This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [8] . The review protocol was registered on PROSPERO: CRD42024518717 and vetted by a professional research librarian. An extensive literature search on the MAO-B inhibitor Rasagiline was performed using PubMed, Cochrane, and EBSCO electronic databases and manual searches. They were searched from inception to March 21st, 2024. Searches were restricted to articles in the English language and randomized controlled trials (RCTs). Appendix 1 provides a detailed list of search terms utilized.

The Unified Parkinson’s Disease Rating Scale (UPDRS) is a frequently used outcome measure to quantify the severity and progression of PD. The UPDRS includes four sections that assess: (1) mentation, behavior, and mood (UPDRS I), (2) activities of daily living (UPDRS II), (3) motor symptoms (UPDRS III), and (4) complications of therapy in patients with PD (UPDRS IV). Clinicians and researchers use the sectional and total scores to assess the status of PD symptoms and monitor the disease progress [9] . The 39-item Parkinson's Disease Questionnaire (PDQ-39) is a patient-reported outcome measure that assesses the quality of life for individuals with PD and includes eight domains: (1) mobility, (2) activities of daily living, (3) emotional well-being, (4) stigma, (5) social support, (6) cognitions, (7) communications, and (8) bodily discomfort [10] . OFF time is a frequently used outcome measure to quantify the time when the motor and non-motor symptoms of individuals with PD return between medication doses. OFF time can occur in the morning before the first dose of medication or it can occur during the day between scheduled doses of medication [11] . UPDRS total, UPDRS Part II, and UPDRS Part III scores, PDQ-39 total, PDQ-39 mobility, PDQ-39 activities of daily living, and PDQ-39 bodily discomfort scores, and OFF time were used to assess the progression of motor symptoms in individuals with PD. UPDRS Part I scores, PDQ-39 emotional well-being, PDQ-39 stigma, PDQ-39 social support, PDQ-39 cognition, and PDQ-39 communication scores were used to assess the progression of non-motor symptoms in individuals with PD.

Studies were included with the following criteria: female and male individuals aged 30 or over with a clinical diagnosis of PD consistent with the UK Brain Bank criteria [12] who have a Hoehn and Yahr (H&Y) Stage 5 or less. The intervention studied is the MAO-B inhibitor Rasagiline and the outcomes assessed are UPDRS total, UPDRS Part I, UPDRS Part II, and UPDRS Part III scores, PDQ-39 total and subdomain scores, and/or OFF time. The study design search was limited to Randomized Controlled Trials (RCTs) published in English ( Table 1 ).

Studies were excluded with the following criteria: individuals with a mini-mental state examination score of 24 or less. Studies were also excluded if the outcomes assessed were not UPDRS total, UPDRS Part I, UPDRS Part II, or UPDRS Part III scores, PDQ-39 total or subdomain scores, or OFF time, or if the study design was expert opinion, editorial, case report, abstracts without full results, and preprints.

Two reviewers (PA, MW) independently screened all titles and abstracts of the identified studies. Full texts were obtained for the studies deemed eligible from the initial screening. Two reviewers (PA, MW) independently reviewed full texts. Any discrepancies were discussed and resolved through discussion between reviewers (PA, MW).

Data were extracted into a standardized form that included lead author, publication date, country, study design, intervention type, sample size, age, and results for UPDRS total, UPDRS Part I, UPDRS Part II, and UPDRS Part III scores, PDQ-39 total and subdomain scores, and OFF time outcome measures by one independent reviewer (PA). A second reviewer (MW) conducted a reliability check. No discrepancies in data extraction were identified between the reviewers. If there was missing data, the authors were contacted for additional information.

Methodological quality was examined using the Cochrane Risk of Bias 2 (RoB 2) tool [13] . The RoB 2 is structured into five domains of bias: (1) randomization process, (2) deviations from the intended interventions (effect of assignment and adhering to intervention), (3) missing outcome data, (4) measurement of the outcome, and (5) selection of the reported result. From the results in each domain, an overall risk of bias was determined. Overall risk of bias was judged as high risk of bias, some concerns, or low risk of bias. Two reviewers (PA, MW) independently conducted the risk of bias analysis. Any discrepancies were discussed and resolved through discussion between reviewers (PA, MW).

We performed a random-effects meta-analysis using the Hedges’ g method to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) of 1 mg/day Rasagiline compared to placebo on UPDRS total, UPDRS Part I, UPDRS Part II, and UPDRS Part III scores, PDQ-39 total and subdomain scores, and OFF time. The SMD and 95% CI were estimated when at least two or more studies included the same outcome measure. An SMD value of less than 0.20 was considered trivial, 0.20 to 0.49 was considered a small effect, 0.50 to 0.79 was considered a medium effect, and 0.80 and above was considered a large effect [14] .

We assessed heterogeneity using Q, p, and I² values and the 95% prediction interval (PI). The I² value of 0% - 40% was interpreted as small heterogeneity, 30% - 60% as moderate heterogeneity, 50% - 90% as substantial heterogeneity, and 75% - 100% as considerable heterogeneity [15] . The 95% PI was estimated when the meta-analysis included more than two studies. Publication bias was assessed in meta-analyses with at least ten studies [16] . Publication bias was assessed by inspection of the standard error funnel plots, trim-and-fill analysis, Egger’s regression test, and Begg and Mezumdar’s rank correlation test. If a meta-analysis did not include at least ten studies, the standard error funnel plot was still generated for qualitative review. All statistical analyses were conducted using STATA 18 (StataCorp. Stata statistical software: release 18. College Station, TX: StataCorp LP. 2023).

Two reviewers (PA, MW) independently assessed the certainty of evidence using the GRADE approach for each meta-analysis (GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University and Evidence Prime, 2022. Available from gradepro.org) [17] . Each meta-analysis was classified as very low, low, moderate, or high-quality certainty of evidence.

The electronic search of databases yielded 528 articles. One-hundred-forty-seven articles were found to be duplicates, leaving a total of 381 articles. Three-hundred-thirty-seven articles were excluded after reviewing titles and abstracts. The remaining 44 articles were retrieved and assessed for eligibility. Thirty articles were excluded because they did not meet the inclusion criteria. Fourteen remaining articles were found eligible and included in the review [18] - [31] ( Figure 1 ). Eleven of the included articles were utilized to perform meta-analyses. Three articles [20] [23] [31] could not be included in the meta-analysis due to missing data.

As summarized in Table 2 , 4621 participants were assessed in studies across Europe [21] , Denmark [20] , Italy [27] , Hungary [18] , Israel [18] [20] [21] [22] , Turkey [24] , China [25] , Japan [29] [30] [31] , Argentina [21] , Canada [23] , and the United States [19] [23] [26] [28] . The duration of the studies ranged between 10 to 72 weeks. Three studies included a 0.5 mg/day Rasagiline group [18] [20] [29] , all studies included a 1 mg/day Rasagiline group [18] - [31] , four studies included a 2 mg/day Rasagiline group [18] [19] [22] [23] , and one study included a 4 mg/day Rasagiline group [19] . All studies included a placebo as the control.

The mean age of individuals ranged from 57.4 to 67.4 years in the Rasagiline groups and from 57 to 67.9 in the placebo groups. The H&Y Stage of individuals was 5 or less. The mean range of H&Y scores for the Rasagiline groups was 1 - 1.9 in three studies [19] [22] [23] , 2 - 2.9 in five studies [20] [24] [28] [30] [31] , and 3 - 4 in one study [29] . The mean range of H&Y scores for the placebo group was 1 - 1.9 in four studies [19] [22] [23] [29] , 2 - 2.9 in four studies [20] [28] [30] [31] , and 3 - 4 in one study [29] . One study reported one individual in the 1 - 1.5 H&Y score range, nine individuals in the 2 - 2.5 range, 16 individuals in the 3 - 4 range for the Rasagiline groups, and three individuals in the 2 - 2.5 range, and three individuals in the 3 - 4 range for the placebo group [18] . One study reported 21 individuals in the 1 - 1.5 H&Y range, 34 individuals in the 2 - 2.5 range, three individuals in the 3-4 range for the Rasagiline group, and 20 individuals in the 1 - 1.5 range, 40 individuals in the 2 - 2.5 range, and five individuals in the 3 - 4 range for the placebo group [27] . The mean percentage of female individuals ranged from 21 to 61.1%.

The overall risk of bias was low for three included studies [19] [21] [25] , some concerns for nine included studies [20] [22] [23] [24] [26] [27] [28] [29] [30] , and high risk for two included studies [18] [31] ( Figure 2 ). In nine studies [18] [20] [23] [24] [26] [27] [28] [29] [30] , the cause of some concern in the first domain was the lack of information regarding intervention allocation techniques. In two studies [20] [22] , the cause of some concern in the second domain was the lack of statistical analyses to account for participants who dropped out. In one study [18] , the cause of high concern in the second domain was inconsistent data with participant drop-out. In one study [31] , the cause of high concern in the first domain was the lack of randomization due to the study being open-label.

All included studies assessed outcomes immediately following the intervention. In four studies [18] [19] [22] [26] , UPDRS total scores were an efficacy endpoint. In two studies [29] [30] , UPDRS Part I scores were an efficacy endpoint. In six studies [21] [24] [26] [28] [29] [30] , UPDRS Part II and UPDRS Part III scores were efficacy endpoints. In three studies [27] [29] [30] , PDQ-39 total, PDQ-39 mobility, PDQ-39 activities of daily living, PDQ-39 emotional well-being, PDQ-39 stigma, PDQ-39 social support, PDQ-39 cognition, PDQ-39 communication, and PDQ-39 bodily discomfort scores were efficacy endpoints. In three studies [21] [25] [29] , OFF time was an efficacy endpoint.

Four studies [16] [18] [19] [22] (n = 1264) investigated the effect of 1 mg/day Rasagiline compared to placebo on UPDRS total scores. There was a small and statistically significant overall effect on UPDRS total scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.31; 95% CI −0.53, −0.08). There was a moderate and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 6.01, p = 0.11, I² = 52.56%; 95% PI −1.14, 0.53) ( Figure 3 ). Asymmetry was observed in the funnel plot ( Appendix 2 ).

Six studies [21] [24] [26] [28] [29] [30] (n = 1484) investigated the effect of 1 mg/day Rasagiline compared to placebo on UPDRS Part II scores. There was a small and statistically significant overall effect on UPDRS Part II scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.37; 95% CI −0.52, −0.21). There was a moderate and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 9.73, p = 0.08, I² = 49.86%; 95% PI −0.79, 0.06) ( Figure 4 ). Asymmetry was not observed in the funnel plot ( Appendix 3 ).

Six studies [21] [24] [26] [28] [29] [30] (n = 1484) investigated the effect of 1 mg/day Rasagiline compared to placebo on UPDRS Part III scores. There was a small and statistically significant overall effect on UPDRS Part III scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.37; 95% CI −0.47, −0.27). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 3.82, p = 0.58, I² = 0.00%; 95% PI −0.52, −0.23) ( Figure 5 ). Asymmetry was not observed in the funnel plot ( Appendix 4 ).

Three studies [27] [29] [30] (n = 624) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 total scores. There was a small and statistically significant overall effect on PDQ-39 total scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.30; 95% CI −0.46, −0.14). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 1.18, p = 0.56, I² = 0.00%; 95% PI −1.32, 0.72) ( Figure 6 ). Asymmetry was not observed in the funnel plot ( Appendix 5 ).

Three studies [27] [29] [30] (n = 624) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 mobility scores. There was a small and statistically significant overall effect on PDQ-39 mobility scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.30; 95% CI −0.46, −0.15). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 1.95, p = 0.38, I² = 0.00%; 95% PI −1.33, 0.72) ( Figure 7 ). Asymmetry was not observed in the funnel plot ( Appendix 6 ).

Three studies [27] [29] [30] (n = 625) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 activities of daily living scores. There was a small and statistically significant overall effect on PDQ-39 activities of daily living scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.41; 95% CI −0.56, −0.25). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 1.22, p = 0.54, I² = 0.00%; 95% PI −1.43, 0.62) ( Figure 8 ). Asymmetry was not observed in the funnel plot ( Appendix 7 ).

Three studies [27] [29] [30] (n = 625) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 bodily discomfort scores. There was a trivial and statistically non-significant overall effect on PDQ-39 bodily discomfort scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.13; 95% CI −0.30, 0.04). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 2.01, p = 0.37, I² = 13.72%; 95% PI −1.45, 1.19) ( Figure 9 ). Asymmetry was not observed in the funnel plot ( Appendix 8 ).

Three studies [21] [25] [29] (n = 954) investigated the effect of 1 mg/day Rasagiline compared to placebo on OFF time. There was a small and statistically significant overall effect on OFF time of 1 mg/day Rasagiline compared to placebo (SMD = −0.47; 95% CI −0.65, −0.28). There was a moderate and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 4.08, p = 0.13, I² = 51.08%; 95% PI −2.40, 1.47) ( Figure 10 ). Asymmetry was not observed in the funnel plot ( Appendix 9 ).

Two studies [29] [30] (n = 513) investigated the effect of 1 mg/day Rasagiline compared to placebo on UPDRS Part I scores. There was a trivial and statistically non-significant overall effect on UPDRS Part I scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.15; 95% CI −0.41, 0.12). There was a moderate and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 2.31, p = 0.13, I² = 56.62%) ( Figure 11 ). Due to only two studies included in the meta-analysis, the 95% prediction interval was not estimated. Asymmetry was not observed in the funnel plot ( Appendix 10 ).

Three studies [27] [29] [30] (n = 625) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 emotional well-being scores. There was a small and statistically significant overall effect on PDQ-39 emotional well-being scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.27; 95% CI −0.43, −0.11). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 0.33, p = 0.85, I² = 0.00%; 95% PI −1.29, 0.75) ( Figure 12 ). Asymmetry was not observed in the funnel plot ( Appendix 11 ).

Three studies [27] [29] [30] (n = 622) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 stigma scores. There was a trivial and statistically non-significant overall effect on PDQ-39 stigma scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.13; 95% CI −0.29, 0.02). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 0.23, p = 0.89, I² = 0.00%; 95% PI −1.15, 0.88) ( Figure 13 ). Asymmetry was not observed in the funnel plot ( Appendix 12 ).

Three studies [27] [29] [30] (n = 623) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 social support scores. There was a trivial and statistically non-significant overall effect on PDQ-39 social support scores of 1 mg/day Rasagiline compared to placebo (SMD = -0.10; 95% CI −0.26, 0.06). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 0.03, p = 0.98, I² = 0.00%; 95% PI −1.12, 0.92) ( Figure 14 ). Asymmetry was not observed in the funnel plot ( Appendix 13 ).

Three studies [27] [29] [30] (n = 624) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 cognition scores. There was a trivial and statistically non-significant overall effect on PDQ-39 cognition scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.11; 95% CI −0.27, 0.05). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 2.80, p = 0.25, I² = 0.00%; 95% PI −1.13, 0.91) ( Figure 15 ). Asymmetry was observed in the funnel plot ( Appendix 14 ).

Three studies [27] [29] [30] (n = 623) investigated the effect of 1 mg/day Rasagiline compared to placebo on PDQ-39 communication scores. There was a trivial and statistically non-significant overall effect on PDQ-39 communication scores of 1 mg/day Rasagiline compared to placebo (SMD = −0.14; 95% CI −0.29, 0.02). There was a small and statistically non-significant degree of heterogeneity identified in the meta-analysis (Q = 0.76, p = 0.68, I² = 0.00%; 95% PI −1.15, 0.88) ( Figure 16 ). Asymmetry was observed in the funnel plot ( Appendix 15 ).

Using the Cochrane GRADE approach, the level of evidence was downgraded by 1 level for all meta-analyses as the overall effect size of 95% CI was deemed trivial or small (imprecision, −1). The overall quality was deemed very low to moderate for all meta-analyses ( Appendix 16 ).

Motor symptoms of PD result from changes to the neural anatomy responsible for action selection, motor sequencing, and coordination and execution of movement. These motor symptoms include tremors, rigidity, bradykinesia, gait disturbance, changes in handwriting, and others [35] . Motor symptoms become increasingly severe in individuals as PD progresses and are associated with reduced quality of life and the progression of disability in individuals with PD. The increased severity of motor symptoms is a leading reason why individuals with PD get detained in a wheelchair or a bed [36] . Although medication can control motor symptoms, individuals with the disease can develop motor fluctuations known as OFF time between their medication doses. The severity and unpredictability of OFF time are reasons for reduced quality of life in individuals with PD [37] .

Consistent with our findings, Rasagiline is known to improve Parkinsonian motor symptoms in individuals with PD compared to placebo [38] . Using Rasagiline to improve motor symptoms can combat individuals’ functional decline and allow for greater independence and quality of life. The effects of Rasagiline have been investigated both as monotherapy and adjunctive therapy compared to placebo, and Rasagiline has been shown to have beneficial effects in both types of therapy [7] [39] .

As adjunctive therapy, Rasagiline is most often administered with oral Levodopa. Although oral Levodopa monotherapy has been the gold standard medication for managing Parkinsonian motor symptoms, its short half-life is associated with increased peaks and valleys in the medication concentration in the blood. Over time, oral Levodopa treatment is associated with the development of additional motor symptoms [40] , such as motor fluctuations and dyskinesia [41] . The short half-life of oral forms of Levodopa is believed to be the reason behind the pathogenesis of motor fluctuations and dyskinesia [42] . Consistent with others [21] , our findings provide low to moderate certainty of evidence that the administration of Rasagiline as adjunctive therapy to oral Levodopa improves motor symptoms and may decrease motor fluctuations and dyskinesia.

Non-motor symptoms of PD result from the loss of neurons in the dopaminergic and non-dopaminergic pathways in the brain. These non-motor symptoms include depression, anxiety, fatigue, pain, insomnia, speech and swallowing issues, hallucinations, constipation, and hyposmia, and may have a greater effect on quality of life than motor symptoms. Non-motor symptoms are common and can precede Parkinsonian motor symptoms by up to a decade [43] [44] . Considering the range and complexity of non-motor symptoms that can present, it was not surprising that we identified mixed results for the effects of Rasagiline.

Motor symptoms of PD are directly linked to the non-motor symptoms of the disease. Both motor and non-motor symptoms result in severe negative social consequences such as stigma, dehumanization, and loneliness. This, in turn, leads to reduced quality of life in individuals with PD [45] . Consistent with others [18] - [31] , our findings suggest Rasagiline can improve both motor and non-motor symptoms in individuals with PD, potentially increasing the ability of these individuals to engage in social activities and improve their quality of life.

Improving both motor and non-motor symptoms is important to improving the quality of life in individuals with PD. Non-motor symptoms become increasingly common and obvious as PD progresses. They also reduce quality of life and contribute to the development of overall disability caused by motor symptoms in individuals with PD [46] [47] . Future research is needed to investigate further the effects of Rasagiline on non-motor symptoms.

Rasagiline is often administered as adjunctive therapy to oral Levodopa to reduce the motor fluctuations caused by oral Levodopa by reducing the OFF time between oral Levodopa doses. [7] However, Rasagiline is not the only MAO-B inhibitor used in the treatment of PD. Other MAO-B inhibitors are Selegiline and Safinamide [48] . Selegiline is a first-generation irreversible MAO-B inhibitor that is associated with higher rates of adverse events due to its chemical structure that contains an amphetamine backbone. When Selegiline undergoes first-pass metabolism in the liver, it is transformed into L-amphetamine and L-methamphetamine which can cause cardiovascular and central nervous system adverse events [49] . Rasagiline is a second-generation irreversible MAO-B inhibitor that does not have an amphetamine backbone and is associated with fewer adverse events [50] . Safinamide is an alpha-aminoamide derivative introduced into the market as a reversible MAO-B inhibitor. Safinamide has a higher MAO-B selectivity than Selegiline or Rasagiline and is linked to fewer adverse events than both Selegiline and Rasagiline [51] .

This study had several limitations. First, due to the limited number of studies included in each meta-analysis, we did not investigate the long-term effects of Rasagiline on motor and non-motor symptoms. Second, our review only included published randomized controlled trials and did not include “gray literature.” Third, due to the limited number of studies, we were unable to adequately assess the potential for publication bias.