{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T01:41:44Z","timestamp":1792892504063,"version":"4.5.0"},"reference-count":111,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T00:00:00Z","timestamp":1640822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Parkinson\u2019s Disease (PD) is a disease that involves neurodegeneration and is characterised by the motor symptoms which include muscle rigidity, tremor, and bradykinesia. Other non-motor symptoms include pain, depression, anxiety, and psychosis. This disease affects up to ten million people worldwide. The pathophysiology behind PD is due to the neurodegeneration of the nigrostriatal pathway. There are many conventional drugs used in the treatment of PD. However, there are limitations associated with conventional drugs. For instance, levodopa is associated with the on-off phenomenon, and it may induce wearing off as time progresses. Therefore, this review aimed to analyze the newly approved drugs by the United States-Food and Drug Administration (US-FDA) from 2016\u20132019 as the adjuvant therapy for the treatment of PD symptoms in terms of efficacy and safety. The new drugs include safinamide, istradefylline and pimavanserin. From this review, safinamide is considered to be more efficacious and safer as the adjunct therapy to levodopa as compared to istradefylline in controlling the motor symptoms. In Study 016, both safinamide 50 mg (p = 0.0138) and 100 mg (p = 0.0006) have improved the Unified Parkinson\u2019s Disease Rating Scale (UPDRS) part III score as compared to placebo. Improvement in Clinical Global Impression\u2014Change (CGI-C), Clinical Global Impression\u2014Severity of Illness (CGI-S) and off time were also seen in both groups of patients following the morning levodopa dose. Pimavanserin also showed favorable effects in ameliorating the symptoms of Parkinson\u2019s Disease Psychosis (PDP). A combination of conventional therapy and non-pharmacological treatment is warranted to enhance the well-being of PD patients.<\/jats:p>","DOI":"10.3390\/ijerph19010364","type":"journal-article","created":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T21:41:21Z","timestamp":1640900481000},"page":"364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Systematic Review on Parkinson\u2019s Disease Medications, Emphasizing on Three Recently Approved Drugs to Control Parkinson\u2019s Symptoms"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-8108","authenticated-orcid":false,"given":"Palanisamy","family":"Sivanandy","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"},{"name":"School of Postgraduate Studies, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan Choo","family":"Leey","sequence":"additional","affiliation":[{"name":"Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan Chi","family":"Xiang","sequence":"additional","affiliation":[{"name":"Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan Chi","family":"Ling","sequence":"additional","affiliation":[{"name":"Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean Ang","family":"Wey Han","sequence":"additional","affiliation":[{"name":"Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha Lia Anak","family":"Semilan","sequence":"additional","affiliation":[{"name":"Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoon Kok","family":"Hong","sequence":"additional","affiliation":[{"name":"Bachelor of Pharmacy (Hons) Programme, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1212\/WNL.0000000000006396","article-title":"Mortality in patients with Parkinson disease psychosis receiving pimavanserin and quetiapine","volume":"91","author":"Moreno","year":"2018","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1159\/000492221","article-title":"Comprehensive Examination of Therapies for Pain in Parkinson\u2019s Disease: A Systematic Review and Meta-Analysis","volume":"51","author":"Qureshi","year":"2018","journal-title":"Neuroepidemiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e01036","DOI":"10.1002\/brb3.1036","article-title":"The factors associated with impulse control behaviors in Parkinson\u2019s disease: A 2-year longitudinal retrospective cohort study","volume":"8","author":"Kon","year":"2018","journal-title":"Brain Behav."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1111\/bcp.13651","article-title":"A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson\u2019s disease","volume":"84","author":"Binde","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1097\/WNF.0000000000000233","article-title":"Determination of Monoamine Oxidase A and B Activity in Long-Term Treated Patients With Parkinson Disease","volume":"40","author":"Riederer","year":"2017","journal-title":"Clin. Neuropharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.2147\/DDDT.S114147","article-title":"Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists","volume":"10","author":"Sadek","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_7","first-page":"95","article-title":"Effects of Safinamide on Pain in Fluctuating Parkinson\u2019s Disease Patients: A Post-Hoc Analysis","volume":"7","author":"Cattaneo","year":"2017","journal-title":"J. Park. Dis."},{"key":"ref_8","first-page":"21","article-title":"Prevalence of Parkinson\u2019s disease across North America","volume":"4","author":"Marras","year":"2018","journal-title":"Jpn. Park. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18l02355","DOI":"10.4088\/PCC.18l02355","article-title":"Pimavanserin for Parkinson Disease Psychosis","volume":"21","author":"Mohanty","year":"2019","journal-title":"Prim. Care Companion CNS Disord."},{"key":"ref_10","first-page":"4598651","article-title":"The Impact of Living with Parkinson\u2019s Disease: Balancing within a Web of Needs and Demands","volume":"2018","author":"Hammarlund","year":"2018","journal-title":"Park. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2217\/nmt-2018-0020","article-title":"Noninvasive options for \u2018wearing-off\u2019 in Parkinson\u2019s disease: A clinical consensus from a panel of UK Parkinson\u2019s disease specialists","volume":"8","author":"Fackrell","year":"2018","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00702-017-1686-y","article-title":"Epidemiology of Parkinson\u2019s disease","volume":"124","author":"Tysnes","year":"2017","journal-title":"J. Neural Transm."},{"key":"ref_13","first-page":"S83","article-title":"Parkinson\u2019s disease and Parkinson\u2019s disease psychosis: A perspective on the challenges, treatments, and economic burden","volume":"23","author":"Fredericks","year":"2017","journal-title":"Am. J. Manag. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S1474-4422(18)30295-3","article-title":"Global, regional, and national burden of Parkinson\u2019s disease, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"17","author":"Dorsey","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_15","unstructured":"(2021, November 10). Department of Statistics Malaysia, Available online: https:\/\/www.dosm.gov.my\/v1\/."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1159\/000107702","article-title":"A Prospective Study of Familial versus Sporadic Parkinson\u2019s Disease","volume":"4","author":"Papapetropoulos","year":"2007","journal-title":"Neurodegener. Dis."},{"key":"ref_17","unstructured":"(2021, February 02). Causes of Parkinson\u2019s Disease. The Michael J. Fox Foundation for Parkinson\u2019s Research|Parkinson\u2019s Disease. Available online: https:\/\/www.michaeljfox.org\/causes."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.tins.2018.09.007","article-title":"Triggers, Facilitators, and Aggravators: Redefining Parkinson\u2019s Disease Pathogenesis","volume":"42","author":"Johnson","year":"2019","journal-title":"Trends Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3988\/jcn.2012.8.1.15","article-title":"Drug-Induced Parkinsonism","volume":"8","author":"Shin","year":"2012","journal-title":"J. Clin. Neurol."},{"key":"ref_20","unstructured":"Association EPD (2020, February 02). Vascular (Arteriosclerotic) Parkinsonism. Available online: https:\/\/www.epda.eu.com\/about-parkinsons\/types\/vascular-arteriosclerotic-parkinsonism\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/j.clinph.2008.03.017","article-title":"Pathophysiology of Parkinsonism","volume":"119","author":"Galvan","year":"2008","journal-title":"Clin. Neurophysiol. Off. J. Int. Fed. Clin. Neurophysiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/978-94-007-5416-4_16","article-title":"Parkinson\u2019s Disease","volume":"65","author":"Mhyre","year":"2012","journal-title":"Subcell. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9541","DOI":"10.1523\/JNEUROSCI.2891-04.2004","article-title":"Dopamine Modulates Release from Corticostriatal Terminals","volume":"24","author":"Bamford","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_24","unstructured":"(2020, January 17). Etiology and Pathogenesis of Parkinson Disease\u2014UpToDate. Available online: https:\/\/www.uptodate.com\/contents\/etiology-and-pathogenesis-of-parkinson-disease."},{"key":"ref_25","unstructured":"Zigmoid, M.J., and Burke, R.E. (2002). Neuropsychopharmacology: The Fifth Generation of Progress, Lippincott, Williams & Wilkins. [5th ed.]. Pathophysiology of Parkinson\u2019s disease."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1016\/S1471-1931(00)00028-8","article-title":"Pathophysiology of the basal ganglia in Parkinson\u2019s disease","volume":"23","author":"Obeso","year":"2000","journal-title":"Trends Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0166-2236(03)00038-9","article-title":"Presymptomatic compensation in Parkinson\u2019s disease is not dopamine-mediated","volume":"26","author":"Bezard","year":"2003","journal-title":"Trends Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1093\/brain\/awh607","article-title":"PET in LRRK2 mutations: Comparison to sporadic Parkinson\u2019s disease and evidence for presymptomatic compensation","volume":"128","author":"Adams","year":"2005","journal-title":"Brain J. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1385\/NMM:4:1-2:21","article-title":"Role of Protein Aggregation in Mitochondrial Dysfunction and Neurodegeneration in Alzheimer\u2019s and Parkinson\u2019s Diseases","volume":"4","author":"Hashimoto","year":"2003","journal-title":"NeuroMolecular Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.2147\/CIA.S6456","article-title":"Levodopa in the treatment of Parkinson\u2019s disease: An old drug still going strong","volume":"5","author":"Antonini","year":"2010","journal-title":"Clin. Interv. Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000215875","article-title":"Levodopa: Past, Present, and Future","volume":"62","author":"Hauser","year":"2009","journal-title":"Eur. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"331","DOI":"10.3389\/fnbeh.2014.00331","article-title":"Spontaneous locomotor activity and L-DOPA-induced dyskinesia are not linked in 6-OHDA parkinsonian rats","volume":"8","author":"Sgroi","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1136\/jnnp.68.6.685","article-title":"Dopamine agonists: Their role in the treatment of Parkinson\u2019s disease","volume":"68","author":"Brooks","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_34","first-page":"603631","article-title":"Dopamine Agonists and Pathologic Behaviors","volume":"2012","author":"Kelley","year":"2012","journal-title":"Park. Dis."},{"key":"ref_35","first-page":"CD003735","article-title":"Anticholinergics for symptomatic management of Parkinson\u2019s disease","volume":"2002","author":"Katzenschlager","year":"2002","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"339","DOI":"10.2174\/1570159X14666151120123025","article-title":"Current Pharmaceutical Treatments and Alternative Therapies of Parkinson\u2019s Disease","volume":"14","author":"Dong","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1017\/S031716710000007X","article-title":"COMT Inhibitors in Parkinson\u2019s Disease","volume":"26","author":"Rivest","year":"1999","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1002\/med.21561","article-title":"Monoamine oxidase-B inhibitors as potential neurotherapeutic agents: An overview and update","volume":"39","author":"Tripathi","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"425","DOI":"10.2174\/1871527316666170124165222","article-title":"Monoamine Oxidase B Inhibitors in Parkinson\u2019s Disease","volume":"16","author":"Dezsi","year":"2017","journal-title":"CNS Neurol. Disord.\u2014Drug Targets"},{"key":"ref_40","unstructured":"Chang, C., and Ramphul, K. (2020, February 14). Amantadine, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK499953\/."},{"key":"ref_41","first-page":"CD003467","article-title":"Amantadine for dyskinesia in Parkinson\u2019s disease","volume":"2003","author":"Crosby","year":"2003","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4938154","DOI":"10.1155\/2016\/4938154","article-title":"The Efficacy and Safety of Antipsychotic Medications in the Treatment of Psychosis in Patients with Parkinson\u2019s Disease","volume":"2016","author":"Divac","year":"2016","journal-title":"Behav. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"St\u0119pnicki, P., Kondej, M., and Kaczor, A.A. (2018). Current Concepts and Treatments of Schizophrenia. Molecules, 23.","DOI":"10.3390\/molecules23082087"},{"key":"ref_44","unstructured":"(2020, March 06). Accessdata.fda.gov, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2010\/019758s062lbl.pdf."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1001\/archneurol.2010.35","article-title":"Serotonin 2A Receptors and Visual Hallucinations in Parkinson Disease","volume":"67","author":"Ballanger","year":"2010","journal-title":"Arch. Neurol."},{"key":"ref_46","unstructured":"Thomas, K., and Saadabadi, A. (2020, January 30). Olanzapine, StatPearls, Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK532903\/."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.euroneuro.2018.05.016","article-title":"The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity","volume":"28","author":"Tollens","year":"2018","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2217\/nmt-2016-0009","article-title":"Parkinson\u2019s disease psychosis: Therapy tips and the importance of communication between neurologists and psychiatrists","volume":"6","author":"Okun","year":"2016","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e00639","DOI":"10.1002\/brb3.639","article-title":"Atypical antipsychotic therapy in Parkinson\u2019s disease psychosis: A retrospective study","volume":"7","author":"Yuan","year":"2017","journal-title":"Brain Behav."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1080\/14656566.2018.1524876","article-title":"Istradefylline for the treatment of Parkinson\u2019s disease: Is it a promising strategy?","volume":"19","author":"Torti","year":"2018","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1176\/jnp.12.3.364","article-title":"Clozapine and Risperidone Treatment of Psychosis in Parkinson\u2019s Disease","volume":"12","author":"Ellis","year":"2000","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1097\/WNF.0b013e31824d5115","article-title":"Ziprasidone Versus Clozapine in the Treatment of Psychotic Symptoms in Parkinson Disease","volume":"35","author":"Pintor","year":"2012","journal-title":"Clin. Neuropharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"609","DOI":"10.2147\/DDDT.S77749","article-title":"Adjuvant therapies for Parkinson\u2019s disease: Critical evaluation of safinamide","volume":"10","author":"Stocchi","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s12325-018-0687-z","article-title":"Long-term Efficacy of Safinamide on Parkinson\u2019s Disease Chronic Pain","volume":"35","author":"Cattaneo","year":"2018","journal-title":"Adv. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1124\/pr.55.3.2","article-title":"Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor\/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons","volume":"55","author":"Agnati","year":"2003","journal-title":"Pharmacol. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1517\/13543784.14.6.729","article-title":"Istradefylline, a novel adenosine A2Areceptor antagonist, for the treatment of Parkinson\u2019s disease","volume":"14","author":"Jenner","year":"2005","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1002\/mds.25418","article-title":"Adenosine A2Areceptor antagonist istradefylline reduces daily OFF time in Parkinson\u2019s disease","volume":"28","author":"Mizuno","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_58","first-page":"1","article-title":"Pimavanserin: Potential Treatment for Dementia-Related Psychosis","volume":"5","author":"Cummings","year":"2018","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1124\/jpet.105.097006","article-title":"Pharmacological and Behavioral Profile of N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N\u2032-(4-(2-methylpropyloxy)phenylmethyl) Carbamide (2R,3R)-Dihydroxybutanedioate (2:1) (ACP-103), a Novel 5-Hydroxytryptamine2A Receptor Inverse Agonist","volume":"317","author":"Vanover","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1007\/s00213-018-5042-1","article-title":"The neuropharmacology of sleep paralysis hallucinations: Serotonin 2A activation and a novel therapeutic drug","volume":"235","author":"Jalal","year":"2018","journal-title":"Psychopharmacology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/jnc.13750","article-title":"Current and experimental treatments of Parkinson disease: A guide for neuroscientists","volume":"139","author":"Oertel","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"PD MED Collaborative Group incl (2014). Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson\u2019s disease (PD MED): A large, open-label, pragmatic randomised trial. Lancet, 384, 1196\u20131205.","DOI":"10.1016\/S0140-6736(14)60683-8"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1056\/NEJMoa033447","article-title":"Levodopa and the Progression of Parkinson\u2019s Disease","volume":"351","author":"Fahn","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1002\/mds.23829","article-title":"The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson\u2019s disease","volume":"26","author":"Fox","year":"2011","journal-title":"Mov. Disord."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Parkinson Study Group CALM Cohort Investigators (2009). Long-term Effect of Initiating Pramipexole vs. Levodopa in Early Parkinson Disease. Arch. Neurol., 66, 563\u2013570.","DOI":"10.1001\/archneur.66.1.nct90001"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1056\/NEJM200005183422004","article-title":"A Five-Year Study of the Incidence of Dyskinesia in Patients with Early Parkinson\u2019s Disease Who Were Treated with Ropinirole or Levodopa","volume":"342","author":"Rascol","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/mds.20724","article-title":"Pergolide versus levodopa monotherapy in early Parkinson\u2019s disease patients: The PELMOPET study","volume":"21","author":"Oertel","year":"2005","journal-title":"Mov. Disord."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1002\/mds.10108","article-title":"Management of Parkinson\u2019s disease: An evidence-based review","volume":"17","author":"Lang","year":"2002","journal-title":"Mov. Disord."},{"key":"ref_69","first-page":"217","article-title":"Are There Benefits in Adding Catechol-O Methyltransferase Inhibitors in the Pharmacotherapy of Parkinson\u2019s Disease Patients? A Systematic Review","volume":"8","author":"Katsaiti","year":"2018","journal-title":"J. Park. Dis."},{"key":"ref_70","unstructured":"Tolcapone (2020, March 06). Ncbi.nlm.nih.gov, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK548573\/."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/bcp.12081","article-title":"Opicapone: A short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects","volume":"76","author":"Rocha","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/S1474-4422(15)00336-1","article-title":"Opicapone as an adjunct to levodopa in patients with Parkinson\u2019s disease and end-of-dose motor fluctuations: A randomised, double-blind, controlled trial","volume":"15","author":"Ferreira","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1007\/s00702-018-1869-1","article-title":"Efficacy and safety of amantadine for the treatment of l-DOPA-induced dyskinesia","volume":"125","author":"Rascol","year":"2018","journal-title":"J. Neural Transm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"205","DOI":"10.2217\/nmt-2019-0011","article-title":"Efficacy and safety of extended-release amantadine in levodopa-induced dyskinesias: A meta-analysis","volume":"9","author":"Pajo","year":"2019","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/mds.27131","article-title":"Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson\u2019s disease (EASE LID 3)","volume":"32","author":"Oertel","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Parkinson Study Group (1999). Low-Dose Clozapine for the Treatment of Drug-Induced Psychosis in Parkinson\u2019s Disease. N. Engl. J. Med., 340, 757\u2013763.","DOI":"10.1056\/NEJM199903113401003"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1136\/jnnp.2003.029868","article-title":"Clozapine in drug induced psychosis in Parkinson\u2019s disease: A randomised, placebo controlled study with open follow up","volume":"75","author":"Pollak","year":"2004","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_78","first-page":"S2","article-title":"The Emerging Role of Pimavanserin in the Management of Parkinson\u2019s Disease Psychosis","volume":"23","author":"Hermanowicz","year":"2017","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrneurol.2016.200","article-title":"The psychosis spectrum in Parkinson disease","volume":"13","author":"Ffytche","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s40266-016-0416-8","article-title":"Psychosis in Parkinson Disease: A Review of Etiology, Phenomenology, and Management","volume":"33","author":"Samudra","year":"2016","journal-title":"Drugs Aging"},{"key":"ref_81","unstructured":"(2020, March 06). UpToDate. Uptodate.com. Available online: https:\/\/www.uptodate.com\/contents\/medical-management-of-motor-fluctuations-and-dyskinesia-in-parkinson-disease#."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.euroneuro.2006.08.007","article-title":"Treating dopamimetic psychosis in Parkinson\u2019s disease: Structured review and meta-analysis","volume":"17","author":"Frieling","year":"2007","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_83","unstructured":"(2020, March 06). Recommendations|Parkinson\u2019s Disease in Adults Guidance|NICE. Available online: https:\/\/www.nice.org.uk\/guidance\/ng71\/chapter\/Recommendations#pharmacological-management-of-motor-symptoms."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/mds.10217","article-title":"Olanzapine treatment for dopaminergic-induced hallucinations","volume":"17","author":"Ondo","year":"2002","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1212\/WNL.55.6.789","article-title":"Olanzapine and clozapine: Comparative effects on motor function in hallucinating PD patients","volume":"55","author":"Goetz","year":"2000","journal-title":"Neurology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1007\/s40266-019-00655-y","article-title":"Pimavanserin for Psychosis in Parkinson\u2019s Disease-Related Disorders: A Retrospective Chart Review","volume":"36","author":"Sellers","year":"2019","journal-title":"Drugs Aging"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1097\/01.wnf.0000164297.91643.ff","article-title":"Use of Ziprasidone in Parkinsonian Patients With Psychosis","volume":"28","author":"Zarranz","year":"2005","journal-title":"Clin. Neuropharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Schapira, A., Fox, S., Hauser, R., Jankovic, J., Jost, W., Kulisevsky, J., Pahwa, R., Poewe, W., and Anand, R. (2013, January 16\u201323). Safinamide add on to L-dopa: At randomized, placebo controlled 24 weeks global trial in patients with Parkinson\u2019s disease and motor fluctuations. Proceedings of the 65th Annual Meeting of the American Academy of Neurology (AAN), San Diego, CA, USA.","DOI":"10.1212\/WNL.80.7_supplement.P01.062"},{"key":"ref_89","first-page":"29130466","article-title":"Safinamide from daily clinical practice: First clinical steps","volume":"65","author":"Pagonabarraga","year":"2017","journal-title":"Rev. Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/mds.25751","article-title":"Randomized trial of safinamide add-on to levodopa in Parkinson\u2019s disease with motor fluctuations","volume":"29","author":"Borgohain","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1002\/mds.25961","article-title":"Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson\u2019s disease","volume":"29","author":"Borgohain","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_92","first-page":"165","article-title":"Safinamide as Add-On Therapy to Levodopa in Mid- to Late-Stage Parkinson\u2019s Disease Fluctuating Patients: Post hoc Analysesof Studies 016 and SETTLE","volume":"6","author":"Cattaneo","year":"2016","journal-title":"J. Park. Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1212\/01.WNL.0000134672.44217.F7","article-title":"Improvement of motor function in early Parkinson disease by safinamide","volume":"63","author":"Stocchi","year":"2004","journal-title":"Neurology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1212\/WNL.67.7_suppl_2.S24","article-title":"Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition","volume":"67","author":"Stocchi","year":"2006","journal-title":"Neurology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/mds.23954","article-title":"A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson\u2019s disease patients","volume":"27","author":"Stocchi","year":"2011","journal-title":"Mov. Disord."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/j.1468-1331.2012.03840.x","article-title":"Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson\u2019s disease","volume":"20","author":"Schapira","year":"2013","journal-title":"Eur. J. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Barone, P., Fernandez, H., Ferreira, J., Mueller, T., Saint-Hilaire, M., Stacy, M., Tolosa, E., and Anand, R. (2013, January 16\u201323). Safinamide as an add-on therapy to a stable dose of a single dopamine agonist: Results from a randomized, placebo-controlled, 24-week multicenter trial in early idiopathic Parkinson disease patients (MOTION Study). Proceedings of the 65th Annual Meeting of the American Academy of Neurology (AAN), San Diego, CA, USA.","DOI":"10.1212\/WNL.80.7_supplement.P01.061"},{"key":"ref_98","first-page":"44","article-title":"Can pimavanserin help patients with Parkinson disease psychosis?","volume":"32","author":"Canal","year":"2019","journal-title":"J. Am. Acad. Phys. Assist."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1002\/mds.27488","article-title":"Pimavanserin for Parkinson\u2019s Disease psychosis: Effects stratified by baseline cognition and use of cognitive-enhancing medications","volume":"33","author":"Espay","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_100","unstructured":"(2020, February 14). Patient Education: Parkinson Disease Treatment Options\u2014Medications (Beyond the Basics)\u2014UpToDate. Available online: https:\/\/www.uptodate.com\/contents\/parkinson-disease-treatment-options-medications-beyond-the-basics#H16."},{"key":"ref_101","first-page":"S51","article-title":"COMT inhibitors and liver toxicity","volume":"55","author":"Watkins","year":"2000","journal-title":"Neurology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1002\/jat.1550","article-title":"DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine","volume":"30","author":"Kaefer","year":"2010","journal-title":"J. Appl. Toxicol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuropharm.2013.10.021","article-title":"Expression of 5-HT2A receptors in prefrontal cortex pyramidal neurons projecting to nucleus accumbens. Potential relevance for atypical antipsychotic action","volume":"79","author":"Mocci","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"643","DOI":"10.2165\/00002018-200326090-00004","article-title":"Treatment of psychosis in Parkinson\u2019s disease: Safety considerations","volume":"26","author":"Fernandez","year":"2003","journal-title":"Drug Saf."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/WNF.0000000000000080","article-title":"Adverse Reactions to Antipsychotics in Parkinson Disease","volume":"38","author":"Lertxundi","year":"2015","journal-title":"Clin. Neuropharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1212\/01.WNL.0000095205.33940.99","article-title":"Anatomy of adenosine A2A receptors in brain: Morphological substrates for integration of striatal function","volume":"61","author":"Rosin","year":"2003","journal-title":"Neurology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1002\/ana.20822","article-title":"Compulsive drug use linked to sensitized ventral striatal dopamine transmission","volume":"59","author":"Evans","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"317","DOI":"10.2174\/092986712803414231","article-title":"The Importance of the Adenosine A2A Receptor-Dopamine D2 Receptor Interaction in Drug Addiction","volume":"19","author":"Filip","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0140-6736(13)62106-6","article-title":"Pimavanserin for patients with Parkinson\u2019s disease psychosis: A randomised, placebo-controlled phase 3 trial","volume":"383","author":"Cummings","year":"2014","journal-title":"Lancet"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/mds.26363","article-title":"Nonpharmacological treatments for patients with Parkinson\u2019s disease","volume":"30","author":"Bloem","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_111","unstructured":"Julie, G.P., Olga, K., Shrey, P., and American Association of Neurological Surgeons (2021, November 16). Deep Brain Stimulation. Available online: https:\/\/www.aans.org\/en\/Patients\/Neurosurgical-Conditions-and-Treatments\/Deep-Brain-Stimulation."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/1\/364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:55:53Z","timestamp":1760169353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/1\/364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,30]]},"references-count":111,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijerph19010364"],"URL":"https:\/\/doi.org\/10.3390\/ijerph19010364","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,30]]}}}