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Among other pathophysiological mechanisms, neuroinflammation, a pathological PD hallmark associated with changes in glutamatergic transmission in basal ganglia, has been proposed as a crucial factor closely related to fatigue. To test the hypothesis that safinamide could represent an effective treatment of fatigue in PD patients, given its dual mechanism of action (it selectively and reversibly inhibits MAOB and modulates glutamate release), we administered the validated versions of fatigue severity scale (FSS) and Parkinson fatigue scale-16 (PFS-16) to 39 fluctuating PD patients with fatigue before and after a 24-week treatment period with safinamide as add-on therapy. An assessment of secondary variables such as depression, quality of life (QoL), and motor and non-motor symptoms (NMS) was conducted. After 24\u00a0weeks of treatment with safinamide, both FSS (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and PF-S16 (<jats:italic>p<\/jats:italic>\u2009=\u20090.02) scores were significantly lower than at baseline. Moreover, 46.2% and 41% of patients scored below the cut-off for the presence of fatigue according to FSS and PFS-16, respectively (responders). At follow-up, a significant difference emerged between responders and non-responders in mood, QoL, and NMS. Fatigue improved in fluctuating PD, and more than 40% of patients were \u201cfatigue-free\u201d after a 6\u00a0month treatment with safinamide. Patients without fatigue at follow-up displayed significantly better scores in QoL domains, such as mobility or activities of daily living, although disease severity remained stable, supporting the hypothesis that fatigue could considerably affect QoL. Drugs that interact with multiple neurotransmission systems, such as safinamide, could be useful in reducing this symptom.<\/jats:p>","DOI":"10.1007\/s00702-023-02654-1","type":"journal-article","created":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T18:01:49Z","timestamp":1684605709000},"page":"915-923","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Fatigue in fluctuating Parkinson\u2019s disease patients: possible impact of safinamide"],"prefix":"10.1007","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3885-9921","authenticated-orcid":false,"given":"Caterina","family":"Pauletti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoletta","family":"Locuratolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Mannarelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Maffucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Petritis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Menini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Fattapposta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,5,20]]},"reference":[{"key":"2654_CR1","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1007\/s10072-012-0943-y","volume":"33","author":"G Abbruzzese","year":"2012","unstructured":"Abbruzzese G, Antonini A, Barone P et al (2012) Linguistic, psychometric validation and diagnostic ability assessment of an Italian version of a 19-item wearing-off questionnaire for wearing-off detection in Parkinson\u2019s disease. 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