Journal of Clinical Neuroscience 90 (2021) 178–183 Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn Review article The role of glutamatergic neurotransmission in the motor and non-motor symptoms in Parkinson’s disease: Clinical cases and a review of the literature Javier Pagonabarraga a,⇑, Michele Tinazzi b, Carla Caccia c, Wolfgang H. Jost d a Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain b Neurology Unit, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy c CNS Preclinical Pharmacology, Independent Advisor, Milan, Italy d Parkinson-Klinik Ortenau, Wolfach, Germany a r t i c l e i n f o a b s t r a c t Article history: Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many Received 18 November 2020 brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal Accepted 26 May 2021 ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson’s disease (PD). However, the basal gan- glia and the associated glutamatergic system also play a role in the modulation of emotion, nociception Keywords: and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anx- Case reports iety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from Glutamic acid Parkinson disease the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor ago- Safinamide nists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of ‘off’ episodes. The drug has both dopaminergic and non-dopaminergic pharmacolog- ical effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by provid- ing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symp- toms, using illustrative real-world examples of patients we have treated with safinamide. Ó 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). 1. Introduction and binds to pre- and post-synaptic receptors (Fig. 1) [3]. The effects of glutamate are mediated via activation of two classes of Glutamate is the principal excitatory neurotransmitter in the receptor – ionotropic glutamate receptors (ion channel-linked) mammalian central nervous system (CNS). While glutamate is an and metabotropic glutamate (mGlu) receptors (G-protein-linked). important component of a healthy CNS, excessive glutamate con- Following its binding to receptors, glutamate is removed from centrations or hyperactivity of glutamatergic nerve terminals can the synaptic cleft by EAATs and glia transporters. The glutamate lead to neuronal damage and may be involved in the neurodegen- taken up into glial cells is converted back to glutamine by glu- eration associated with Parkinson’s disease (PD) [1,2]. tamine synthetase [4]. Glutamate is synthesised from its precursor glutamine, which is The glutamatergic system is involved in various functions of the released from glial cells and taken into presynaptic terminals of healthy brain, including the control of movement via the basal gan- glutamatergic neurons by excitatory amino acid transporters glia circuitry in direct and indirect pathways (Fig. 2) [4]. In PD, the (EAATs). Here, glutaminase converts glutamine to glutamate. Upon degeneration of nigrostriatal dopaminergic neurons causes chain neuronal stimulation, glutamate is released into the synaptic cleft reactions that ultimately result in glutamatergic overstimulation of the basal ganglia output nuclei and substantia nigra pars com- pacta, leading to motor symptoms/motor complications that char- ⇑ Corresponding author at: C/ Mas Casanovas 90, Barcelona 08041, Spain. acterise the disease [5]. E-mail addresses: JPagonabarraga@santpau.cat (J. Pagonabarraga), michele. tinazzi@univr.it (M. Tinazzi), caccia.carla@gmail.com (C. Caccia), w.jost@parkin- Thus, glutamatergic neurotransmission is a potential focus for son-klinik.de (W.H. Jost). pharmacotherapy in PD. This paper describes cases of patients https://doi.org/10.1016/j.jocn.2021.05.056 0967-5868/Ó 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). J. Pagonabarraga, M. Tinazzi, C. Caccia et al. Journal of Clinical Neuroscience 90 (2021) 178–183 mus and, ultimately, reduces facilitatory input to motor areas in the frontal cortex. Consequently, PD patients have difficulty initiat- ing movement, and once initiated, movement is slow and may be difficult to stop [4]. Levodopa is a dopamine precursor used to increase dopaminer- gic neurotransmission in patients with PD. Yet despite treatment, PD symptoms frequently re-emerge and patients experience fluc- tuation between mobility and immobility (‘on’ and ‘off’ states, respectively) [4]. Such motor fluctuations are a significant problem, since they occur in the majority of patients after a few years of tak- ing levodopa and significantly impact patients’ mobility and ability to perform activities of daily living, and they can be difficult to manage [14]. An additional complication of long-term levodopa use is troublesome involuntary movements, referred to as levodopa-induced dyskinesia (LID) [15]. Long-term levodopa treatment is thought to lead to overactivity of the direct pathway and underactivity of the indirect pathway, resulting in cortical excitation and dyskinesia [15]. While the patho- physiology of LID is complex, overactivity of glutamatergic corticos- triatal projections is a critical factor in the dysfunction of the direct pathway and therefore the development of LID [15]. These findings Fig. 1. Schematic representation of a glutamatergic neuronal synapse, showing the suggest that a drug that reduces glutamatergic activity may even synthesis and release of glutamate (Glu), its receptors and modes of deactivation. have an anti-dyskinetic effect. Indeed, both safinamide and aman- Glutamine (Gln) is converted to Glu by glutaminase [though glutamate may also be tadine (an N-methyl-D-aspartate [NDMA] receptor antagonist) derived from the TCA cycle (not shown)]. Glu is packaged into presynaptic vesicles dose-dependently reduced dyskinesia in a primate model of LID by vesicular Glu transporter (VGluT) proteins and synaptically released in a voltage- [16]. Further, abnormal cortical facilitation was found in PD patients dependent manner through vesicular interactions with SNARE proteins. Synapti- cally-released Glu is recycled from the extracellular space by excitatory amino acid experiencing LID (n = 20), indicating overactive glutamatergic neu- transporters (EAATs) expressed predominantly on astroglia. In astrocytes, Glu is rotransmission in the primary motor cortex [17]. The degree of converted to Gln by Gln synthetase and exported extracellularly to be taken up abnormality correlated with the severity of dyskinesia. Two weeks’ again by neurons. Additionally, system x-C is a cystine/glutamate antiporter safinamide treatment normalised cortical facilitation markers. expressed on glia that also contributes to Glu recycling. Glu receptors are present on presynaptic and postsynaptic neurons as well as on glial cells. These include both Importantly, a phase III trial findings suggested safinamide may ionotropic receptors (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid have a positive impact in patients with moderate-to-severe dyski- [AMPA], N-methyl-D-aspartate [NMDA] and kainite) and metabotropic receptors nesia at baseline [11]. The case reported below provides real- (mGluRs). The effect of Glu is determined by the receptor subtype, localisation world evidence of successful management of motor fluctuations (synaptic, perisynaptic and extrasynaptic) [3]. BDNF, brain derived neurotrophic and a reduction in LID after safinamide initiation. factor. 2.1. Case report 1 who benefited from the use of safinamide [(S)-(+)-2-[4-(3-fluoro benzyloxy-benzylamino) propionamide], an agent targeting the A 65-year-old male diagnosed with PD 6 years previously (con- glutamatergic system. Safinamide is a dual-mechanism drug that firmed by Betacid-SPECT, with normal findings on magnetic reso- acts on both dopaminergic and non-dopaminergic targets, particu- nance imaging) had initial symptoms of resting tremor of the larly dopaminergic and glutamatergic neurotransmission. It selec- legs and right arm, and hyposmia. Levodopa/carbidopa/entacapone tively and reversibly inhibits monoamine oxidase-B (MAO-B), thus 100/25/200 mg/day was initially prescribed. Two years later, trans- restoring striatal dopaminergic tone and reduces subthalamic/ni- dermal rotigotine patch (4 mg/24 h) was prescribed, but this was gral glutamatergic hyperactivity through use-dependent sodium associated with the onset of psychosis. Clozapine 12.5 mg/day channel blockade, which prevents calcium channel opening and was then added, resulting in a reduction in hallucinations and good results in the inhibition of abnormal glutamate release [6,7]. Safi- control of tremor (clozapine is used in our hospital as treatment of namide is approved in over 20 countries globally, including 14 in last resort for therapy-resistant tremor with good effect [18]). One the European Union, the United States, and Canada, for the treat- year later, the patient had developed wearing off and end-of-dose ment of PD as add-on therapy to levodopa regimens for the man- dyskinesias while receiving levodopa 400 mg/day. Safinamide was agement of ‘off’ episodes (i.e. when levodopa efficacy wanes) initiated at 50 mg/day and 2 weeks later increased to 100 mg/day. [8,9]. In clinical studies, safinamide significantly reduced ‘off’ time This was associated with good effects on motor fluctuations and and increased ‘on’ time without troublesome dyskinesia in patients dyskinesia, as shown by a decrease in the patient’s total Unified receiving levodopa who were experiencing wearing-off phe- Parkinson’s Disease Rating Scale (UPDRS) score in the on state from nomenon [10–13]. 65 before safinamide to 59 during safinamide. The most marked improvement was seen in UPDRS Part IV, which changed from 9 to 5; other UPDRS subscores showed small decreases (Part II from 2. Motor symptoms and glutamate 19 to 18 and Part III from 36 to 35) or remained unchanged (Part I was 1 before and during safinamide). However, the patient stopped PD is characterised by motor symptoms, including resting tre- taking safinamide 6 months later because of leg oedema (the mor, bradykinesia and rigidity in the neck and/or extremities [4]. patient suspected a relationship and could not be convinced other- These symptoms arise primarily as a result of decreased dopamin- wise; he would not consider rotigotine as a possible cause because ergic tone due to degeneration of dopamine neurons in the sub- he did not want to discontinue it). The leg oedema did not resolve stantia nigra. This is accompanied by glutamate overactivity in after discontinuing safinamide. Rasagiline 1 mg/day was pre- projections from the subthalamic nucleus, leading to increased scribed in place of safinamide, with no reduction of his leg oedema, activity in the basal ganglia output nuclei that inhibits the thala- and the dyskinesia and motor fluctuations re-emerged. At consul- 179 J. Pagonabarraga, M. Tinazzi, C. Caccia et al. Journal of Clinical Neuroscience 90 (2021) 178–183 Fig. 2. The role of neurotransmitters in the basal ganglia functional motor circuitry. D1/D2 = dopamine type 1 or 2 receptors expressed in striatal neurons; GABA = gamma- aminobutyric acid; GPe = external globus pallidus; GPi = internal globus pallidus; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; VA/VL = ventral anterior/ventral lateral [4]. tation, the patient’s UPDRS score was 65. It was not possible to add 3.1. Pain in Parkinson’s disease amantadine because of the previous hallucinations and a QTc of 452 ms. Rasagiline was stopped and safinamide was restarted Pain is prevalent in patients with PD, estimated to affect 68– (50 mg/day for 2 weeks, then 100 mg/day). The higher dosage 95% of patients, depending on the type of pain assessed [22]. Pain was also associated with good reductions in dyskinesia and motor in PD is classified into five different types: musculoskeletal (felt as fluctuations; his UPDRS score was then 59. The leg oedema an ache around the joints, arms or legs), dystonia-related, radicular remained unchanged. or neuropathic, primary/central and akathisia-related [22]. There is The above case illustrates the importance of effective motor a high incidence of depression and reduced QOL in patients with control for patients with PD. In this patient, safinamide signifi- PD who report pain symptoms [23]. Pain in patients with PD is cantly improved motor symptoms, including LID. Although the poorly managed and characterised by underuse of analgesics [23]. patient believed safinamide had caused his leg oedema, leading There is clinical evidence that pain may be a premotor sign in him to discontinue its use, the most likely causative agent was early disease [24]. PD patients may also be predisposed to the the dopamine agonist rotigotine. Further, the superior effect of development of pain, as evidenced by a low heat pain threshold safinamide in controlling motor fluctuations compared with rasag- and abnormal pain-evoked responses in PD patients both with iline meant it was reintroduced and became the therapy of choice and without pain (whether in an ‘on’ or ‘off’ state) [25,26]. This for this patient. suggests that the increased risk of pain may be linked to PD patho- physiology. The nigrostriatal damage associated with PD may dis- rupt the usual control by the basal ganglia of cerebral areas that 3. Non-motor symptoms and glutamate process nociceptive input [27]. Abnormal central nociceptive pro- cessing may result from nigral and extra-nigral pathology, involv- The occurrence of non-motor symptoms, including pain, ing the cortical areas, brainstem nuclei and spinal cord [28]. depression and anxiety, is a significant component of PD. Indeed, While the neurobiology of pain in PD is complex, involving mul- patients often refer to non-motor disturbances as being even more tiple neurotransmitter systems [29] the glutamatergic system is of distressing and disabling than the classical motor symptoms of PD. particular interest because of its role in pathophysiological noci- Non-motor symptoms can be problematic at all stages of disease ception [2]. The primary afferent neurons that transmit peripheral development, including early PD, where symptoms such as consti- sensory information and pain signals to the spinal cord are mostly pation and loss of smell can have a detrimental impact on daily life glutamatergic; stimulation results in the excessive release of gluta- [19]. In advanced PD, non-motor complications, such as hallucina- mate from central terminals in the spinal cord and the activation of tions, cognitive impairment, depression and autonomic distur- ionotropic receptors on secondary neurons [2]. Abnormal central bances, have been described as the predominant problems, nociceptive processing can be targeted using antagonists of iono- occurring in 70% of patients [20,21]. Maintenance of QOL is a sig- tropic glutamate receptors, including NMDA, a-amino-3-hydrox nificant unmet need in PD management, and effective treatment of y-5-methyl-4-isoxazolepropionic acid and kainate receptor antag- non-motor symptoms should lead to improved QOL. onists, which decrease nociceptive transmission [30]. However, 180 J. Pagonabarraga, M. Tinazzi, C. Caccia et al. Journal of Clinical Neuroscience 90 (2021) 178–183 these agents have a narrow therapeutic window due to their sity (20 vs 14), BPI Interference (53 vs 15), NRS (9 vs 2), PDQ39 adverse effects. The development of selective mGluR ligands has bodily discomfort (8 vs 4), UPDRS part III (21 vs 8), UPDRS part allowed researchers to further investigate the role of glutamate IV (9 vs 4), and total PDQ39 (48.72 vs 30.77). No treatment- in the modulation and control of pain [31] and whether they can emergent adverse effects were reported in this patient. potentiate the effect of other drugs (such as antidepressants or opi- The improvement of motor fluctuations seen in the above oids) used in neuropathic pain therapy. patient after safinamide initiation (i.e. reduction of UPDRS part III Post-hoc analyses of 24-week and 2-year studies of safinamide and IV scores) was as expected. However, independent of the examined the effect of the drug on concomitant pain treatments motor improvement, this case confirms the effect of safinamide and scores on pain-related items of the Parkinson’s Disease Ques- on pain symptoms. The fact that pain was present and persisted tionnaire 39 (PDQ39) [32,33]. The analyses found significant despite the use of dopaminergic agents (pramipexole and levo- improvements in ‘painful cramps or spasms’ and ‘unpleasantly dopa) suggests that the unique anti-glutamatergic properties of hot or cold’ scores, and a significant reduction in the number of safinamide may have been responsible for its effects on this non- concomitant pain treatments, with significantly more patients motor symptom. Indeed, a recent systematic review and meta- receiving safinamide than placebo not using pain treatments at analysis found that safinamide was the most efficacious among the end of the treatment periods. all studied therapies for reducing pain in PD [35]. The PAINinPD study [34] directly assessed the effect of safi- namide on pain in 13 patients with mild-to-moderate PD, motor 3.3. Anxiety and mood disorders fluctuations while receiving levodopa and a history of pain for the preceding 12 weeks who received safinamide 100 mg/day for Depression and anxiety are common in PD, occurring with a 12 weeks. Pain was assessed using the King’s Parkinson’s Disease prevalence of approximately 17% and 31%, respectively [36,37], Pain Scale (KPPS), the Intensity and Interference subscales of the although frequencies vary between studies. Mood disorders have Brief Pain Inventory (BPI), and the Numerical Rating Scale (NRS) a significant negative impact on a patient’s prognosis and QOL [38]. [primary outcomes]. Secondary outcomes included effects on the Depression and anxiety are thought to develop before dopa- PDQ39, Clinical Global Impression of Change (CGI-C) and UPDRS mine cell loss in the substantia nigra pars compacta, and therefore parts III and IV. Significant effects were seen on all primary out- before motor symptoms are evident. They may originate from comes, and on the UPDRS parts III and IV, PDQ39 total and bodily brainstem monoamine pathology affecting the locus coeruleus discomfort scores, CGI-C and proportion of pain responders (de- and dorsal raphe nucleus at the early stages of the disease fined as those patients having a >50% improvement from baseline [39,40], whereas depression and anxiety manifesting later in the on the NRS). No correlation was found between the mean change course of PD probably reflect alterations in multiple neurotrans- in UPDRS part III-IV and any pain outcome, except for a correlation mitter pathways [40]. These changes primarily affect the between change in the UPDRS part IV and the NRS score. These monoamines (such as dopamine, noradrenaline, and serotonin) results, along with others from previous post-hoc analyses and [39] but there is increasing evidence from preclinical and clinical meta-analyses [32,33,35], indicate that safinamide mainly directly studies for the involvement of glutamatergic and GABAergic trans- affects pain in PD and only partially improves pain through an indi- mission in depression and anxiety in PD [2]. rect pathway secondary to the improvement in motor complica- Proof-of-concept regarding the involvement of the glutamater- tions, probably through its dual mechanism of action. The next gic system in mood disorders was based on clinical data with keta- case report discusses the use of safinamide in a patient from the mine, an NMDA receptor antagonist found to exert a rapid PAINinPD study. antidepressant effect in patients with depression [41]. Post- mortem studies provide evidence of glutamate abnormalities in 3.2. Case report 2 mood disorders [42] and magnetic resonance spectroscopy studies found increased glutamate and/or glutamine levels in the basal A 68-year-old male first presented 10 years previously with tre- ganglia of patients with depression [43,44]. In preclinical models mor and bradykinesia/rigidity of the right (dominant) hand. Initial of depression, striatal mGlu5 receptor expression was increased, treatment was pramipexole prolonged-release (PR) 1.05 mg/day leading to hyperactivity of mGlu5 receptor signalling [45] and and selegiline 5 mg/day, which provided significant improvement thereby contributing to depression-like symptoms, which are pre- of both tremor and bradykinesia. Over the next 5 years, the clinical vented by mGluR5 antagonists [46–48]. picture remained stable with resting tremor localised to the upper Anxiety disorders are also associated with glutamate hyperactiv- right limb and bradykinesia/rigidity to both right upper and lower ity, especially in excitatory synapses of the amygdala, which like the limbs. At 5 years after treatment initiation, the dosage of basal ganglia, form part of the limbic system. Limbic and paralimbic pramipexole PR was 1.57 mg/day and of selegiline was 10 mg/day. brain structures have been extensively implicated in the mediation His bradykinesia/rigidity of the right limbs had worsened and of fear and anxiety, and are richly innervated by glutamatergic pyra- spread to both the left upper and lower limbs. For this reason, midal cells [49,50]. Drugs such as NMDA and AMPA receptor antag- levodopa/carbidopa 100/25 mg three times/day was added, which onists and allosteric mGluR modulators have anxiolytic effects resulted in significant improvements in parkinsonian motor according to studies in animal models and in humans [51]. symptoms. Clinical studies have shown an effect of safinamide on mood Over the following years, the patient developed motor compli- symptoms in patients with PD. For example, Cattaneo et al. [52] cations characterised by wearing-off phenomena and nocturnal performed a post-hoc analysis of two phase III trials of safinamide bradykinesia associated with musculoskeletal, radicular neuro- that focused on mood outcomes. They found significant improve- pathic and dystonic pain localised to the lumbar back and lower ments in mood as determined by the ‘emotional well-being’ limbs, which was only partially improved by increasing levodopa/- domain of the 39-item Parkinson’s disease questionnaire carbidopa 100/25 mg to five times/day. (PDQ39). In addition, real-world clinical practice data in patients This patient was then enrolled in the PAINinPD study. The with PD and depression showed an improvement in depression patient was examined in the ‘on’ phase before and 12 weeks after symptoms (based on the Hamilton Depression Rating Scale) 1 add-on therapy with safinamide 100 mg/day. A significant and 3 months after starting safinamide [53]. In a recent open- improvement between baseline and the final assessment was label prospective study specifically designed to assess the change observed for the following scores: total KPPS (48 vs 24), BPI Inten- in non-motor symptom burden in PD patients after initiating treat- 181 J. Pagonabarraga, M. Tinazzi, C. Caccia et al. Journal of Clinical Neuroscience 90 (2021) 178–183 ment with safinamide, a significant and consistent improvement in able to manage the full constellation of symptoms experienced by mood status was found using the Non-Motor Symptoms Scale, the patient. It was only when a non-dopaminergic agent (i.e. the Beck Depression Inventory-II and the emotional wellbeing domain anti-glutamatergic effect of safinamide) was added that all the of PDQ-39 [54]. patient’s symptoms were well controlled. The following real-world case specifically illustrates the effect of safinamide on anxiety. 4. Conclusions 3.4. Case report 3 Glutamatergic neurotransmission within the basal ganglia is involved in the development of numerous symptoms in patients A 58-year-old woman was diagnosed with PD after presenting with PD, from classic motor symptoms to non-motor symptoms, with resting tremor and re-emergent postural tremor in her left such as anxiety/mood disorders and pain. This neurotransmission hand, bilateral asymmetric rigid-akinetic syndrome predominant is, therefore, an additional target for the pharmacotherapy of PD. on her left side and persistent pain in her left shoulder. Her gait Safinamide is an approved treatment for PD with a unique was slow with decreased left arm swing. In addition to motor mechanism of action that includes inhibition of excessive gluta- symptoms, she reported increasing anxiety and mood instability mate release when nerve terminals are overactive. While the direct during the previous 2 years, reporting worrying about her temper effects of safinamide on glutamate release have only been demon- and medical condition, losing interest in her usual activities and strated in animal models [6,7,55,56], there is indirect evidence of troubles with concentrating. Passage hallucinations were reported such an effect in humans [17]. Safinamide as add-on therapy to when she was directly asked about different perceptual problems. levodopa reduces ‘off’ time and increases ‘on’ time without trou- Rotigotine 4 mg/day was initiated, which improved the blesome dyskinesia [10–13], and may be effective in managing patient’s anxiety, motivation and shoulder pain; there were clear pain and mood disorders. Other PD drugs, including other MAO-B improvements in her slowness, rigidity and tremor only after the inhibitors, do not share safinamide’s anti-glutamatergic effects, dosage was increased to 8 mg/day. which may explain its effectiveness for both motor and non- Three years after starting treatment with rotigotine, and in motor symptoms. It must be noted, however, that the clinically rel- order to better control her resting tremor, levodopa 150 mg three evant improvements in motor symptoms occurring during safi- times daily (450 mg/day) was added, with good control of tremors namide can contribute considerably to the improvement of non- and improvement of general mobility and hand dexterity. Two motor symptoms. years later, the patient reported worsening anxiety, lack of energy Clinical trial data provides robust evidence on efficacy and tol- and motivation. The pain in her shoulder had returned, and symp- erability in highly selected groups of patients, whereas data from toms in her left foot had characteristics of early morning akinesia real-world studies and case reports (such as those described here) or an initial manifestation of wearing-off. She reported that her can provide useful additional information, such as effects on symp- anxiety was the symptom that fluctuated most during the day, toms that may not have been assessed directly in clinical trials. The and that 15–20 min after taking levodopa, the symptoms improved cases described in this article illustrate clinical scenarios where or dissipated. Despite frequent fatigue and anergia, she had diffi- safinamide is an appropriate choice as add-on treatment in culty falling asleep because of inner tension and uncomfortable patients with PD. generalised body sensations. The Neuropsychiatric Fluctuations Scale for PD detected severe inability to relax during ‘off’ episodes, Sources of funding with associated mild sadness, lack of energy and confidence, and concentration difficulties. No specific neuropsychiatric symptoms This manuscript, and medical writing assistance in the prepara- were detected during ‘on’ periods. By using a visual analogue scale tion of this manuscript, was funded by Zambon S.p.A., Italy. (VAS = 0–10) the patient’s ‘off’ episodes were characterised pre- dominantly by anxiety (9/10), fatigue (8/10), pain (6/10) and mild sadness (2/10). During the follow-up after starting safinamide Declaration of Competing Interest therapy, changes in anxiety, fatigue, anergia, and pain were subse- quently assessed by VAS for each symptom. Javier Pagonabarraga has received honoraria as Speaker and as Safinamide 50 mg/day was initiated. During the first month of member of Advisory Boards for UCB, Abbvie, Bial, Zambon, Allergan treatment, ‘off’ episode duration decreased from 45 to 60 min to and Ipsen. Michele Tinazzi declares no conflict of interest. Carla Cac- 15 min before the 14:00 h levodopa dose, with no new episodes cia is a preclinical consultant for Zambon SpA. Wolfgang Jost has or of fatigue and anergia in the evenings; episodes of early-morning had speaker and advisor roles for Abbvie, Bial, Desitin, UCB and anxiety were still present (VAS 4/10). At 1 month, safinamide Zambon. was increased to 100 mg/day (taken in the morning), and 2 weeks later, her anxiety had completely resolved, both when she was Acknowledgements walking at midday and when waking up (VAS 0/10), and no epi- sodes of foot dystonia appeared. Six months after starting safi- We would like to thank Kate Palmer and Tracy Harrison, both of namide, the patient remained free of wearing-off phenomena, Springer Healthcare Communications who, under the guidance of and the improvements in her anxiety, fatigue, anergia and shoulder the authors, provided medical writing assistance. This assistance pain had had a major impact on her daily life and family was funded by Zambon S.p.A., Italy. relationships. The above case illustrates the complexity of symptoms seen in Conflicts of interest/financial disclosures patients with PD and the differing impact of each PD symptom for patients. Over her disease course, this patient had presented with Javier Pagonabarraga has received honoraria as Speaker and as both classic motor symptoms and some non-motor symptoms member of Advisory Boards for UCB, Abbvie, Bial, Zambon, Allergan (pain and anxiety). It appears that the latter symptoms, particu- and Ipsen. Michele Tinazzi declares no conflict of interest. Carla larly anxiety, most significantly affected her QOL. While the effect Caccia is a preclinical consultant for Zambon SpA. Wolfgang Jost of safinamide on anxiety may simply reflect a dopaminergic effect, has or had speaker and advisor roles for Abbvie, Bial, Desitin, prior dopamine-based therapy (rotigotine and levodopa) were not UCB and Zambon. 182 J. Pagonabarraga, M. Tinazzi, C. Caccia et al. Journal of Clinical Neuroscience 90 (2021) 178–183 Informed consent [29] Barone P. Neurotransmission in Parkinson’s disease: beyond dopamine. Eur J Neurol 2010;17:364–76. [30] Bleakman D, Alt A, Nisenbaum ES. Glutamate receptors and pain. Semin Cell All patients gave informed written consent for publication. Dev Biol 2006;17:592–604. [31] Montana MC, Cavallone LF, Stubbert KK, Stefanescu AD, Kharasch ED, Gereau, RWt.. The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical References antagonist 2-methyl-6-(phenylethynyl)-pyridine. J Pharmacol Exp Ther 2009;330:834–43. [1] Meldrum BS. Glutamate as a neurotransmitter in the brain: review of [32] Cattaneo C, Kulisevsky J, Tubazio V, Castellani P. Long-term efficacy of physiology and pathology. J Nutr 2000;130:1007S–15S. safinamide on Parkinson’s disease chronic pain. Adv Ther 2018;35:515–22. [2] Miladinovic T, Nashed MG, Singh G. Overview of glutamatergic dysregulation [33] Cattaneo C, Barone P, Bonizzoni E, Sardina M. Effects of safinamide on pain in in central pathologies. Biomolecules 2015;5:3112–41. fluctuating Parkinson’s disease patients: a post-hoc analysis. J Parkinsons Dis [3] Niciu MJ, Kelmendi B, Sanacora G. Overview of glutamatergic 2017;7:95–101. neurotransmission in the nervous system. Pharmacol Biochem Behav [34] Geroin C, Di Vico IA, Squintani G, Segatti A, Bovi T, Tinazzi M. Effects of 2012;100:656–64. safinamide on pain in Parkinson’s disease with motor fluctuations: an [4] Jenner P, Caccia C. The role of glutamate in the healthy brain and in the exploratory study. J Neural Transm (Vienna) 2020;127:1143–52. pathophysiology of Parkinson’s Disease. Eur Neurol Rev 2019;14:2–12. [35] Qureshi AR, Rana AQ, Malik SH, Rizvi SFH, Akhter S, Vannabouathong C, et al. [5] Blandini F, Porter RH, Greenamyre JT. Glutamate and Parkinson’s disease. Mol Comprehensive examination of therapies for pain in Parkinson’s Disease: Neurobiol 1996;12:73–94. a systematic review and meta-analysis. Neuroepidemiology 2018;51: [6] Morari M, Brugnoli A, Pisano CA, Novello S, Caccia C, Melloni E, et al. 190–206. Safinamide differentially modulates in vivo glutamate and GABA release in the [36] Broen MP, Narayen NE, Kuijf ML, Dissanayaka NN, Leentjens AF. Prevalence of rat hippocampus and basal ganglia. J Pharmacol Exp Ther 2018;364:198–206. anxiety in Parkinson’s disease: A systematic review and meta-analysis. Mov [7] Pisano CA, Brugnoli A, Novello S, Caccia C, Keywood C, Melloni E, et al. Disord 2016;31:1125–33. Safinamide inhibits in vivo glutamate release in a rat model of Parkinson’s [37] Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF. A systematic review disease. Neuropharmacology 2020;167:108006. of prevalence studies of depression in Parkinson’s disease. Mov Disord [8] Valeo Pharma Inc. ONSTRYV (Safinamide tables) Product Monograph 2019. 2008;23:183–9; quiz 313. [9] Valeo Pharma., Zambon. Valeo Pharma announces the Canadian launch of [38] Szatmari S, Illigens BM, Siepmann T, Pinter A, Takats A, Bereczki D. OnstryvÒ (safinamide tablets) for the treatment of Parkinson’s disease 2019. Neuropsychiatric symptoms in untreated Parkinson’s disease. [10] Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, Chirilineau D, et al. Neuropsychiatr Dis Treat 2017;13:815–26. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with [39] Lim SY, Fox SH, Lang AE. Overview of the extranigral aspects of Parkinson motor fluctuations. Mov Disord 2014;29:229–37. disease. Arch Neurol 2009;66:167–72. [11] Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt MH, Chirilineau D, et al. [40] Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders Two-year, randomized, controlled study of safinamide as add-on to levodopa associated with Parkinson’s disease. Neurotherapeutics 2014;11:78–91. in mid to late Parkinson’s disease. Mov Disord 2014;29:1273–80. [41] Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. [12] Hattori N, Tsuboi Y, Yamamoto A, Sasagawa Y, Nomoto M, Group MES. Efficacy Antidepressant effects of ketamine in depressed patients. Biol Psychiatry and safety of safinamide as an add-on therapy to L-DOPA for patients with 2000;47:351–4. Parkinson’s disease: A randomized, double-blind, placebo-controlled, phase II/ [42] McCullumsmith RE, Meador-Woodruff JH. Novel approaches to the study of III study. Parkinsonism Relat Disord 2020;75:17-23. postmortem brain in psychiatric illness: old limitations and new challenges. [13] Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C, et al. Biol Psychiatry 2011;69:127–33. Assessment of safety and efficacy of safinamide as a levodopa adjunct in [43] Haroon E, Fleischer CC, Felger JC, Chen X, Woolwine BJ, Patel T, et al. patients with Parkinson Disease and motor fluctuations: a randomized clinical Conceptual convergence: increased inflammation is associated with increased trial. JAMA Neurol 2017;74:216–24. basal ganglia glutamate in patients with major depression. Mol Psychiatry [14] Jankovic J, Stacy M. Medical management of levodopa-associated motor 2016;21:1351–7. complications in patients with Parkinson’s disease. CNS Drugs [44] Godlewska BR, Masaki C, Sharpley AL, Cowen PJ, Emir UE. Brain glutamate in 2007;21:677–92. medication-free depressed patients: a proton MRS study at 7 Tesla. Psychol [15] Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM. The pharmacology of L- Med 2018;48:1731–7. DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol Rev [45] Mao LM, Wang JQ. Alterations in mGlu5 receptor expression and function in 2013;65:171–222. the striatum in a rat depression model. J Neurochem 2018;145:287–98. [16] Gregoire L, Jourdain VA, Townsend M, Roach A, Di Paolo T. Safinamide reduces [46] Wieronska JM, Szewczyk B, Branski P, Palucha A, Pilc A. Antidepressant- dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian like effect of MPEP, a potent, selective and systemically active mGlu5 monkeys. Parkinsonism Relat Disord 2013;19:508–14. receptor antagonist in the olfactory bulbectomized rats. Amino Acids [17] Guerra A, Suppa A, D’Onofrio V, Di Stasio F, Asci F, Fabbrini G, et al. Abnormal 2002;23:213–6. cortical facilitation and L-dopa-induced dyskinesia in Parkinson’s disease. [47] Palucha A, Branski P, Szewczyk B, Wieronska JM, Klak K, Pilc A. Potential Brain Stimul 2019;12:1517–25. antidepressant-like effect of MTEP, a potent and highly selective mGluR5 [18] Yaw TK, Fox SH, Lang AE. Clozapine in Parkinsonian rest tremor: A review of antagonist. Pharmacol Biochem Behav 2005;81:901–6. outcomes, adverse reactions, and possible mechanisms of action. Mov Disord [48] Liu CY, Jiang XX, Zhu YH, Wei DN. Metabotropic glutamate receptor 5 Clin Pract 2016;3:116–24. antagonist 2-methyl-6-(phenylethynyl)pyridine produces antidepressant [19] Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, Group effects in rats: role of brain-derived neurotrophic factor. Neuroscience NV. The impact of non-motor symptoms on health-related quality of life of 2012;223:219–24. patients with Parkinson’s disease. Mov Disord 2011;26:399–406. [49] Cortese BM, Phan KL. The role of glutamate in anxiety and related disorders. [20] Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter CNS Spectr 2005;10:820–30. study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov [50] Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Disord 2008;23:837–44. Neuropsychopharmacology 2010;35:169–91. [21] Zhang TM, Yu SY, Guo P, Du Y, Hu Y, Piao YS, et al. Nonmotor symptoms in [51] Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, Baca- patients with Parkinson disease: A cross-sectional observational study. Garcia E. New perspectives in glutamate and anxiety. Pharmacol Biochem Medicine (Baltimore) 2016;95:e5400. Behav 2012;100:752–74. [22] Buhmann C, Kassubek J, Jost WH. Management of Pain in Parkinson’s Disease. J [52] Cattaneo C, Muller T, Bonizzoni E, Lazzeri G, Kottakis I, Keywood C. Long-term Parkinsons Dis 2020;10:S37–48. effects of safinamide on mood fluctuations in Parkinson’s Disease. J Parkinsons [23] Rana AQ, Kabir A, Jesudasan M, Siddiqui I, Khondker S. Pain in Parkinson’s Dis 2017;7:629–34. disease: analysis and literature review. Clin Neurol Neurosurg [53] Pena E, Borrue C, Mata M, Martinez-Castrillo JC, Alonso-Canovas A, Chico JL, 2013;115:2313–7. et al. Impact of SAfinamide on depressive symptoms in Parkinson’s disease [24] Defazio G, Berardelli A, Fabbrini G, Martino D, Fincati E, Fiaschi A, et al. Pain as patients (SADness-PD study): a multicenter retrospective study. Brain Sci a nonmotor symptom of Parkinson disease: evidence from a case-control 2021;11:232. study. Arch Neurol 2008;65:1191–4. [54] Santos Garcia D, Labandeira Guerra C, Yanez Bana R, Cimas Hernando MI, Cabo [25] Djaldetti R, Shifrin A, Rogowski Z, Sprecher E, Melamed E, Yarnitsky D. Lopez I, Paz Gonalez JM, et al. Safinamide improves non-motor symptoms Quantitative measurement of pain sensation in patients with Parkinson burden in Parkinson’s disease: an open-label prospective study. Brain Sci disease. Neurology 2004;62:2171–5. 2021;11:316. [26] Tinazzi M, Del Vesco C, Defazio G, Fincati E, Smania N, Moretto G, et al. [55] Caccia C, Maj R, Calabresi M, Maestroni S, Faravelli L, Curatolo L, et al. Abnormal processing of the nociceptive input in Parkinson’s disease: a study Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology with CO2 laser evoked potentials. Pain 2008;136:117–24. 2006;67:S18–23. [27] Chudler EH, Dong WK. The role of the basal ganglia in nociception and pain. [56] Gardoni F, Morari M, Kulisevsky J, Brugnoli A, Novello S, Pisano CA, et al. Pain 1995;60:3–38. Safinamide modulates striatal glutamatergic signaling in a rat model of [28] Blanchet PJ, Brefel-Courbon C. Chronic pain and pain processing in Parkinson’s levodopa-induced dyskinesia. J Pharmacol Exp Ther 2018;367:442–51. disease. Prog Neuropsychopharmacol Biol Psychiatry 2018;87:200–6. 183