Experimental Brain Research (2019) 237:435–442 https://doi.org/10.1007/s00221-018-5434-9

RESEARCH ARTICLE

5-HT2A blockade for dyskinesia and psychosis in Parkinson’s disease: is there a limit to the efficacy of this approach? A study in the MPTP- lesioned marmoset and a literature mini-review

Cynthia Kwan1,2 · Imane Frouni1,3 · Dominique Bédard1 · Stephen G. Nuara4 · Jim C. Gourdon4 · Adjia Hamadjida1,2 · Philippe Huot1,2,3,5,6

Received: 13 October 2018 / Accepted: 12 November 2018 / Published online: 15 November 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract Virtually every patient affected by Parkinson’s disease (PD) eventually requires treatment with l-3,4-dihydroxyphenylalanine (l-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT2A) receptors appears to be an effective way to reduce both dyskinesia and psychosis, whether it has the potential to eliminate the two phenomena remains to be determined. In a previous study, we showed that highly selective 5-HT2A receptor block- ade with EMD-281,014, at plasma levels comparable to those achieved in the clinic, reduced dyskinesia and psychosis-like behaviours (PLBs), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine whether further increasing the dose would result in greater therapeutic benefit or if maximal effectiveness was achieved at lower doses. Six MPTP-lesioned marmosets with stable dyskinesia and PLBs were administered EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle in combination with l-DOPA and the effect on dyskinesia, PLBs and parkinsonism was assessed. Administration of EMD-281,014 (0.1, 1 and 10 mg/kg) in combination with l-DOPA resulted in a significant reduction in the severity of dyskinesia, by up to 63%, 64% and 61% (each P < 0.001), when compared to l-DOPA/vehicle. Similarly, the addition of EMD-281,014 (0.1, 1 and 10 mg/kg) to l-DOPA also significantly decreased the severity of PLBs, by up to 54%, 55% and 53% (each P < 0.001), when compared to l-DOPA/vehicle. Our results suggest that there might be a ceiling to the reduction of dyskinesia and psychosis that can be achieved through antagonism of 5-HT2A receptors.

Keywords EMD-281,014 · Parkinson’s disease · Dyskinesia · Psychosis · MPTP · Marmoset

Introduction

Cynthia Kwan and Imane Frouni are co-first authors. The dopamine precursor l-3,4-dihydroxyphenylalanine * Philippe Huot (l-DOPA) remains the most effective treatment for relief [email protected] of motor symptoms of Parkinson’s disease (PD) (Fox et al. 2011; Connolly and Lang 2014). However, with long-term 1 Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, BT 209, Montreal, administration of l-DOPA, patients experience complica- QC H3A 2B4, Canada tions such as dyskinesia and psychosis (Hely et al. 1999, 2 Integrated Program in Neuroscience, McGill University, 2005). Given that treatments for these complications are few Montreal, QC, Canada and their efficacy is partial, there is a major unmet need to 3 Département de Pharmacologie et Physiologie, Université de develop therapies for patients with PD that are afflicted with Montréal, Montreal, QC, Canada these conditions. 4 Comparative Medicine and Animal Resource Centre, McGill There is post-mortem evidence of altered serotonin University, Montreal, QC, Canada (5-HT) 2A (5-HT2A) receptor levels in l-DOPA-induced 5 Department of Neuroscience, McGill University, Montreal, dyskinesia (Riahi et al. 2011; Huot et al. 2012) and visual QC, Canada hallucinations (Huot et al. 2010) in PD. Pharmacologically, 6 Division of Neurology, McGill University Health Centre, 5-HT2A receptor blockade (Hamadjida et al. 2018a) or par- Montreal, QC, Canada tial agonism (Huot et al. 2011) reduced each of dyskinesia

Vol.:(0123456789)1 3 436 Experimental Brain Research (2019) 237:435–442 and psychosis-like behaviours (PLBs) in the 1-methyl- primate toys and perches. Prior to the beginning of studies, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mar- animals were acclimatised to handling, administration of moset, while in the clinic, the 5-HT2A inverse agonist pima- sub-cutaneous (s.c.) treatments, and transfer to observation vanserin reduced psychosis (Cummings et al. 2014). Other cages for behavioural assessment. molecules such as clozapine and ritanserin, both of which harbour affinity for 5-HT2A receptors, also alleviated dyski- Induction of parkinsonism, dyskinesia and PLBs nesia (Maertens de Noordhout and Delwaide 1986; Meco in the marmoset et al. 1988; Durif et al. 2004) and psychosis (French Clo- zapine Parkinson Study Group 1999; Parkinson Study Group Animals were rendered parkinsonian by daily injection of 1999) in the clinic, but their lack of selectivity makes it MPTP hydrochloride (MilliporeSigma, Canada) dissolved in difficult to determine the extent to which 5-HT2A receptor 0.9% sterile saline (2 mg/kg s.c.) for up to 5 days. Following antagonism contributed to their benefit. a 6-week recovery period, a stable parkinsonian phenotype EMD-281,014 (also known as pruvanserin or was observed. Dyskinesia and PLBs were then induced by LY-2,422,347) is a highly selective 5-HT2A neutral antago- chronic administration of l-DOPA/benserazide (henceforth nist, with approximately 2000-fold selectivity (Bartoszyk termed l-DOPA, 15/3.75 mg/kg, MilliporeSigma, Canada) et al. 2003). EMD-281,014 entered clinical testing and target per os, once daily for at least 1 month. This treatment regi- plasma levels and in vivo brain receptor occupancy have men has been shown to produce a stable phenotype of dys- been determined (Mamo et al. 2004). Recently, we have kinesia and PLBs (Huot et al. 2011; Hamadjida et al. 2017, shown that doses of EMD-281,014 leading to plasma levels 2018c). in the range of those that were achieved in the clinic were effective at reducing both dyskinesia and PLBs in the par- Administration of EMD‑281,014 with l‑DOPA kinsonian marmoset (Hamadjida et al. 2018a). In this study, to MPTP‑lesioned marmosets EMD-281,014 (0.03 and 0.1 mg/kg) reduced dyskinesia by ≈ 54%, while PLBs were diminished by ≈ 45%. Although On experimental days, at 08:00, marmosets received ther- these were important reductions, whether higher doses of apeutic doses of l-DOPA, 15/3.75 mg/kg s.c. (Millipore- EMD-281,014 could further alleviate dyskinesia and PLBs Sigma, Canada), in combination with either vehicle (0.9% has not been demonstrated. Whereas such doses would not NaCl) or EMD-281,014 (0.1, 1 or 10 mg/kg s.c.; Cedarlane be clinically relevant, they may nevertheless be informa- Laboratories, Canada). Drugs were administered according tive as to whether there is a ceiling to the potential anti- to a randomised within-subject design, in which all animals dyskinetic and anti-psychotic benefit conferred by 5-HT2A received all treatments, in a random order. After administra- receptor blockade. Here, we sought to find an answer to this tion of a given treatment, each marmoset was placed individ- question, by administering high doses of EMD-281,014 in ually into an observation cage (36 × 33 × 22 in.) containing combination with l-DOPA to the MPTP-lesioned marmo- food, water and a wooden perch, and left undisturbed for 6 h. set, a non-human primate model of PD with high predictive At least 72 h were left between each treatment in any ani- value and low false positive rate of the translational success mal and behaviour was recorded via webcam and analysed of drugs (Veyres et al. 2018). post hoc by a movement disorder neurologist blinded to the treatment given.

Materials and methods Behavioural analysis

Animals Behavioural analysis was performed according to scales pre- viously described (Fox et al. 2010; Huot et al. 2014; Hama- Six common marmosets (Callithrix jacchus; WorldWide djida et al. 2017, 2018b, 2018c). Primates, USA and McGill University breeding colony; 3 males and 3 females), weighing 300–450 g, were housed Parkinsonian disability in groups of 2–3 under controlled conditions of tempera- ture (23 ± 1 °C), humidity (50%) and light (12 h light/dark Parkinsonian disability was scored for 5 min every 10 min cycle, lights on at 07:15). Animals were cared for in accord- using a scale that combined measures of range of move- ance with a protocol approved by McGill University and the ment, bradykinesia, posture, and attention/alertness. Range Montreal Neurological Institute Animal Care Committees, of movement was rated on a 0–9 scale: 0 = running, jumping in accordance with the regulations defined by the Canadian between roof, walls, perch, using limbs through a wide range Council on Animal Care. Food, fresh fruits and water were of activity; 1: climbing up and down the cage walls or along available ad libitum and home cages were enriched with perch; 2: climbing onto cage wall or perch; 3: hopping on

1 3 Experimental Brain Research (2019) 237:435–442 437 floor of cage; 4: walking around floor; 5: on cage wall or The PLBs score attributed reflected the most disabling of perch, movement of limbs, but no locomotion; 6: on cage any of the four sub-scores during the observation period. wall or perch, movement of head or trunk; 7: on the floor The scores for parkinsonism, dyskinesia and PLBs were of the cage, movement of limb, but no locomotion; 8: on cumulated for each hour across the entire 6 h observation the floor of the cage, movement of head; 9 = no movement. period and during the peak-effect period (60–150 min fol- Bradykinesia was rated from 0 to 3: 0 = normal initiation lowing l-DOPA administration). Duration of anti-parkinso- and speed of movement; 1: slight slowing of movement; nian action, referred to as on-time, was defined as the num- 2: moderate slowing of movement, marked freezing, diffi- ber of minutes for which bradykinesia was absent (score 0). culty initiating and maintaining movement; 3 = prolonged freezing, akinesia, inability to move. Postural abnormali- Data analysis ties were rated 0 or 1: 0 = normal balance, upright posture, head held up; 1 = impaired balance, crouched posture, head Time course data for parkinsonian disability, dyskinesia down. Attention/alertness was rated 0 or 1; 0 = normal head and PLBs scores were sorted by ranking in ascending order checking movements, movement of neck in variable direc- (Howell 2011) and analysed by two-way repeated measures tions, smooth, small movements; 1 = reduced or absent head analysis of variance (RM ANOVA) followed by Tukey’s post checking, head in one position for more than 50% of obser- hoc test. On-time parameters are presented as the mean ± vation period. The score attributed to each of the behaviours standard error of the mean (SEM) and were analysed by assessed was the most representative of the 5 min observa- one-way RM ANOVA followed by Tukey’s post hoc test. tion period. The higher the score, the more severe the dis- Statistical significance was assigned when P < 0.05. Statis- ability. The global parkinsonian disability was calculated tical analyses were computed using GraphPad Prism 7.03 as a combination of the above behaviours according to the (GraphPad Software Inc, La Jolla, USA). following formula: (range of movement × 1) + (bradykin- esia × 3) + (posture × 9) + (attention/alertness × 9). With this method, the maximal parkinsonian disability score per 5 min Results observation period was 36. EMD‑281,014 attenuates the severity of l‑DOPA‑induced dyskinesia l‑DOPA induced dyskinesia and PLBs As illustrated in Fig. 1a, a significant effect of treatment Dyskinesia and PLBs were simultaneously assessed and and interaction between treatment and time on the sever- scored using a scale from 0 to 4. For dyskinesia, chorei- ity of dyskinesia were observed [Ftime(5, 120) = 0, P > 0.05; form and dystonic dyskinesia were assessed separately for Ftreatment(3, 120) = 24.92, P < 0.001; and Finteraction(15, 5 min every 10 min as follow: 0 = absent; 1 = mild, present 120) = 4.41, P < 0.001; two-way RM ANOVA following less than 30% of the observation period; 2 = moderate, not ranking of data]. Thus, EMD-281,014 (0.1, 1 and 10 mg/ interfering with normal activity, present more than 30% kg) significantly reduced the severity of dyskinesia when of the observation period; 3 = marked, at times interfering administered in combination with l-DOPA, especially dur- with normal activity, present less than 70% of the observa- ing the first 3 h. During the first hour, EMD-281,014 (0.1, 1 tion period; 4 = severe, continuous, replacing normal activ- and 10 mg/kg) combined with l-DOPA reduced the severity ity, present more than 70% of the observation period. The of dyskinesia by ≈ 41% (P < 0.001), ≈ 44% (P < 0.001) and most disabling dyskinesia score, either chorea or dystonia, ≈ 31% (P < 0.05), respectively, when compared to l-DOPA/ reflected the severity of the dyskinesia disability for each vehicle (Tukey’s post hoc test). By the second hour, EMD- observation period. 281,014 (0.1, 1 and 10 mg/kg), when added to l-DOPA, For PLBs, hyperkinesia, response to non-apparent stimuli diminished the severity of dyskinesia by ≈ 36%, ≈ 34% and (hallucinatory-like behaviour), repetitive grooming and ste- ≈ 33%, when compared to l-DOPA/vehicle (each P < 0.001, reotypies were assessed in 5 min observation periods every Tukey’s post hoc test). At the third hour, dyskinesia was sig- 10 min for 6 h. Each of these was rated according to a vali- nificantly decreased, by ≈ 63%, ≈ 64% and ≈ 61%, respec- dated scale (Fox et al. 2010), where 0 = absent; 1 = mild, pre- tively, when l-DOPA/EMD-281,014 (0.1, 1 and 10 mg/kg) sent less than 30% of the observation period; 2 = moderate, was compared to l-DOPA/vehicle (each P < 0.001, Tukey’s not interfering with normal activity, present more than 30% post hoc test). of the observation period; 3 = marked, at times interfering Duration of on-time with disabling dyskinesia signifi- with normal activity, present less than 30% of the obser- cantly decreased when EMD-281,014 was administered in vation period; 4 = severe, at times interfering with normal combination with l-DOPA, as shown in Fig. 1b [Ftreatment(3, activity, present more than 30% of the observation period. 15) = 25.15, P < 0.001; one-way RM ANOVA]. Thus, after

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Fig. 1 Effect of EMD-281,014 on dyskinesia in the MPTP-lesioned ate = 12, marked = 18 and severe = 24. b On-time with disabling dys- marmoset. a Time course of l-DOPA-induced dyskinesia in marmo- kinesia in MPTP-lesioned marmosets treated with l-DOPA in com- sets administered EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle in bination with EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle. Data combination with l-DOPA. The maximal possible dyskinesia score are expressed as the median (a) and the mean ± SEM (b). *P < 0.05; (most severe disability) was 24. On the Y-axis, mild = 6, moder- ***P < 0.001 administration of l-DOPA/vehicle, duration of on-time with As shown in Fig. 2b, administration of l-DOPA/EMD- disabling dyskinesia was ≈ 123 ± 9 min, whereas it was 281,014 resulted in a significant reduction of duration of ≈ 30 ± 6 min following administration of l-DOPA/EMD- on-time with disabling PLBs [Ftreatment(3, 15) = 20.33, 281,014 0.1 mg/kg, (76% reduction, P < 0.001, Tukey’s post P < 0.001; one-way RM ANOVA]. Following administration hoc test), while it was ≈ 40 ± 13 min and ≈ 40 ± 14 min after of l-DOPA/vehicle, duration of on-time with disabling PLBs administration of l-DOPA/EMD-281,014 1 and 10 mg/kg, was ≈ 152 ± 7 min, whereas treatment with l-DOPA/EMD- respectively (both 68% reduction, both P < 0.001, Tukey’s 281,014 0.1 mg/kg shortened the duration to 70 ± 10 min post hoc test). (54% of reduction, P < 0.001, Tukey’s post hoc test), while it diminished to 53 ± 12 min and 72 ± 17 min, respectively, fol- EMD‑281,014 diminishes l‑DOPA‑induced PLBs lowing treatment with l-DOPA/EMD-281,014 1 and 10 mg/ kg (65% and 53% of reduction, both P < 0.001, Tukey’s post As shown in Fig. 2a, the addition of EMD-281,014 to hoc test). l-DOPA resulted in a significant reduction of the severity l of PLBs [Ftime(5, 120) = 0, P > 0.05; Ftreatment(3, 120) = 21.6, High dose EMD‑281,014 may alter ‑DOPA P < 0.001; and Finteraction(15, 120) = 3.919, P < 0.001; two- anti‑parkinsonian action way RM ANOVA following ranking of data]. Thus, dur- ing the first hour, the addition of EMD-281,014 (0.1, 1 and As illustrated in Fig. 3a, the addition of EMD-281,014 to 10 mg/kg) led to a significant decrease in the severity of l-DOPA mildly but significantly increased parkinsonian dis- PLBs, by ≈ 31% (P < 0.001), ≈ 38% (P < 0.001) and ≈ 27% ability [Ftime(5, 120) = 0, P > 0.05; Ftreatment(3, 120) = 3.817, (P < 0.01), respectively, when compared to l-DOPA/vehicle P < 0.05; and Finteraction(15, 120) = 1.368, P > 0.05; two-way (Tukey’s post hoc test). Subsequently, at the second hour, the RM ANOVA following ranking of data]. Thus, 5 h after severity of PLBs was reduced by ≈ 27%, ≈ 33% and ≈ 23%, treatment administration, the severity of parkinsonism was when compared to l-DOPA/vehicle (each P < 0.001, Tukey’s significantly higher with EMD-281,014 10 mg/kg (by 7%, post hoc test). By the third hour, EMD-281,014 (0.1, 1 and P < 0.05, Tukey’s post hoc test), whereas neither EMD- 10 mg/kg) diminished PLBs by ≈ 54%, ≈ 55% and ≈ 53% 281,014 0.1 nor 1 mg/kg worsened parkinsonian disability when compared to l-DOPA/vehicle (each P < 0.001, Tukey’s (both P > 0.05, Tukey’s post hoc test), when compared to post hoc test). l-DOPA/vehicle. In contrast, duration of on-time was similar

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Fig. 2 Effect of EMD-281,014 on PLBs in the MPTP-lesioned marked = 18 and severe = 24. b Duration of on-time with disabling marmoset. a Time course of l-DOPA-induced PLBs in marmo- PLBs in MPTP-lesioned marmosets administered l-DOPA in com- sets administered EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle in bination with EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle. Data combination with l-DOPA. The maximal possible PLBs score (most are expressed as the median (a) and the mean ± SEM (b). **P < 0.01; severe disability) was 24. On the Y-axis, mild = 6, moderate = 12, ***P < 0.001

Fig. 3 Effect of EMD-281,014 on l-DOPA anti-parkinsonian action disability) was 216. On the Y-axis, mild = 54, moderate = 108, in the MPTP-lesioned marmoset. a Time course of parkinsonian dis- marked = 162 and severe = 216. b Duration of on-time in MPTP- ability in MPTP-lesioned marmosets following administration of lesioned marmosets treated with l-DOPA in combination with EMD- l-DOPA in combination with EMD-281,014 (0.1, 1 and 10 mg/kg) 281,014 (0.1, 1 and 10 mg/kg) or vehicle. Data are expressed as the or vehicle. The maximal possible parkinsonian score (most severe median (a) and the mean ± SEM (b). *P < 0.05

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Table 1 Effect of selective 5-HT2A “antagonists” on l-DOPA-induced dyskinesia and psychosis-like behaviours in the MPTP-lesioned primate Drug Mechanism of action Effect on dyskinesia and PLBs References

EMD-281,014 5-HT2A neutral antagonist ↓ Dyskinesia and ↓ psychosis in the marmoset, Bartoszyk et al. (2003), Hamadjida et al. (2018a) ceiling for both at ≈ 50% and ≈ 60% reduction

Pimavanserin 5-HT2A inverse agonist ↓ Dyskinesia in the macaque, by ≈ 25%, uncer- Vanover et al. (2006), Vanover et al. (2008) tain if higher doses would have further reduced dyskinesia

R-MDMA 5-HT2A partial agonist ↓ Dyskinesia in the marmoset, with a ceiling at ≈ Nash et al. (1994), Huot et al. (2011) 30% reduction

↓: reduction PLBs psychosis-like behaviours, R-MDMA R-3,4-methylenedioxymethamphetamine across all treatments and averaged approximately 186 min a certain limit, around 50% for each. Unlike activation of (Fig. 3b). 5-HT1A receptors (Iravani et al. 2006; Goetz et al. 2007), however, antagonising 5-HT2A receptors does not seem to hinder l-DOPA anti-parkinsonian action at clinically rel- Discussion evant doses, although high dose may slightly reduce the effect ofl -DOPA. Our results are in agreement with pre- In this study, we expanded on previous work performed by vious experiments with 5-HT2A antagonists performed in our group with EMD-281,014 (Hamadjida et al. 2018a), and the MPTP-lesioned primate (Table 1), where ceiling effects demonstrated that higher doses of EMD-281,014 reduced were apparently reached, without impairing l-DOPA anti- the severity of dyskinesia and duration of on-time with disa- parkinsonian effect (Vanover et al. 2008; Huot et al. 2011). bling dyskinesia. Moreover, treatment with EMD-281,014, However, caution is advised when interpreting these last two also resulted in a significant decrease in the severity of PLBs studies, as the drugs under investigation, R-3,4-methylene- and duration of on-time with disabling PLBs in parkinso- dioxymethamphetamine (R-MDMA) (Huot et al. 2011) and nian marmosets. Our results also suggest that, at high dose, pimavanserin (Vanover et al. 2006), are not as selective as 5-HT2A receptor blockade might compromise, albeit slightly, EMD-281,014 for 5-HT2A receptors. Moreover, R-MDMA l-DOPA therapeutic efficacy. is a partial agonist (Nash et al. 1994), while pimavanserin is In that previous study, we determined the pharmacoki- an inverse agonist (Vanover et al. 2006) at 5-HT2A receptors; netic profile of EMD-281,014 in the marmoset and found how these different actions at 5-HT2A receptors compare to that administration of doses of 0.1 mg/kg s.c. led to plasma the neutral antagonism of EMD-281,014 (Bartoszyk et al. levels comparable to those that were achieved and report- 2003) in experimental parkinsonism is uncertain. edly well-tolerated in the clinic, ≈ 11 ng/ml (Mamo et al. To the best of our knowledge, EMD-281,014, pimavan- 2004). At these levels, ≈ 95% 5-HT2A receptor occupancy serin and R-MDMA are the most selective 5-HT2A “antago- was reached in the frontal cortex of human subjects (Mamo nists” that were assessed in the MPTP-lesioned primate. Of et al. 2004), but the 5-HT2A receptor occupancy of other these, only pimavanserin was tested in clinical settings for brain areas, notably the basal ganglia, was not mentioned, PD-related endpoints. Pimavanserin apparently had a mod- although there is little reason to believe that it would mark- est anti-dyskinetic effect in an early report (Roberts2006 ), edly differ to the neocortex. Nevertheless, because dopamine but randomised controlled trials on dyskinesia have not acts as a partial agonist at 5-HT2A receptors (Bhattacharyya been published, and this early report awaits confirmation. et al. 2006), we hypothesised that it could displace a cer- In contrast, pimavanserin reduced PD psychosis in a Phase tain amount of EMD-281,014 from its target, which is why III trial, but here again the effect was relatively modest, ≈ we have administered doses that were, respectively, 10- and 13% (Cummings et al. 2014). Whereas these modest benefits 100-fold higher than 0.1 mg/kg s.c. Although we did not achieved clinically with pimavanserin are not necessarily determine plasma levels associated with EMD-281,014 1 indicative of a ceiling effect of the drug or of antagonising and 10 mg/kg s.c., it is plausible to assume that they were 5-HT2A receptors, they nevertheless suggest that the benefit significantly higher than these attained with 0.1 mg/kg in conferred by 5-HT2A blockade for both dyskinesia and psy- our first study. chosis may be limited. Unlike what we expected, we did not achieve greater anti- Perhaps more surprisingly, given the benefits encoun- dyskinetic or anti-psychotic effects with these higher doses. tered in the parkinsonian primate and in the clinic, 5-HT2A This suggests that selective 5-HT2A receptor blockade may blockade does not appear to be an effective anti-dyskinetic not reduce l-DOPA-induced dyskinesia and psychosis over approach in the 6-hydroxydopamine (6-OHDA)-lesioned

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Table 2 Effect of selective Drug Mechanism of action Effect on dyskinesia References 5-HT2A “antagonists” on l-DOPA-induced AIMs in the EMD-281,014 5-HT2A neutral antagonist No effect Bartoszyk 6-OHDA-lesioned rat et al. (2003), Frouni et al. (2018)

Volinanserin 5-HT2A inverse agonist No effect Taylor et al. (2006), Vanover et al. (2006)

rat (Table 2). Thus, the selective 5-HT2A inverse agonist serotonin 2A receptor by dopamine. Proc Natl Acad Sci USA volinanserin [MDL-100,907, M-100,907] (Vanover et al. 103:15248–15253. https​://doi.org/10.1073/pnas.06065​78103​ Connolly BS, Lang AE (2014) Pharmacological treatment of Parkin- 2006) was ineffective at reducingl -DOPA-induced abnor- son disease: a review. JAMA 311:1670–1683 mal involuntary movements (AIMs) in the rat (Taylor et al. Cummings J, Isaacson S, Mills R et al (2014) Pimavanserin for 2006). In addition, we recently showed that EMD-281,014, patients with Parkinson’s disease psychosis: a randomised, at doses leading to clinically relevant plasma levels, was placebo-controlled phase 3 trial. Lancet 383:533–540. https​:// doi.org/10.1016/S0140​-6736(13)62106​-6 also ineffective at reducingl -DOPA-induced AIMs in the Durif F, Debilly B, Galitzky M et al (2004) Clozapine improves parkinsonian rat (Frouni et al. 2018). Taken together, these dyskinesias in Parkinson disease: a double-blind, placebo-con- two studies in the rodent suggest that 5-HT2A blockade, trolled study. Neurology 62:381–388 whether with an inverse agonist or a neutral antagonist, does Fox SH, Visanji N, Reyes G, Huot P, Gomez-Ramirez J, Johnston T, Brotchie JM (2010) Neuropsychiatric behaviors in the MPTP not stand out as an effective anti-dyskinetic approach in the marmoset model of Parkinson’s disease. Can J Neurol Sci 6-OHDA-lesioned rat. 37:86–95 In summary, this study provides further support that Fox SH, Katzenschlager R, Lim SY et al (2011) The Movement Dis- highly selective 5-HT receptor blockade is effective at order Society evidence-based medicine review update: treatments 2A for the motor symptoms of Parkinson’s disease. Mov Disord alleviating both l-DOPA-induced dyskinesia and psychosis 26(Suppl 3):S2–S41 in PD. However, our results suggest that the magnitude of French Clozapine Parkinson Study Group (1999) Clozapine in drug- the benefits conferred by 5-HT2A blockade may be limited induced psychosis in Parkinson’s disease. The French Clozapine and that, at very high dose, an interference with the anti- Parkinson Study Group. Lancet 353:2041–2042 Frouni I, Kwan C, Bedard D et al (2018) Effect of the selective 5-HT2A l parkinsonian effect of -DOPA may emerge. This study, cou- receptor antagonist EMD-281,014 on l-DOPA-induced abnormal pled with the reviewed literature, also suggest that, while involuntary movements in the 6-OHDA-lesioned rat. Exp Brain antagonising 5-HT2A receptors reduces both dyskinesia and Res. https​://doi.org/10.1007/s0022​1-018-5390-4 psychosis, it may be impossible to eradicate these two treat- Goetz CG, Damier P, Hicking C et al (2007) Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo- ment-related complications by relying solely on selective controlled trial. Mov Disord 22:179–186. https://doi.org/10.1002/​ modulation of this target. mds.21226​ Hamadjida A, Nuara SG, Veyres N et al (2017) The effect of mirtazap- Acknowledgements PH has research support from Parkinson Canada, ine on dopaminergic psychosis and dyskinesia in the parkinsonian Fonds de Recherche Québec—Santé, the Natural Sciences and Engi- marmoset. Psychopharmacology 234:905–911 neering Research Council of Canada, the Michael J Fox Foundation for Hamadjida A, Nuara SG, Bedard D, Gaudette F, Beaudry F, Gour- Parkinson’s Research and the Weston Brain Institute. don JC, Huot P (2018a) The highly selective 5-HT2A antagonist EMD-281,014 reduces dyskinesia and psychosis in the l-DOPA- Compliance with ethical standards treated parkinsonian marmoset. Neuropharmacology 139:61–67. https​://doi.org/10.1016/j.neuro​pharm​.2018.06.038 Hamadjida A, Nuara SG, Gourdon JC, Huot P (2018b) The effect of Conflict of interest There are no conflicts of interest. PH has received mianserin on the severity of psychosis and dyskinesia in the par- payments from UCB. kinsonian marmoset. Prog Neuropsychopharmacol Biol Psychia- try 81:367–371 Hamadjida A, Nuara SG, Gourdon JC, Huot P (2018c) Trazodone alleviates both dyskinesia and psychosis in the parkinsonian marmoset model of Parkinson’s disease. J Neural Transm References (Vienna)125(9):1355–1360 Hely MA, Morris JG, Traficante R, Reid WG, O’Sullivan DJ, Wil- Bartoszyk GD, van Amsterdam C, Bottcher H, Seyfried CA (2003) liamson PM (1999) The sydney multicentre study of Parkinson’s EMD 281014, a new selective serotonin 5-HT2A receptor antago- disease: progression and mortality at 10 years. J Neurol Neurosurg nist. Eur J Pharmacol 473:229–230 Psychiatry 67:300–307 Bhattacharyya S, Raote I, Bhattacharya A, Miledi R, Panicker Hely MA, Morris JG, Reid WG, Trafficante R (2005) Sydney Mul- MM (2006) Activation, internalization, and recycling of the ticenter Study of Parkinson’s disease: non-l-dopa-responsive

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