Introduction: Parkinson’s disease (PD) involves the progressive loss of dopaminergic neurons, leading to motor and non-motor symptoms that significantly impact patients’ quality of life. Safinamide modulates dopaminergic and glutamatergic systems, offering a promising treatment approach. Methods: This meta-analysis evaluated the efficacy of safinamide as an add-on therapy to levodopa for PD patients with motor fluctuations. Following PRISMA guidelines, literature searches were conducted in PubMed and Embase (2014–2022). Inclusion criteria were studies on adult PD patients receiving safinamide with levodopa. Outcomes included on-time without troublesome dyskinesia, off-time, UPDRS Part III motor scores, UPDRS Part II activities of daily living scores, PDQ-39 emotional well-being, and GRID-HAMD scores. Results: Among thirteen eligible studies, safinamide significantly improved on-time without troublesome dyskinesia at 100 mg/day (mean difference [MD]: −0.90; 95% CI: −1.12 to −0.67; p < 0.00001) and 50 mg/day (MD: −0.77; 95% CI: −1.21 to −0.34; p = 0.0005) compared to placebo. It also reduced off-time (100 mg/day: MD: −0.94; 95% CI: −1.19 to −0.70; p < 0.00001; 50 mg/day: MD: −0.72; 95% CI: −1.03 to −0.41; p < 0.00001) and improved UPDRS-III motor scores (100 mg/day: MD: −3.01; 95% CI: −4.15 to −1.86; p < 0.00001; 50 mg/day: MD: −2.93; 95% CI: −5.14 to −0.71; p = 0.001). Mood improvements were noted in PDQ-39 emotional well-being scores (MD: −5.22; 95% CI: −6.90 to −3.54) and GRID-HAMD scores (MD: −0.60; 95% CI: −0.95 to −0.25; p = 0.0009). Safinamide also positively affected pain (RR: 1.10; 95% CI: 1.03 to 1.18). Conclusion: Compared to placebo, safinamide significantly benefits motor and non-motor symptoms in PD patients, but further research is necessary to fully explore its therapeutic potential.

Parkinson’s disease (PD) is a progressive disorder characterized by the neurodegeneration of dopaminergic neurons in the nigrostriatal system [1‒3]. It leads to significant disability, reduced health-related quality of life, and a substantial economic burden on health systems [1, 2, 4].

Secondly only to Alzheimer’s among neurodegenerative disorders, the prevalence of PD is increasing globally [2, 4]. In Western Europe alone, there were an estimated 1.24 million cases in 2019, a 70% increase since 1990 [4]. Based on population projections by the US Census Bureau, it is estimated that in the USA, the number of individuals with PD will increase to 1,238,000 by 2030 [5].

The loss of dopaminergic innervation leads to motor symptoms such as rest tremor, rigidity, and bradykinesia, as well as some non-motor symptoms like cognitive impairment, depression, pain, sleep disorders, and urinary problems [1, 2]. However, not all non-motor symptoms can be attributed to the loss of dopaminergic innervation. Non-motor symptoms result from the spreading of aggregated alpha-synuclein in the brain and autonomic nervous system. Additionally, other degenerative processes, vascular lesions, and drug treatments may also contribute to the development of these symptoms [6]. No disease-modifying treatments are available [3, 7, 8]. The mainstay of Parkinson’s treatment involves administering levodopa in combination with carbidopa or benserazide [9, 10]. Levodopa, a dopamine precursor, helps replenish dopamine levels in the brain [10], while the co-administration of levodopa with a peripheral decarboxylase inhibitor (carbidopa or benserazide) inhibits the peripheral metabolism of levodopa to dopamine [1, 3, 7, 9, 10]. However, the short plasma half-life of levodopa introduces motor complications such as “wearing-off” and dyskinesia (the so-called motor fluctuations) [11, 12]. Due to the progressive nature of PD, symptoms tend to worsen over time, and patients can develop resistance to treatment [3, 8, 10, 13]. Motor fluctuations can be managed through various strategies, including adjusting oral dopamine agonists, using extended-release levodopa formulations, fractionating levodopa doses, or employing medications that inhibit the breakdown of levodopa, such as monoamine oxidase B (MAO-B) inhibitors and catechol-O-methyltransferase inhibitors.

MAO-B, an enzyme located in the outer mitochondrial membrane, plays a crucial role in breaking down dopamine and converting it into 3,4-dihydroxyphenylacetic acid within glial cells in the striatum [14]. Three MAO-B inhibitors, namely, selegiline, rasagiline, and safinamide, have received approval for use. Unlike the other two drugs in the class, safinamide (Xadago®, Zambon S.p.A., Bresso, Italy) has a unique dual mechanism of action: it is a potent and reversible MAO-B inhibitor and a glutamate modulator [8]. Studies have demonstrated that safinamide improves motor fluctuations in PD patients [7, 8]. However, due to its distinctive dual mechanism of action, safinamide may offer benefits beyond treating motor fluctuations, potentially improving some non-motor symptoms such as pain, mood, and sleep [15‒17].

This meta-analysis aims to address the effects of safinamide as an add-on therapy to levodopa in patients with PD experiencing motor fluctuations. Our study extends the findings of previous reviews, by incorporating additional studies, providing a more comprehensive evaluation of non-motor symptoms, and including real-world observational data to enhance the generalizability of our findings.

Search Strategy and Study Selection

This meta-analysis was prepared in compliance with the PRISMA guidelines [18]. To identify relevant studies, a comprehensive literature search was performed using the PubMed and Embase databases with the search terms “safinamide” and “Parkinson’s disease.” The specific search strategies used are detailed in Table 1. The inclusion criteria for selecting studies were as follows:

  • 1.

    The study involved adult patients diagnosed with idiopathic PD according to the UK Parkinson’s Disease Society Brain Bank Criteria; patients at any stage of PD, ranging from mid to advanced stages, were considered eligible.

  • 2.

    The patients received safinamide as an add-on therapy to levodopa.

  • 3.

    Safinamide was compared with either a placebo or another treatment.

Table 1.

Details of the search strategies

DatabaseSearch termsFiltersResults
PubMed “safinamide,” “Parkinson’s disease” Timeline: 2014–2022 27 
MeSH strategy: (“safinamide” [Supplementary Concept] OR “safinamide” [All Fields]) AND (“parkinson disease” [MeSH Terms] OR (“parkinson” [All Fields] AND “disease” [All Fields]) OR “parkinson disease” [All Fields] OR “parkinson s disease” [All Fields]) English, humans, case reports, clinical study, clinical trial, comment, controlled clinical trial, multicentre study, observational study, pragmatic clinical trial, RCT 
Embase “safinamide,” “Parkinson’s disease” Limited to 2014–2022 31 
Article 
English language 
Clinical trial, RCT, controlled clinical trial, multicentre study, phase 1 clinical trial, phase 2 clinical trial, phase 3 clinical trial, phase 4 clinical trial 
DatabaseSearch termsFiltersResults
PubMed “safinamide,” “Parkinson’s disease” Timeline: 2014–2022 27 
MeSH strategy: (“safinamide” [Supplementary Concept] OR “safinamide” [All Fields]) AND (“parkinson disease” [MeSH Terms] OR (“parkinson” [All Fields] AND “disease” [All Fields]) OR “parkinson disease” [All Fields] OR “parkinson s disease” [All Fields]) English, humans, case reports, clinical study, clinical trial, comment, controlled clinical trial, multicentre study, observational study, pragmatic clinical trial, RCT 
Embase “safinamide,” “Parkinson’s disease” Limited to 2014–2022 31 
Article 
English language 
Clinical trial, RCT, controlled clinical trial, multicentre study, phase 1 clinical trial, phase 2 clinical trial, phase 3 clinical trial, phase 4 clinical trial 

MeSH, Medical Subject Headings.

Inclusion criteria also covered real-world observational studies to enhance the generalizability of our findings. No risk-of-bias assessment was performed on the selected studies as it falls beyond the scope of this meta-analysis.

Data Extraction

The extracted data included the number of patients randomized in each treatment arm and the results of prespecified efficacy outcomes, divided into three categories: mood, motor symptoms, and non-motor symptoms. For motor symptoms, several outcomes were analysed, including on-time without troublesome dyskinesia, off-time, Unified Parkinson’s Disease Rating Scale [UPDRS] Part III motor scores during on-time, and UPDRS Part II activities of daily living scores during on-time, all analysed separately for safinamide 100 mg/day and 50 mg/day. For non-motor symptoms, mood (assessed using the Parkinson’s Disease Questionnaire 39 [PDQ-39] emotional well-being score and GRID-Hamilton Depression Rating Scale [GRID-HAMD] score), pain, sleep, daytime sleepiness (assessed using PDSS2, PSQI, and ESS), and urinary problems (assessed using SCOPA-AUT-U) were examined.

Statistical Analysis

Meta-analysis was performed where there were at least two included studies with available data for assessed outcomes. Some studies were excluded from individual meta-analyses for specific outcomes due to methodological and statistical reasons. For continuous outcomes, the mean difference (MD) and 95% confidence intervals (CIs) were calculated with the method of the weighted generic inverse variance on MD. For dichotomous outcomes, the Mantel-Haenszel method was used to estimate measures of effect as odds ratios with 95% CI. Both random- and fixed-effects modelling were used, with the random-effects modelling being applied to both continuous and dichotomous data.

Homogeneity was tested through the I-squared statistic (I2). Statistical analysis and forest plots were generated using IBM SPSS Statistics for Windows, version 21.0, Armonk, NY: IBM Corp.

Meta-Analysis

Thirteen studies fulfilled the eligibility criteria for inclusion in this meta-analysis and reported data for the outcomes of interest. Nine studies were excluded from the meta-analysis as none of them included a comparator arm (shown in Fig. 1). The selected studies consisted of six randomized controlled trials (RCTs; n = 2,502), four post hoc/pooled analyses of data from the RCTs, and three smaller real-world (observational/retrospective) studies (n = 201). Most studies compared safinamide 100 mg/day and/or 50 mg/day with placebo, except for the real-world studies which used other treatments (e.g., rasagiline) or no treatment as a comparator. In the double-blind, parallel-group, 24-week trial of safinamide (50–100 mg/day orally) versus placebo conducted by Schapira et al. [19] (the SETTLE study), patients started with a 50 mg dose, which could be increased to 100 mg if tolerated. Since 90.9% and 94.1% of patients in the safinamide and placebo groups, respectively, assumed the 100 mg dose, we considered all patients in the safinamide arm of this trial to be treated with this dosage for analysis purposes. Details of the papers included are shown in Table 2.

Fig. 1.

PRISMA flow diagram for the study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Fig. 1.

PRISMA flow diagram for the study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

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Table 2.

Details of all included studies reporting data for the outcomes of interest

StudyStudy designPatients, nTreatmentSettingOutcomes of interest
Borgohain et al. [20] (Study 016; NCT01187966) Multinational (India, Italy, Romania), phase III, 24-week, randomized, double-blind, placebo-controlled, parallel-group study 669 Safinamide 50 mg/day versus safinamide 100 mg/day versus placebo Mid- to late-stage PD and motor fluctuations with levodopa Mood 
  • PDQ-39 emotional well-being scores

  • GRID-HAMD scale scores

 
Motor symptoms 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Borgohain et al. [21] (Study 018; NCT01286935) Multinational (India, Italy, Romania), 18-month, randomized, double-blind, placebo-controlled, parallel-group, extension of Study 016 554 Safinamide 50 mg/day versus safinamide 100 mg/day versus placebo Mid- to late-stage PD and motor fluctuations with levodopa; completed Study 016 and/or completed scheduled week 12 and 24 efficacy evaluations Motor symptoms 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Cattaneo et al. [22Post hoc analysis of pooled data from the double-blind phases of Study 016 and SETTLE 971 Safinamide 100 mg/day versus placebo Mid- to late-stage PD, experiencing motor fluctuations while receiving levodopa 
  • Motor symptoms

 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Cattaneo et al. [23Post hoc analysis of pooled 6-month data from Study 016 and SETTLE 995 Safinamide 100 mg/day versus placebo Mid- to late-stage PD, experiencing motor fluctuations while receiving levodopa Pain 
Cattaneo et al. [24Post hoc analysis of pooled 6- and 24-month data from Study 016 and Study 018 846 Safinamide 100 mg/day versus placebo Mid- to late-stage PD, experiencing motor fluctuations while receiving levodopa 
  • Mood

 
  • PDQ-39 emotional well-being scores

  • GRID-HAMD scale scores

 
Cattaneo et al. [25Post hoc analysis of 2-year data from Study 018 355 Safinamide 100 mg/day versus placebo Mid- to late-stage PD and motor fluctuations with levodopa Pain 
Gómez-López et al. [26] (SURINPARK) Single-centre, retrospective cohort study 110 Safinamide versus other treatment (i.e., no change, levodopa/COMT inhibitor, dopamine agonist, MAO-I, dopamine agonist + levodopa) PD and motor fluctuations with levodopa Urinary problems 
Hattori et al. [3] (JapicCTI-153056) 24-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group study 395 Safinamide 50 mg/day versus safinamide 100 mg/day versus placebo Japanese patients with PD and wearing-off and modified H&Y stage II–IV during off-time phase; receiving levodopa for ≥24 weeks 
  • Motor symptoms

 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Kulisevsky et al. [27Multicentre, 24-week, randomized, double-blind, placebo-controlled, parallel-group study 30 Safinamide 50 mg/day (2 weeks) then 100 mg/day (22 weeks) versus placebo PD with mild-to-moderate motor severity and apathy 
  • Apathy

 
  • PDQ-39 emotional well-being scores

  • GRID-HAMD scale scores

 
Liguori et al. [28Observational, retrospective study 61 Safinamide versus rasagiline PD with motor fluctuations Sleep 
Plastino et al. [16Single-centre, longitudinal, population-based case-control study 30 Safinamide 50 mg/day (3 months), then no treatment (3 months) versus no treatment (3 months), then safinamide 50 mg/day (3 months) PD and rapid eye movement sleep behaviour disorder Sleep 
Schapira et al. [19] (SETTLE; NCT00627640) Multicentre, 24-week, phase III, randomized, double-blind, parallel-group study 549 Safinamide 50 mg/day (2 weeks), then safinamide 100 mg/day (22 weeks) versus placeboa Mid- to late-stage PD and motor fluctuations with levodopa 
  • Mood

 
  • GRID-HAMD scale scores

  • Motor symptoms

  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Wei et al. [29] (XINDI; NCT03881371) 16-week, phase III, multicentre, randomized, double-blind, placebo-controlled study 305 Safinamide 50 mg (2 weeks), then safinamide 100 mg (14 weeks) versus placebo Chinese patients with PD and motor fluctuations with levodopa Mood 
  • PDQ-39 emotional well-being scores

 
Motor symptoms 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
StudyStudy designPatients, nTreatmentSettingOutcomes of interest
Borgohain et al. [20] (Study 016; NCT01187966) Multinational (India, Italy, Romania), phase III, 24-week, randomized, double-blind, placebo-controlled, parallel-group study 669 Safinamide 50 mg/day versus safinamide 100 mg/day versus placebo Mid- to late-stage PD and motor fluctuations with levodopa Mood 
  • PDQ-39 emotional well-being scores

  • GRID-HAMD scale scores

 
Motor symptoms 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Borgohain et al. [21] (Study 018; NCT01286935) Multinational (India, Italy, Romania), 18-month, randomized, double-blind, placebo-controlled, parallel-group, extension of Study 016 554 Safinamide 50 mg/day versus safinamide 100 mg/day versus placebo Mid- to late-stage PD and motor fluctuations with levodopa; completed Study 016 and/or completed scheduled week 12 and 24 efficacy evaluations Motor symptoms 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Cattaneo et al. [22Post hoc analysis of pooled data from the double-blind phases of Study 016 and SETTLE 971 Safinamide 100 mg/day versus placebo Mid- to late-stage PD, experiencing motor fluctuations while receiving levodopa 
  • Motor symptoms

 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Cattaneo et al. [23Post hoc analysis of pooled 6-month data from Study 016 and SETTLE 995 Safinamide 100 mg/day versus placebo Mid- to late-stage PD, experiencing motor fluctuations while receiving levodopa Pain 
Cattaneo et al. [24Post hoc analysis of pooled 6- and 24-month data from Study 016 and Study 018 846 Safinamide 100 mg/day versus placebo Mid- to late-stage PD, experiencing motor fluctuations while receiving levodopa 
  • Mood

 
  • PDQ-39 emotional well-being scores

  • GRID-HAMD scale scores

 
Cattaneo et al. [25Post hoc analysis of 2-year data from Study 018 355 Safinamide 100 mg/day versus placebo Mid- to late-stage PD and motor fluctuations with levodopa Pain 
Gómez-López et al. [26] (SURINPARK) Single-centre, retrospective cohort study 110 Safinamide versus other treatment (i.e., no change, levodopa/COMT inhibitor, dopamine agonist, MAO-I, dopamine agonist + levodopa) PD and motor fluctuations with levodopa Urinary problems 
Hattori et al. [3] (JapicCTI-153056) 24-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group study 395 Safinamide 50 mg/day versus safinamide 100 mg/day versus placebo Japanese patients with PD and wearing-off and modified H&Y stage II–IV during off-time phase; receiving levodopa for ≥24 weeks 
  • Motor symptoms

 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Kulisevsky et al. [27Multicentre, 24-week, randomized, double-blind, placebo-controlled, parallel-group study 30 Safinamide 50 mg/day (2 weeks) then 100 mg/day (22 weeks) versus placebo PD with mild-to-moderate motor severity and apathy 
  • Apathy

 
  • PDQ-39 emotional well-being scores

  • GRID-HAMD scale scores

 
Liguori et al. [28Observational, retrospective study 61 Safinamide versus rasagiline PD with motor fluctuations Sleep 
Plastino et al. [16Single-centre, longitudinal, population-based case-control study 30 Safinamide 50 mg/day (3 months), then no treatment (3 months) versus no treatment (3 months), then safinamide 50 mg/day (3 months) PD and rapid eye movement sleep behaviour disorder Sleep 
Schapira et al. [19] (SETTLE; NCT00627640) Multicentre, 24-week, phase III, randomized, double-blind, parallel-group study 549 Safinamide 50 mg/day (2 weeks), then safinamide 100 mg/day (22 weeks) versus placeboa Mid- to late-stage PD and motor fluctuations with levodopa 
  • Mood

 
  • GRID-HAMD scale scores

  • Motor symptoms

  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 
Wei et al. [29] (XINDI; NCT03881371) 16-week, phase III, multicentre, randomized, double-blind, placebo-controlled study 305 Safinamide 50 mg (2 weeks), then safinamide 100 mg (14 weeks) versus placebo Chinese patients with PD and motor fluctuations with levodopa Mood 
  • PDQ-39 emotional well-being scores

 
Motor symptoms 
  • On-time without troublesome dyskinesia

  • Off-time

  • UPDRS-III motor scores during on-time

  • UPDRS-II activities of daily living scores during on-time

 

COMT, catechol-O-methyltransferase; GRID-HAMD, GRID-Hamilton Depression Rating Scale; H&Y, Hoehn & Yahr; MAO-I, monoamine oxidase inhibitor; PD, Parkinson’s disease; PDQ-39, Parkinson’s Disease Questionnaire 39; UPDRS, Unified Parkinson’s Disease Rating Scale.

aSince 90.9% and 94.1% of patients in the safinamide and placebo groups, respectively, received safinamide at the higher dose of 100 mg/day, data were analysed as safinamide 100 mg/day.

Efficacy Outcomes

Motor Symptoms

On-Time without Troublesome Dyskinesia. Six studies reported data on time without troublesome dyskinesia: Borgohain et al. [20] from now on Study 016; Borgohain et al. [21] from now on Study 018; Cattaneo et al. [22], Schapira et al. [19], Hattori et al. [3], and Wei et al. [23]. All studies reported data for safinamide at doses of 100 mg/day and 50 mg/day and were included in the meta-analysis. On-time without troublesome dyskinesia was significantly improved with both safinamide 100 mg/day versus placebo (MD = −0.90; 95% CI: −1.12 to −0.67; p < 0.00001; shown in Fig. 2a) and safinamide 50 mg/day versus placebo with random-effects modelling (MD = −0.77; 95% CI: −1.21 to −0.34; p = 0.0005; shown in Fig. 2c). Similar results were obtained with fixed-effects modelling (shown in Fig. 2b, d).

Fig. 2.

Meta-analysis of on-time without troublesome dyskinesia with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b) and with safinamide 50 mg/day using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

Fig. 2.

Meta-analysis of on-time without troublesome dyskinesia with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b) and with safinamide 50 mg/day using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

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Off-Time. Six studies reported data regarding off-time, all of which were included in the meta-analysis [3, 19‒23], and all of them reported data for safinamide at doses of 100 mg/day and 50 mg/day. Off-time was significantly improved with both safinamide 100 mg/day versus placebo (MD = −0.94; 95% CI: −1.19 to −0.70; p < 0.00001; shown in Fig. 3a) and safinamide 50 mg/day versus placebo with random-effects modelling (MD = −0.72; 95% CI: −1.03 to −0.41; p < 0.00001; shown in Fig. 3c). Similar results were obtained with fixed-effects modelling (shown in Fig. 3b, d).

Fig. 3.

Meta-analysis of off-time with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b) and with safinamide 50 mg/day using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

Fig. 3.

Meta-analysis of off-time with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b) and with safinamide 50 mg/day using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

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UPDRS-III (Motor Scores) On-Time. Four out of the six studies reporting data regarding UPDRS-III during on-time were included in the meta-analysis for safinamide 100 mg/day (Study 016, Schapira et al. [19], Hattori et al. [3], Wei et al. [23]), and two, i.e., Study 016 and Hattori et al. [3], were included in the meta-analysis for safinamide 50 mg/day. Study 018 and the study by Cattaneo and colleagues [22] were excluded from the meta-analysis for safinamide 100 mg/day because they did not report the least squares means for the difference between safinamide and placebo. UPDRS-III motor scores during on-time were significantly improved with both safinamide 100 mg/day versus placebo (MD = −3.01; 95% CI: −4.15 to −1.86; p < 0.00001; shown in Fig. 4a) and safinamide 50 mg/day versus placebo with random-effects modelling (MD = −2.93; 95% CI: −5.14 to −0.71; p = 0.001; shown in Fig. 4c). Similar results were obtained with fixed-effects modelling (shown in Fig. 4b, d).

Fig. 4.

Meta-analysis of UPDRS-III motor scores during on-time with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b) and with safinamide 50 mg/day using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

Fig. 4.

Meta-analysis of UPDRS-III motor scores during on-time with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b) and with safinamide 50 mg/day using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

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UPDRS-II (Activities of Daily Living) Scores with Safinamide 100 mg/Day. Six studies reported data for UPDRS-II during on-time, but only three were included in the meta-analysis [3, 19, 23]. Study 016, Study 018, and the study by Cattaneo and colleagues were excluded because they did not report the least squares means for the difference between safinamide and placebo. The scores for UPDRS-II activities of daily living during on-time were significantly improved with safinamide versus placebo (MD = −0.71; 95% CI: −1.26 to −0.17; p = 0.01; shown in Fig. 5a). Similar results were obtained with fixed-effects modelling (shown in Fig. 5b).

Fig. 5.

Meta-analysis of UPDRS-II activities of daily living scores during on-time with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

Fig. 5.

Meta-analysis of UPDRS-II activities of daily living scores during on-time with safinamide 100 mg/day using random- (a) and fixed-effects modelling (b). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SE, standard error.

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Non-Motor Symptoms

Mood

PDQ-39 Emotional Well-Being Domain Scores. The meta-analysis of PDQ-39 emotional well-being data included only the studies by Cattaneo, Müller [24], and Kulisevsky et al. [25]. Safinamide significantly improved mood according to PDQ-39 emotional well-being scores compared with placebo, with an overall MD of −5.22 (95% CI: −6.90 to −3.54) in the random-effects model (p < 0.00001; shown in Fig. 6a) and fixed-effects model (shown in Fig. 6b).

Fig. 6.

Meta-analysis of PDQ-39 emotional well-being scores using random- (a) and fixed-effects modelling (b), and GRID-HAMD scale scores using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SD standard deviation.

Fig. 6.

Meta-analysis of PDQ-39 emotional well-being scores using random- (a) and fixed-effects modelling (b), and GRID-HAMD scale scores using random- (c) and fixed-effects modelling (d). Pooled effect estimates use fixed-effects modelling. CI, confidence interval; SD standard deviation.

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GRID-HAMD Scale Scores. Only three of the studies that reported GRID-HAMD scale score data were included in the meta-analysis [19, 24, 25]. It is worth noting that Kulisevsky and colleagues used the original HAMD Scale. In our analysis, safinamide significantly improved mood according to GRID-HAMD scores compared with placebo, with an overall MD of −0.60 (95% CI: −0.95 to −0.25) in the random-effects model (p < 0.0009; shown in Fig. 6c) and fixed-effects model (shown in Fig. 6d).

Pain. Only the studies by Cattaneo et al. [26] and Cattaneo et al. [27] reported data on the use of concomitant pain drugs and were included in our meta-analysis. Safinamide had a beneficial effect on pain compared with placebo (shown in Fig. 7), with a greater probability of not requiring concomitant pain medication with safinamide than with placebo (pooled effect estimate: risk ratio 1.10; 95% CI: 1.03 to 1.18).

Fig. 7.

Forest plot for the proportion of patients not using concomitant pain treatments during the study period. The RR and 95% CI for each study are displayed on a logarithmic scale. The pooled effect estimate used random-effects modelling. CI, confidence interval; RR, risk ratio.

Fig. 7.

Forest plot for the proportion of patients not using concomitant pain treatments during the study period. The RR and 95% CI for each study are displayed on a logarithmic scale. The pooled effect estimate used random-effects modelling. CI, confidence interval; RR, risk ratio.

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Side Effects. The most commonly reported adverse events in patients treated with safinamide were dyskinesia (as expected with drugs that increase levodopa bioavailability), nausea, and insomnia. Dyskinesia was always mild or moderate and did not require drug interruption. In the placebo group, the main adverse events were nausea and headache. There was no statistically significant difference in the number or percentage of adverse events between safinamide and placebo.

Sleep. Of the two studies that reported sleep data [16, 28], only one paper contained relevant data [16]; therefore, meta-analysis was not possible. The other study was excluded from the meta-analysis because it did not report the least squares mean for the difference between safinamide and rasagiline [28].

PD is a complex disorder that extends beyond motor dysfunction, encompassing a wide range of non-motor symptoms including fatigue, mood and sleep disorders, cognitive dysfunction, dementia, psychosis, hallucinations, pain, and urinary incontinence [29, 30]. Pain, experienced by 30–85% of PD patients, is usually managed with a range of treatments including analgesics, anti-inflammatory drugs, anti-rheumatic drugs, and topical products. Mood disorders, particularly depression and anxiety, are also prevalent in PD patients (depression and anxiety range from 2.7 to 90% and 6 to –55%, respectively) and significantly impact their quality of life [31].

In PD, the degeneration of nigrostriatal dopaminergic neurons triggers chain reactions leading to the glutamatergic overstimulation of the basal ganglia output nuclei and substantia nigra pars compacta. Ultimately, this results in the motor and non-motor symptom characteristics of PD (i.e., dyskinesia, chronic pain, and mood disorders) [26, 32]. These observations suggest that glutamatergic neurotransmission could be a potential target for PD pharmacotherapy.

In this context, safinamide, an orally administered α-aminoamide derivative, emerges as an effective treatment. Its unique dual mechanism of action includes potent, selective, and reversible MAO-B inhibition, and blockade of voltage-dependent Na+ and Ca2+ channels, which inhibits stimulated glutamate release. This dual action enables safinamide to target both dopaminergic and glutamatergic receptors [33].

Our meta-analysis shows that safinamide, at doses of 100 or 50 mg/day, benefits motor symptoms when used as an add-on therapy to levodopa in PD patients with motor fluctuations. The positive effects extend to non-motor symptoms, such as pain and mood, which are particularly relevant for PD patients. However, the limited data on safinamide’s effects on sleep and urinary symptoms, as well as the need for comparisons with other therapies, necessitate further investigation. The included studies did not provide sufficient data to calculate the PDQ-39 total score. Therefore, we were unable to provide a detailed analysis of this overall score. However, PDQ-39 emotional well-being scores provide a meaningful assessment of patients’ quality of life. Future studies should include a more comprehensive evaluation of the PDQ-39 total score to obtain a more comprehensive picture of the treatment effect.

Our review differs from previous safinamide analyses in several aspects. Our analysis included a detailed assessment of non-motor symptoms, such as emotional well-being and depression, as measured by the PDQ-39 and GRID-HAMD scores. This expands the scope of previous reviews that have focused primarily on the motor symptoms of Parkinson’s. To improve the generalizability of the results and provide a more complete picture of the effectiveness of safinamide in clinical practice, our meta-analysis integrated data from real-world observational studies. Previous reviews have mainly compared safinamide with other MAO-B inhibitors (e.g., [34, 35]) or focused on specific symptoms such as pain [17] or depression [36]. We took a more comprehensive approach to evaluate the effects of safinamide on both motor and non-motor domains. Our review also includes more recent studies that may not have been included in previous analyses and covers a longer research period from 2014 to 2022. Overall, this review offers a more exhaustive evaluation of the efficacy of safinamide in PD, positioning itself as a unique and complementary contribution to existing literature.

Several other studies corroborate our findings. Systematic reviews and meta-analyses have examined the effects of safinamide in various PD settings. A recent systematic review specifically investigating the efficacy and safety of different safinamide dosages versus placebo, with or without concurrent dopaminergic treatment, found support for the use of safinamide at 100 and 50 mg/day as an add-on to levodopa for PD patients with motor fluctuations. This review also emphasized the need for more research on relevant non-motor symptoms [13].

In contrast to the review by Giossi et al. [13], who focused primarily on motor symptoms and overall safety, our meta-analysis presents a new perspective. Our study provides a more thorough assessment of non-motor symptoms such as pain and mood and incorporates additional investigations. Furthermore, our analysis increases the generalizability of our results and provides a broader scope of application by incorporating current real-world data and observational studies.

Similarly, another systematic review and meta-analysis confirmed the benefits of safinamide on motor fluctuations (i.e., on time without troublesome dyskinesia, off-time, and UPDRS-III score) and quality of life (i.e., UPDRS-II, PDQ-39, and HAMD scores) compared with placebo in patients with PD and motor fluctuations [7]. Safinamide is effective in controlling non-motor symptoms of PD. A systematic review confirmed the beneficial effects of safinamide on motor fluctuations and non-motor symptoms when administered as monotherapy or add-on therapy in patients with PD [15]. Two meta-analyses of RCTs specifically evaluating the effectiveness of various therapies against non-motor symptoms showed that safinamide was more effective at reducing pain than other therapies (such as cannabinoids, opioids, catechol-O-methyltransferase inhibitors) [17], and that MAO-B inhibitors (including safinamide, selegiline, and rasagiline) relieve depression, especially in patients with early PD [36].

Studies using the Non-Motor Symptoms Scale (NMSS) for PD have demonstrated the positive impact of safinamide on various non-motor symptoms, resulting in a significant reduction of the overall burden of the disease [37‒40]. Moreover, safinamide has shown promising effects on mood and emotional well-being, as well as pain relief. Multiple studies have reported its positive influence on mood [24], pain, and pain management [26, 27, 39, 41]. Some studies have observed an improvement of up to 43% (p < 0.0001) in pain [39], along with a reduced reliance on pain medications [26, 27]. Furthermore, when compared to placebo, safinamide has also shown improvements in GRID-HAMD scores for depression [24, 42] and PDQ-39 “emotional well-being” domain scores [39, 43].

Our meta-analysis findings suggest that safinamide, modulating both the dopaminergic and glutamatergic systems, shows promise as an effective treatment for PD patients with both motor and non-motor symptoms, potentially leading to an improved quality of life. However, further research is needed to fully comprehend its potential, particularly in addressing sleep and urinary issues, and to compare its efficacy with other treatments. However, caution is warranted in interpreting our results due to the absence of the risk-of-bias assessments in the selected studies.

The current study is a comprehensive meta-analysis of the clinical efficacy of safinamide, an α-aminoamide derivative, in addressing motor and non-motor symptoms in PD patients. The findings suggest that, compared to placebo, safinamide, with its unique dual mechanism of action on dopaminergic and glutamatergic systems, significantly improves motor symptoms such as on-time without troublesome dyskinesia, off-time, and UPDRS-III motor scores during on-time when used as an add-on therapy to levodopa. More significantly, this study also highlights the potential of safinamide in positively influencing non-motor symptoms, specifically mood and pain, which are often overlooked in PD treatment. However, the effects of safinamide on sleep and urinary symptoms remain somewhat unclear due to the limited data available. Therefore, further comprehensive research is required to fully comprehend the therapeutic potential of safinamide in these domains, as well as its comparison with other treatments.

Editorial assistance was provided by Andrea Bothwell and Maurizio Tarzia on behalf of Springer Healthcare Communications, and statistical assistance for the meta-analysis was provided by Giorgio Reggiardo. All assistance was funded by Zambon S.p.A.

A statement of ethics is not applicable because this study is based exclusively on published literature. All authors have provided their consent for the publication of this meta-analysis. They agree with the content, and there are no conflicts regarding the submission and dissemination of the findings.

A.S. and H.F. declare no conflict of interest. H.R. has received consulting fees and conference fees from Zambon, BIAL, UCB, Kyowa Kirin, DESITIN, and Stadapharm. J.K. has received consulting fees from Roche, Zambon, Sanofi, Esteve, SOM Biotech, Lundbeck, AC Immune, and Merck Sharp & Dohme; conference fees from Zambon, Teva, BIAL, UCB, Roche, General Electric, AbbVie, and Britannia; and research funds from CIBERNED, Carlos III Health Institute, and Fundació La Marató de TV3.

This work was supported by Zambon S.p.A.

J.K., H.F., A.S., and H.R. provided critical intellectual contributions to the interpretation of data for the work and to the manuscript drafts, and have read and agreed to the published version of the manuscript.

The data supporting this meta-analysis are from previously reported studies that have been cited and are therefore publicly available. Further inquiries can be directed to the corresponding author Jaime Kulisevsky Bojarski, [email protected].

1.
Gilbert
R
,
Khemani
P
.
Treatment of advanced Parkinson’s disease
.
J Geriatr Psychiatry Neurol
.
2022
;
35
(
1
):
12
23
.
2.
Bloem
BR
,
Okun
MS
,
Klein
C
.
Parkinson’s disease
.
Lancet
.
2021
;
397
(
10291
):
2284
303
.
3.
Hattori
N
,
Tsuboi
Y
,
Yamamoto
A
,
Sasagawa
Y
,
Nomoto
M
;
ME2125-3 Study Group
.
Efficacy and safety of safinamide as an add-on therapy to L-DOPA for patients with Parkinson’s disease: a randomized, double-blind, placebo-controlled, phase II/III study
.
Parkinsonism Relat Disord
.
2020
;
75
:
17
23
.
4.
Ou
Z
,
Pan
J
,
Tang
S
,
Duan
D
,
Yu
D
,
Nong
H
, et al
.
Global trends in the incidence, prevalence, and years lived with disability of Parkinson’s disease in 204 countries/territories from 1990 to 2019
.
Front Public Health
.
2021
;
9
:
776847
.
5.
Marras
C
,
Beck
JC
,
Bower
JH
,
Roberts
E
,
Ritz
B
,
Ross
GW
, et al
.
Prevalence of Parkinson’s disease across north America
.
NPJ Parkinsons Dis
.
2018
;
4
:
21
.
6.
Mendoza-Velásquez
JJ
,
Flores-Vázquez
JF
,
Barrón-Velázquez
E
,
Sosa-Ortiz
AL
,
Illigens
B-MW
,
Siepmann
T
.
Autonomic dysfunction in α-synucleinopathies
.
Front Neurol
.
2019
;
10
:
363
.
7.
Abdelalem Aziz Ahmed
M
.
A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson’s disease
.
F1000Res
.
2019
;
8
:
2078
.
8.
Alborghetti
M
,
Nicoletti
F
.
Different generations of type-B monoamine oxidase inhibitors in Parkinson’s disease: from bench to bedside
.
Curr Neuropharmacol
.
2019
;
17
(
9
):
861
73
.
9.
Pringsheim
T
,
Day
GS
,
Smith
DB
,
Rae-Grant
A
,
Licking
N
,
Armstrong
MJ
, et al
.
Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of the aan guideline subcommittee
.
Neurology
.
2021
;
97
(
20
):
942
57
.
10.
Beckers
M
,
Bloem
BR
,
Verbeek
MM
.
Mechanisms of peripheral levodopa resistance in Parkinson’s disease
.
NPJ Parkinsons Dis
.
2022
;
8
(
1
):
56
.
11.
Stocchi
F
.
The levodopa wearing-off phenomenon in Parkinson’s disease: pharmacokinetic considerations
.
Expert Opin Pharmacother
.
2006
;
7
(
10
):
1399
407
.
12.
Stocchi
F
,
Jenner
P
,
Obeso
JA
.
When do levodopa motor fluctuations first appear in Parkinson’s disease
.
Eur Neurol
.
2010
;
63
(
5
):
257
66
.
13.
Giossi
R
,
Carrara
F
,
Mazzari
M
,
Lo Re
F
,
Senatore
M
,
Schicchi
A
, et al
.
Overall efficacy and safety of safinamide in Parkinson’s disease: a systematic review and a meta-analysis
.
Clin Drug Investig
.
2021
;
41
(
4
):
321
39
.
14.
Binda
C
,
Hubálek
F
,
Li
M
,
Herzig
Y
,
Sterling
J
,
Edmondson
DE
, et al
.
Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class
.
J Med Chem
.
2004
;
47
(
7
):
1767
74
.
15.
Sharaf
J
,
Williams
KAD
,
Tariq
M
,
Acharekar
MV
,
Guerrero Saldivia
SE
,
Unnikrishnan
S
, et al
.
The efficacy of safinamide in the management of Parkinson’s disease: a systematic review
.
Cureus
.
2022
;
14
(
9
):
e29118
.
16.
Plastino
M
,
Gorgone
G
,
Fava
A
,
Ettore
M
,
Iannacchero
R
,
Scarfone
R
, et al
.
Effects of safinamide on REM sleep behavior disorder in Parkinson disease: a randomized, longitudinal, cross-over pilot study
.
J Clin Neurosci
.
2021
;
91
:
306
12
.
17.
Qureshi
AR
,
Rana
AQ
,
Malik
SH
,
Rizvi
SFH
,
Akhter
S
,
Vannabouathong
C
, et al
.
Comprehensive examination of therapies for pain in Parkinson’s disease: a systematic review and meta-analysis
.
Neuroepidemiology
.
2018
;
51
(
3–4
):
190
206
.
18.
Liberati
A
,
Altman
DG
,
Tetzlaff
J
,
Mulrow
C
,
Gøtzsche
PC
,
Ioannidis
JP
, et al
.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration
.
PLoS Med
.
2009
;
62
(
10
):
e1
34
.
19.
Schapira
AH
,
Fox
SH
,
Hauser
RA
,
Jankovic
J
,
Jost
WH
,
Kenney
C
, et al
.
Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations: a randomized clinical trial
.
JAMA Neurol
.
2017
;
74
(
2
):
216
24
.
20.
Borgohain
R
,
Szasz
J
,
Stanzione
P
,
Meshram
C
,
Bhatt
M
,
Chirilineau
D
, et al
.
Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations
.
Mov Disord
.
2014
;
29
(
2
):
229
37
.
21.
Borgohain
R
,
Szasz
J
,
Stanzione
P
,
Meshram
C
,
Bhatt
MH
,
Chirilineau
D
, et al
.
Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease
.
Mov Disord
.
2014
;
29
(
10
):
1273
80
.
22.
Cattaneo
C
,
Sardina
M
,
Bonizzoni
E
.
Safinamide as add-on therapy to levodopa in mid-to late-stage Parkinson’s disease fluctuating patients: post hoc analyses of studies 016 and SETTLE
.
J Parkinsons Dis
.
2016
;
6
(
1
):
165
73
.
23.
Wei
Q
,
Tan
Y
,
Xu
P
,
Tao
E
,
Lu
Z
,
Pan
X
, et al
.
The XINDI study: a randomized phase III clinical trial evaluating the efficacy and safety of safinamide as add-on therapy to levodopa in Chinese patients with Parkinson’s disease with motor fluctuations
.
CNS Drugs
.
2022
;
36
(
11
):
1217
27
.
24.
Cattaneo
C
,
Müller
T
,
Bonizzoni
E
,
Lazzeri
G
,
Kottakis
I
,
Keywood
C
.
Long-Term effects of safinamide on mood fluctuations in Parkinson’s disease
.
J Parkinsons Dis
.
2017
;
7
(
4
):
629
34
.
25.
Kulisevsky
J
,
Martínez-Horta
S
,
Campolongo
A
,
Pascual-Sedano
B
,
Marín-Lahoz
J
,
Bejr-Kasem
H
, et al
.
A randomized clinical trial to evaluate the effects of safinamide on apathetic non-demented patients with Parkinson’s disease
.
Front Neurol
.
2022
;
13
:
866502
.
26.
Cattaneo
C
,
Barone
P
,
Bonizzoni
E
,
Sardina
M
.
Effects of safinamide on pain in fluctuating Parkinson’s disease patients: a post-hoc analysis
.
J Parkinsons Dis
.
2017
;
7
(
1
):
95
101
.
27.
Cattaneo
C
,
Kulisevsky
J
,
Tubazio
V
,
Castellani
P
.
Long-term efficacy of safinamide on Parkinson’s disease chronic pain
.
Adv Ther
.
2018
;
35
(
4
):
515
22
.
28.
Liguori
C
,
Stefani
A
,
Ruffini
R
,
Mercuri
NB
,
Pierantozzi
M
.
Safinamide effect on sleep disturbances and daytime sleepiness in motor fluctuating Parkinson’s disease patients: a validated questionnaires-controlled study
.
Parkinsonism Relat Disord
.
2018
;
57
:
80
1
.
29.
Barone
P
,
Antonini
A
,
Colosimo
C
,
Marconi
R
,
Morgante
L
,
Avarello
TP
, et al
.
The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease
.
Mov Disord
.
2009
;
24
(
11
):
1641
9
.
30.
Hussl
A
,
Seppi
K
,
Poewe
W
.
Nonmotor symptoms in Parkinson’s disease
.
Expert Rev Neurother
.
2013
;
13
(
6
):
581
3
.
31.
Cui
S-S
,
Du
J-J
,
Fu
R
,
Lin
Y-Q
,
Huang
P
,
He
Y-C
, et al
.
Prevalence and risk factors for depression and anxiety in Chinese patients with Parkinson disease
.
BMC Geriatr
.
2017
;
17
(
1
):
270
.
32.
Jenner
P
,
Caccia
C
.
The role of glutamate in the healthy brain and in the pathophysiology of Parkinson’s disease
.
Eur Neurol Rev
.
2019
;
14
:
2
12
.
33.
Olanow
CW
,
Stocchi
F
.
Safinamide: a new therapeutic option to address motor symptoms and motor complications
. In:
Mid-to late-stage Parkinson’s disease
.
Touchmedical Media
;
2016
.
34.
Binde
CD
,
Tvete
IF
,
Gåsemyr
J
,
Natvig
B
,
Klemp
M
.
A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson’s disease
.
Br J Clin Pharmacol
.
2018
;
84
(
9
):
1917
27
.
35.
Binde
CD
,
Tvete
IF
,
Gåsemyr
JI
,
Natvig
B
,
Klemp
M
.
Comparative effectiveness of dopamine agonists and monoamine oxidase type-B inhibitors for Parkinson’s disease: a multiple treatment comparison meta-analysis
.
Eur J Clin Pharmacol
.
2020
;
76
(
12
):
1731
43
.
36.
Huang
YH
,
Chen
JH
,
Loh
EW
,
Chan
L
,
Hong
CT
.
The effect of monoamine oxidase-B inhibitors on the alleviation of depressive symptoms in Parkinson’s disease: meta-analysis of randomized controlled trials
.
Ther Adv Psychopharmacol
.
2021
;
11
:
2045125320985993
.
37.
De Masi
C
,
Liguori
C
,
Spanetta
M
,
Fernandes
M
,
Cerroni
R
,
Garasto
E
, et al
.
Non-motor symptoms burden in motor-fluctuating patients with Parkinson’s disease may be alleviated by safinamide: the VALE-SAFI study
.
J Neural Transm
.
2022
;
129
(
11
):
1331
8
.
38.
De Micco
R
,
Satolli
S
,
Siciliano
M
,
De Mase
A
,
Giordano
A
,
Tedeschi
G
, et al
.
Effects of safinamide on non-motor, cognitive, and behavioral symptoms in fluctuating Parkinson’s disease patients: a prospective longitudinal study
.
Neurol Sci
.
2022
;
43
(
1
):
357
64
.
39.
Santos García
D
,
Labandeira Guerra
C
,
Yáñez Baña
R
,
Cimas Hernando
MI
,
Cabo López
I
,
Paz Gonález
JM
, et al
.
Safinamide improves non-motor symptoms burden in Parkinson’s disease: an open-label prospective study
.
Brain Sci
.
2021
;
11
(
3
):
316
.
40.
Bianchi
MLE
,
Riboldazzi
G
,
Mauri
M
,
Versino
M
.
Efficacy of safinamide on non-motor symptoms in a cohort of patients affected by idiopathic Parkinson’s disease
.
Neurol Sci
.
2019
;
40
(
2
):
275
9
.
41.
Geroin
C
,
Di Vico
IA
,
Squintani
G
,
Segatti
A
,
Bovi
T
,
Tinazzi
M
.
Effects of safinamide on pain in Parkinson’s disease with motor fluctuations: an exploratory study
.
J Neural Transm
.
2020
;
127
(
8
):
1143
52
.
42.
Pena
E
,
Borrue
C
,
Mata
M
,
Martinez-Castrillo
JC
,
Alonso-Canovas
A
,
Chico
JL
, et al
.
Impact of SAfinamide on depressive symptoms in Parkinson’s disease patients (SADness-PD Study): a multicenter retrospective study
.
Brain Sci
.
2021
;
11
(
2
):
232
11
.
43.
Stocchi
F
,
Vacca
L
,
Grassini
P
,
Tomino
C
,
Caminiti
G
,
Casali
M
, et al
.
Overnight switch from rasagiline to safinamide in Parkinson’s disease patients with motor fluctuations: a tolerability and safety study
.
Eur J Neurol
.
2021
;
28
(
1
):
349
54
.