Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease.

CNS Drugs DOI 10.1007/s40263-014-0205-z

REVIEW ARTICLE

Pharmacological Strategies for the Management of LevodopaInduced Dyskinesia in Patients with Parkinson’s Disease Eva Schaeffer • Andrea Pilotto • Daniela Berg

Ó Springer International Publishing Switzerland 2014

Abstract L-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson’s disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of L-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic E. Schaeffer A. Pilotto D. Berg (&) Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, Hoppe Seyler-Strasse 3, 72076 Tu¨bingen, Germany e-mail: [email protected] E. Schaeffer D. Berg German Center of Neurodegenerative Diseases (DZNE), Tu¨bingen, Germany A. Pilotto Neurology Unit, Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Brescia, Italy

glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.

Key Points The pathophysiology of L-dopa-induced dyskinesias (LID) involves complex pre- and postsynaptic mechanisms, including a wide range of modulations in dopaminergic and non-dopaminergic transmitter systems. Despite great research efforts and a large numbers of new drugs proposed, only a few trials have shown promising results. These need to be replicated in larger cohorts. For clinical application, amantadine and clozapine are the only effective drugs for LID reduction that are currently available, besides the adjustment of dopaminergic therapy.

1 Introduction L-3,4-Dihydroxyphenylalanine

(L-Dopa), the initial ‘gold standard therapy’ for Parkinson’s disease (PD), is still one of the most effective and widely used therapeutic options in

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the treatment of this neurodegenerative disorder. However, its use is still limited by the development of motor fluctuations and L-dopa-induced dyskinesia (LID) [1], which manifests in the majority of patients after varying lengths of treatment. Nearly 40 % of PD patients develop LID after 4–6 years of L-dopa treatment [2]. In recent decades, considerable efforts have been made to understand the underlying pathological mechanisms to either prevent or at least alleviate LID. This review gives an overview on the most important pathomechanisms involved in LID, summarizing pre- and postsynaptic changes and describing the wide range of possibly involved transmitter systems. The second part of the manuscript focuses on the several pharmacological strategies applied to date for the treatment and prevention of LID. In order to point out the most recent and important findings, an extensive electronic search on PubMed and clinicaltrials.gov was conducted up to September 2014 using a combination of the following terms:

‘Parkinson’, ‘Parkinson’s disease’, ‘dyskinesia’, ‘L-dopa’, ‘levodopa’, ‘LID’, ‘levodopa-induced dyskinesia’, ‘dyskinesias’, ‘trial’. Only placebo-controlled randomized trials were included in the description of pharmacological management.

Fig. 1 Pathophysiology of levodopa-induced dyskinesia. Physiological activation, pathological alterations in LID, pathological alterations in LID, modulation, 11 increased activation, 22 decreased activation. A2A adenosine receptor, a2a and a2ab noradrenergic receptors, AMPA a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid, Cb1 cannabinoid receptor, D1

and D2 dopaminergic receptors, DA dopamine, DA-autoR dopamine autoreceptor, DAT dopamine transporter, GABA c-aminobutyric acid, Glu glutamate, H3 histamine receptor, LID levodopa-induced dyskinesia, mGluR metabotropic glutamate receptor, NA noradrenaline, nAchR nicotinic acetylcholine receptors, NMDA N-methyl-D-aspartate, OP opioid receptor

2 Pathophysiology Major insights into the pathophysiology of dyskinesia have been gained by two specific animal models of PD: the rodent model of the 6-hydroxydopamine (6-OHDA)lesioned rat, and the primate model of the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkey. Both models are suitable for the induction and assessment of abnormal involuntary movements (AIMs), which are suggested to correspond to LID in humans [3–7]. Analyses of these two models, together with findings in

Pharmacological Strategies for the Management of Levodopa-Induced Dyskinesia

neurological patients, led to the overall impression that the development of LID is caused by a complex interaction of both pre- and postsynaptic changes, taking place not only in the dopaminergic system but also involving a variety of other neurotransmitters (Fig. 1). In combination, the basic pathophysiology can be seen in the combination of progressive nigrostriatal degeneration and the non-physiologic dopamine receptor stimulation during L-dopa therapy, both leading to a wide range of molecular and biochemical changes in the basal ganglia circuit (reviewed by Cenci and Konradi [8]). 2.1 Nigrostriatal Degeneration Disease severity has been suggested as one of the main risk factors for LID in PD [9]. Thus, it is reasonable to presume that progressive dopaminergic (DA) denervation plays a key role for the manifestation of LID [10, 11]. This presumption is confirmed by the finding that even long-term intake of L-dopa in general does not induce LID in patients without an impairment of the nigrostriatal DA system, for example in patients with restless legs syndrome or doparesponsive dystonia or in healthy individuals [12–14] (some exceptions do exist, please see below). Moreover, some studies have described that the first onset of dyskinesia tends to be on the body side more affected by parkinsonian symptoms, corresponding to the contralateral side of more advanced dopaminergic degeneration in the nigrostriatal system [15–17]. An association of LID development and disease duration has been observed, with a lower threshold for LID in the more advanced stages of PD [18]. This is supported in the MPTP-treated monkey model, in which more severe nigrostriatal DA lesions led to a dramatically lower threshold dose of L-dopa for LID [19, 20]. Regarding the rodent model, AIMs could only be observed in rats with more than 80 % nigrostriatal damage [21], and the implantation of ventral mesencephalic DA grafts reduced AIMs [22]. Disruption of the physiological dopamine release system provides an explanation for the essential role of nigrostriatal denervation for LID development. In the early stages of the disease, exogenously administered L-dopa is transformed into dopamine, stored and released in vesicles into the synaptic cleft by a sufficient number of DA terminals. The continuous release of dopamine is secured additionally by a system of auto-regulation, including dopamine-autoreceptors and the dopamine transporter (DAT) [23, 24]. Progressive loss of functional presynaptic DA neurons in the course of neurodegeneration entails a reduced storage capacity, and the release of dopamine is increasingly dependent on the pharmacokinetics of L-dopa (reviewed Cenci and Lundblad [25]). Subsequently, the administration of L-dopa leads to unphysiologically high extracellular

striatal dopamine levels, which could be demonstrated in dyskinetic rodent models after exogenous L-dopa administration [26, 27]. In positron emission tomography (PET) studies of PD patients, levels of synaptic DA after L-dopa administration correlated positively with more advanced disease stages and with the extent of LID [28, 29]. A recent functional magnetic resonance imaging (fMRI) study in PD patients with LID revealed a markedly increased activation of the putamen bilaterally after exposure to L-dopa, indicating increased metabolism exactly in the part of the brain most affected by DA degeneration [30]. Additionally, degeneration of presynaptic dopaminergic neurons entails the downregulation of DAT levels, which are essential for the homeostasis of synaptic dopamine [31]. The reduced reuptake of dopamine out of the synaptic cleft may first help to improve general PD symptoms; however, oscillating extracellular DA levels are the longterm consequence [32, 33]. Accordingly, Hong et al. [34] recently showed that decreased DAT activity in the putamen was associated with the development of LID in a prospective cohort of PD patients. Taken together, uncontrolled high extracellular dopamine levels in addition to the unphysiological pharmacokinetics of L-dopa lead to a pulsatile stimulation of striatal dopamine receptors, inducing abnormal postsynaptic responses and molecular changes. 2.2 Pharmacokinetics of L-Dopa By the time the degeneration of nigrostriatal neurons becomes more extensive, the release of dopamine into the synaptic cleft is increasingly dependent on the special pharmacokinetics of L-dopa (reviewed by Nutt [35]). The short half-life, variable gastrointestinal absorption, and usually intermittent administration of L-dopa eventually results in an unphysiological, pulsatile stimulation of dopaminergic receptors (reviewed in Olanow et al. [36– 38] and Contin and Martinelli [36–38]). As a consequence, the outflow of the basal ganglia changes, with different signal firing patterns between basal ganglia, thalamus, and cortex inducing abnormal motor responses [37]. It has been observed that another major risk factor for the development of LID is the daily dose of L-dopa [15, 39]. It can be argued that this finding is related to the above-mentioned advanced DA degeneration in patients and their need for higher doses of L-dopa [2], especially as dopamine agonists, which stimulate the postsynaptic receptors by passing the presynaptic neurons, induce less dyskinesia. However, studies in primate models showed an earlier development of LID in primates with L-dopa therapy than in primates with monotherapy of dopamine agonists, independently of the progression of dopaminergic denervation [40, 41]. In randomized, prospective

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studies, PD patients receiving dopamine agonist monotherapy developed less LID than the patient group with early levodopa therapy [42, 43], indicating that L-dopa per se has an influence on LID development apart from DA degeneration. These findings hold especially true for the long-lasting agonists, with a markedly longer plasma halflife and therefore more physiological stimulation of striatal DA receptors [2, 42]. Moreover, some forms of continuous or longer-acting dopaminergic drug delivery have been shown to have considerable influence on the manifestation and severity of LID [44–47] (see also Sect. 3). In this respect, it is assumed that some sort of ‘priming’ mechanism, understood as a sensitization of the basal ganglia system, follow the repeated exposure to L-dopa. It is noteworthy that, once LID are established in a patient, they return frequently with increasing severity under the same dosage of L-dopa (reviewed in Brotchie [48, 49] and Nutt [48, 49]). Even after a ‘drug holiday’, patients may react again in a similar way to exposure to L-dopa (reviewed in Nadjar et al. [50]). As an exception to the observation of priming mechanisms, some primate models need to be considered, in which LID appeared after the very first administration of Ldopa [51, 52]. Here, it seems likely that striatal receptors try to compensate for the insufficient and non-physiological DA innervation by inducing a higher sensitivity to DA. This ‘supersensitivity’ is associated with a wide range of postsynaptic maladaptive plastic changes, which could be demonstrated in a variety of studies. Beyond that, there is ongoing debate that the lower incidence of LID under dopamine agonists is not so much due to their long-lasting pharmacokinetics, but rather dependent on their affinity to DA D2 instead of D1 receptors. As further described below, D1 receptors have been attributed an important role in the development of LID. Indeed, the long-lasting dopamine agonists are mostly D2 agonists (such as cabergoline and ropinirole), some dopamine agonists are even partly D1 antagonists (such as bromocriptine) [53–55], while levodopa is non-selective and therefore activates both D1 and D2 receptors. Furthermore, the antidyskinetic effect of clozapine might be due to its D1-antagonistic features [56]. However, this hypothesis alone does not seem to be sufficient. Apomorphine, similar to L-dopa, is a non-selective agonist at the D1 and D2 receptor, but induces far less LID than L-dopa [57]. In particular, the continuous application of apomorphine has been shown to induce less LID than intermittent application via injections in the MPTP primate [45]. Furthermore, the application of a selective D1-dopamine agonist (A-86929) induced less LID than L-dopa [58], contrary to the assumption that the activation of D1 receptors alone leads to LID.

2.3 Postsynaptic Changes Findings in patients with tyrosine hydroxylase deficiency and dopa-responsive dystonia argue for the additional involvement of postsynaptic changes in the pathophysiology of LID. Although nigrostriatal degeneration is not part of the pathophysiological process in these patients, treatment with L-dopa did induce LID in some [59, 60]. Additionally, the fact that dopamine agonists, which act independently of presynaptic terminals, may also induce LID [51] argues for an involvement of the postsynaptic system in the generation of LID. Medium spiny neurons (MSN) of the striatum have been identified as being involved in postsynaptic changes leading to LID [61–64] (reviewed by Iravani and Jenner [65]). Overall, 90 % of striatal neurons are MSN. They act as striatal output neurons, which receive their DA input via two different kinds of DA receptors: D1 and D2. Both receptors are part of the basal ganglia circuit and are stimulated by the DA input of the substantia nigra. As a result of the specific stimulation of D1 or D2 receptors, the GABAergic MSN activate different neuronal pathways, inducing different motor responses: (1) the stimulation of D2 receptors activates the indirect, striatopallidal pathway, which lessens locomotion by using GABA and enkephalin as neurotransmitters and co-transmitters; or (2) the stimulation of D1 receptors activates the direct, striatonigral pathway, which provides locomotion and uses GABA, substance P, and preproenkephalin p [66–68]. According to current studies, it seems that mainly the D1 receptors and therefore the direct, motor-activating pathway contribute to the development of LID [69]. The increased sensitivity of MSN neurons and particularly D1 receptors can be attributed to a multitude of molecular changes, following unphysiological postsynaptic stimulation and leading to maladaptive plasticity. In the rat and the primate model, variances of intracellular receptor trafficking lead to a higher density of postsynaptic D1 receptors at the plasma membrane of striatal MSN [61, 70]. Furthermore, the ‘supersensitivity’ of D1 receptors is induced by changes in signaling pathways, including modifications of second messenger systems and leading to alterations in gene and protein expression. In particular, rodent and primate models showed a decline of cyclic adenosine monosphosphate (cAMP), together with different activation and regulation of the extracellular signalingregulated protein kinases 1 and 2, mitogen-activated protein kinase, mitogen- and stress-activated kinase-1, arrestin, g-protein-coupled receptor kinases, and cAMPregulated phosphoprotein of 32 kDa. Abnormal regulation of transcription factors with different protein expression was demonstrated for, among others, c-Fos, FosB, prodynorphin, and mammalian target of rapamycin complex 1


[63, 64, 71–78]. Additionally, the transcriptional activity of striatal D1 receptors was found to be upregulated in dyskinetic rats, with a different messenger RNA (mRNA) expression profile [79]. 2.4 Involvement of Non-Dopaminergic Neurotransmitter Systems 2.4.1 Glutamatergic System A further important aspect of postsynaptic maladaptive changes seems to be the interplay between DA activation of the D1-mediated direct pathway and the corticostriatal glutamatergic input. As central switchpoint of the basal ganglia circuit, the striatum receives neuronal input of the cortex by the excitatory neurotransmitter glutamate. Glutamate excites postsynaptic neurons through ionotropic (iGluR) receptors, particularly N-methyl-D-aspartate (NMDA), a-amino-3hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA), and metabotropic (mGluR) receptors. Thus, an increasing number of studies propose that another key mechanism for the development of LID may lie in an abnormal, supersensitive responsiveness of this glutamatergic corticostriatal input, interacting with DA innervation and thus leading to an overactivity of the direct striatonigral pathway [80– 82]. Glutamatergic and dopaminergic terminals converge at the same MSN synapses in the striatum. Here, DA D1 and glutamatergic NMDA receptors form heteromeric complexes [83]. Fiorentini et al. [84] postulated a downregulation of a special DA1/NMDA complex at corticostriatal synapses, involving both the glutamatergic and the DA system in the development of LID. Moreover, differences in NMDA-receptor trafficking were found to be modulated by D1-receptor activation [85]. Depending on the glutamatergic subtype, activation of corticostriatal synapses induces electrophysiological neuronal changes as long-term depression or long-term potentiation (LTP). Changes in these processes seem to be connected with ‘priming’ mechanisms in LID. Normally, after the stimulation of striatal neuronal inputs, LTP is followed by depotentation. A lack of depotentation after high-frequency stimulation was seen in dyskinetic rodent models and connected to an aberrant activation of D1 receptor-signaling pathways [86, 87]. However, changes in the glutamatergic system were also seen independently from DA innervations. Abnormal receptor trafficking with altered subcellular localization of striatal NMDA- and AMPA-receptor subunits could be demonstrated in the primate and rodent model of PD [88– 91]. Additionally, a plurality of molecular changes in glutamatergic subunits could be shown. Modified phosphorylation of some of these subunits enhanced the

sensitivity of striatal NMDA receptors and therefore altered glutamatergic neurotransmission in dyskinetic rodents [62, 92]. PET studies of PD patients showed higher activation of NMDA-receptors in the ‘on’ state of dyskinetic patients [93]. Higher striatal extracellular levels of glutamate could be demonstrated in rodent models with AIMs [94]. Finally, some studies showed higher binding to NMDA and mGluR receptors of the putamen in patients and monkeys with LID development [82, 95]. Further evidence for the participation of the glutamatergic systems is provided by the effectiveness of the NMDA-antagonist amantadine to alleviate LID, which has been proven in several patient studies [96–99]. Likewise, recent findings suggested a possible antidyskinetic effect by modulators of mGluR [100–102] (see also Sect. 3). 2.4.2 Serotonergic System An increasing number of studies indicate that the serotonergic system might play a key role in the development of LID [103, 104]. Serotonergic neurons contain similar enzymatic and transporter proteins as DA neurons, more precisely, the amino acid aromatic decarboxylase and vesicular monoamine transporter (VMAT)-2. They therefore have the capacity to decarboxylate exogenous administered L-dopa to dopamine and release it to the synaptic cleft [105–107]. The ‘false transmitter’ hypothesis postulates that, in the course of the progressive DA degeneration, serotonergic neurons take over parts of the DA function [108]. Immunohistochemical studies in rodents demonstrated DA reactions in serotonergic neurons after exogenous L-dopa administration [109]. However, since serotonergic neurons lack the mechanisms of autoregulation, dopamine is released in an uncontrolled and irregular manner, adding up to the pulsatile pharmacokinetics of L-dopa and the postulated supersensitivity of postsynaptic DA receptors (reviewed by Carta et al. [110, 111] and Carta and Bezard [110, 111]). Several dyskinesia studies of the rodent model underline this hypothesis. Exogenous L-dopa administered to 6-OHDA-lesioned rats with a completely destroyed nigrostriatal system was shown to still be efficient [112]. Clinical observation in patients in advanced disease stages are in line with the observation that, in spite of extensive presynaptic degeneration, L-dopa is still effective (although only for a short time interval). Thus, metabolization of Ldopa into dopamine under these circumstances needs to be provided by other mechanisms. Indeed, it could be demonstrated that the induction of toxic lesions in the serotonergic system of dyskinetic rats, more precisely in 5-hydroxytryptamin (5-HT) cells of the dorsal raphe nucleus, lowered extracellular dopamine levels after L-dopa administration and attenuated already manifest AIMs [113,

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114]. On the other hand, the transplantation of embryonic serotonergic cells in the striatum exacerbated AIMs in the 6-OHDA-lesioned rat [115]. The initial manifestation of LID depended on the severity of DA denervation in these models, which indicates that the ratio of DA degeneration and serotonergic hyperactivity might be the determining factor for LID [22, 103]. As mentioned above, a significant correlation between higher extracellular dopamine levels in the striatum after Ldopa administration and the manifestation of LID has been described. Additionally, involvement of an over-activated serotonergic system could be demonstrated by parallel measurement of higher striatal levels of serotonin and its metabolite 5-hydroxyindoleacetic acid in the rodent model [116]. Moreover, 5-HT1A and 5-HT1B agonists have been seen to be able to reduce extracellular dopamine levels after exogenous administered L-dopa and to attenuate LID in parkinsonian rodent and primate models, as well as in patients [117–120] (see also Sect. 3). However, higher extracellular dopamine levels in correlation with serotonergic activity were seen not only in striatal neurons but also in neurons of the substantia nigra, hippocampus, and prefrontal cortex [121]. In this respect, interesting observations have also been made in patients after transplantation of ventral mesencephalic DA neurons. Those patients showed pronounced offstate dyskinesia that were also responsive to 5-HT1 agonists [122–124]. Post mortem immunohistochemical analyses of rodents, monkeys, and PD patients even indicated that L-dopa therapy may induce morphological changes of serotonergic axons. In the majority of studies, a serotonergic hyperinnervation of the striatum could be demonstrated, and evidence was seen for the induction of serotonergic axonsprouting by L-dopa [125–127]. Combined, these findings underline the assumption of an altered serotonergic function with unphysiological release of dopamine. 2.4.3 Noradrenergic System An important role in the pathophysiology of PD has been identified for the noradrenergic system. The loss of noradrenaline is a well described phenomenon in the development of parkinsonian symptoms (reviewed by Fornai et al. [128]). Several studies revealed an interaction between the DA and noradrenaline systems, leading to changes in motor function in PD patients [129, 130]. One of the most important aggregations of noradrenergic neurons can be found in the locus coeruleus [131], which directly stimulates nigrostriatal DA receptors in the midbrain and influences dopamine release in the basal ganglia [132, 133]. In this process, a2A and a2C receptors in particular have been found to occur in high concentrations in

the striatum [134, 135] and to modulate striatal GABA release [136, 137]. Alachkar et al. [138] showed changes of a2A and a2C mRNA expression in association with L-dopa treatment (see also Sect. 3). However, the role of the noradrenaline system in the development of LID is not yet fully understood, and contradictory results have been found, showing on one hand a reduction and on the other hand an exacerbation of AIMs in noradrenaline-lesioned rat models [139, 140]. 2.4.4 Other Neurotransmitter Systems Apart from the serotonergic, glutamatergic, and noradrenergic systems, a connection to the development of LID is being discussed for a variety of other neurotransmitter systems, which have led to pharmacological intervention with partly positive results (see also Sect. 3). Changes in the opioid system have been detected with different methods. Among others, PET studies have shown reduced striatal and thalamic opioid receptor binding in dyskinetic patients and MPTP monkeys [141, 142]. In the primate model, decreased opioid-derived neurotransmission with reduced opioid receptor binding could also be demonstrated by changes in mRNA levels [143]. It is presumed that stimulation of striatal cannabinoid receptors, particularly CB1, modulates GABAergic and glutamatergic neurotransmission within the basal ganglia circuit [144, 145]. Modifications in cannabinoid receptors therefore maybe connected to changes in striatal synaptic plasticity leading to the development of LID [146]. Furthermore, adenosine A2a receptors have been found to be represented in different areas of the basal ganglia, interacting closely with the DA system (especially D2 receptors) and modulating the striatopallidal pathway [147, 148]. An increase of A2A receptors could be associated with the development of LID in PD patients [149]. Moreover, the ablation of forebrain adenosine A2a receptors has been found to attenuate LID in the rodent model [150]. Another target for new treatment strategies is nicotine, which interacts with striatal pathways via nicotinic acetylcholine receptors (nAChRs). Several studies have shown an influence of nAChR activation on dopamine release [151, 152]. Furthermore, an interaction between striatal nAChR and adenosine A2a receptors was demonstrated recently [153]. Finally, histamine H3 receptors, which are distributed widely in the basal ganglia, have been found to influence glutamatergic and DA projections, as well as striatal GABAergic neurotransmission of the striatonigral and -pallidal pathway [154–156]. Gomez-Ramirez et al. [157] showed an antidyskinetic effect on chorea of histamine H3 agonists in the primate model.


2.5 Angiogenesis In the context of an increased D1 receptor stimulation, an induction of L-dopa levels by endothelial proliferation has been observed in the rodent model, which correlated positively with AIMs [158]. The additional impairment of blood–brain barrier integrity in the basal ganglia led to different pharmacokinetics of L-dopa in different areas of the brain and therefore may be an additional reason for higher extracellular dopamine levels in dyskinetic individuals [159]. Moreover, higher levels of vascular endothelial growth factor, together with higher density of striatal capillaries have been shown [160].

3.1.2 Controlled-Release and Rapid-Onset L-Dopa Formulations

3.1 L-Dopa Formulations

Multiple oral doses of standard L-dopa produce pulsatile plasma peaks, which are also presumed to be transferred in this pulsatile way to the striatum, thereby contributing to the development of late motor complications. L-dopa controlled-release formulations have been developed to smooth L-dopa plasma levels and prolong clinical effects due to more continuous dopamine receptor stimulation. Several studies compared these controlled-release formulations with standard L-dopa therapy in the amelioration of motor fluctuations without any conclusive result [165– 170] (see Table 1 for details). Furthermore, several studies showed that, after 5 years of follow-up, slow-release preparations did not show any efficacy in reducing the incidence of motor fluctuations and LID compared with standard L-dopa [171–173]. A number of strategies have been used to improve gastrointestinal absorption of L-dopa in order to minimize its pulsatile plasma peaks. MeL-dopa, a lipophilic L-dopa formulation that is 250 times more soluble than conventional L-dopa, has been evaluated for treatment of motor fluctuations in two different double-blind studies [174, 175]. No differences on total ‘on’ time and LID severity were detected compared with the standard formulation. L-Dopa ethylester, another highly soluble prodrug of L-dopa, was studied to overcome the impaired absorption of regular L-dopa. However, the only study comparing this formulation with standard L-dopa found no statistically significant difference in LID severity and only a small influence on fluctuation control [176].

3.1.1 Standard L-Dopa Formulations

3.1.3 Intraduodenal L-Dopa Formulations

The role of dopaminergic treatment on LID development has been indirectly addressed by several trials. In 2004, the ‘earlier versus later levodopa therapy in Parkinson’s disease study’, which primarily focused on the possible toxic effect of L-dopa on disease progression, obtained the most interesting results [164]. Naive PD subjects were randomized to placebo, 150, 300, or 600 mg L-dopa for 40 weeks, followed by a 2-week washout period. Without providing any solid result on the neuroprotective or toxic effect of L-dopa, a higher incidence of dyskinesia in the 600-mg group (16.5 %), compared with 3.3 % in the placebo and 150-mg/ day groups and 2.3 % in the 300-mg/day group (P \ 0.001), was found. Additionally, high-dose L-dopa was associated with dyskinesias and wearing-off anticipation [164]. This study supported the assumption that the L-dopa dose should be kept as low as possible, balancing between symptomatic effectiveness and motor complications.

To enable continuous levodopa administration and thus stable plasma levels, another strategy has been developed: direct intra-intestinal infusion using a suspension of micronized L-dopa in a methylcellulose gel (DuodopaÒ) and a portable infusion pump. Using this application, constant L-dopa delivery with similar plasma level profiles to intravenous infusions [177] could be demonstrated. A single double-blind, placebo-controlled, crossover study in ten patients with motor fluctuations showed a significantly improved functional ‘on’ time [178]. Several open-label and retrospective studies have also showed LID reduction and fluctuation improvement using intraduodenal duodopa compared with standard oral L-dopa–carbidopa [179–181]. In clinical studies, the most common reason for discontinuing therapy were problems with the gastrostomy or infusion device (such as infection, dislocation, skin irritation, and pain or leakage at the stoma). Thus, duodopa can

2.6 Interhemispheric Connections Recently, new studies in the MPTP-primate model showed some evidence that changes in interhemispheric striatal connections may be included into the pathophysiological concepts of LID [161]. Some primates with unilateral nigrostriatal degeneration of more than 90 % showed no signs of AIMs in the course of L-dopa treatment [162]. Moreover, in clinic, it has been observed that LID seem to only occur in patients with a bilateral affection of the disease [163]. Both observations have led to the hypothesis that, in the course of bilateral nigrostriatal degeneration, interhemispheric nigrostriatal connections get lost, entailing the manifestation of LID.

3 Pharmacological Management

L-dopa

standard

CO 24 weeks L-dopa vs. SR L-dopa (n = 170): increased ON times in SR arm, no differences in global evaluation CO 8 weeks L-dopa vs. SR-L-dopa (n = 103): no LID difference

Wolters et al. [170]

UK Madopar CR SG [306]

3 treated groups vs. PL and pramipexole 6 M (n = 606): improve parkinsonism, increase LID 28 weeks DF (n = 351): increase ON time without dyskinesia, not efficacious on LID already present

Poewe et al. [308]

LeWitt et al. [312]

Rotigotine

See sumanirole

Barone et al. [310]

24 weeks (n = 393): increase ON time without LID, decrease OFF time, decease Ldopa

16 weeks (n = 243): improve parkinsonism, increase LID

Pahwa et al. [311]

Phase III, 6 M (n = 347): decrease OFF time, partial LID reduction

Mizuno et al. [309]

See rotigotine

Poewe et al. [308]

NCT01154166

Phase III, 32 weeks (n = 354): improve parkinsonism, motivation/initiative, increase LID

CO blind PL-controlled (n = 10): improved ON-time 1.1 h, good safety

Moller et al. [307]

Kurth et al. [178]

4 weeks ? first morning and first post-lunch dose change (n = 62): turning on latency reduction (possible increase in ON time), no LID difference

CO 24 weeks L-dopa vs. SR L-dopa (n = 24): no parkinsonism difference, potential benefit on LID

Liebermann et al. [169]

12 ? 4 weeks L-dopa vs. melevodopa (n = 221): no parkinsonism/LID difference

CO 24 weeks L-dopa vs. SR L-dopa (n = 20): increased ON in SR arm; increased LID in open-label phase

Jankovic et al. [168]

Djaldetti et al. [176]

CO 24 weeks L-dopa vs. SR L-dopa (n = 202): no parkinsonism/LID difference

Hutton et al. [167]

Stocchi et al. [175]

CO 24 weeks L-dopa vs. SR L-dopa (n = 25): more pts with improvement in ON in SR L-dopa arm

Sage and Mark [165]

4 ? 8 weeks L-dopa vs. melevodopa afternoon dose (n = 74): no parkinsonism/LID difference

5 years standard L-dopa vs. SR L-dopa (n = 618): no parkinsonism/LID difference

Koller et al. [173]


5 years standard L-dopa vs. SR L-dopa (n = 134): no parkinsonism difference, no effect on LID incidence

40-week dose-response L-dopa study: 150, 300, 600 mg/day vs. PL (n = 361): parkinsonism increase in PL group, increased incidence of LID and fluctuations in L-dopa at high dose

Trial vs. PL: design and results

Dupont et al. [171]

Fahn [163]

Clinical trials

Ropinirole PR

Ropinirole

Pramipexole

Dopamine agonist

Duodenal infusion

Rapid-onset formulation (vs. standard L-dopa, no PL studies available)

Slow-release L-dopa (vs. standard L-dopa, no PL studies available)

L-Dopa

L-Dopa

Drug

Table 1 Placebo-controlled clinical trials for the treatment of levodopa-induced dyskinesia in Parkinson’s disease

Improvement PD: IE, I CMF: E, CU TL: IE, I

No effect/increased LID, parkinsonism

PD: E, CU CMF: E, CU TL: IE, I

No effect/increased LID, parkinsonism improvement


No effect/increased LID, parkinsonism improvement


Increased LID, parkinsonism improvement

PD: LE, PU CMF: IE, I TL: LE, PU (C)

Good safety SE: local infusion problems (skin irritation, dislocation, infections), improve ON-time no LID effect (seen in retrospective and open-label studies)

PD: IE, I CMF: IE, I TL: IE, I

Possible increased in ON time, no effect on LID

PD: IE, I CMF: IE, I TL: IE, I

SR L-dopa did not decrease LID incidence vs. standard L-dopa no differences on parkinsonism and LID control

High dose at risk of motor fluctuations, no conclusion on neuroprotective L-dopa role

Summary of safety, efficacy and SE

E. Schaeffer et al.

ACR325 (ordopidine)

NMDA antagonist

Tolcapone

Entacapone

COMT inhibitor

Safinamide

Selegiline

Rasagiline

MAO-B inhibitor

See perampanel

Rascol et al. [242]

Phase III, 3 M (n = 202): decrease L-dopa, decrease OFF time, increase LID

13 weeks (n = 341): increase ON time, increase LID

Mizuno et al. [319]

Rajput et al. [322]

See LARGO study, rasagiline

Rascol et al. [214]

Phase III, 6 M (n = 298): decrease L-dopa, mild increase LID

Phase IV, 13 weeks (n = 270): improvement ADL mild increase LID in treated and PL groups

Reichmann et al. [318]

Phase III, DF 3 M (n = 118): decrease OFF time, increase LID

Phase III, 6 M (172 PD with motor fluctuation ? 128 PD): increase mean ON time, Ldopa reduction, increase LID

Brooks and Sagar [317]

Waters et al. [321]

Phase III, DF 3 M (n = 162): L-dopa reduction in treated group, increase LID

Baas et al. [320]

Phase III, 24 weeks (n = 301): ameliorate ADL, mild LID increase

Borgohain et al. [313, 314]

Poewe et al. [315]

Phase III, 6 M (n = 669): increase ON time without dyskinesia Phase III, extension 2 years (n = 544): good safety, increase ON time without LID

NCT01187966

Fenelon et al. [316]

Phase II, 7 weeks DF with escalation (n = 26): study completed, not published Phase III, add-on therapy for MF (n = 549): study completed, not published

NCT01113320

Phase III, rapidly disintegrating tablet formulation (Zidys-selegiline): no parkinsonism/LID difference

Ondo et al. [201]

NCT00627640

Phase III, 12 weeks rapidly disintegrating tablet formulation (Zidys-selegiline) (n = 140): good safety, increase ON time without LID

Phase III, 18 weeks vs. PL vs. entacapone (n = 687): decrease OFF time, increase ON time without dyskinesia, no effect on LID already present

Rascol et al. LARGO Study [214]

Waters et al. [200]

Phase III, 26 weeks (n = 473): increase ON time without LID, decrease OFF time

Phase I, 4 weeks (n = 40): study completed, not published

PSG PRESTO study [196]

NCT01023282

Phase II, 3 M skin patch lisuride vs. L-dopa dose finding (n = 40) LID improvement Phase II–III SC minipump (n = 60): study completed, not published

NCT00089622

NCT00408915

Phase III, 7 ? 12 weeks (n = 294): decrease OFF time increase ON time without LID, high drop-out rate

Rascol et al. [194]

Lisuride

Phase II, 13 weeks vs. pramipexole (n = 30): study completed, not published

NCT00903838

Pardoprunox (SLV308)

3 treated group vs. ropinirole vs. PL 40 weeks (n = 948); improved parkinsonism, no LID difference


Barone et al. [310]

Clinical trials

Sumanirole

Drug

Table 1 continued

PD:IE, I CMF: E, CU (A) TL: IE, I

No effect/increased LID parkinsonism improvement

PD:NE, NCU CMF: E, CU (A) TL: IE, I

No effect on/increased LID parkinsonism improvement

Good safety

Increased ON time without LID, less effective on already present LID, parkinsonism improvement

PD:NE, NCU CMF: IE, I TL: IE, I

Possible efficacy on LID with Zidys-selegiline formulation

PD:IE, I CMF: E, CU (A) TL: IE, I

Partial efficacy on LID, parkinsonism improvement

Study completed, not published

PD:IE, I CMF: IE, I TL: IE, I

Efficacy on LID, waiting for further results

Possible efficacy on LID parkinsonism improvement

No effect on LID, parkinsonism improvement



mGLUr antagonist

NCT00607451

Neu-120

Phase II, 3 weeks (n = 15): no parkinsonism/LID difference

Bara-Jimenez [291]

Nutt et al. [231]

Braz et al. [226]

Riluzole

CP-101.606

Phase II short-term effect on apomorphine-induced dyskinesia(n = 16): mild parkinsonism reduction, no LID difference

Parkinson SG [323]

Remacemide

Phase I–II CO ascending dose administered as a single (n = 20): study completed, not published

Phase I–II dose augmentation study (n = 12): mild dyskinetic effect; dissociation and amnesia as very common side effect

Phase II, double-blind randomized DF study (n = 39): no LID difference

Phase II, CO 2 weeks; study under recruitment

NCT01767129

AVP-923

Phase II, CO study 3 weeks (n = 6): 30–50 % LID reduction vs. PL; confusion at high dose, complaints of decreased erection during DM use

Verhagen Metman et al. [225]

Phase IV, 13-week study to assess possible MEM effect on axial signs of PD (n = 25); effective in LID reduction, not effective on axial symptoms reduction

Moreau et al. [222]

DM

Phase II, CO (n = 12): no LID effects on single-dose L-dopa

Merello et al. [223]

Memantine

Phase III, 24-week study under recruitment Phase III, 16-week study under recruitment

NCT02136914

NCT02153645

Phase II–III DF with augmentation (n = 80): study completed, not published

Phase IV, 3 M wash out study IC: pts with stable AMA therapy, mean 3.4 years (n = 57); good long-term efficacy (develop of LID in wash out to PL)

Ory-Magne et al. [212]

NCT01397422 (Pahtwa 2013)

CO 4 weeks (n = 36): 50 % LID reduction vs. PL

3 weeks IC: patients with stable AMA therapy since 1 year (n = 32); no effect on LID or parkinsonism; good long-term efficacy in selected pts

Wolf et al. [99]

Phase IV, 8 weeks (n = 66): LID reduction vs. PL using different scales

3 weeks (n = 18): AMA decrease LID duration and disability vs. PL

da Silva-Junior et al. [209]

Sawada et al. [210]

12 M (n = 40): 45 % LID reduction in the first month the benefit of AMA lasted \8 months; common rebound effect after withdrawal

Thomas et al. [211]

Goetz et al. [302]

CO 2 weeks (n = 24): 26 % LID reduction vs. PL CO IV AMA infusion study (n = 9): 50 % acute LID reduction vs. PL

Snow et al. [97]

Del Dotto et al. [208]

Study completed, data NA

SE: depersonalization and amnesia

Possible efficacy on LID

Not effective on LID or parkinsonism

Not effective on LID or parkinsonism

Under recruitment

Effective on LID, limitation of use: CYP2D6-dependen kinetic

Possible effective on LID, good tolerability and safety

Under recruitment

One study completed, not published and one study under recruitment

PD:IE, I CMF: IE, I TL: E, CU (A)

Withdrawal effect: LID increase, delirium

SE: hallucinations, cognitive impairment or psychosis, livedo reticularis, pedal edema; common dizziness, and GI symptoms

1-year extension of previous study (n = 17); good long-term efficacy in selected pts CO 2 weeks (n = 11): 50 % LID reduction vs. PL

Metman et al. [98]

Luginger et al. [96]

Summary of safety, efficacy and SE Effective against LIDs, controversy concerning duration of antidyskinetic effect (long effect in selected pts)

Trial vs. PL: design and results CO 3 weeks (n = 18): 60 % LID reduction vs. PL improvement motor fluctuation

Verhagen Metman et al. [207]

Clinical trials

AMA XR

AMA XR (ADS-5102)

AMA

Drug

Table 1 continued

E. Schaeffer et al.

Phase II, 13 weeks DF (n = 197); LID reduction according to dose, significant at high dose vs. PL; possible dose-dependent illusions Phase II, 6 weeks associated with increase L-dopa (n = 23); study completed, data not available Phase II, 12-week fixed-dose (n = 78); study completed, data NA Phase II, 13 weeks AFQ056 modified-release (n = 154); study completed, data NA


NCT01092065

NCT01385592

NCT01491529

5HT agonist

Topiramate

12 weeks DF (n = 347): ameliorate parkinsonism, no LID difference

6 weeks (n = 13): poor tolerability, increase LID Phase II topiramate add therapy to AMA, under recruitment

Kobylecki et al. [248]

NCT01789047

6 ? 4 weeks washout CO (n = 16): no parkinsonism/LID difference

11 weeks DF (250–1,000 mg) (n = 32): no parkinsonism difference, partial LID improvement CO 1,000 mg/day (n = 38): no parkinsonism difference, increase ON time without dyskinesia

Levetiracetam

Wong et al. [250]

Murata et al. [247]

Wolz et al. [251]

Zonisamide

CO (n = 12): no parkinsonism/LID difference CO 4 weeks (n = 20): good tolerability, mild parkinsonism amelioration, no LID difference

Stathis et al. [249]

Price et al. [245]

Phase III, 3 arms vs. PL and vs. entacapone, 6 weeks L-dopa adjustment, 12 weeks maintenance (n = 480): good safety, no effect on motor symptoms or LID

Rascol et al. [242]

Van Blercom et al. [246]

Phase III, DF, 30 weeks vs. PL (n = 751); good safety, no parkinsonism/LID difference

Lees

Sodium valproate

Phase III DF, 20 weeks vs. PL (n = 743); good safety, no parkinsonism/LID difference

Lees et al. [241]

Phase I–II, 3 weeks (n = 22) vs. PL (n = 22): study completed, not published Phase II, DF 12 weeks vs. PL (n = 263); good safety, no parkinsonism/LID difference

NCT00036296

Eggert et al. [324]

Phase II, 3 weeks vs. PL (n = 20): study completed, not published Phase II DF, short-term effect with IV L-dopa (n = 40): study completed, not published

NCT00004576

NCT00108667

Phase II, 4 weeks placebo-controlled trial (n = 83); good safety, LID reduction, improve Parkinsonism, good safety profile (study completed and presented, not yet published)

Phase II, 16 days (severe LID patients) (n = 28): LID reduction vs. PL; one case of psychosis, possible increase dyskinesias at high dose

Berg et al. [101]

NCT01336088

Phase II, 16 days (moderate to severe LID) (n = 31): LID reduction vs. PL; possible increase dyskinesia at high dose


Berg et al. [101]

Clinical trials

Gabapentin

Anticonvulsants

Perampanel

Talampanel

AMPA antagonist

Dipraglurant (AX48621)

Mavoglurant (AFQ056)

Drug

Table 1 continued

Not effective on LID poor tolerability

Possible efficacy on LID, no effect on parkinsonism

Not effective on LID



Not effective on LID, good safety

Studies completed, not published

Effective on LID and parkinsonism, good safety

SE: concerns regarding safety for dizziness, hallucinations, and illusions, data NA for the other studies

Effective on LID in the first 3 trials



Phase III, DF (n = 381): no parkinsonism/LID difference

Goetz et al. [258]

Phase II, CO 10 weeks IV L-dopa DF (n = 40): study completed, not published

Katzenschlager et al. [183]

NCT00086294

Quetiapine

ACP-103 (pimvanserin)

CO 4 weeks (n = 19): good safety, no efficacy on LID reduction or motor fluctuation

Carroll et al. [280]

Cannabis

Preladenant (SCH420814)

Phase II, 12 weeks DF vs. PL (n = 253): efficacy in improving ‘off’ time, mild LID increase Phase II, 36 weeks open-label extension study (n = 108): reduction in ‘off’ state, LID increase

Hauser et al. [288]

Factor et al. [289]

Adenosine A2A receptor antagonist

CO (n = 7) single peak efficacy: effective on LID reduction, no data on long-term safety

CO (n = 14): L-dopa increase duration of efficacy no efficacy vs. PL on LID reduction

Sieradzan et al. [279]

Fox et al. [275]

CO 2.5 weeks (n = 10): 250–300 mg: small LID reduction on diary, no efficacy vs. PL in objective measures

Manson et al. [274]

Phase I–II, 5 weeks CO DF (n = 27): study completed, not published Phase I, 8 weeks vs. PL DF with escalation (n = 40): study completed, not published

NCT01149811

NCT01140841

CO 4 weeks (group 1 with motor fluctuation n = 10; group 2 with LID n = 8), 100 mg: no parkinsonism/LID difference

Phase II, dose escalating 4 weeks vs. PL 2 cohorts USA (n = 115) and India (n = 64): good safety, LID reduction only in US cohort

Lewitt et al. [271]

Rascol et al. [273]

Phase I, proof-of-concept study, increase dose vs. PL (n = 10): good safety increase ON time 20–30 %, LID reduction

Phase II, CO single-dose effect with dose finding after acute oral challenge of L-dopa (n = 18): possible HR and BP increase, nausea or flushing; small but significant reduction in LID

Rascol et al. [270]

Dimitrova et al. [326]

Phase II, 3 weeks CO vs. PL (n = 8): possible nausea and flushing, no effect on ‘on’ time and LID

Manson et al. [269]

Nabilone

Endocannabinoid agonist

Naloxone

Naltrexone

Opioid antagonist

Fipamezole

Idaxozan

a2 Adrenergic receptor antagonist

30 days CO 25 or 50 mg/day (n = 9): no parkinsonism/LID difference

Durif et al. [264]

Clozapine

10 weeks CO study (n = 50): effective on LID

Phase II (n = 27): study completed, not published

Phase III, 12 weeks (n = 596): no parkinsonism/LID difference

Mu¨ller and Russ (PADDI-II) [325]

NCT00623363

Phase III, 24 weeks (n = 609): no parkinsonism/LID difference


Rascol et al. (PADDII) [42]

Clinical trials

5-HT antagonist/atypical antipsychotics

Piclozotan

Sarizotane

Drug

Table 1 continued

Increased LID, parkinsonism improvement

Controversial efficacy on LID

No effect on LID, increase L-dopa duration of efficacy

Good safety also at high dose, no effect on LID

Controversial efficacy on LID, good safety, data NA for the other studies

Controversial results for effectiveness and SE (BP and HR increase, nausea or flushing)



PD:IE, I CMF: IE, I TL: E, CU (C)

Effective on LID




E. Schaeffer et al.

Phase II, 1 week CO response to IV L-dopa (n = 30): study completed, not published Phase II, DF 12 weeks (n = 420): good safety, improvement parkinsonism, no LID difference

Hauser et al. [334]

Phase III, 12 weeks DF under recruitment

NCT01968031

NCT00605553

Phase III, 12 weeks DF (n = 610): no parkinsonism/LID difference Phase III, 12 weeks DF (n = 373): good safety, reduction OFF time, increase LID

Mizuno and Kondo [332]

Mizuno and Kondo [332]

Pourcher et al. [333]

Phase II, 12 weeks (n = 196): good safety, reduction OFF time, mild LID increase Phase II, 12 weeks DF (n = 363): good safety, reduction OFF time, increase LID

LeWitt et al. [331]

Phase III, 12 weeks (n = 231): good safety reduction OFF time, no LID difference

Phase II, 12 weeks DF (n = 395): good safety, reduction OFF time, increase LID

Stacy et al. [329]

Hauser et al. [330]

Phase II, 12 weeks CO fixed dose (n = 64): study completed, not published Phase III, 16 weeks vs. PL and entacapone (n = 405): study completed, not published

NCT00199394

Phase II, 12 weeks DF (n = 591): good safety, reduction OFF time

LeWitt [328]

NCT00955526

Phase II, 6 weeks PC DF (n = 15): good safety, parkinsonism improvement, no LID difference

NCT01474421

Phase II, 4 weeks DF (n = 71): study completed, not published

Phase I–II, 14 weeks drug: NP002 (n = 65): study completed, not published Phase II, 28 weeks drug: transdermal nicotine (n = 40): study completed, not published

NCT00957918

NCT00873392

Waiting for definitive results

Waiting for definitive results low tolerability in previous studies

Not effective on LID, parkinsonism improvement

Good safety

No effect/increased LID parkinsonism improvement


5-HT 5-hydroxytryptamine, (A) level of evidence A, ADL activities of daily living, AMA amantadine, AMPA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, BP blood pressure, btw between, (C) level of evidence C, CMF control motor fluctuations, CO crossover, COMT catechol-O-methyltransferase, CYP cytochrome P450, DF dose finding or drugs at different dose, DM dextromethorphan, EFNS European Federation of Neurological Societies, GI gastrointestinal, HR heart rate, IC inclusion criteria, IV intravenous, LARGO lasting effect in adjunct therapy with rasagiline given once daily, LID levodopa-induced dyskinesia, MAO monoamine oxidase, MDS Movement Disorder Society, MDS-ES MDS-European section, MEM memantine, MF motor fluctuation, mGLUr metabotropic glutamate receptor, n number of participants (published or presented by http://www.clinicaltrials.gov), NA not available, NMDA N-methyl-D-aspartate, PC proof of concept study, PD preventing dyskinesia, PL placebo, PRESTO Parkinson’s rasagiline efficacy and safety in the treatment of ‘OFF’, PSG Parkinson study group, pts patients, RCT randomized controlled trial, SC subcutaneous, SE side effect, SG study group, SR sustained release, t titration period, TL treatment of LID, XR extended release

Clinical utility: (CU) [clinically useful]: for a given situation, evidence available is sufficient to conclude that the intervention provides clinical benefit. (PU) [possibly useful]: for a given situation, available evidence suggests but insufficient to conclude that the intervention provides clinical benefit. (I) [investigational]: available evidence is insufficient to support the use of the intervention in clinical practice; further study is warranted. (UU) [unlikely useful]: available evidence suggests that the intervention does not provide clinical benefit. (NU) [not useful]: for a given situation, available evidence is sufficient to say that the intervention provides no clinical benefit

Efficacy conclusion: (E) [efficacious]: evidence shows that the intervention has a positive effect on studied outcomes. Supported by data from at least one high-quality (score [75 %) RCT without conflicting level I data. (LE) [likely efficacious]: evidence suggests but is not sufficient to show that the intervention has a positive effect on studied outcomes. Supported by data from any level I trial without conflicting level I data. (UE) [unlikely efficacious]: evidence suggests that the intervention does not have a positive effect on studied outcomes. Supported by data from any level I trial without conflicting level I data. (NE) [non-efficacious]: evidence shows that the intervention does not have a positive side effect on studied outcomes. Supported by data from at least one high-quality (score[75 %) RCT without conflicting level I data. (IE) [insufficient evidence]: there is not enough evidence either for or against efficacy of the intervention in treatment of Parkinson’s disease. All the circumstances not covered by the previous statements

The status was verified on 5 September 2014. The MDS [188] reviewed the clinical evidence and utility in clinical practice of the different drugs to prevent dyskinesia (PD), control motor fluctuations, and treat LID (TL) in Parkinson’s disease pts. When available, the review conclusions have been included in the table. The level of evidence has also been added, according to the current EFNS/MDS-ES recommendation when available [206]

AQW051

Nicotine


Bara-Jimenez et al. [327]

Clinical trials

Acetylcholine nicotinic receptor agonist

Tozadenant (SYN115)

Istradefylline

Drug

Table 1 continued


E. Schaeffer et al.

be regarded as a valid alternative for the treatment of advanced L-dopa-responsive PD when standard oral medication treatment fails. 3.2 Dopamine Agonists 3.2.1 Apomorphine Infusion Apomorphine is a nonergoline DA agonist acting on D2, D3, and D4 receptors, with an additional effect on adrenergic and serotonin 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. Continuous subcutaneous apomorphine infusions are primarily used for the treatment of on–off motor fluctuations in PD patients. Its use leads to a reduction of oral dopamine intake and may, with less fluctuating plasma levels, diminish LID [182]. One prospective and one retrospective study confirmed significant LID reduction in patients with apomorphine infusion [183, 184]. Although placebo-controlled trials are lacking, it may thus be worth considering apomorphine in patients with severe motor complications in an adequate home monitoring situation. Cognitive or psychiatric disturbances (psychosis, hallucinations, confusion, sedation) have been reported as side effects. Moreover, dermatologic complications (skin nodules, panniculitis) are the most common reasons for treatment discontinuation. 3.2.2 Dopamine Agonists Delay L-Dopa-Induced Dyskinesias (LID) but May Exacerbate Dyskinesia

tone and prevent the appearance of motor fluctuations and LID, especially when a mild antiparkinsonian effect is required. Pardoprunox (SLV308), a partial D2 agonist, lead to anti-parkinsonian effects with less dyskinesia in animal models compared with L-dopa [190, 191] and was proposed for monotherapy or add-on therapy in PD patients [192, 193]. In advanced PD with motor fluctuations pardoprunox decreased ‘off’ time and increased ‘on’ time without LID [194]. However, when LID was already present, pardoprunox worsened the symptoms and was poorly tolerated at a higher dose ([25 mg). A smaller study evaluated the efficacy of pardoprunox on motor fluctuations compared with pramipexole (NCT00903838), but results are not yet available. An open-label study compared L-dopa therapy with lisuride, another partial dopamine agonist, which was given as an infusion. After 4 years, lisuride-treated patients improved their baseline dyskinesia scores (measured by AIMs) by 50 % and reduced ‘off’ time [195]. Two further placebo-controlled studies were completed, but data are yet to be published (see Table 1). Dopidines are a new pharmacological class of drugs acting at the same time as partial agonists and antagonists on DA D2 receptors. Based on unpublished preclinical data and phase I results, a clinical study on ACR325 (odopidine), focusing primarily on safety and tolerability and secondly on LIDs, has been initiated. The trial has ended, but no published data are available as yet (NCT01023282). 3.3 Monoamine Oxidase-B Inhibitors

Several placebo-controlled studies have shown that the long-term use of dopamine agonists such as ropinirole, pramipexole, and cabergoline decrease the amount of L-dopa needed and thus lower the risk for LID significantly [43, 185–187]. However, once a patient has established LID, none of the dopamine agonists showed efficacy in reducing dyskinesia despite a significant amelioration of parkinsonian symptoms (see Table 1 for recent studies) [188, 189]. Conversely, a large meta-analysis on placebocontrolled studies demonstrated that the use of dopamine agonists, especially pergolide and ropinirole, increases the threshold-time risk of dyskinesia in patients with motor fluctuations [189]. However, clear guidelines on the reduction of L-dopa in adjunct dopamine agonist therapy are still lacking. 3.2.3 Partial Dopamine Agonists Partial dopamine agonists are pharmacological agents able to occupy dopamine receptors completely (mainly D2 or D3), without producing the maximum pharmacological response, as full agonists do. This might stabilize the DA

Monoamine oxidase (MAO)-B inhibitors are commonly used as initial therapy in early PD and as add-on therapy to L-dopa. MAO-B inhibitors block brain enzymatic metabolism of dopamine, thus increasing its concentration and effectiveness. Rasagiline efficacy on motor fluctuations was tested in two blind controlled studies: against placebo (Parkinson’s rasagiline efficacy and safety in the treatment of ‘off’) and against entacapone and placebo (LARGO [lasting effect in adjunct therapy with rasagiline given once daily]). In both studies, rasagiline increased ‘on’ time and decreased ‘off’ time without a clear effect on LID [196]. Therefore, the Movement Disorder Society (MDS) suggests rasagiline for the treatment of motor complications, but not for dyskinesia treatment (see Table 1) [188]. Selegiline was also tested, with effects similar to rasagiline [197]. Its variable pharmacokinetic profile was ascribed to an extensive first-pass metabolism of the normal formulation, resulting in only 10 % bioavailability of the parent compound [198]. An orally disintegrated tablet (Zydis selegiline) was then developed and proposed as


adjunct therapy for PD with motor fluctuations [199]. Zydis selegiline showed an increase in ‘on’ time without LID in the placebo-controlled trial performed by Waters et al. [200], but these results were not replicated in a similarly designed trial [201]. Surprisingly, long-term selegiline treatment was associated with slower motor decline but higher risk of LID development [197], probably due to the increased availability of dopamine at the nigrostriatal synapse caused by the addition of the MAO-B inhibitor [202]. Moreover, it needs to be considered that MAO-B inhibitors are contraindicated in patients taking selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and that relevant adverse events in later disease stages, such as confusion, hallucinations, and orthostatic hypotension have been reported. Safinamide, a novel MAO-B and glutamate-release inhibitor reduced LID and ameliorated parkinsonian symptoms in PD animal models [203]. The drug was tested as add-on therapy in early PD patients with promising results [204]. In PD with motor fluctuations, several placebo-controlled studies (see Table 1) evaluated the efficacy of safinamide in terms of LID reduction and control of parkinsonian symptoms. Safinamide showed good tolerability and safety and improved parkinsonism, with increasing ‘on’ time without LID after 2 years of follow-up [205]. 3.4 Catechol-O-Methyltransferase (COMT) Inhibitors The catechol-O-methyltransferase (COMT) inhibitors enhance bioavailability of L-dopa by inhibiting its metabolism. The currently available COMT inhibitors entacapone and tolcapone are added to L-dopa in patients with motor fluctuations. Two extensive meta-analyses [189, 202] and a review by the MDS [188] indicate that both drugs are efficacious in the treatment of motor fluctuations, but ineffective in reducing dyskinesia, as shown in several trials (see Table 1). On the contrary, both drugs, but especially tolcapone, increased the risk for developing or worsening of LID [189]. Therefore, European Federation of Neurological Societies (EFNS) guidelines for PD dyskinesia suggest discontinuation or reduction of COMT (which is the same for MAO-B), when LID develop [206]. However, for both classes of compounds, it needs to be considered that reduction of Ldopa metabolism inevitably leads to higher L-dopa concentrations with a LID-enhancing influence. Thus, clear schemes for L-dopa reduction are necessary for further evaluation of the effect of COMT (and MAO-B) inhibitors on LID.

3.5 Glutamatergic System 3.5.1 Amantadine: A Non-Selective NMDA Receptor Antagonist The NMDA glutamate receptor antagonist amantadine is, to date, the most commonly used drug for the treatment of dyskinesia. It is the sole compound considered as ‘clinically useful’ for the treatment of LID in a recent evidencebased review by the MDS [188]. Indeed, a significant number of clinical trials confirmed the efficacy of amantadine in reducing 30–50 % of LID in PD patients (see Table 1) [96, 97, 207–210], although some trials reported only minor efficacy compared with placebo [99, 209]. On the other hand, the duration of the antidyskinetic effect of amantadine is a topic of some controversy. Thomas et al. [211] reported that the benefit of amantadine in biphasic dyskinesia lasted\8 months, with a mean of\6 months. A much longer effect has been presented in the recent publication of the amantadine for dyskinesia trial, which could show, with class II evidence, that amantadine can retain its antidyskinetic properties over several years [212]. This is in line with one previous trial [98]. However, as the authors pointed out, these two trials evaluated only selected patients, who were treated with amantadine for several years. Both studies thus excluded patients discontinuing the treatment for efficacy loss or occurrence of side effects. The most important side effects reported in clinical studies using amantadine were hallucinations, livedo reticularis, and ankle edema. Given its anti-NMDA and partial anticholinergic profile, amantadine can also worsen psycho-cognitive functions and should be used carefully in patients with Parkinson dementia or psychiatric disturbances. As there is frequently an association between dyskinesia and cognitive impairment in the later stages of PD [213], amantadine still has a limited use in clinical practice to date. For example, in the large cohort of PD patients with motor fluctuations participating in the LARGO trial for rasagiline (n = 687), less than one-third (n = 211) received amantadine at baseline [214]. Furthermore, clinicians should remember the possible rebound effect (on motor and cognitive functions) during the amantadine withdrawal phase [215]. Given its proven efficacy, there is growing interest in understanding whether early use of amantadine may delay or reduce the incidence of LID. Indeed, some animal and indirect evidence suggests a protective role of amantadine on development of LID as well as a possible neuroprotective and antiparkinsonian effect [216, 217]. However, a retrospective study by Jahangirvand and Rajput [218] showed that amantadine treatment prior to use of L-dopa did not influence the incidence or the onset of LID. Thus,

E. Schaeffer et al.

prospective studies are needed to reach a definitive conclusion. ADS-5102 is an oral capsule containing an extendedrelease formulation of amantadine. The use of ADS-5102 once daily is expected to improve safety and tolerability of amantadine via the stabilization of its plasma concentrations during the day and overnight [219]. The final results of a multicenter, randomized, double-blind, placebo-controlled study (NCT01397422) evaluating the tolerability and efficacy of ADS-5102 have not yet been published. 3.5.2 Other Non-Selective NMDA Antagonists Memantine is a potent non-selective NMDA inhibitor. Its efficacy against LID has been proposed based on several observations when added to oral L-dopa therapy in PD patients [220, 221]. A recent placebo-controlled pilot study testing the possible effect of memantine on reduction of axial symptoms in PD patients with motor fluctuations showed a slight reduction of LID when compared with placebo [222]. However, the only placebo-controlled study, which specifically focused on the antidyskinetic effect of memantine, was a small crossover study in 12 patients with a single-dose L-dopa challenge, which could not show a potential benefit [223]. Compared with other anti-NMDA agents, memantine has a good tolerability and safety profile and has a potentially beneficial effect on cognition in PD patients with dementia [224]. Therefore, if a positive effect on LID is proven, the use of memantine may also be extended to those patients who cannot benefit from amantadine because of the presence of cognitive impairment or hallucinations. Thus, larger clinical trials, and especially a clinical trial evaluating the efficacy of memantine on LID in PD patients with different cognitive profiles, would be interesting. Dextromethorphan (DM), a widely used and well tolerated anti-tussive, is a relatively low-affinity, non-competitive NMDA receptor antagonist. In a single doubleblind study conducted by Verhagen Metman et al. [225], use of DM reduced LID about 30–50 % compared with placebo without affecting the L-dopa effect. DM is extensively metabolized by the hepatic cytochrome P450 (CYP)2D6, and its plasma levels are strictly dependent on CYP2D6 activation. Therefore, the effect of DM increases with the co-administration of a CYP2D6 inhibitor, like quinidine. A clinical trial to evaluate the efficacy, safety, and tolerability of AVP-923 capsules (containing 45 mg DM and 10 mg quinidine) versus placebo for the treatment of LID is currently recruiting participants (NCT01767129). Other non-selective NMDA antagonists have been evaluated for the treatment of LID: remacemide (a noncompetitive NMDA-receptor antagonist) and riluzole (a drug with several effects and a non-competitive NMDA

inhibitor) did not show any antidyskinetic effects in double-blind placebo-controlled trials [226]. 3.5.3 Selective NMDA Antagonists Recently, a number of studies in rodent and primate models of PD tested selective NMDA antagonists in the treatment of LID with promising results [227–229]. NMDA receptors contain four subunits, two NR1 subunits, for which there are seven isoforms and two NR2 subunits with four variants (A–D). NMDA receptors with different subunit compositions localize in the nervous system in regionally specific patterns. The highest concentration of NMDA receptors with NR2-B subunits is found in the motor cortical regions, hippocampus and the striatum [230]. Specific NMDA subunit antagonists may offer selective therapeutic benefit on LID without the cognitive and psychiatric adverse effects encountered with non-selective glutamate antagonists. The NMDA-subunit NR2B-specific inhibitor CP-101.606 (traxoprodil) has been tested in a randomized, double-blind, placebo-controlled clinical trial. Besides a mild antidyskinetic effect without improvement of parkinsonism, tolerability issues have been raised, since doserelated amnesia and depersonalization have been reported [231]. Neu-120 is a selective non-competitive NMDA-receptor modulator with MAO-B and glycogen synthase kinase-3b inhibition properties in vitro. After positive unpublished pre-clinical and early clinical phases, Neu-120 has been tested for LID in a double-blind clinical study (NCT00607451). Results have not yet been published. 3.5.4 Metabotropic Glutamate-Receptor Antagonist mGluRs are found abundantly in the basal ganglia. They regulate neuronal excitability and synaptic function and have been shown to be involved in the pathophysiology of LID. Animal dyskinesia models have shown a great variety of changes in all mGluRs, including the mGlu2/3 receptor [232]. However, most consistently, a distinct increase in the density of the postsynaptic mGluR5 was found [233]. Reduction of glutamatergic transmission by a wider range of selective mGluR5 antagonists (MPEP, MTEP, fenobam, and AFQ-056) was linked to a significant attenuation of LID in rodent and monkey models of PD [203, 234–236]. Antidyskinetic actions are thought to reflect blockade of abundant mGlu5 receptors on projection neurons of the direct striatal output pathway [236]. The antidyskinetic efficacy of AFQ056 in clinical practice has been tested in three different double-blind, randomized clinical trials in patients with moderate to severe LID. In the first two studies, AFQ056 successfully alleviated established LID without worsening other parkinsonian features [101]. A


larger trial tested AFQ056 in several doses versus placebo and confirmed that 200 mg AFQ056 daily had a significant antidyskinetic effect [100]. Mild side effects, such as fatigue, gastrointestinal disorders, and, most commonly, dizziness, were reported in all studies; the most common serious adverse event was worsening of dyskinesia after discontinuation of treatment. A small percentage of patients also developed delusions or transient psychiatric psychoses. Given these promising results, three more randomized trials and two open-label studies were conducted to expand the early observations and test the efficacy of a modified-release drug (see Table 1 for further details). All three placebo-controlled studies have been completed; however, the final results have not yet been published. Dipraglurant (AX48621), a negative allosteric modulator of mGluR5, has been recently tested in a randomized, double-blind, placebo-controlled clinical study. In this first experience, dipraglurant improved both dyskinesia and parkinsonian symptoms, reducing daily ‘off’ time. No safety or tolerability issues have been raised (NCT01336088) [237].

show any effect on LID reduction or parkinsonism improvement [245–248]. Levetiracetam, a promising drug within this class of agents, showed variable and very mild antidyskinetic effects in three different placebo-controlled trials, even with a wide range of doses [249–251].

3.5.5 AMPA Antagonists

Animal models have suggested that 5-HT1A-receptor agonists may interrupt the dopamine release of dorsal raphe neurons and reduce striatal glutamate levels [253]. In the clinical setting, different open-label trials with 5-HT1Areceptor agonists have shown a paradoxical worsening of parkinsonism instead of an amelioration of LID [254, 255]. Sarizotan, a full 5-HT1A-receptor agonist with high D3 and D4 receptor affinity, which initially showed promising antidyskinetic effects [254], failed to improve dyskinesia in two later double-blinded, placebo-controlled trials [256– 258]. Piclozotan, a new partial 5-HT1A-receptor agonist, significantly reduced hyperkinesias and improved motor complications in a rat model of advanced PD [259]. A small phase II trial testing the adverse effects and pharmacokinetic data of the drug has been recently completed (NCT00623363, see Table 1); however, data are not yet available. Specific stimulation of 5-HT1A receptors, or combined subthreshold doses of 5-HT1A and 5-HT1B-receptor agonists, has been suggested to treat dyskinesia without exacerbating parkinsonism. In the MPTP-lesioned macaque, this approach was more effective on LID than stimulation of each receptor alone [119]. Eltoprazine, a mixed 5-HT1B/1B-receptor agonist had promising results on LID in different animal models; thus, further clinical studies are warranted [260].

The glutamatergic AMPA receptor has been proposed to contribute to LID expression [232]. AMPA antagonists potentiate the antiparkinsonian effects of L-dopa and appear effective against LID in animal models [238, 239]. Several clinical studies (see Table 1) evaluated the effect of talampanel, an AMPA receptor antagonist in PD and LID, but no data have yet been published. Perampanel, a potent selective non-competitive AMPA antagonist, also reduced motor symptoms and LID in rats [240] and prompted examination of the antidyskinetic potential of this compound in patients. Disappointingly, four double-blinded, placebo-controlled trials, involving more than 1,500 subjects, failed to show any significant reduction in LID, besides the good safety and tolerability of this drug [241, 242]. Given the importance of calciumdependent signaling pathways in the pathogenesis of LID [243], it will be interesting to see whether or not selective calcium-permeable AMPA receptor antagonists like IEM1460, which are efficacious in animal models of LID [244], open up a more promising line of investigation. 3.5.6 Anticonvulsants Anticonvulsants have been considered as potential LID therapy for their desynchronizing properties on basal ganglia circuitry and for their secondary effects on neurotransmitters (particularly in dopamine- and NMDAdependent systems). However, valproate, gabapentin, zonisamide, and—recently—topiramate have failed to

3.6 Serotonergic System The serotonergic system modulates the two neurotransmitter systems with the greatest influence on the dyskinetic phenotype, the dopaminergic and glutamatergic systems. Following degeneration of the nigrostriatal system, serotonergic terminals of dorsal raphe neurons are capable of releasing dopamine, altering the normal autoregulatory mechanisms, and probably contributing to LID manifestation [252]. Both serotonergic 5-HT1A and 5-HT1B have been studied extensively in LID, identifying the anatomical sites of action and pharmacological mechanisms underlying a potential antidyskinetic effect. 3.6.1 5-HT1A and 5-HT1B Agonists

3.6.2 5-HT2A Antagonists Post mortem and pharmacological studies have provided indirect evidence of altered 5-HT22A-mediated

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neurotransmission in the dyskinetic state. Antagonizing 5-HT2A receptors with the atypical antipsychotics clozapine and quetiapine reduced LID severity in rat and primate PD models [3, 261]. After some reports and open-label studies evaluating different 5-HT2A-receptor antagonists [262], several placebo-controlled trials focusing on LID control were performed. Quetiapine was not effective in LID reduction at a dose of 25 and 50 mg in a small crossover placebo-controlled trial [263]. On the other hand, in the double-blind placebo-controlled trial published by Durif et al. [264], clozapine increased the mean ‘on’ time without dyskinesia, with no changes in duration of ‘off’ time. Hence, the MDS evidence-based review indicates clozapine as ‘‘efficacious and possibly useful’’ in dyskinesia treatment [188]. Furthermore, it might be useful in patients with hallucinations. However, the use of clozapine in the treatment of LID is still limited in clinical practice because of its side effects, especially agranulocytosis. Several other specific 5-HT2A-receptor antagonists have been studied in animal models and pimvanserin (ACP-103) has also been tested in a small trial; however, results are not yet published (see Table 1). 3.7 a2-Adrenergic-Receptor Antagonists and Adrenergic Transmission a and b-adrenergic receptors appear to play an important role in the expression of a dyskinetic phenotype [265]. Most studies have focused on a2-adrenergic-receptors, abundantly expressed on GABAergic striatal neurons. While a2-receptor blockade appears to effectively alleviate LID without impairing L-dopa antiparkinsonian action, stimulation of a2 receptors also seems effective in reducing LID, although with deleterious effects on L-dopa antiparkinsonian benefit. The mechanisms underlying the antidyskinetic action of a2-receptor antagonists remain hypothetical: effect on striatal cell bodies was assumed, reducing excitability, or on terminals of the direct pathway in the output regions of the basal ganglia, reducing GABA release [266]. Although the a2-receptor antagonists idazoxan and fipamezole significantly reduced LID in animal models [267, 268], efficacy of these compounds is still controversial in the clinical setting (see Table 1). Two small clinical trials on idazoxan found, at the same dosage, different safety profiles and only partial efficacy, if any, on LID reduction [269, 270]. Fipamezole was tested in a large double-blind, randomized, placebo-controlled, dose-escalating study in patients from the USA and India and was found to be effective only in the American subpopulation [271]. Two other studies evaluating safety, tolerability, and the maximum tolerated dosage in L-dopa PD patients have been

conducted (NCT01140841, NCT01149811), but the findings have not yet been published. 3.8 Opioid Antagonists Opioid peptide transmission is enhanced in the striatum of animal models and PD patients with L-dopa-induced motor complications. Opioid receptor antagonists reduce LID in primate PD models [272]. Naltrexone, despite a good safety profile, was not associated with any significant change in motor function or in LID reduction in two different studies comparing low (100 mg) and high (250–300 mg) doses versus placebo [273, 274]. In 2004, the non-subtype-selective opioid receptor antagonist naloxone failed to reduce LID in a placebo-controlled study on 14 PD patients with motor fluctuations [275]. 3.9 Cannabinoid Antagonists Animal models have suggested that cannabinoid agonists may exert an antidyskinetic function by augmenting GABAergic transmission in the indirect pathway [276, 277]. This model is supported clinically by the finding that 14 % of PD patients report improvement of dyskinesia with cannabis use [278]. In a small randomized trial, nabilone was associated with a 22 % mean reduction of ‘on’-period LID compared with placebo [279]. However, only seven patients completed this study, and nabilone was administered only twice prior to an acute L-dopa challenge. In 2004, a 4-week dose-escalation cross-over placebo-controlled study evaluated the potential benefit of oral cannabis in 19 PD patients [280]. The drug administration was well tolerated, but no objective or subjective improvement on dyskinesias or parkinsonism was observed. 3.10 Adenosine A2A-Receptor Antagonists Adenosine is a purinergic neurotransmitter that exerts its effects via four types of receptors: A1, A2A, A2B, A3 [281]. In PD, attention was drawn to A2A receptors, localized in the caudate and accumbens nuclei, globus pallidus, and olfactory tubercles. A2A receptors on striatal neurons participate in the planning and execution of movements, probably by influencing D2- and D1-receptor activity, and are part of the indirect pathway [282, 283]. A2A-adenosine receptors can also modulate glutamatergic and GABAergic synaptic transmission by increasing the excitability of MSN in the striatum and by enhancing GABA inhibition in projection neurons of the globus pallidus [284]. Via regulation of specific neuropeptides, such as dynorphin and encephalin, the A2A-receptor antagonists modulate the effects of chronic L-dopa administration in synaptic plasticity and contribute to the expression of LID [285]. Thus,


regarding A2A, it may be supposed that receptor antagonists may modulate striatopallidal output balance and alleviate parkinsonian symptoms by preventing the excessive activity of striatopallidal neurons and restoring the D1/ D2 (direct/indirect) pathway equilibrium [284, 286]. Preladent, a potent and selective competitive A2A-receptor antagonist showed promising results in animal models of PD [287]. In two different phase II double-blind randomized studies, preladent showed efficacy on improvement of parkinsonism, but without any beneficial effect on LID. Conversely, in both studies, the treated group showed a mild increase in dyskinesia rates [288, 289]. Istradefylline, another adenosine A2A-receptor antagonist, was tested in numerous phase II–III trials and proved to be mildly effective in relieving wearing-off fluctuations in PD patients (see Table 1). However, the addition of the drug to L-dopa was associated with a slight increase of dyskinesia in ‘on’ time and dyskinesia as an adverse event was more commonly reported in the istradefylline groups. Tozadenant (SYN115), a selective A2a-receptor antagonist was recently tested in a phase II double-blind, randomized, placebo-controlled study. Interestingly, the treated patients reported a significant improvement in parkinsonism without any increase in LID [290]. In conclusion, A2A-receptor antagonists may be a promising target in patients with motor fluctuations. Despite the mild increase of LID observed in clinical trials, it may be interesting to again test the possible antidyskinetic effect, after lowering L-dopa once parkinsonian symptoms are ameliorated by the compound, as suggested in earlier studies [291]. 3.11 Nicotinic Acetylcholine-Receptor Agonists Nicotinic receptors co-localize with dopamine receptors and seem to be involved in the expression and modulation of LID [292]. There is growing evidence of improvement of LID with the use of different acetylcholine-receptor agonists in animal models [293–295]. In the clinical setting, nicotinicreceptor agonists have been tested as possible add-on therapy to improve parkinsonian symptoms. However, all studies showed low tolerability and no clear efficacy as an add-on therapy [296]. The antidyskinetic effect of nicotine was tested in two clinical trials, with oral capsule and transdermal patch. Another nicotin receptor partial agonist, namely AQW051, was tested in a Phase 2 double blind study. All studies are completed but no data have been published, yet.

4 Trial Limitations and Future Perspectives Despite extensive efforts in LID research, there remains a substantial difference between promising preclinical results

and the failure or inconsistent results of clinical trials. There are no easy answers to this issue. However, it is important to consider limitations in translation from animal studies into the clinic and study design as two major aspects. Most PD animal models are based mainly on monolateral denervation of the DA system [297, 298]. In contrast, patients with LID show a bilateral and complex pattern of neurodegeneration, involving also non-DA systems, as mentioned above. Moreover, age, adaptive processes, and L-dopa doses differ substantially between animals and PD patients. Furthermore, while a placebo effect is unlikely to play a role in experimental LID, it is particularly important in PD patients, especially in elderly subjects [299]. Moreover, to date, the role of genetics in LID modulation has not been clarified [300]. Whereas animal models can be based on homogenous study groups, it is well known that PD in humans is heterogeneous. This holds true not only for the pathophysiology of the development of neurodegeneration but also for the development of dyskinesia [301]. A compound effective in one person may thus not influence LID to the same extent in another. With regard to study design, it needs to be considered that assessment of dyskinesia remains a major challenge in clinical trials. To date the Unified Dyskinesia Rating Scale is considered the most sensitive tool to detect treatment effect, as it combines patient-based medical history and clinical evaluation of disability by a physician [302]. However, a single assessment during clinical evaluation offers insufficient insight into the severity and manifestation forms of dyskinesia in daily life. On the other hand, patients may be unaware of the severity of their LID, probably because of the complex interplay involving anosognosic and proprioceptive mechanisms [303]. Even if they realize their LID, most patients judge akinesia as worse than dyskinesia. Thus, amelioration of dyskinesia may not be weighted adequately by patients. Hence, both the physician’s assessment and the perception of the patient are subjective. Quantitative, objective techniques for dyskinesia assessment, for example as a wearable, ambulatory assessment, need to be further developed as a very promising approach and should be considered in the design of future trials [304, 305]. Moreover, compounds used as levodopa add-on therapy that do lead to an improvement of parkinsonism complicate the scenario in patients; however, often at the cost of worsening of dyskinesia (see Table 1). Indeed, patients with motor fluctuations and LID require antithetical multimodal therapy to balance these symptoms. A personalized approach with regard to patient stratification and assessment thus seems to be the future of LID therapy. In the meantime, research on promising compounds like safinamide and AFQ056 needs to be further

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substantiated. Also, the extended-release formulation of amantadine is awaited with interest. Moreover, in the absence of clearly effective compounds, research on easily administered continuous (low-dose) L-dopa medication will need to be continued.

5 Conclusion Preclinical research has explored the wide spectrum of mechanisms involved in LID that may be effectively targeted in therapeutic strategies. However, many of the promising compounds developed in experimental models have failed to reproduce efficacy in clinical settings. At the present, according to evidence-based indications, amantadine and clozapine should be used in LID treatment. Nevertheless, data from as yet unpublished studies, and further understanding of the underlying pathophysiology leading to new translational approaches, may contribute to a more effective LID therapy in the future. Disclosure The authors Eva Schaeffer, Andrea Pilotto, and Daniela Berg report no conflicts of interest and no funding.

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