Selegiline or levodopa treatment has been suggested as a therapeutic method for Parkinson’s disease (PD) in many clinical trial reports. However, the combined effects of two drugs still remain controversial. The aim of this report was to evaluate the clinical efficacy and safety of selegiline plus levodopa (S + L) combination therapy in the treatment of PD compared to that of L monotherapy, to provide a reference resource for rational drug use.
Randomized controlled trials (RCTs) of S + L for PD published up to September, 2018 were searched. Mean difference (MD), odds ratio (OR), and 95% confidence interval (CI) were calculated and heterogeneity was assessed with the I2 test. Sensitivity analysis was also performed. The outcomes measured were as follows: the unified Parkinson’s disease rating scale (UPDRS) scores, modified Webster score, adverse events and mortality.
Fourteen RCTs with 2008 participants were included. Compared with L monotherapy, the pooled effects of S + L combination therapy on UPDRS score were (eleven trials; MD − 7.00, 95% CI − 8.35 to − 5.65, P < 0.00001) for total UPDRS score (nine trials; MD − 5.74, 95% CI − 7.71 to − 3.77, P < 0.00001) for motor UPDRS score (seven trials; MD − 1.61, 95% CI − 2.18 to − 1.04, P < 0.00001) for activities of daily living UPDRS score (three trials; MD − 0.38, 95% CI − 0.61 to − 0.14, P = 0.002) for mental UPDRS score. The Webster score showed significant decrease in the S + L combination therapy compared to L monotherapy (four trials; MD − 5.71, 95% CI − 7.11 to − 4.32, P < 0.00001). Compared with L monotherapy, S + L combination therapy did not increase the number of any adverse events significantly in PD patients (ten trials; OR 1.58, 95% CI 0.83–3.00, P = 0.16).
S + L combination therapy is superior to L monotherapy for the improvement of clinical symptoms in PD patients. Moreover, the safety profile of S + L combination therapy is comparable with that of L monotherapy.
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Oertel W, Schulz JB (2016) Current and experimental treatments of Parkinson disease: a guide for neuroscientists. J Neurochem 139:325–337. https://doi.org/10.1111/jnc.13750
Wang L, Li J, Chen J (2018) Levodopa-Carbidopa intestinal gel in Parkinson’s disease: a systematic review and meta-analysis. Front Neurol 9:620. https://doi.org/10.3389/fneur.2018.00620
Vijayakumar D, Jankovic J (2016) Drug-induced dyskinesia, part 1: treatment of levodopa-induced dyskinesia. Drugs 76:759–777. https://doi.org/10.1007/s40265-016-0566-3
Ceravolo R, Rossi C, Del Prete E et al (2016) A review of adverse events linked to dopamine agonists in the treatment of Parkinson’s disease. Expert Opin Drug Saf 15:181–198. https://doi.org/10.1517/14740338.2016.1130128
Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease: a review. JAMA 311:1670–1683. https://doi.org/10.1001/jama.2014.3654
Zhao Q, Cai D, Bai Y (2013) Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease. Int J Mol Med 32:883–891. https://doi.org/10.3892/ijmm.2013.1450
Szökő É, Tábi T, Riederer P et al (2018) Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease. J Neural Transm (Vienna) 125:1735–1749. https://doi.org/10.1007/s00702-018-1853-9
Mizuno Y, Hattori N, Kondo T et al (2017) A randomized double-blind placebo-controlled phase III trial of selegiline monotherapy for early parkinson disease. Clin Neuropharmacol 40:201–207. https://doi.org/10.1097/wnf.0000000000000239
Cereda E, Cilia R, Canesi M et al (2017) Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case-control study. J Neurol 264:1254–1263. https://doi.org/10.1007/s00415-017-8523-y
Kumar S, Dang S, Nigam K et al (2018) Selegiline nanoformulation in attenuation of oxidative stress and upregulation of dopamine in the brain for the treatment of Parkinson’s disease. Rejuvenation Res 21:464–476. https://doi.org/10.1089/rej.2017.2035
Krishna R, Ali M, Moustafa AA (2014) Effects of combined MAO-B inhibitors and levodopa vs. monotherapy in Parkinson’s disease. Front Aging Neurosci 6:180. https://doi.org/10.3389/fnagi.2014.00180
Zhuo C, Zhu X, Jiang R et al (2017) Comparison for efficacy and tolerability among ten drugs for treatment of Parkinson’s disease: a network meta-analysis. Sci Rep 8:45865. https://doi.org/10.1038/srep45865
Marconi S, Zwingers T (2014) Comparative efficacy of selegiline versus rasagiline in the treatment of early Parkinson’s disease. Eur Rev Med Pharmacol Sci 18:1879–1882. https://doi.org/10.1016/j.neuropharm.2013.11.014
Pålhagen S, Heinonen E, Hagglund J et al (2006) Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 66:1200–1206. https://doi.org/10.1212/01.wnl.0000204007.46190.54
Lees AJ (1995) Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease. Parkinson’s Disease Research Group of the United Kingdom. BMJ 311:1602–1607
Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6:e1000100. https://doi.org/10.1371/journal.pmed.1000100
Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12
Moher D, Pham B, Jones A et al (1998) Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 352:609–613. https://doi.org/10.1016/s0140-6736(98)01085-x
Jiang DQ, Zhao SH, Li MX et al (2018) Prostaglandin E1 plus methylcobalamin combination therapy versus prostaglandin E1 monotherapy for patients with diabetic peripheral neuropathy: a meta-analysis of randomized controlled trials. Medicine (Baltimore) 97:e13020. https://doi.org/10.1097/md.0000000000013020
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. https://doi.org/10.1002/sim.1186
Bai YJ, Zhu B, Feng LD (2017) Clinical efficacy of selegiline in combination with levodopa for the treatment of dyskinesias in Parkinson’s disease. China Pract Med 12:115–116. https://doi.org/10.14163/j.cnki.11-5547/r.2017.15.065
Chen F, Guan Q, Zheng YG et al (2013) Efficacy and safety of selegiline combined with compound levodopa in patients with Parkinson’s disease. Chin J Neuroimmunol Neurol 20:352–356. https://doi.org/10.3969/j.issn.1006-2963.2013.05.013
Cheng SZ (2014) Clinical observation of selegiline combined with compound levodopa for treatment of Parkinson’s disease. Guide China Med 12:162–163. https://doi.org/10.15912/j.cnki.gocm.2014.22.252
Gan ZZ (2018) The efficacy of selegiline combined with compound levodopa in treatment of Parkinson’s disease. China Health Care Nutr 28:333–334. https://doi.org/10.3969/j.issn.1004-7484.2018.02.498
Larsen JP, Boas J, Erdal JE (1999) Does selegiline modify the progression of early Parkinson’s disease? Results from a five-year study. The Norwegian-Danish Study Group. Eur J Neurol 6:539–547
Li L, Sun YR, Wang JM et al (2013) Clinical efficacy and safety of selegiline in patients with Parkinson’s disease. Chin J Clin Rational Drug Use 6:67–68. https://doi.org/10.15887/j.cnki.13-1389/r.2013.14.128
Olanow CW, Hauser RA, Gauger L et al (1995) The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 38:771–777. https://doi.org/10.1002/ana.410380512
Shoulson I, Oakes D, Fahn S et al (2002) Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 51:604–612. https://doi.org/10.1002/ana.10191
Sun Q (2016) Clinical therapeutic effects of selegiline and levodopa polytherapy on the treatment of Parkinsonism dyskinesia. J Prev Med Chin PLA 34:7–8. https://doi.org/10.13704/j.cnki.jyyx.2016.s1.008
Takahashi M, Yuasa R, Imai T et al (1994) Selegiline (l-deprenyl) and l-dopa treatment of Parkinson’s disease: a double-blind trial. Intern Med 33:517–524
Wang JM (2017) Clinical efficacy of selegiline in combination with compound levodopa in patients with Parkinson’s disease. Chin J Pract Nerv Dis 20:108–110. https://doi.org/10.3969/j.issn.1673-5110.2017.08.048
Weng ZF, Zhang J, Wang Y et al (2002) Clinical efficacy of selegiline added to levodopa/decarboxylase inhibitor in Parkinson’s disease. Mod J Neurol Neurosurg 2:281–284. https://doi.org/10.3969/j.issn.1672-6731.2002.05.006
Binde CD, Tvete IF, Gasemyr J et al (2018) A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson’s disease. Br J Clin Pharmacol 84:1917–1927. https://doi.org/10.1111/bcp.13651
Inaba-Hasegawa K, Shamoto-Nagai M, Maruyama W et al (2017) Type B and A monoamine oxidase and their inhibitors regulate the gene expression of Bcl-2 and neurotrophic factors in human glioblastoma U118MG cells: different signal pathways for neuroprotection by selegiline and rasagiline. J Neural Transm (Vienna) 124:1055–1066. https://doi.org/10.1007/s00702-017-1740-9
Chiu WH, Carlsson T, Depboylu C et al (2014) Selegiline normalizes, while l-DOPA sustains the increased number of dopamine neurons in the olfactory bulb in a 6-OHDA mouse model of Parkinson’s disease. Neuropharmacology 79:212–221. https://doi.org/10.1016/j.neuropharm.2013.11.014
Riederer P, Youdim MB (1986) Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl. J Neurochem 46:1359–1365
Rodríguez-Gómez JA, Venero JL, Vizuete ML et al (1997) Deprenyl induces the tyrosine hydroxylase enzyme in the rat dopaminergic nigrostriatal system. Brain Res Mol Brain Res 46:31–38
Hamaue N, Minami M, Terado M et al (2004) Comparative study of the effects of isatin, an endogenous MAO-inhibitor, and selegiline on bradykinesia and dopamine levels in a rat model of Parkinson’s disease induced by the Japanese encephalitis virus. Neurotoxicology 25:205–213. https://doi.org/10.1016/s0161-813x(03)00100-1
Müller T, Möhr JD (2018) Long-term management of Parkinson’s disease using levodopa combinations. Expert Opin Pharmacother 19:1003–1011. https://doi.org/10.1080/14656566.2018.1484108
Lees AJ, Ferreira J, Rascol O et al (2017) Opicapone as adjunct to levodopa therapy in patients with parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol 74:197–206. https://doi.org/10.1001/jamaneurol.2016.4703
Peretz C, Segev H, Rozani V et al (2016) Comparison of selegiline and rasagiline therapies in Parkinson disease: a real-life study. Clin Neuropharmacol 39:227–231. https://doi.org/10.1097/wnf.0000000000000167
Keating GM, Lyseng-Williamson KA, Hoy SM (2012) Rasagiline: a guide to its use in Parkinson’s disease. CNS Drugs 26:781–785. https://doi.org/10.2165/11207570-000000000-00000
This study was supported by grants from the Natural Science Foundation of Guangxi Zhuang Autonomous Region of China (No. 2018GXNSFAA050002), the National Natural Science Foundation of China (No. 31860228), the Key projects of Natural Science Foundation of the Guangxi Zhuang Autonomous Region (2018GXNSFDA281007) and the Doctoral Scientific Research Foundation of Yulin Normal University of China (No. G20160006).
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Jiang, D., Li, M., Jiang, L. et al. Comparison of selegiline and levodopa combination therapy versus levodopa monotherapy in the treatment of Parkinson’s disease: a meta-analysis. Aging Clin Exp Res 32, 769–779 (2020). https://doi.org/10.1007/s40520-019-01232-4
- Parkinson’s disease