Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in approximately 20% of patients with PD. While depression can occur anytime in the disease process, it p...

Drug treatment strategies for depression in Parkinson disease.

Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson's disease (PD) All three drugs improve motor signs of PD, and are effective in reducing motor fluctuations in patients undergoing long-term L-DOPA treatment The effect of MAOB inhibitors on non-motor symptoms is not uniform and may not be class-related Selegiline and rasagiline are irreversible inhibitors forming a covalent bond within the active site of MAOB In contrast, safinamide is a reversible MAOB inhibitor, and also inhibits voltage- sensitive sodium channels and glutamate release Safinamide is the prototype of a new generation of multi-active MAOB inhibitors, which includes the antiepileptic drug, zonisamide Inhibition of MAOB-mediated dopamine metabolism largely accounts for the antiparkinsonian effect of the three drugs Dopamine metabolism by MAOB generates reactive oxygen species, which contribute to nigro-striatal degeneration Among all antiparkinsonian agents, MAOB inhibitors are those with the greatest neuroprotective potential because of inhibition of dopamine metabolism, induction of neurotrophic factors, and, in the case of safinamide, inhibition of glutamate release The recent development of new experimental animal models that more closely mimic the progressive neurodegeneration associated with PD will allow to test the hypothesis that MAOB inhibitors may slow the progression of PD

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Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson's Disease: From Bench to Bedside.

Abnormal cortical facilitation and L-dopa-induced dyskinesia in Parkinson's disease.

The primary endpoint of this work was to evaluate the effect of safinamide on non-motor symptoms (NMS) in patients affected by idiopathic Parkinson's disease (PD) complicated by motor fluctuations. We retrospectively collected data from 20 subjects affected by idiopathic PD in treatment with L-dopa alone or in combination with dopamine agonists, who began to be treated with safinamide due to the occurrence of motor fluctuations. Secondary endpoints included SCales for Outcomes in Parkinson's disease (SCOPA) Motor Scale, cognitive assessment, the Hoehn and Yahr stage, Clinical Impression of Severity Index for Parkinson's Disease, Hospital Anxiety And Depression Scale, Physical and Mental Fatigue, Parkinson's disease Sleep Scale, Parkinson's Disease Questionnaire-8 (PDQ-8) and EQ-5D. Each one of these scales/questionnaires was performed at baseline and T1. For efficacy analyses, continuous variables were treated with descriptive statistics, using mean and standard deviations. A non-parametric test (the Friedman test) was carried out to evaluate the statistical significance of the results observed. We found a statistically significant reduction of the total score of NMS, of 6 domains out of 9, and 13 items out of 30. A statistically significant reduction of SCOPA Motor Scale, PDQ-8, and CISI was also detected. In conclusion, our data showed a positive effect of safinamide on NMS and confirm its positive effect on motor symptomatology.

Efficacy of safinamide on non-motor symptoms in a cohort of patients affected by idiopathic Parkinson's disease

Background Parkinson's disease (PD) is characterized by a wide range of motor and non-motor symptoms. Levodopa is still the most effective drug; however, its long-term use is associated with motor complications which may deteriorate patient's quality of life. Safinamide is a unique treatment modulating both dopaminergic and glutamatergic systems. Previous results from two six months, double-blind, placebo-controlled studies demonstrated that safinamide has positive effects on both motor functions and quality of life in PD patients. Objective To investigate the effects of safinamide 100 mg/day over two-year treatment on PD symptoms severity and quality of life, using data from the study 018. Methods Data from 352 patients were analyzed to evaluate the effects of safinamide on OFF time and ON time (with no or non-troublesome dyskinesia) in the overall population and in subgroups of patients (receiving levodopa monotherapy or with other anti-Parkinson therapies), and the effects of safinamide on motor symptoms/clinical fluctuations (by means of UPDRS III and IV) and on health-related quality of life (using UPDRS II and PDQ-39 summary index score). Results Safinamide, administered as add-on to standard therapy in fluctuating PD patients, significantly improved motor symptoms and clinical fluctuations in the overall population and in some subgroups of patients. Additionally, safinamide improved quality of life and activities of daily living, maintaining the efficacy in the long-term. Conclusions The findings of these analyses suggest that safinamide may be considered an appropriate adjunct therapy in patient not sufficiently controlled. Further investigations are desirable to confirm these results in usual care setting.

Long-Term Efficacy of Safinamide on Symptoms Severity and Quality of Life in Fluctuating Parkinson's Disease Patients

Background Mood disorders are very frequent in Parkinson's Disease (PD), and their effective treatment is still a major unresolved issue: growing evidence suggests that glutamatergic system dysfunction is directly involved. Safinamide is a drug with an innovative mechanism of action, dopaminergic and non-dopaminergic, that includes the reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and the modulation of excessive glutamate release through the use- and state-dependent blockade of the sodium channels. Objective To investigate the effects of safinamide on mood over two-year treatment in PD patients with motor fluctuations. Methods This was a post-hoc analysis of the data from studies 016 and 018. The analysis focused on outcomes related to mood, namely: scores of the "Emotional well-being" domain of the Parkinson's Disease Questionnaire (PDQ-39), scores of the GRID Hamilton Rating Scale for Depression (GRID-HAMD) and the proportion of patients reporting depression as an adverse event over the entire treatment period. Results Safinamide, compared to placebo, significantly improved the PDQ-39 "Emotional well-being" domain after6-months (p = 0.0067) and 2 years (p = 0.0006), as well as the GRID-HAMD (p = 0.0408 after 6 months and p = 0.0027 after 2 years). Significantly fewer patients in the safinamide group, compared to placebo, experienced depression as adverse event (p = 0.0444 after 6 months and p = 0.0057 after 2 years). Conclusion The favorable effect of safinamide on mood may be explained by the improvement in wearing off and by its modulation of glutamatergic hyperactivity and reversible MAO-B inhibition. Prospective studies are warranted to investigate this potential benefit.

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Ioannis Kottakis

Papers

Long-Term Effects of Safinamide on Mood Fluctuations in Parkinson's Disease.