The Effects of Safinamide Adjunct Therapy on Depression and Apathy in Patients With Parkinson's Disease: Post-hoc Analysis of a Japanese Phase 2/3 Study

Kogo, Yuki; Koebis, Michinori; Ishida, Takayuki; Suzuki, Ippei; Tsuboi, Yoshio; Nomoto, Masahiro

doi:10.3389/fneur.2021.752632

Cited by 5 publications

(6 citation statements)

References 56 publications

(70 reference statements)

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“…In contrast to our findings, earlier studies showed SAF might suppress I Na magnitude in different preparations [ 21 , 26 – 29 ]. It will be important to determine whether the inhibitory effect of SAF on I Na is associated with either the decrease of the activity of monoamine oxidase or the production of reactive oxygen species [ 13 , 14 , 22 – 25 ]. Of note, although SAF was considered a potential anticonvulsant based on prior reports of I Na attenuating property, clinically, the anticonvulsive activity of SAF was not proven, as only open-label studies comparing with baseline were provided [ 70 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

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Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current

Hung,

Wu,

Huang

2024

BMC Pharmacol Toxicol

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Background Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys(V)] of ionic currents remains unknown. Methods With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (NaV) channels in pituitary GH3 cells. Results SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (INa) in pituitary GH3 cells. The conductance–voltage relationship of transient INa [INa(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of INa(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of INa(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window INa induced by an ascending ramp voltage Vramp. Furthermore, SAF enhanced the Hys(V) behavior of persistent INa induced by an upright isosceles-triangular Vramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of NaV channels. Molecular docking revealed SAF interacts with both MAO and NaV channels. Conclusion SAF may interact directly with NaV channels in pituitary neuroendocrine cells, modulating membrane excitability.

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Section: Discussionmentioning

confidence: 99%

“…Several studies also reported the efficacy of SAF as an add-on treatment to subthalamic nucleus deep brain stimulation [ 19 , 20 ]. SAF exerts its effects through various mechanisms, including inhibition of monoamine oxidase (MAO)-B activity [ 2 , 13 – 15 , 21 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current

Hung,

Wu,

Huang

2024

BMC Pharmacol Toxicol

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“… 29 Notably, reductions in depression were associated with changes in daily ON-time of at least 1 hour, the presence of pain during the OFF-time at baseline, and female sex. 28 …”

Section: Methodsmentioning

confidence: 99%

“…27 Hattori et al did a post-hoc analysis of data from II and III-phase clinical trials, and reported that safinamide exhibited significant improvement in patients with PD experiencing wearing-off symptoms, regardless of whether they received the 50 mg or 100 mg dose. 28 The initial study focused on evaluating changes in the UPDRS Part I item 3 score (depression) and item 4 (apathy), as well as the PDQ-39" emotional well-being. 29 Notably, reductions in depression were associated with changes in daily ON-time of at least 1 hour, the presence of pain during the OFF-time at baseline, and female sex.…”

Section: Dovepressmentioning

confidence: 99%

“…29 Notably, reductions in depression were associated with changes in daily ON-time of at least 1 hour, the presence of pain during the OFF-time at baseline, and female sex. 28 Several studies have described that cognitive dysfunction in PD is due to cholinergic neurotransmitter impairment. 30 This fact might account for the lack of cognitive improvement after imitating levodopa therapy and explain the cognitive benefit provided by cholinesterase inhibitors like rivastigmine.…”

Section: Dovepressmentioning

confidence: 99%

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Impact of Safinamide on Patient-Reported Outcomes in Parkinson’s Disease

Espinoza-Vinces,

Villino-Rodríguez,

Atorrasagasti-Villar

et al. 2023

PROM

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Introduction Parkinson’s disease (PD) is a chronic and progressive neurodegenerative condition due to the degeneration of nigral dopaminergic cells. Both motor and non-motor symptoms (NMS) of PD produce a marked impairment in PD patients’ quality of life (QoL), but contrary to motor features, NMS do not improve with dopamine replacement. Novel therapeutic interventions for PD have successfully controlled most motor manifestations of PD, but the management of NMS is still challenging. Since NMS have a negative impact on the QoL of PD patients, researchers are currently looking for drugs that can modulate the activity of neurotransmitter systems other than dopamine in the hope that can alleviate NMS in PD. Among the recently approved drugs for patients experiencing fluctuations in motor symptoms, safinamide stands out as an effective add-on therapy to levodopa. Safinamide is a monoamine oxidase type-B inhibitor (MAOB-I), with proven efficacy in reducing motor fluctuations. Its distinctive mechanism of action impacts dopaminergic pathways via MAOB inhibition and glutamatergic pathways by blocking sodium and calcium channels. Findings from Phase III clinical trials, meta-analysis, post-hoc analysis, and real-life experiences indicate that safinamide benefits motor symptoms such as tremor, bradykinesia, rigidity, and gait. Additionally, it shows promise for improving NMS like fatigue, pain, mood, and sleep disturbances in patients with PD. Areas Covered In this article, the authors explore the impact of safinamide on patient-reported outcomes in PD. A thorough search was conducted on PubMed focusing on studies published between 2018 and 2023 in English. The inclusion criteria encompassed clinical trials, randomized controlled trials, systematic reviews, meta-analyses, and reviews. The search strategy revolved around the implementation of MeSH terms related to safinamide and its impact on the quality of life in PD. Conclusion Our data strongly support the improving effect on QoL, reducing the disabling NMS reported in patients with PD.

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Pharmacotherapy of motor symptoms in early and mid-stage Parkinson’s disease: guideline “Parkinson’s disease” of the German Society of Neurology

Höllerhage,

Becktepe,

Classen

et al. 2024

J Neurol

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Background and objective There are multiple pharmacological treatment options for motor symptoms of Parkinson’s disease (PD). These comprise multiple drug classes which are approved for the condition, including levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, NMDA-receptor antagonists, anticholinergics, and others. Some of the drugs are approved for monotherapy and combination therapy while others are only approved as adjunctive therapy to levodopa. Furthermore, treatment for special treatment situations, e.g., rescue medication for off-phases, for tremor, treatment during pregnancy and breast feeding is discussed and recommendations are given with further details. Methods The recommendations were based on systematic literature reviews, drafted by expert teams, consented in online polls followed by online consensus meetings of the whole German Parkinson’s Guideline Group, and publicly released in November 2023. Results In the new S2k (i.e., consensus-based) guidelines, the pharmacotherapy of the motor symptoms of PD is discussed in five chapters. These comprise “Parkinson medication”, “Initial monotherapy”, “Early combination therapy”, “Fluctuations and dyskinesia”, and “Parkinsonian tremor”. Furthermore, there is a chapter for special treatment situations, including perioperative management, freezing of gait, and pregnancy and breastfeeding. Conclusion The recommendations for the pharmacotherapy of motor symptoms of PD have been updated. Newly available drugs have been added, while other drugs (e.g., ergoline dopamine agonists, anticholinergics, budipine) have been removed from the recommendations.

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The Effects of Safinamide Adjunct Therapy on Depression and Apathy in Patients With Parkinson's Disease: Post-hoc Analysis of a Japanese Phase 2/3 Study

Cited by 5 publications

References 56 publications

Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current

Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current

Impact of Safinamide on Patient-Reported Outcomes in Parkinson’s Disease

Pharmacotherapy of motor symptoms in early and mid-stage Parkinson’s disease: guideline “Parkinson’s disease” of the German Society of Neurology

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