Efficacy of rasagiline for the treatment of Parkinson’s disease: an updated meta-analysis

Abstract

Objective: Rasagiline is a second-generation potent selective inhibitor of monoamine oxidase-B. The aim of the study was to analyze the effectiveness of rasagiline in treatment of Parkinson’s disease (PD), both as monotherapy and combination therapy.

Methods: Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 9 March 2016 using the keywords: Rasagiline, Azilect, Parkinson’s disease. Randomized controlled trials of patients with PD who were randomized to treatment with rasagiline or placebo were included. Outcomes were unified Parkinson’s disease rating scale (UPDRS) and the three subscales.

Results: Ten studies fulfilled the inclusion criteria and 2709 patients were evaluated. The overall analysis revealed a significant improvement in change of total UPDRS scores in 1 mg/day and 2 mg/day rasagiline groups compared to placebo. Significant improvement in Part I (Mentation) of UPDRS scores was observed in 1 mg/day, but not in 2 mg/day rasagiline treatment group. Part II (ADL) and Part III (Motor) subscales significantly improved with both doses of rasagiline. Both monotherapy and combination therapy significantly improved total UPDRS scores.

Conclusions: Our results confirm the efficacy of rasagiline in PD. Further studies are required to establish the optimal dose of rasagiline, as well as to determine its effectiveness in different combination therapy protocols.

KEY MESSAGES

• Rasagiline treatment was associated with significant improvement of UPDRS scores and the scores of the subscales.

• Both monotherapy and combination therapy significantly improved total UPDRS scores.

• Effect of rasagiline on total UPDRS scores was not dose-dependent.

Keywords:

• Azilect
• combination therapy
• monotherapy
• Parkinson’s disease
• rasagiline
• UPDRS scores

Introduction

Originally described by James Parkinson in early nineteenth century, Parkinson’s disease (PD) is a chronic, progressive, incurable, neurodegenerative disorder characterized by motor symptoms of bradykinesia, rigidity, rest tremor, and postural instability (1). The mean age of PD symptom onset is 55, and with age, the incidence increases significantly, from 20/100,000 overall to 120/100,000 at age 70. Available treatments are symptomatic in nature, and majority of PD patients suffer significant motor disability after diagnosis (2). The economic cost of PD was nearly $14.4 billion per year in the USA alone in 2010, and it is predicted to grow considerably over the next few decades with the growth of the size of the elderly population (3). Therefore, there is an urgent need for effective therapeutic approaches to ameliorate the pathophysiological process of this disease.

PD is attributed to loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). These neurons form the nigrostriatal dopaminergic pathway and their loss leads to DA deficiency in striatum, subsequently resulting in PD symptoms. Most of PD symptoms can be initially controlled with DA precursor levodopa, which can replenish the level of striatal DA. Although levodopa usually allows effective treatment of PD symptoms for several years after diagnosis, most patients eventually develop involuntary, uncontrollable movements that significantly affect their quality of life (2).

Alternative PD treatment strategy uses inhibitors of dopamine-metabolizing enzymes: catechol-O-methyl transferase (COMT) and monoamine oxidase B (MAO B) (4,5). This therapeutic approach increases concentration of endogenous dopamine, and consequently reduces PD symptoms. The main MAO B inhibitor used for treatment of PD for more than 40 years is selegiline (deprenyl) (6), a selective and irreversible propargylamine-based compound. Another propargylamine-based, irreversible selective MAO B inhibitor that became available little over a decade ago is rasagiline (Azilect^®) (7). Rasagiline has an advantage compared to selegiline, as its metabolites do not include potentially toxic amphetamines (4).

The aim of this study was to analyze the current literature regarding the use of rasagiline for treatment of PD, both as monotherapy and combination therapy. Efficacy of rasagiline versus placebo was determined using statistical meta-analysis techniques by evaluating changes in UPDRS scores. In addition, efficacy of different doses of rasagiline was analyzed.

Material and methods

Search strategy

We followed the PRISMA guidance for systematic reviews of observational and diagnostic studies (8). We searched the published literature using Medline, Cochrane, EMBASE, Google Scholar databases with various combinations of following keywords: Rasagiline, Azilect, Parkinson’s disease. References in relevant primary publications were hand-searched to identify other eligible trials. The described searches included original literature published up to 9 March 2016.

For this meta-analysis, we included trials that assessed the effectiveness of Rasagiline versus placebo treatment in patients diagnosed with PD in randomized controlled trials, and two-arm studies. We excluded Letters, Comments, Editorials, Case reports, Proceedings, Personal communications, Cohort studies, One-arm studies, as well as studies that did not report quantitative outcome.

Data extraction

Data were extracted independently by two reviewers. A third reviewer was consulted in case of disagreements. We extracted data on study population (number, age, and gender of subjects in each group, disease duration and follow-up time), study design, and the major outcomes.

Quality assessment

We assessed the studies’ quality using the Cochrane Collaboration’s Tool (9). Briefly, the risk of bias was assessed via seven different criteria: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome), reporting bias (selective outcome reporting), and inclusion of intention-to-treat analysis. Quality assessment was performed by two independent reviewers, and a third reviewer was consulted if no consensus could be reached.

Statistical analysis

Primary outcome measure was unified Parkinson’s disease rating scale (UPDRS) score and scores of the three subscales [UPDRS Part I (mentation), Part II (activity of daily living, ADL), and Part III (motor)]. We performed the following comparisons: (i) 1 mg/day rasagiline versus placebo, (ii) 2 mg/day rasagiline versus placebo, and (iii) 2 mg/day rasagiline versus 1 mg/day rasagiline. Data of mean differences in the UPDRS scores between groups, mean change of UPDRS scores for each group, and/or pre- and post-UPDRS scores for each group were extracted from eligible articles. The difference in means and its 95% confidence interval (95% CI) were used as the measure of treatment effect of rasagiline. The difference in means greater than 0 indicated benefit of rasagiline treatment compared to placebo, or superior benefit with 2 mg/day rasagiline compared to 1 mg/day rasagiline. Subgroup analysis evaluated outcomes in patients receiving rasagiline alone versus levodopa combination therapy. Pooled estimate for difference in means was calculated by DerSimonian–Laird random-effects model. A two-sided p-value <0.05 was considered statistically significant.

Heterogeneity assessment

We performed a χ²-based homogeneity test and determined the Q statistics and the inconsistency index (I²). The Q-statistic was defined as the weighted sum of the squared deviations of the estimates of all studies; p < 0.10 was considered statistically significant for heterogeneity. For the I² statistic, I²< 25% indicates low heterogeneity, I²> 50% indicates moderate to high heterogeneity, and I²> 75 indicates extreme heterogeneity.

Sensitivity analysis was carried out using the leave one-out approach. All analyses were performed using Comprehensive Meta-Analysis statistical software, version 2.0 (Biostat, Englewood, NJ).

Results

Basic characteristics of included studies

Using the keyword-based search, we initially identified 476 articles. Exclusion of irrelevant articles left 37 studies for full-text reviewing. Of these, 13 did not report an outcome of interest, 2 analyzed duplicate patient population, 2 reported combined outcomes of included trials, 1 was single-arm study, 1 was meta-analysis study, 1 reported outcomes in patients receiving rasagiline with or without levodopa, full text was not available for 5 studies, 1 reported outcome in different age groups, and 1 reported long-term follow-up results of the TEMPO study expressed in mean values and standard errors and could not be included in the meta-analysis. Thus, we identified 10 eligible publications (10–19). The flow chart describing selection of the trials for the analysis is presented in Figure 1.

Figure 1. PRISMA flow diagram.

The 10 studies recruited a total of 2709 patients: 964 in the 1 mg/day rasagiline group, 457 in the 2 mg/day rasagiline group, and 1288 in the placebo group. The characteristics of the studies are summarized in Table 1. Patients’ age ranged from 56.6 to 67.6 years. The proportion of patients that were male ranged from 33.3% to 77.8%. Duration of PD ranged from 2.1 months to 9.7 years. Follow-up times ranged from 8 to 36 weeks. Treatment details as well as outcomes for each individual study are summarized in Table 2.

Table 1. Basic characteristics of selected studies.

Author (year)	Trial name	Intervention	Dosage/frequency/duration of treatment	Monotherapy or combined therapy	No. of patients	Male (%)	Mean age (years)	Duration of PD (months)	Follow-up time
Hauser (2014)	NCT01049984	Rasagiline	1 mg/day	Dopamine agonist (ropinirole 6 mg/day or pramipexole 1.0 mg/day)	159	67.9%	62.3	2.2	18 weeks
		Placebo			162	68.5%	62.8	2.1
Zhang (2013)		Rasagiline	1 mg/day	Levodopa	119	53.8%	61.6	5.57 years	12 weeks
		Placebo			125	53.6%	61.6	5.40 years
Korchounov (2012)		Rasagiline	1 mg/day	Monotherapy	3	66.7%			8 weeks
		Rasagiline	2 mg/day		3	33.3%
Hanagasi (2011)		Rasagiline	1 mg/day	Levodopa and/or dopamine agonist	23	73.9%	65.2	4.09	12 weeks
		Placebo			25	64.0%	67.6	3.96
Stern (2004)		Rasagiline	1 mg/day for 10 weeks s	Monotherapy	15	66.7%	59.3	1.3 years	10 weeks
		Rasagiline	2 mg/day (1 mg/day for 1 weeks, then 2 mg/day for 9 weeks s)		14	71.4%	60.3	0.4 years
		Placebo			13	76.9%	64.8	0.8 years
Rabey (2000)		Placebo		Adjunct to Levodopa	13	53.8%	57.0	6.5	18 weeks
		Rasagiline	1 mg/day, 12 weeks		18	66.7%	56.7	5.9
		Rasagiline	2 mg/day, 12 weeks		18	77.8%	56.6	5.7
Barone (2015)	ACCORDO	Rasagiline	1 mg/day	Levodopa	58	46.6%	66.0	3.7	12 weeks
		Placebo		Levodopa	65	58.5%	66.1	4.8
Parkinson’s Study Group (2005)	PRESTO	Placebo		Adjunct to Levodopa	159	65.4%	64.5	9.7 years	26 weeks
		Rasagiline	1 mg/day		149	66.4%	62.9	8.8 years
Rascol (2011)	ADAGIO	Placebo			588				72 weeks
		Rasagiline	1 mg/day		286
		Rasagiline	2 mg/day		290
Parkinson’s Study Group (2002)	TEMPO	Rasagiline	1 mg/day	Monotherapy	134	67.2%	61.6	0.92 years	26 weeks
		Rasagiline	2 mg/day		132	56.1%	60.4	1.15 years
		Placebo			138	67.4%	60.5	0.94 years

Table 2. Descriptions of outcome measures of selected studies.

Author (year)	Trial name	Intervention	No. of patients	Total UPDRS*	UPDRS Part I*	UPDRS Part II*	UPDRS Part III*
Hauser (2014)	NCT01049984	Rasagiline (1 mg/day)	159	Diff: −2.4 ± 0.95†		−0.4 ± 0.37†	−1.8 ± 0.67†
		Placebo	162	Ref.		Ref.	Ref.
Zhang (2013)		Rasagiline (1 mg/day)	119	−8.33 ± 5.98		−3.51 ± 3.15	−4.45 ± 3.53
		Placebo	125	−4.22 ± 6.21		−1.66 ± 2.94	−2.41 ± 3.61
Korchounov (2012)		Rasagiline (1 mg/day)	3			−2.0 ± 1.0	−6.7 ± 0.6
		Rasagiline (2 mg/day)	3			−4.0 ± 1.0	−7.0 ± 1.0
Hanagasi (2011)		Rasagiline (1 mg/day)	23			−0.53 ± 1.09†	−2.15 ± 1.34†
		Placebo	25			Ref.	Ref.
Stern (2004)		Rasagiline (1 mg/day)	15	−1.8 ± 1.3†
		Rasagiline (2 mg/day)	14	−3.6 ± 1.7†
		Placebo	13	−0.5 ± 0.8†
Rabey (2000)		Placebo	13	Pre: 34.7 ± 19.3 Post: 34.3 ± 2.8
		Rasagiline (1 mg/day)	18	Pre: 30.3 ± 16.0 Post: 27.3 ± 15.9
		Rasagiline (2 mg/day)	18	Pre: 34.8 ± 20.7 Post: 32.6 ± 25.1
Barone (2015)	ACCORDO	Rasagiline (1 mg/day)	58		−0.96 ± 0.16†	−1.37 ± 0.35†	−0.88 ± 0.56†
		Placebo	65		−0.49 ± 0.15†	0.06 ± 0.32†	0.42 ± 0.51†
Parkinson’s Study Group (2005)	PRESTO	Placebo	159			Ref.	Ref.
		Rasagiline (1 mg/day)	149			0.06 (–0.73 to 0.84)^‡	−2.87 (−4.58 to −1.16)^‡
Rascol (2011)	ADAGIO	Placebo	588	4.25 (3.70 to 4.81)‡	0.18 (0.09 to 0.27)‡	1.64 (1.43 to 1.85)‡	2.38 (1.96 to 2.79)‡
		Rasagiline (1 mg/day)	286	1.22 (0.46 to 1.99)‡	−0.04 (−0.17 to 0.08)‡	0.78 (0.49 to 1.06)‡	0.50 (−0.07 to 1.07)‡
		Rasagiline (2 mg/day)	290	1.06 (0.30 to 1.83)‡	0.12 (−0.01 to 0.24)‡	0.76 (0.47 to 1.04)‡	0.20 (−0.37 to 0.76)‡
Parkinson’s Study Group (2002)	TEMPO	Rasagiline (1 mg/day)	134	0.1 ± 6.8	Diff: −0.14 (−0.44, 0.15)‡	−1.04 (−1.60, −0.48)‡	−2.71 (−3.86, −1.55)‡
		Rasagiline (2 mg/day)	132	0.7 ± 5.8	Diff: −0.26 (−0.56, 0.04)‡	−1.22 (−1.78, −0.65)‡	−1.68 (−2.84, −0.51)‡
		Placebo	138	3.9 ± 7.5	Ref.	Ref.	Ref.

* Mean change from baseline ± SD was presented if not specified.

† Mean change from baseline ± standard error was presented.

‡ Mean change from baseline and 95% confidence interval were presented.

Treatment effect of rasagiline on UPDRS score

A total of 6 studies were included in the analysis of change of total UPDRS score in the 1 mg/day rasagiline treatment group compared to placebo group (10,11,14,15,18,19). There was low heterogeneity among included studies (Q = 5.4, p = 0.375, I²=6.5%). The overall analysis revealed a significant improvement in change of total UPDRS scores in 1 mg/day rasagiline-treated patients compared to placebo (difference in means = 3.305, 95% CI = 2.613 to 3.997, p < 0.001).

There was no heterogeneity among 4 studies (14,15,18,19) comparing change of total UPDRS score in 2 mg/day rasagiline versus placebo treatment groups (Q = 0.2, p = 0.975, I²=0%) and 4 studies (14,15,18,19) comparing 2 mg/day versus 1 mg/day rasagiline treatment groups (Q = 0.7, p = 0.875, I²=0%). The overall analysis revealed a significant benefit of 2 mg/day rasagiline treatment compared to placebo (difference in means = 3.287, 95% CI = 2.504 to 4.071, p < 0.001). On the other hand, no significant difference in the change of UPDRS scores were found between 2 mg/day and 1 mg/day rasagiline treatment groups (difference in means = 0.374, 95% CI = −0.486 to 1.235, p = 0.394) (Figure 2(A)).

Figure 2. Forest plots for treatment effect of rasagiline on (A) total UPDRS score, (B) mentation subscale score, (C) ADL subscale, and (D) motor subscale.

There was low heterogeneity across 3 studies (16,18,19) comparing change of UPDRS score Part I (mentation) in 1 mg/day rasagiline versus placebo treatment groups and in 2 studies (18,19) comparing change of UPDRS score Part I in 2 mg/day rasagiline versus placebo treatment groups. There was significant improvement in change of Part I UPDRS scores in 1 mg/day rasagiline treatment group compared to placebo (difference in means = 0.237, 95% CI = 0.105 to 0.369, p < 0.001), while no significant improvement was found for 2 mg/day rasagiline dose (difference in means = 0.118, 95% CI = −0.060 to 0.295, p = 0.194) (Figure 2(B)).

There was significant heterogeneity among 7 studies (10,11,13,16–19) comparing ADL subscale of UPDRS for 1 mg/day rasagiline versus placebo treatment groups (Q = 13.9, p = 0.031, I²=56.8%) and 2 studies (12,19) comparing 2 mg/day versus 1 mg/day rasagiline treatment groups (Q = 5.5, p = 0.019, I²=81.9%). There was no heterogeneity across 2 studies (18,19) comparing 2 mg/day rasagiline and placebo (Q = 1.0, p = 0.318, I²=0%). The overall analysis revealed a significant improvement of ADL subscale of UPDRS score for patients treated with rasagiline (1 mg/day: difference in means = 0.909, 95% CI = 0.497 to 1.322, p < 0.001; 2 mg/day: difference in means = 0.979, 95% CI = 0.676 to 1.282, p < 0.001). No significant difference in the treatment effect was found between 1 mg/day and 2 mg/day rasagiline doses (difference in means = 0.852, 95% CI = −1.063 to 2.768, p = 0.383) (Figure 2(C)).

Similarly to the results of ADL subscale analysis, the pooled results for motor subscale of UPDRS score showed significant improvement in patients treated with both doses of rasagiline (1 mg/day rasagiline versus placebo: difference in means = 2.044, 95% CI = 1.616 to 2.471, p < 0.001; 2 mg/day rasagiline versus placebo: difference in means = 2.043, 95% CI = 1.437 to 2.650, p < 0.001; 2 mg/day versus 1 mg/day rasagiline: difference in means = 0.300, 95% CI = −0.385 to 0.985, p = 0.391) (Figure 2(D)).

Subgroup analysis

Patients treated with 1 mg/day rasagiline either as monotherapy or as a part of levodopa combination therapy protocol had greater improvement of total UPDRS score compared to patients in the placebo group (combination therapy: difference in means = 3.412, 95% CI = 2.236 to 4.589, p < 0.001; monotherapy: difference in means = 3.240, 95% CI = 2.077 to 4.403, p < 0.001) (Figure 3(A)). Only 1 study recruited patients treated with 2 mg/day rasagiline as combination therapy (difference in means = 1.800, 95% CI = −13.349 to 16.949, p = 0.816). In the 3 monotherapy studies, the total UPDRS improved significantly in patients treated with 2 mg/day rasagiline compared to the placebo group (difference in means = 3.291, 95% CI = 2.507 to 4.076, p < 0.001) (Figure 3(B)). There was no association between rasagiline dose and total UPDRS score improvement in both combination therapy (difference in means = 0.800, 95% CI = −12.212 to 13.812, p = 0.904) and monotherapy subgroups (difference in means = 0.372, 95% CI = −0.490 to 1.235, p = 0.398) (Figure 3(C)).

Figure 3. Subgroup analysis for treatment effect of rasagiline according to combination therapy and monotherapy of rasagiline. (A) 1 mg/day rasagiline versus placebo; (B) 2 mg/day rasagiline versus placebo; (C) 2 mg/day versus 1 mg/day rasagiline.

Sensitivity analysis

Sensitivity analyses were performed using the leave-one-out approach. Two studies (14,15) had impact on the pooled results of total UPDRS scores comparison in the 1 mg/day rasagiline versus placebo and 2 mg/day rasagiline versus placebo groups (Figure 4(A)). For UPDRS Part I subscale, removal of the TEMPO study influenced the pooled results in both 1 mg/day and 2 mg/day rasagiline subgroups (Figure 4(B)). Three studies (10,13,17) had impact on the pooled results of ADL subscale comparison in the 1 mg/day rasagiline versus placebo groups. In addition, the pooled results of comparison between ADL subscale of UPDRS in the 2 mg/day and 1 mg/day rasagiline treatment groups were impacted by Korchounov et al.’s (12) study (Figure 4(C)). Finally, with removal of the Hanagasi et al. (13) or ACCORDO studies, the change of the motor subscale of UPDRS became statistically insignificant (Figure 4(D)).

Figure 4. Sensitivity analysis for (A) 1 mg/day rasagiline versus placebo, (B) 2 mg/day rasagiline versus placebo, and (C) 2 mg/day versus 1 mg/day rasagiline on total UPDRS score.

Quality assessment

The quality assessment showed that all included studies had low risk of bias in random sequence generation, incomplete outcome data, and selective reporting (Figure 5). Five studies (10,11,14,16,17) had low risk of bias in allocation concealment and double blinding, and only one study (12) had low risk of bias in blinding of outcome assessment (Figure 5(B)). Overall, included studies had low risk of attrition and reporting bias; however, they had higher risk of detection bias, selection bias, and blinding of outcome assessment bias possibly due to study design.

Figure 5. Quality assessment (A) risk of bias of all included trials, (B) summary of risk of bias.

Discussion

We employed meta-analysis techniques to investigate the efficacy of rasagiline in patients with PD. Our analysis showed that rasagiline at both 1 mg and 2 mg/day doses improved UPDRS scores in PD patients, without significant difference between the investigated doses. The drug was beneficial for patients receiving it as a monotherapy as well as part of combination therapy. The scores of UPDRS Part I (mentation) improved in 1 mg/day, but not 2 mg/day rasagiline treatment groups. The scores of UPDRS Part II (ADL) and Part III (motor) significantly improved in 1 mg/day and 2 mg/day rasagiline treatment groups, and there was no significant difference between the investigated doses. Overall, analyzed studies reported that rasagiline was well tolerated, and common side effects included nausea, headaches, dizziness, and somnolence. No obvious differences between the occurrence of complications in placebo and rasagiline treatment groups was noticed in the included studies.

Several review and meta-analysis studies focused on treatment options for PD. Ives et al. (20) were the first to compare three different MAO-B inhibitors (rasagiline, selegiline, and lazabemide) with either levodopa or placebo in early PD using meta-analysis techniques. Authors analyzed 17 randomized trials; however, only one of the included trials was conducted with rasagiline (18). Overall, it was concluded that MAO-B inhibitors reduce disability, the need for levodopa, and the incidence of motor fluctuations, without substantial side effects or increased mortality (20). Clarke at al. (21) analyzed data from studies with a delayed-start design of treatment (18,19). No significant difference between the delayed and regular start treatment groups was found (95% CI 0.01–1.8, p = 0.05) (21). Marconi et al. (22) compared 5 studies with selegiline and 4 with rasagiline. Authors found that rasagiline showed significant standardized mean differences (SMDs) compared to placebo (−1.025, 95% CI −1.230, −0.820), indicating a significant effect of rasagiline on UPDRS scores. The SMD between selegiline and rasagiline was not significantly different (SMD 0.079; 95% CI −0.010, +0.167) (22). Minguez-Minguez at al. (23) performed a meta-analysis study that specifically focused on rasagiline. Rasagiline efficacy was assessed using the overall UPDRS score in three clinical trials (19). Authors found that rasagiline was effective at doses of 1 mg/day or 2 mg/day when compared to placebo (−3.06 points on UPDRS score, 95% CI −2.31 to −3.81, p < 0.00001; −3.17 points on UPDRS score, 95% CI −3.91 to −2.42, p < 0.00001, respectively). Similarly to results of our analysis, 1 mg/day and 2 mg/day doses of rasagiline were equivalent (mean difference 0.00, 95% CI −0.82 to 0.81). In the present meta-analysis, we analyzed changes in the subscales of UPDRS score, and found that while UPDRS Part II (ADL) and Part III (motor) scores significantly improved in both 1 mg/day and 2 mg/day rasagiline treatment groups, the UPDRS Part I (mentation) scores improved in 1 mg/day, but not 2 mg/day rasagiline treatment groups. We included trials published up to 9 March 2016; therefore, it is the most up to date meta-analysis on the subject.

Rasagiline, as a MAO-B inhibitor, requires the presence of dopamine; therefore, its treatment efficacy depends on the severity of PD and decreases with PD progression. However, loss of more than 50% of dopaminergic neurons occurs early in the course of PD (24), prior to the onset of motor symptoms and hence the actual diagnosis, leading to a substantial decrease in dopamine levels prior to start of any treatment. It would be interesting to determine if rasagiline effects are more pronounced if used during early stages of disease, when higher numbers of dopaminergic neurons are still present. This will require development of novel methods allowing early PD detection.

Rasagiline enhances bioavailability of dopamine and therefore improves pharmacokinetics of levodopa. Consequently, it is often used in combination with levodopa, especially in advanced PD patients. Our analysis showed that patients treated with 1 mg/day rasagiline either as monotherapy or as a part of levodopa combination therapy protocol had greater improvement of total UPDRS score compared to patients in the placebo group. While the therapeutic effectiveness of rasagiline both as early monotherapy and as an adjunct to levodopa therapy in advanced PD becomes universally accepted, its efficacy in combination with other drugs used in symptomatic treatment of PD is less established. Dopamine agonists (DAs), for example, have been used in the treatment of PD for almost 40 years (18,25). While DAs can be successfully used as monotherapy during early stages of the disease, their efficacy in the prolonged treatment is poor and levodopa is added to about 50% of patients after 5 years (26). Since levodopa is associated with the development of motor complications, the onset which depends on the time of levodopa initiation and duration of exposure (27), it would be important to evaluate if addition of rasagiline to DAs can delay the need of levodopa. The results of Hauser et al.’s study (10) included in our analysis demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline/DA combination therapy group compared with the DA monotherapy. Although this study provides promising results, further RCTs addressing the rasagiline therapeutic efficacy within different combination therapy protocols are necessary to establish the best treatment regimen.

Despite the successful use of rasagiline in clinic, the exact mechanisms of its action are still not well understood. Considerable effort has been devoted to investigate the neuroprotective properties of the rasagiline (28). Under experimental conditions, rasagiline demonstrated neuroprotective and antiapoptotic properties and National Institute of Neurological Disorders and Stroke recognized it as potential disease-modifying agent (29). Interestingly, there is increasing evidence suggesting that rasagiline possesses neuroprotective activity independent of MAO-B inhibition (30,31), namely through stabilizing mitochondrial membranes (32) or regulating antioxidant enzymes (33). The rasagiline metabolite, aminoindan, may also possess neuroprotective properties but the data are not conclusive (31,34). Neuroprotective effect of rasagiline is a topic of great interest in clinical practice and was tested in two randomized delayed-start trials (19,35). Unfortunately, these trials did not provide clear evidence of neuroprotective effects of rasagiline. Hopefully, future well-designed trials will address this important aspect of rasagiline function.

There are several limitations to this meta-analysis. First, there was significant heterogeneity among the studies comparing effect of 1 mg/day rasagiline versus placebo on total UPDRS score, and 1 mg/day rasagiline versus placebo and 2 mg/day versus 1 mg/day on mentation part of the UPDRS score. It is possible that the observed heterogeneity is related to variability in the duration of PD and follow up times. Analysis of the effectiveness of rasagiline in combination therapy was primarily limited to combinations with levadopa, and only one study evaluated the effectiveness of rasagiline in combination with DAs. Further trials are required to assess rasagiline therapeutic efficacy within different combination therapy protocols.

In conclusion, the results of our meta-analysis support the efficacy of rasagiline in PD patients for improvement of UPDRS scores. More large-scale, well-designed RCTs evaluating efficacy of different rasagiline doses as well as its performance in different combination therapy protocols are warranted.

Disclosure statement

The authors report no conflicts of interest.