Fabrizio Stocchi

Introduction: Parkinson’s disease (PD) affects approximately 1% of individuals over the age of 60, with its prevalence increasing in older populations. Clinical manifestations can be effectively controlled during the first years of disease but progressively medications effect shortens with appearance of motor complications and dyskinesia. Areas covered: Management of PD primarily aims to restore dopaminergic activity through pharmacological interventions such as levodopa, which effectively alleviates motor symptoms and extends life expectancy. Early initiation of treatment improves bradykinesia, rigidity, and tremor; however, as the disease advances, the therapeutic response to levodopa shortens, leading to complications such as motor fluctuations and dyskinesia. In advanced Parkinson’s disease (aPD), the emergence of the “wearing-off” phenomenon and unpredictable “on/off” fluctuations—where symptoms reappear despite medications—poses significant challenges for disease management. Expert opinion: Device-aided therapies, including deep brain stimulation and continuous infusion of apomorphine or levodopa, provide effective management options for advanced Parkinson’s disease (aPD) when oral medications fail to adequately control symptoms. Continuous subcutaneous apomorphine infusion (CSAI) has demonstrated both efficacy and long-term tolerability; however, its clinical adoption remains limited due to challenges in patient selection and referral, treatment initiation and handling of the device. This review examines the available infusion therapies, with a particular focus on CSAI, and aims to provide clinicians with evidence-based guidance for optimizing treatment selection in aPD.

Since its first use in the early 1960s for the treatment of Parkinson’s disease (PD), dopamine substitution therapy with oral levodopa continues to be the most effective primary treatment of this c...

As of today, levodopa remains the cornerstone of symptomatic management in Parkinson’s disease (PD). As PD progresses, the limitations of immediate-release (IR) levodopa/carbidopa, such as its short half-life and inconsistent absorption, result in unstable fluctuating levodopa plasma concentrations. These fluctuations contribute to motor complications including wearing off, delayed ON responses, and dyskinesias. To maintain symptom control, patients often require frequent dosing or, eventually, transition to device-aided therapies (DATs). Although effective, these therapies are invasive and require intensive clinical monitoring. IPX203, a next-generation modified-release (MR) levodopa/carbidopa formulation, may address these challenges. Approved by the US Food and Drug Administration (FDA) in 2024, IPX203 combines IR granules and extended-release (ER) pellets within a single capsule. IPX203 is designed to improve levodopa delivery and absorption, enhancing therapeutic benefit. It ensures both rapid onset and sustained levodopa plasma concentrations, minimising peak-to-trough fluctuations and reducing dosing frequency. The formulation delivers 100% of the carbidopa and 25% of the levodopa dose via IR granules, while the remaining 75% of levodopa is gradually released from ER pellets engineered with sustained release, mucoadhesive, and enteric coatings to optimise proximal small intestinal absorption. Clinical studies have shown that IPX203 significantly reduces OFF time, increases Good ON time, and improves motor symptom control compared with IR levodopa/carbidopa. It may also extend symptom relief into the following morning. This review outlines the pharmacological rationale and clinical evidence supporting IPX203 therapy, highlighting its potential to enhance motor control and improve patients’ quality of life, thereby supporting a more personalised and sustained approach to PD management.

Background Progressive supranuclear palsy (PSP) is a rare neuro-degenerative disease. The Deep Transcranial Magnetic Stimulation (DTMS) has been proposed as a therapeutic approach in Parkinson’s Disease but there are few studies that have evaluated its efficacy in PSP. Aim and Methods This was a pilot, randomized, cross-over, double blind trial, with the aim to evaluate the effect of DTMS on motor functions, freezing of gait, and cognitive performance in patients with PSP. Nineteen subjects were recruited and randomly assigned to one of the study sequences: real-sham or sham-real. Each cycle consisted of 12 sessions of high frequency DTMS over a 4-week period, separated by a 5-week wash-out period. The targets were the motor cortex and the dorsolateral prefrontal cortex. Results After adjusting for baseline scores, an interaction effect between DTMS and period of administration emerged for the PSP scale; it was estimated that the real treatment applied to the first period induced a decrease of about 0.79 points (p=0.41) and 4 point (p=0.01) when administered in the second period. Improvement in gait and be relevant since early falls and gait dysfunction have a great impact on disability. Patients and caregivers appreciated the improvements but for a short period of time (about a week). Conclusion This is the first crossover, double blind, randomized clinical trial to use DTMS in patients with PSP. DMTS was associated with a motor and non-motor improvement in PSP patients. Trial registration clinicaltrial.gov: NCT02734485

Dysphagia is a manifestation of swallowing dysfunction frequently observed in Parkinson’s disease (PD). It can lead to serious clinical consequences when the patient experience aspiration or chest infections. Even in less severe cases, dysphagia significantly affects patients' quality of life. Understanding the pathophysiology underlying PD-related dysphagia is important for proper classification and for objectifying swallowing abnormalities with clinical evaluation. This review explores the mechanisms of swallowing, the various aspect of swallowing abnormalities, and their impact on the quality of life of PD patients—especially in relation to impaired responses to levodopa—and discusses suggested therapeutic approaches. In our opinion, true dysphagia in PD is less common than often believed. Swallowing difficulties may reflect oropharyngeal and/or lingual bradykinesia. Hypokinesia, a hallmark motor symptom of PD, may affect swallowing reflex and result in prolonged pharyngeal reflex times due to slow, sequential muscle movements. Symptoms such ad difficulty swallowing, food retention, sensation of food in the esophagus, and the need to drink liquids to aid bolus transit are more indicative of bradykinesia than dysphagia. Therefore, swallowing abnormalities should be carefully assessed and properly classified, with tailored pharmacological treatment and dietary adjustments for each individual case.

Objective To evaluate the efficacy of istradefylline in Parkinson’s disease patients experiencing motor fluctuations with and without dyskinesia and characterize potential predictors for treatment-emergent dyskinesia with istradefylline.Methods Pooled analysis of 8 phase 2b/3 trials of istradefylline (20 or 40 mg/day) versus placebo.Results Data from 2,719 patients, 56% of whom presented with baseline dyskinesia, were analyzed post hoc. The presence of baseline dyskinesia did not affect the mean decrease in “OFF” time with dyskinesia, increase in “ON” time without troublesome dyskinesia, or improvement in the Unified Parkinson’s Disease Rating Scale motor score associated with istradefylline treatment. Dyskinesia was reported in 17% of patients receiving istradefylline, with higher rates for women (21%), patients with a BMI <18.5 kg/m2 (22%), and patients receiving catechol-o-methyltransferase inhibitors plus dopamine agonists (22%) and monoamine oxidase B inhibitors (25%).Conclusion Istradefylline treatment resulted in greater reductions in total “OFF” hours/day and increases in “ON” time without troublesome dyskinesia than did placebo, regardless of the presence or absence of preexisting dyskinesia.

Background: Parkinson's disease (PD) is a neurodegenerative disorder associated with motor and nonmotor symptoms. Objectives: This study assesses levodopa dose management, the therapeutic goals of clinicians, the factors that influence clinicians' choice of therapy, and the role of nonmotor symptoms using real‐world evidence from Germany, Italy, and Spain. Methods: To assess the management of unstable PD patients on levodopa‐containing regimens, neurologists were asked to complete questionnaires (n = 181) and prospective electronic patient records (EPR) were collected (n = 2687). Neurologists were asked questions about their practice and approach to unstable PD patients. EPRs were completed by neurologists after each visit with patients, and the objectives of any changes to therapy were recorded. Results: Seventy‐four percent of neurologists cited “improving motor symptoms” as the main objective for increasing daily levodopa dose. This was also the main objective when starting an add‐on (50%) and the main reason for selecting a new add‐on therapy (29%). In comparison, reducing nonmotor symptoms, depression, and pain was rarely cited as either the main or secondary objective for a therapy selection (15%, 9%, and 9%, respectively) even when over 60% of unstable patients had pain or depression and 29% had both. When the importance of add‐on therapy features was rated, “improve quality of life (QoL)” had the highest average score. Improving nonmotor symptoms, pain, and depression was among the lowest‐rated therapy feature. Conclusions: These findings suggest that improving motor symptoms is a key driver of therapeutic choice. In prioritizing motor symptoms, neurologists may unintentionally neglect nonmotor symptoms, despite most patients suffering from pain or depression.

Background: Parkinson's disease (PD) is often associated with depression, which poses an additional burden for patients and their families. However, evidence regarding the optimal treatment for depression in PD remains limited, with insufficient data supporting the efficacy of most antidepressant drugs. Methods: The primary objective of this pilot, prospective, open-label, single-arm study was to analyze the safety and tolerability of vortioxetine drops on depressive symptoms in PD patients over 16 weeks of treatment. The secondary objective was to study vortioxetine';s effectiveness on depression. Results: Sixteen out of 20 PD patients who completed the study demonstrated that the treatment was safe and well tolerated; no change in PD symptom severity, abnormality of clinical parameters, body weight, or ECG emerged. The most common side effect was nausea. Depressive symptoms rated by the Beck Depression Inventory and the Hamilton Depression Rating Scale score (HAM-D-17) showed a significant improvement at the end of the study period without a worsening of motor functions, as measured by UPDRS part III. The majority of patients also reported an improvement in depressive symptoms measured by the Patient Global Impression of Improvement scale. Conclusion: Vortioxetine is a safe and well-tolerated therapeutic approach for depression in Parkinson's disease. As a secondary objective, an improvement in depressive symptoms was observed. However, the study's open-label design and small sample size limit the generalizability of the findings.

Background: Evidence suggests that female gender represents a risk factor for the development of motor/nonmotor fluctuations and dyskinesia in Parkinson's disease (PD). So far, no prospective study has analyzed this aspect in relation to the introduction of levodopa treatment. Objective: This prospective multicenter study aims to assess the development of motor/nonmotor fluctuations and dyskinesia based on gender over a 2‐year observation period in PD patients starting levodopa. Methods: Two hundred and eighty‐nine PD patients requiring levodopa at baseline were enrolled at 17 Movement Disorders Centers and followed for 2 years. Gender differences in the development of fluctuations, defined as a score ≥2 in the 19‐item Wearing‐Off Questionnaire, and dyskinesia, defined by Movement Disorders Society Unified Parkinson's Disease Rating Scale Part IV (MDS‐UPDRS‐IV) score >0 on item 4.1 were assessed. Baseline predictors of such complications were evaluated by stepwise multivariate logistic regression analysis. Results: Two hundred and sixteen patients (139 men, 77 women) completed the follow‐up (M24). By M24, 53,2% of men and 64.9% of women had fluctuations ( P = 0.048), whereas 5% of men and 14.3% of women developed dyskinesia ( P = 0.0185). Multivariate analysis showed that female gender significantly predicted wearing‐off (Odds ratio [OR] = 1.930; P = 0.0333), whereas older age was a significant protective factor (for 5‐year increase: OR = 0.712; P < 0.0001). Multivariate analysis showed that gender (OR = 3.405; P = 0.0228) and MDS‐UPDRS Part III score (for a 5‐unit increase: OR = 1.281; P = 0.0239) were significant predictors of dyskinesia at M24. Conclusions: Female gender was the strongest predictor of fluctuations and dyskinesia after 2‐year intake of levodopa. This finding could have important implications for the development of gender‐oriented therapeutic recommendations in early PD.