smaller case series where severe neuropsychiatric complications were frequent. The authors suggest that continuous round-the-clock stimulation may promote mesolimbic hyperactivation and receptor desensitization, disrupting sleep architecture and precipitating nocturnal hallucinations in vulnerable brains. Reducing or pausing the nighttime infusion proved to be an effective first-line intervention, and the team also advocates inpatient initiation, slow titration, and preventive low-dose antipsychotics or acetylcholinesterase inhibitors for patients deemed high risk.

Encouragingly, patients who entered treatment with active but controlled hallucinations or impulse control disorders generally fared well, and the shift away from oral dopamine agonists appeared to ease compulsive behaviors, echoing the favorable pattern long reported with intestinal levodopa gel. The overall message is one of reassurance tempered by vigilance: LDp/CDp infusion is generally well tolerated even in a frail, cognitively mixed population, provided that frontal executive function is formally screened before treatment, titration is gradual, nighttime doses are kept low, and patients are monitored closely during the first weeks, when most events declare themselves. The researchers caution that their study was retrospective, uncontrolled, and limited to two expert centers, and they call for prospective multicenter trials with standardized infusion protocols to confirm the findings. For now, the results give clinicians a concrete roadmap for making this increasingly popular therapy safer for the patients who need it most.

Subject of Research: Real-world neuropsychiatric safety of continuous subcutaneous foslevodopa/foscarbidopa infusion in advanced Parkinson's disease

Article Title: Real-world neuropsychiatric safety profile of foslevodopa/foscarbidopa infusion in advanced Parkinson's disease

Article References: Real-world neuropsychiatric safety profile of foslevodopa/foscarbidopa infusion in advanced Parkinson's disease. (n.d.). https://doi.org/10.1007/s00415-026-14113-4

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14113-4

Keywords: Parkinson's disease, foslevodopa/foscarbidopa, subcutaneous levodopa infusion, neuropsychiatric adverse events, hallucinations, psychosis, impulse control disorders, frontal executive function, Frontal Assessment Battery, device-aided therapy, continuous dopaminergic stimulation, real-world evidence

The clinical backdrop is well understood. Levodopa, the gold-standard oral treatment introduced more than half a century ago, delivers dramatic symptom relief early in the disease. But as dopaminergic neurons continue to die, the therapeutic window of each dose narrows. Patients begin cycling unpredictably between “on” states, when medication controls their movement, and “off” states, when symptoms return with disabling force. To compensate, treatment regimens grow into complex schedules of multiple daily doses and adjunct drugs from several classes. Even then, many patients endure five or more hours of daily “off” time, alongside dyskinesia, adherence problems, and side effects. At that point, international guidelines agree that device-aided therapies should be considered: deep brain stimulation, levodopa-carbidopa intestinal gel, continuous subcutaneous apomorphine infusion, and, more recently, subcutaneous foslevodopa-foscarbidopa.

What has been missing until now is rigorous longitudinal evidence about what actually happens to these patients under real-world conditions. Previous data linking poor symptom control to disability, diminished quality of life, and caregiver strain came largely from retrospective analyses, cross-sectional snapshots, or follow-ups too brief to capture disease evolution. PROSPECT, led by Alberto J. Espay of the University of Cincinnati together with an international team, was designed to close that gap. Enrolled patients had a mean age of 67.8 years, roughly equal numbers of men and women, and had lived with Parkinson’s for an average of 8.9 years, with motor fluctuations present for about six years. All had at least 2.5 hours of daily “off” time despite an adequate trial of oral therapy, and none had previously used a device-aided treatment.

The study deliberately imposed no treatment protocol. Clinicians adjusted medications and offered device-aided therapies according to their own judgment, exactly as they would in routine care. Patients kept home diaries for three days before each six-month visit, logging their state every 30 minutes as asleep, off, or on, and noting any dyskinesia. The primary endpoint was the change in daily “off” time from baseline to month 24, normalized to a 16-hour waking day. Secondary measures spanned the MDS-UPDRS Part II for activities of daily living, the Non-Motor Symptoms Scale, sleep quality on the PDSS-2, disease-specific and generic quality of life on the PDQ-39 and EQ-5D-5L, activity impairment, treatment satisfaction, and caregiver strain.

The results split the cohort into two starkly different trajectories. Among the 184 patients, or 80.3 percent, who stayed solely on oral medications, “off” time fell only modestly, from a mean of 5.0 hours per day at baseline to 4.2 hours at month 24, an adjusted reduction of 0.7 hours that the authors characterize as statistically significant but clinically negligible. Meanwhile, scores for activities of daily living worsened, quality of life declined on both the PDQ-39 and EQ-5D-5L, and caregiver strain crept upward. Sleep disturbance also worsened at the 18-month mark. In short, these patients experienced the natural progression of their disease with little meaningful relief, despite regular contact with specialist care and ongoing medication optimization.

The contrasting group told a different story. Roughly half of all participants, 49.8 percent, were offered a device-aided therapy at some point during the study, most commonly neurosurgical options such as deep brain stimulation, followed by levodopa-carbidopa intestinal gel and subcutaneous apomorphine infusion. Of the 114 patients offered such a therapy, 44.7 percent declined. The most frequent reasons were needing more time to decide, cited by 54.9 percent of decliners, feeling the therapy was not yet necessary, at 45.1 percent, and safety concerns about the procedure, at 25.5 percent. Ultimately only 45 patients, 19.7 percent of the cohort, initiated a device-aided therapy during the two years.

Those who made the switch saw benefits that dwarfed anything achievable with pills alone. Their “off” time dropped from a mean of 4.8 hours per day at baseline to 2.6 hours at month 24, an adjusted reduction of 2.2 hours daily that was sustained from month 6 onward. This was accompanied by a significant 2.4-hour increase in “on” time without any dyskinesia, and both improvements were significantly greater than in the oral-medication group. Patients who initiated device-aided therapy also avoided the gradual worsening in daily functioning seen in their pill-only counterparts, and their levodopa-equivalent daily doses fell dramatically, from a mean of 1,149 milligrams at baseline to 553 milligrams at month 24, compared with essentially unchanged oral dosing in the other group. Sleep quality improved transiently, and treatment satisfaction rose at 18 months, although several quality-of-life measures in this smaller subgroup remained statistically unchanged.

The adoption gap exposes barriers on both sides of the consultation room. More than 40 percent of eligible patients were never even offered a device-aided option, a decision that rested entirely on physician judgment in the absence of standardized selection criteria or clear timing guidance. The authors point to prior evidence that clinicians’ recommendations vary with personal experience, perceived logistical hurdles, geographic availability, and the lack of head-to-head comparative data among modalities. Local access mattered too: continuous subcutaneous apomorphine infusion was commercially available in only four of the seven participating countries during the study, and a survey of Japanese neurologists showing a preference for non-surgical options may explain the disproportionately low uptake among Japanese patients. On the patient side, hesitancy, indecision, and the perception that invasive procedures can wait reflect a broader problem of inadequate shared decision-making, with studies showing patients often feel uninformed about their advanced-therapy options.

There are important caveats. The cohort was recruited from experienced movement disorder and general neurology clinics, so outcomes may differ for patients without access to expert care. Patient-reported diaries are vulnerable to recall bias and Hawthorne effects, in which awareness of being monitored alters behavior and perception. The device-aided subgroup was small, and patients could initiate therapy at any point, limiting statistical power and complicating comparisons among modalities. The authors also note that the study population appeared somewhat less severely affected at baseline than cohorts in previous device-therapy trials, likely because PROSPECT captured routine practice rather than trial-selected patients, and because the most symptomatic patients may have already initiated device therapy before enrollment. The 24-month window, while long for observational work in this space, may still have been too short to capture the full toll of progressive disease.

Even with those limitations, the message is difficult to ignore. Patients who remained on oral medications alone stayed largely uncontrolled for two years while their disability and quality of life slowly eroded, whereas those who accepted device-aided therapy achieved sustained, clinically meaningful reductions in “off” time consistent with the established efficacy of these treatments. The authors argue that earlier, proactive conversations among clinicians, patients, and caregivers, supported by structured decision aids and tools such as MANAGE-PD for identifying candidates, could help close the gap between eligibility and treatment. Whether earlier intervention ultimately translates into better long-term outcomes will require dedicated comparative studies with extended follow-up. For now, PROSPECT provides the clearest real-world picture yet of what happens when effective advanced therapies sit on the shelf: the disease simply keeps moving, and the patients move with it.

Subject of Research: Real-world treatment patterns and 24-month outcomes of Parkinson's disease patients with uncontrolled motor fluctuations, comparing continued oral medication with initiation of device-aided therapy in the PROSPECT observational study.

Article Title: Impact of Uncontrolled Motor Fluctuations in Parkinson’s Disease: Real-World Insights from the PROSPECT Observational Study

Article References: Espay, A. J., Defebvre, L., de Fabregues, O., Falconer, D., Hasegawa, K., Houghton, D., Ledingham, D., Lehn, A., Mestre, T. A., Oeda, T., Ory-Magne, F., Sarna, J. R., Safarpour, D., Colman, S., Bergmann, L., Kukreja, P., Onuk, K., Yan, C. H., & Alonso, P. S. (2026). Impact of Uncontrolled Motor Fluctuations in Parkinson’s Disease: Real-World Insights from the PROSPECT Observational Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03793-z

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03793-z

Keywords: Parkinson's disease, motor fluctuations, device-aided therapy, deep brain stimulation, levodopa-carbidopa intestinal gel, off time, quality of life, PROSPECT study, observational study, advanced Parkinson's disease, levodopa, real-world evidence