ORIGINAL RESEARCH published: 02 June 2022 doi: 10.3389/fneur.2022.866502 A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson’s Disease Jaime Kulisevsky 1,2,3,4,5*, Saul Martínez-Horta 1,2,3,4 , Antonia Campolongo 1,2,3,4,5 , Berta Pascual-Sedano 1,2,3,4,5 , Juan Marín-Lahoz 1 , Helena Bejr-kasem 1,2,3,4 , Ignacio Aracil-Bolaños 1,2,3,4 , Andrea Horta-Barba 1,2,3,4 , Arnau Puig-Davi 1,2,3 and Javier Pagonabarraga 1,2,3,4 1 Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Barcelona, Spain, 2 Medicine Department, Universitat Autònoma de Barcelona (U.A.B.), Barcelona, Spain, 3 Institut d’Investigacions Biomèdiques- Sant Pau (IIB-Sant Pau), Edited by: Barcelona, Spain, 4 Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Cáceres, Spain, 5 Pedro J. Garcia-Ruiz, Neurology Department—Hospital Quirón Dexeus—Universitat Oberta de Catalunya (UOC), Barcelona, Spain University Hospital Fundación Jiménez Díaz, Spain Background: Apathy is highly prevalent and disabling in Parkinson’s disease (PD). Reviewed by: Santiago Perez-Lloret, Pharmacological options for its management lack sufficient evidence. Consejo Nacional de Investigaciones Científicas y Técnicas Objective: We studied the effects of safinamide on apathy in PD. (CONICET), Argentina Methods: Prospective, 24-week, two-site, randomized, double-blind, Juan Carlos Martinez Castrillo, Ramón y Cajal University placebo-controlled, parallel-group exploratory study in non-demented PD on stable Hospital, Spain dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks *Correspondence: and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change Jaime Kulisevsky jkulisevsky@santpau.cat from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of Specialty section: change, and safety and tolerability measures. This article was submitted to Movement Disorders, Results: In total, 30 participants (active treatment = 15; placebo = 15; 80% showing a section of the journal clinically significant apathetic symptoms according to the AS) were enrolled, and included Frontiers in Neurology in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance Received: 31 January 2022 Accepted: 02 May 2022 [p = 0.059] mediated by a more marked decrease in AS score with safinamide (−7.5 ± Published: 02 June 2022 6.9) than with placebo (−2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant Citation: positive change in the AS score between 12-week and 24-week [p = 0.001] only in Kulisevsky J, Martínez-Horta S, the active group. No significant or trend changes were found for any of the secondary Campolongo A, Pascual-Sedano B, Marín-Lahoz J, Bejr-kasem H, outcome variables. Adverse events were few and only mild in both treatment groups. Aracil-Bolaños I, Horta-Barba A, Puig-Davi A and Pagonabarraga J Conclusions: Safinamide was safe and well-tolerated, but failed to provide evidence of (2022) A Randomized Clinical Trial to improved apathy. The positive trend observed in the post-hoc analyses deserves to be Evaluate the Effects of Safinamide on studied in depth in larger studies. Apathetic Non-demented Patients With Parkinson’s Disease. Trial Registration: EudraCT 2017-003254-17. Front. Neurol. 13:866502. doi: 10.3389/fneur.2022.866502 Keywords: Parkinson’s disease, apathy, safinamide, RCT-randomized controlled trial, clinical trial Frontiers in Neurology | www.frontiersin.org 1 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD INTRODUCTION Substantial evidence implicates the nucleus accumbens glutamine-to-glutamate ratio on the prediction of specific Apathy, is one of the more common and debilitating components of motivated behavior (34), and glutamine-to- neuropsychiatric disturbances in Parkinson’s disease (PD) glutamate ratio in the nucleus accumbens predicts effort-based (1, 2). It substantially contributes to reductions in quality of life, motivated performance in humans (34). These arguments added higher levels of care dependency, increased caregiver distress, to preliminary evidence from post-hoc and open-label studies and increased risk of developing dementia (2–5). showing some improvement in apathy in patients treated with Apathy is manifested as a quantitative reduction of goal- safinamide (27, 28, 35) moved us to formally explore whether a directed activity in comparison to the person’s previous level therapeutic strategy using a drug targeting both, dopaminergic of functioning, which can be observed in behavioral, cognitive, and glutamatergic systems, could help to ameliorate apathetic emotional, or social dimensions (1, 6). Considering all the stages symptoms in PD. of PD, estimates of the prevalence of apathy range from 35 to Accordingly, in this study we explored the effects of 70%(1, 7). Safinamide, a multimodal drug with a dual mechanism of action, While apathy highly overlaps along the course of the disease dopaminergic (reversible mono amine oxidase-B inhibition) with symptoms of depression, anxiety, and cognitive impairment and non-dopaminergic [modulation of the abnormal glutamate (8–11), it is a distinct neuropsychiatric syndrome (12) that can release(cites)]. It has a predictable beneficial effect on motor be properly identified using appropriate instruments (7, 13– fluctuations (35, 36) and was suggested to decrease non-motor 16). symptom burden as well (27, 28). Safinamide has a good Apathy in PD is thought to mainly be due to the denervation safety profile even in special group of PwP with psychiatric of ascending dopaminergic pathways causing dysfunction of complications (37), and was not tested formally in a RCT for the prefrontal cortex-basal ganglia circuits (1, 6, 17) but other apathy in PD. degenerated neurotransmitter systems can be compromised as well. Among the behavioral complications of PD, apathy is likely MATERIALS AND METHODS the most underserved in terms of specific drug therapy. Very Study Design few high-quality randomized-control trials (RCTs) used apathy This was a 24-week, randomized, double-blind, placebo- as an inclusion criterion (18). Two small-sized RCT in people controlled, add-on, parallel-group study to assess the effect of with PD (PwP)–one with the dopamine agonist piribedil in safinamide on apathy in patients with PD conducted in two PwP that turned apathetic after STN–DBS (19) and one with centers in Spain. Eligible PwP were randomized (1:1) to 24 weeks the anticholinesterase agent rivastigmine (20)—showed some of oral treatment with either safinamide 50 mg/day (first 2 weeks) positive results, the but evidence was not considered enough and 100 mg/day (22 weeks) or matching placebo, added to their to qualify these compounds both as “efficacious” and useful’ current, stable PD medications that were to remain unchanged agents for the treatment of apathy in PD (18). Two studies throughout the study. using rotigotine for apathy in PwP were negative (21, 22), and one using 5-hydroxytryptophan observed positive effect on Sample and Assessments depression but not on apathy (23). Among non-RCT studies, Inclusion Criteria rivastigmine failed to improve apathy in a 1-year open-label study Key inclusion criteria were: (1) non-demented PwP with a clinical in PD dementia (24), and positive effects in some non-motor diagnosis of PD according to the Movement Disorder Society symptoms, including apathy, were reported in open-label or post- (MDS) PD Criteria (38), aged 45–85 years; (2) Hoehn and hoc studies with rotigotine (25), pramipexole (17), istradefylline Yahr Stage (39) of I to III (mild-to-moderate motor severity) (26), and safinamide (27, 28). at screening; (3) a total score ≥20 on the Montreal Cognitive Thus, there are no guidelines currently for managing apathy in Assessment scale (MoCA) (40); (3) scoring 1 or more on the PD (18, 29) and recommendations are limited to debatable expert Apathy Item of the Neuropsychiatric Inventory (NPI) (41); (4) opinion (1, 18, 29, 30). Hence, there is an urgent unmet need to clinical diagnosis of apathy as defined by Diagnostic Criteria for adequately explore treatments to improve apathy in PD. Apathy in Clinical Practice (42); (5) to be able to speak, read, and The dopaminergic system plays a core role in the regulation of understand in the language in which the tests are written; (6) goal-directed and motivating effortful behavior for reward, and receiving treatment with dopaminergic therapy: levodopa (with its dysfunction has been proposed to play a crucial role in the or without entacapone) and/or dopamine agonists at a stable etiology of apathy in PD (31). In this line, there is remarkable dose for at least 4 weeks prior to screening and for the duration evidence regarding the involvement of the mesolimbic system of the study; (7) understand and sign the appropriate approved and structures such as the nucleus accumbens—which play a Informed Consent Form of the Study. central role in motivation—in the etiology of apathy in PD (1, 32, 33). However, dopaminergic replacement therapy generally has a Exclusion Criteria partial or no effect on apathy in PD (19). Therefore, considering Key exclusion criteria were: (1) diagnosis of moderate-to- the role of other neurotransmitter systems involved in the normal severe dementia associated with PD, according to the MDS functioning of the basal ganglia deserves to be taken into account criteria (43); (2) active psychosis or major hallucinations, severe in order to develop effective therapies. depression or delirium; history of alcohol or drug abuse for 3 Frontiers in Neurology | www.frontiersin.org 2 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD months prior to screening; (3) mental/physical/social condition differences in a quantitative variable) or three-way ANOVA (if that could preclude performing efficacy or safety assessments; there are differences in a categorical variable). For the analysis (4) severe white matter disease, multiple lacunar infarcts, or of secondary variables, we applied the same model as that for signs of significant vascular changes on MRI; (5) clinically the primary variable. Statistical analysis was performed using the significant or unstable medical or surgical condition that would, statistical software package SPSS 19.0 for Windows (SPSS Inc., in the opinion of the investigator, preclude participation to the Chicago, IL). study; (6) currently experiencing significant motor complications (moderate or severe wearing off defined as score >2 on Item 4.4 of MDS-UPDRS Part IV) or disabling dyskinesia (defined as Sample-Size Calculation score >2 on Item 4.2 of MDS-UPDRS Part IV) (44); (7) previous Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two- treatment with safinamide; (8) treatment with anticholinergic, sided hypothesis test, we calculated that a sample size of 18 antidopaminergic medication or acetylcholinesterase inhibitors; subjects per group (N = 36) provided 80% power to detect a and (9) use of MAO-B inhibitors (e.g., selegiline, rasagiline) difference in mean change of the AS between safinamide and within 4 weeks prior to screening. placebo. The SD was assumed in 9, and a dropout rate of 20% was expected among subjects who might discontinue study Primary Efficacy Endpoint participation, require safinamide dose suspension or increase The primary efficacy endpoint was the mean change from dopaminergic dosages. baseline to week 24 in the 14-item Starkstein Apathy Scale (AS) (45) total score (range 0–42; higher scores indicating more severe apathy). Ethics This study (EudraCT 2017-003254-17) was approved by the Secondary Endpoints local Ethics Committee which complies with the regulatory Key secondary endpoints were changed from baseline to week requirements and the Declaration of Helsinki. Written informed 24 in: (1) Parkinson’s Disease–Cognitive Rating Scale (PD–CRS) consent was obtained before any study procedures from all the total score; (2) Parkinson’s disease–Cognitive Functional Rating patients. The data that support the findings of this study are Scale (PD–CFRS) total score; (3) NPI; (4) Hamilton Depression available on request from the corresponding author. The data are Rating Scale (HAM-D); (5) MDS–UPDRS motor subscale (Part not publicly available due to privacy or ethical restrictions. III) total score; and (6) Parkinson’s Disease Questionnaire (PDQ- 39) total score; both (7) Patient’s Clinical Global Impression of Change (P–CGI) of Apathy and (8) Clinical Global Impression RESULTS of Change (CGI) of apathy, were administered at the final visit of the study. Ratings in the P–CGI and CGI were based on a Early termination of the study due to restrictions caused by the Likert-type scale (0 = not assessed, 1 = very much improved, global COVID-19 pandemic precluded the recruitment of the 2 = much improved, 3 = minimally improved, 4 = no change, planned sample size (N = 36). This was decided in accordance 5 = minimally worse, 6 = much worse, 7 = very much worse); with the Ethics Committee and communicated to the Spanish maximum score on the scales was 7. Safety and tolerability regulatory authorities. While all the subjects who were active were assessed through adverse event (AE) reporting and physical at the beginning of the restrictions were able to complete their examination, body weight and vital signs and electrocardiogram pending visits in a timely manner, screening and recruitment and laboratory test with hematology and biochemistry obtained of new subjects were stopped because of security reasons. at baseline, 4, 12, and 24 weeks’ visits. Considerations favoring early termination instead of temporary suspension were: the exploratory nature of the study with the Statistical Analyses recruitment close to the planned sample size; the uncertainty in For the planned data analysis, a type 1 error of 5% for the the duration of the mobility restrictions and accessing to Hospital primary hypothesis (alpha 0.05) was assumed. All the efficacy facilities; and the relatively close caducity data of the supplied analysis were performed in the modified-intention to treat (ITT) medication and placebo. population, therefore, all those subjects randomized and who Screening, enrollment, and participation information is received at least one evaluation visit were included. We also shown in Figure 1. Following screening (N = 34), eligible included all those subjects in the safety analysis who have subjects (N = 30) were randomized to the safinamide or placebo been randomized and have taken at least one dose of study groups. It supposed six fewer patients than the initially estimated medication. As a method of imputation of missing values, the as a total sample. The target dosage (100 mg/day) was achieved on Last Observation Carried Forward (LOCF) method was used. all the participants in the safinamide group except in one subject The primary efficacy endpoint was the mean change in the who discontinued the study at visit 2 for mild dizziness. Other AS total score from baseline to week 24. If there were no subject in the safinamide group complained of increase in anxiety differences between groups in age, gender, and education, the and left the study at week 10. One subject on the placebo group statistical model to follow was a two-way ANOVA. If there left the study on week 16 due to hallucinations. According to the were differences between groups in age, gender, or education, estimated dropout rate of 20% of the participants, the resulting the statistical model to follow was an ANCOVA (if there are sample was considered still valid in terms of sample size. Because Frontiers in Neurology | www.frontiersin.org 3 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD FIGURE 1 | CONSORT diagram of participants in a study of safinamide for apathy in non-demented Parkinson’s disease. of the planned ITT analysis in case of discontinuation, the results treatment (AT) arm and fifteen to the placebo arm. The main from all the 30 subjects participating in the study are reported. clinical and sociodemographic variables at baseline of the whole The study sample consisted on 30 patients (mean age = 69.4 ± sample and of the two different treatment groups are described in 9.9 years; mean disease duration = 53 ± 38.6; mean UPDRS-III Table 1. = 29.9 ± 7.7; mean H&Y = 2 ± 0.4). As per inclusion criteria, T-tests showed absence of significant between-group all the patients scored ≥1 in the apathy sub-score of the NPI. differences in the main clinical variables associated with PD. After randomization, fifteen subjects were allocated to the active Thus, no differences were found with respect to age, disease Frontiers in Neurology | www.frontiersin.org 4 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD TABLE 1 | Sociodemographic and clinical characteristics of the entire sample and the two treatment groups at baseline. Entire sample Active treatment Placebo Mean ± SD Range Mean ± SD p Age 69.5 ± 9.8 44–84 66.7 ± 9.2 72.3 ± 10 0.149 Gender (f/m) 9/18 - 5/9 4/9 0.785 Education 12.3 ± 4.06 7–22 14.3 ± 4.6 10.2 ± 2.5 0.009 Disease duration 53 ± 38.6 8–134 57.8 ± 41.1 47.8 ± 36.6 0.512 UPDRS-III 29.9 ± 7.6 11–46 29.9 ± 8.3 29.9 ± 7.5 0.999 H&Y 2.1 ± 0.4 1–3 2.1 ± 0.3 2.1 ± 0.5 0.812 LEDD 609.2 ± 291.6 105–1,400 543 ± 213.8 631 ± 298.7 0.385 MoCA 25 ± 3 20–30 25.8 ± 3 23.9 ± 2.6 0.106 PD-CRS Total 89.1 ± 15.6 59–120 94.5 ± 16.2 81.1 ± 12.1 0.023 PD-CRS frontal-subcortical 59.44 ± 15.5 29–90 66.5 ± 14.6 51.7 ± 12.8 0.010 PD-CRS posterior-cortical 28.67 ± 6.2 22–30 28 ± 2.1 29.3 ± 8.7 0.571 PDQ-39 28.3 ± 17.1 2–59 25.4 ± 15.8 27.5 ± 17.1 0.742 NPI Apathy 4.1 ± 2.5 1–12 4.5 ± 2.9 3.8 ± 2 0.526 AS total score 19.5 ± 7.1 3–34 19.6 ± 7.2 19.3 ± 7.2 0.811 HAM-D 9 ± 5.1 1–23 9.6 ± 5.5 8.4 ± 5.1 0.594 Pharmacological treatment (%) Antidepressants 40.7 - 50 30.8 0.310 Anxiolytics 33.3 - 35.7 30.8 0.785 Neuroleptics 0 - 0 0 - Anticholinergics 3.7 - 0 7.7 0.290 IMAOs 0 - 0 0 - Amantadine 0 - 0 0 - Anticholinesterases 7.4 - 7.1 7.7 0.957 Methylphenidate 0 - 0 0 - duration, H&Y stage, LEDD, pharmacological treatments, and Primary Efficacy Endpoint Analysis UPDRS-III. Significant differences were found in education Repeated measures ANOVA applied to explore the primary level [t (30) = 2.81; p = 0.009], and in the PD–CRS total [t (30) outcome measure (change in the AS score between 24-week and = 2.42; p = 0.023] and frontal-subcortical scores [t (30) = 2.78; baseline) showed a trend to a significant group × time interaction p = 0.010] with lower education level and PD–CRS scores in [F (1,29) = 3.06; p = 0.059]. Post-hoc analysis showed that this the placebo group. Despite baseline differences in the PD–CRS effect was mediated by a more marked, and nearly significant (used as secondary measure of the study), both the groups decrease on the AS score in the AT group [t (30) = −1.95; p = were equivalent in terms of global cognitive status measured at 0.062]. Thus, the mean change from baseline at 24 week was of baseline with the MoCA. Accordingly, the proportion of patients −7.5 ± 6.9 in the AT group and of −2.8 ± 5.7 in the placebo scoring in the lower range of the PD–CRS was of 6.7% in the AT group. As depicted in Figure 2, this effect was observed at 24 group and of 7.1% in the placebo group, and the proportion of week in the AT group, while equivalent scores were obtained in patients scoring in the medium and higher range was of 93.3% the two groups at baseline and at 12 week. in the AT group and of 92.9% in the placebo group, with no Paired t-test within each group showed that in the AT significant differences between the groups. group, no differences existed between baseline and 12-week AS Both treatment groups showed at baseline an NPI apathy total score [t (13) = 1.03; p = 0.318], but a significant difference was score (frequency × severity) equal or higher than 1, and a mean found between 24 week and 12 week [t (13) = 4.22; p = 0.001], AS above the clinical cut-off for apathy (AS ≥ 13), indicating and between 24 week and baseline [t (13) = 4.06; p = 0.001]. that almost all the patients (75% in the AT groups; 85% in In the placebo group, no significant differences were found the placebo group; and 80% in the total sample) had clinically between visits. significant apathetic symptoms according to the AS, with no When analyzing the change from clinically relevant apathetic differences between groups in the proportion of this prevalence symptoms at baseline (AS > 13) to non-apathy (AS < 14) at (×2 = 0.361). 24 week, we observed that the significant decrease in the mean Frontiers in Neurology | www.frontiersin.org 5 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD FIGURE 2 | Mean change from baseline in the Apathy Scale in each consecutive visit. apathy severity score occurred in 46.6% of the subjects in the AT AT group compared with 2.5 ± 10.5 in the placebo group group compared with just 21.4% of those in the placebo group. (Figure 4B). This difference in the rate of conversion from clinically relevant apathy to non-apathy was significantly different between groups (x2 = 0.042; Figure 3). Other Secondary Endpoints No significant effects or trends were found in the repeated measures ANOVA and post-hoc comparisons focusing on Secondary Efficacy Endpoints Analysis cognitive performances (PD–CRS), cognitive-functional status Neuropsychiatric Inventory (NPI) (PD–CFRS), quality of life (PDQ-39), and patient and clinical Repeated measures ANOVA showed no significant effects impression of change (P–CGI, P–CGI–QOL, and CGI). between groups and visits in the NPI total score for apathy (frequency × severity). However, as depicted in Figure 4A, post- hoc t-test comparison showed a trend to significance [t (30) = −2.06; p = 0.053] at 24-week mediated by a mean change from Safety and Tolerability baseline of −1.9 ± 2.2 points in the AT group compared with 0 Safinamide at the doses of 50 and 100 mg/daily was safe and ± 2.7 in the placebo group. No effects were found with respect well-tolerated, and no major or unexpected safety concerns were to the other neuropsychiatric symptoms covered with the NPI. identified. As reported, early discontinuation occurred in the The statistics for the primary and secondary efficacy endpoints three patients. One on the safinamide left the study due to mild analysis are described in Table 2. dizziness at visit 2 without being scaled to receive the 100 mg/day dose, and the other due to increase in anxiety who left the study UPDRS-III on week 10 while on 100 mg/day (Table 3). The one belonging to No significant effects neither trend were found in the repeated the placebo group left the study on week 16 due to hallucinations. measures ANOVA. Post-hoc t-test comparisons showed a trend No differences were found in vital signs and electrocardiogram, to significance [t (30) = −1.73; p = 0.094] at 24 week mediated body weight and laboratory test, neither between groups in the by a mean change from baseline of −3.64 ± 8 in the baseline visit, nor in the successive follow-ups. Frontiers in Neurology | www.frontiersin.org 6 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD FIGURE 3 | Percentage of participants scoring in the clinical range for apathy based on the Apathy Scale. FIGURE 4 | (A) Mean change from baseline in the NPI total apathy score; (B) Mean change from baseline in the UPDRS-III. DISCUSSION The results of the study are positive in terms of safety, but negative in terms of the effect of Safinamide on apathy. This is the first RCT study exploring the effects of safinamide in Nevertheless, the results show a tendency toward static non-demented patients with PwP, and one of the few prospective significance that we believe deserves consideration. Thus, the PD studies in which apathy was an inclusion criterion and the addition of safinamide in subjects with PD with significant primary outcome. apathy is well-tolerated and may result in a discrete beneficial Frontiers in Neurology | www.frontiersin.org 7 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD TABLE 2 | Primary and secondary outcome measures analysis. Active treatment Placebo Difference AT - Placebo Mean ± SD Mean ± SD Estimate (95% CI) p AS total score −7.5 ± 6.9 −2.8 ± 5.7 −4.71 (−9.68 to 0.25) 0.062 NPI apathy −1.9 ± 2.2 0 ± 2.7 −1.92 (−3.88 to 0.02) 0.053 PD-CRS total score 1.5 ± 8.9 −4.6 ± 10.6 6.21 (−1.42 to 13.8) 0.306 PD-CFRS −0.5 ± 2.5 −0.1 ± 2.1 −0.33 (−2.24 to 1.57) 0.722 HAM-D −1.5 ± 6.6 −0.9 ± 4.1 −0.57 (−4.85 to 3.7) 0.786 UPDRS-III −3.6 ± 8 2.5 ± 10.5 −6.14 (−13.4 to 1.11) 0.094 PDQ-39 −5.6 ± 19.1 −0.6 ± 12.5 6.95 (−18.6 to 6.1) 0.312 P-CGI 4.08 ± 2.1 4.5 ± 1.9 −0.46 (−2.98 to 1.15) 0.562 P-CGI-QOL 3.08 ± 2.1 2.52 ± 2.1 0.66 (−1.03 to 2.35) 0.428 CGI 4 ± 1.5 3.5 ± 1.5 0.42 (−1.34 to 2.19) 0.607 TABLE 3 | Adverse events. contributed to the modest benefit of associated with safinamide in our study. Visit (Week) N cases/% Dosage Study group Although apathy is highly prevalent in PD from its early Mild dizziness 4 1/3.33% 50 mg Active stages, the exact pathogenesis of apathy in PD are partially Anxiety 10 1/3.33% 100 mg Active understood at present (46), being likely a combination of Visual hallucinations 16 1/3.33% 100 mg Placebo progressive alteration of dopaminergic pathways (43, 47), brain atrophy in strategic reward nodes (24) with impaired incentive processing (33), synergistically acting alpha- synuclein and Alzheimer’s disease (AD) protein aggregates effect observed in this study in the form of a trend toward and increased burden of vascular and inflammatory changes significance. Although only reaching a trend to significance in the (48) that may limit the response to the pharmacological primary analysis, a beneficial effect of safinamide in comparison treatment (1, 49). to placebo was observed between weeks 12 to 24 in the AT group While partial correction of an altered neurotransmission in the post-hoc analysis. This was accompanied by a significant may not suffice for apathy to significantly improve in PD, change favoring safinamide in the proportion of subjects moving safinamide may have exerted a positive effect on dopamine- from clinically significant apathetic symptoms at baseline to not dependent apathetic symptoms. Still, considering that its action clinically relevant symptoms at the end of the study. No relevant is not stronger than that of other dopaminergic agents that changes were found for any other explored variable, although in showed uneven results in improving apathy (49), other factors consistence with the objective of the study, the only additional might concur to explain the partial response of apathy seen in statistical trend was a reduction from baseline in the mean NPI this study. apathy score. A glutamate hypothesis for apathy arises from drug trials that In addition to not having observed a statistically significant suggests a link between the glutamatergic system and apathy effect in the primary analysis, a number of lessons supporting symptoms in psychiatric and neurodegenerative diseases other further research of safinamide in PD-related apathy can be than PD (50–52). While memantine, an agent that blocks the collected from this exploratory study. The temporal curve effects of pathologically elevated levels of glutamate, seems showed a trend to significance between weeks 12 and 24 not to influence apathetic symptoms in AD, mibampator, a in the safinamide group observed in the exploratory post- glutamate receptor potentiator, significantly improved apathy hoc analysis suggests that the beginning of the eventual in a RCT in AD (50). On this basis, the dual action of positive effect of safinamide can be a delayed one. It is a drug that reinforces dopaminergic transmission and blocks possible that a more consistent effect could have been observed the effects of pathologically elevated levels of glutamate, may with a longer follow-up and a larger number of patients. conceivably improve the synaptic connectivity and trigger the Importantly, these positive signals were detected only for functional recovery of damaged neuronal network, which is the main variable and were not related to motor, mood, or typical of apathy. cognitive changes. At last, safinamide was well-tolerated in a In this line, blockade of sodium channels and modulation of cohort of subjects with PD not selected for having levodopa- calcium channels that is the base of the antiglutamatergic activity related fluctuations. of safinamide, is not expected to be complete below dosing of Besides not reaching the planned sample size, other factors 100 mg/day, which were not achieved until the third week of the related both with the pathogenesis of the apathy syndrome study. This could explain the significant but delayed reduction in PD and the characteristics of the tested drug, could have in the mean apathy scores compared with the placebo observed Frontiers in Neurology | www.frontiersin.org 8 June 2022 | Volume 13 | Article 866502 Kulisevsky et al. Safinamide and Apathy in PD in the post-hoc analysis of the second half of our study. Future DATA AVAILABILITY STATEMENT studies should explore whether higher doses of safinamide and/or more prolonged treatment period have a significant clinical effect. The raw data supporting the conclusions of this article will be Consistent with the good safety profile of the drug observed made available by the authors, without undue reservation. in phase III and large-sample observational studies (37), almost all the apathetic subjects randomized to safinamide ETHICS STATEMENT treatment completed the study, with a dropout rate of just 13% (two participants). Safinamide was generally well- The studies involving human participants were reviewed and tolerated over 24 weeks by patients who were receiving approved by ERB Hospital de la Santa Creu i Sant Pau. The polypharmacy without substantial differences in the number patients/participants provided their written informed consent to or severity of adverse events compared with the placebo. participate in this study. Particularly, adding safinamide in apathetic patients did not worsen motor status, cognition and other important AUTHOR CONTRIBUTIONS behavioral aspects including mood, hallucinations, or impulse control behavior. JK and SM-H: conception and design of the study. JK, SM- A major strength of our study is that we selected patients H, BP-S, AC, JM-L, HB-k, IA-B, AH-B, and JP: recruitment of accomplishing clinical criteria for apathy and tried to generate participants and assessments. SM-H and AP-D: data analysis. high-quality data using a validated instrument as primary JK, SM-H, and JP: interpretation, draft manuscript, and review. outcome to address an important unmet in PD. Consequently, All authors contributed to the article and approved the the average apathy rating scale scores obtained at baseline submitted version. in the AS reflects a PD population with clinically significant apathy. Nevertheless, being apathy scores above the cut-off of FUNDING apathy (45), they were not in the high range. This may be partially explained by the exclusion of demented patients and This work was partially supported by CERCA and CIBERNED the diminished motivation of severely apathetic patients for funding, and grants from la Marató de TV3 (grants #2014/U/477 participating in a research study. and #20142910), Fondo de Investigaciones Sanitarias (FIS) Main limitation of our study was its early termination from the Instituto de Salud Carlos III (ISCIII), and Fondo that precluded the recruitment of the planned sample, and Europeo de Desarrollo Regional (FEDER) grants #PI15/00962 possibly, reaching statistical significance in the primary objective. and #PI18/01717. Drug and placebo treatments were facilitated Nevertheless, our results provide valuable information to inform by the Zambon Italy that also provided an unrestricted grant the design of future trials. 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Neurology. this article, or claim that may be made by its manufacturer, is not guaranteed or (2007) 68:1008–12. doi: 10.1212/01.wnl.0000260240.46070.7c endorsed by the publisher. 51. Sepehry AA, Sarai M, Hsiung GR. Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. Can J Neurol Sci. (2017) 44:267–75. doi: 10.1017/cjn.2016.426 Copyright © 2022 Kulisevsky, Martínez-Horta, Campolongo, Pascual-Sedano, 52. Zink M, Correll CU. Glutamatergic agents for Schizophrenia: current Marín-Lahoz, Bejr-kasem, Aracil-Bolaños, Horta-Barba, Puig-Davi and evidence and perspectives. Expert Rev Clin Pharmacol. (2015) 8:335– Pagonabarraga. This is an open-access article distributed under the terms of 52. doi: 10.1586/17512433.2015.1040393 the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) Conflict of Interest: JK has received honoraria for advisory boards or lecturing and the copyright owner(s) are credited and that the original publication in from: Teva, Zambon, UCB, Bial, General Electric, Sanofi, and Roche. JP has served this journal is cited, in accordance with accepted academic practice. No use, on advisory or speakers’ boards, and received honoraria from: UCB, Zambon, distribution or reproduction is permitted which does not comply with these AbbVie, Italfarmaco, Allergan, Ipsen, Bial. terms. Frontiers in Neurology | www.frontiersin.org 11 June 2022 | Volume 13 | Article 866502