Drugs (2014) 74:645–657 DOI 10.1007/s40265-014-0209-5

REVIEW ARTICLE

Early Versus Delayed Initiation of Pharmacotherapy in Parkinson’s Disease Matthias Lo¨hle • Carl-Johan Ramberg • Heinz Reichmann • Anthony H. V. Schapira

Published online: 23 April 2014 Ó Springer International Publishing Switzerland 2014

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and pathologically is characterised by a progressive loss of dopaminergic cells of the nigrostriatal pathway. Clinically, PD is mainly defined by the presence of the motor symptoms of bradykinesia, rigidity, rest tremor and postural instability, but non-motor symptoms such as depression, dementia and autonomic disturbances are recognised as integral parts of the disease. Although pharmacotherapy for PD was introduced almost 50 years ago, and has improved significantly over the intervening period, the timing of initiation of treatment in newly diagnosed PD remains controversial. While some physicians favour an early start of pharmacotherapy at or soon after diagnosis, others prefer to delay pharmacological treatment until a certain degree of disability has developed. This article aims to discuss the advantages and disadvantages of both strategies by exploring their effects on symptoms, disease progression and quality of life.

M. Lo¨hle
H. Reichmann Department of Neurology, Dresden University of Technology, Dresden, Germany M. Lo¨hle Center for Regenerative Therapies Dresden (CRTD), Dresden University of Technology, Dresden, Germany M. Lo¨hle
A. H. V. Schapira (&) University Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill St., London NW3 2PF, UK e-mail: [email protected] C.-J. Ramberg Department of Neurology, Innlandet Hospital Trust, Lillehammer, Brumunddal, Norway

Although the data on putative disease-modifying effects of early pharmacological intervention in PD are still inconclusive, we believe that the most important indication for an early initiation of anti-parkinsonian treatment should be to maintain the quality of life of PD patients and to secure their socioeconomic status as long as possible.

1 Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder, which affects about 1 % of the population over the age of 65 years. As life expectancy increases worldwide, the estimated number of PD patients in the most populous nations is projected to reach 8.7 million in 2030, posing an enormous challenge for public health to offer cost-effective treatment to all affected patients [1–4]. The diagnosis of idiopathic PD is based on the presence of its cardinal symptoms, bradykinesia, rigidity, rest tremor and postural imbalance, and is most accurately made by movement disorder specialists [5]. It is helpful for physicians to use standardised consensus guidelines for diagnosing PD, such as the United Kingdom PD Brain Bank clinical diagnostic criteria [6], although there is a pressing need for re-evaluation of these criteria in the light of recent advances in genetics and pathology [7]. Once PD has been diagnosed, patients and their physicians eventually will be faced with the question of when to initiate treatment for the disease. While non-pharmacological interventions, such as patient education, nutrition and physical exercise, are generally supported, the question of when pharmacological treatment should be initiated remains controversial and is subject to ongoing debate [8– 11], which may be surprising given that pharmacotherapy has been available for almost 50 years [12]. Many

646

physicians still prefer the traditional ‘watch and wait’ strategy [9], which favours a delay of treatment until the patient’s clinical state requires pharmacological intervention, while others propose an earlier onset of therapy [8]. This article aims to discuss advantages and disadvantages of both strategies and examines the scientific evidence that has emerged from clinical trials during the recent past.

2 Symptomatic Effects of Early and Delayed Treatment in Early Parkinson’s Disease (PD) Non-motor symptoms are recognised as an integral part of the phenomenology of even early PD [13–20]. However, the early symptomatic stages of the disease are primarily defined by the emergence of motor symptoms, such as rigidity, rest tremor and bradykinesia, which prompt patients to seek medical advice. If anti-parkinsonian treatment is delayed after diagnosis, PD will follow its natural course and induce a progressive increase in motor symptoms, with most deterioration in patients with older age at disease onset [21, 22], with longer disease duration [21, 23], and in individuals with more severe motor [23] or cognitive impairment at baseline [23, 24]. Patients with tremor-dominant PD appear to have a more favourable course, in contrast to those with postural instability and gait disturbance [25]. Data from placebo groups of randomised controlled intervention trials of 6–18 months duration provide information on the progression of symptoms in the natural course of PD without therapy [26–32]. In these trials, placebo-treated patients with early PD showed an annual decline of 5.5 to 14 points in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS). It is notable that there appears to be a trend for more recent studies to report lower progression scores. For instance, the ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) and PROUD (PRamipexole On Underlying Disease) studies had an annualised progression of 6.2 and 5.5 UPDRS points, respectively. This may simply reflect a greater proportion of patients with a slower rate of progression being included in these trials. Indeed, both were delayed-start studies that anticipated that patients could remain on placebo for 9 months. Thus, there was an inherent bias towards the inclusion of slower progressing patients. This may also be reflected in the UPDRS score: those with a lower score progressed more slowly [33]. Observational clinical studies have shown that UPDRS motor scores decline by 5.1 % per annum [34]. Slower loss in later disease is suggested by neuropathological studies and serial positron emission tomographic (PET) measurements of putaminal 18F-fluorodopa uptake indicating a negative exponential loss of dopaminergic neurons in the course of PD [35–37]. Since the rates of initial symptom

M. Lo¨hle et al.

progression exceed the minimal change on the UPDRS that has been shown to represent a clinically meaningful difference in early PD [38], patients are likely to notice a significant worsening of their symptoms even if treatment is only delayed in the first year after diagnosis. This was seen in the PROUD study, where there was a difference in quality of life between the treated (pramipexole 1.5 mg daily) and placebo groups that was significantly different at 9 months, with a total UPDRS difference of 4.8 [32]. If physicians decide to initiate symptomatic treatment early they have the choice between three classes of pharmacological agents: the dopamine precursor levodopa, dopamine receptor agonists and monoamine oxidase type B (MAO-B) inhibitors [39]. Clinical trials have provided information regarding the symptomatic efficacy of these drug classes in early PD (Table 1), although we emphasise that direct comparison between studies is difficult given the differences in population, study designs, etc. Levodopa remains the gold standard for anti-parkinsonian treatment, with superior symptomatic efficacy in comparison with dopamine agonists [40, 41] and MAO-B inhibitors [42]. Although the primary aim in early PD is to improve motor function, there are some reports that the agents used in early disease may also benefit non-motor problems [43– 45]. Initiation of levodopa treatment leads to a significant amelioration of motor symptoms, which in clinical studies has been illustrated by a decrease of up to 8 points on the UPDRS part III, depending on dose (Table 1). Slightly smaller, but still clinically meaningful symptomatic effects of about 5 points can be achieved by treatment with modern dopamine agonists, although varying dosages and treatment protocols limit direct comparison between individual studies [41, 46–51]. Although the data in Table 1 provide only an approximate guide to relative drug efficacies, it is notable that in those trials comparing initiation of levodopa with dopamine agonists, patients on dopamine agonists were deemed by the investigators to be as adequately treated as those in the levodopa arm. Those requiring greater symptom relief could have either received a higher dose of dopamine agonist or been given levodopa. Therefore, the difference between the arms in favour of levodopa may speak in part to the limitations of the UPDRS in capturing all of the benefits of dopamine agonist therapy. This may have included an antidepressant effect of dopamine agonists [52] that was not seen with levodopa. Moreover, initial monotherapy with dopamine agonists has also been shown significantly to decrease the incidence of dyskinesias and motor fluctuations [53, 54]. This reduction or delay in the incidence of dyskinesias with dopamine agonists may reflect either a more sustained activation of dopamine receptors due to their longer half-life [55–57], or a levodopa-sparing effect, or both [58]. Patients can be

Early vs. Delayed Initiation of Pharmacotherapy in PD

647

Table 1 Symptomatic efficacy of anti-parkinsonian agents in patients with early Parkinson’s disease Substance

Study reference

N

Treatment length

Dose (mg/day)

Change vs. baseline (UPDRS part III)

Change vs. placebo (UPDRS part III)

Levodopa Levodopa

Rascol et al. [41]

6 months

464 (mean)

-8.4

n/a

Parkinson Study Group [40]

150

89

23.5 months

509 (mean)

-7.3

n/a

Shannon et al. [47]

164

31 weeks

3.8 (mean)

-4.7

-6.0

Hauser et al. [51]

103

18 weeks

3.03 (mean)

-5.9

-3.2

Poewe et al. [48] Schapira et al. [32]

213 262

33 weeks 36 weeks

2.9 (mean) 1.5 (mean)

-6.4 -0.6

-5.3 -3.3

Hauser et al. [51]

106

18 weeks

3.05 (mean)

-5.9

-3.2

Poewe et al. [48]

223

33 weeks

2.9 (mean)

-6.1

-5.0

Rascol et al. [41]

179

6 months

9.7 (mean)

-5.8

n/a

Dopamine agonists Pramipexole IR

Pramipexole ER Ropinirole IR

Singer et al. [46]

205

40 weeks

0.75–24

-4.34

-4.12

Ropinirole ER

Stocchi et al. [135]

140

12 weeks

18 (mean)

-10.4

n/a

Rotigotine

Giladi et al. [49]

215

37 weeks

2–8

-5.2

-3.1

Watts et al. [50]

181

6 months

5.7 (mean)

-3.5

n/a

81

3 months

10

-1.1

-1.5

MAO-B inhibitors Selegiline

Pa˚lhagen et al. [61]

Rasagiline

Parkinson Study Group [29] Olanow et al. [30]

134

26 weeks

1

n/a

-2.71

132

26 weeks

2

n/a

-1.68

286

36 weeks

1

-0.35

-1.88

290

36 weeks

2

-0.19

-2.18

ER extended release, IR immediate release, MAO-B monoamine oxidase type B, N number of patients in the specific treatment arm, n/a not applicable, UPDRS Unified Parkinson’s Disease Rating Scale

controlled on dopamine agonist monotherapy with estimates of 50 % still on monotherapy at 2 years [40]. Longterm follow-up of dopamine agonist studies indicate that, although delay in onset of dyskinesias may be prolonged, troublesome dyskinesias are uncommon even in those initiated on levodopa [54, 59, 60]. Motor function and activities of daily living (ADL) scores are comparable, although the 14-year study with bromocriptine favoured levodopa [59]. Compared with levodopa and dopamine agonists, MAOB inhibitors exhibit less symptomatic effect [26, 61–64]. However, clinical studies were able to demonstrate that early treatment with MAO-B inhibitors is capable of delaying the need to start with levodopa in PD patients [26, 61–64] and that primary treatment with the MAO-B inhibitor selegiline may reduce the incidence of motor fluctuations compared with placebo [65] as well as with levodopa treatment [66]. Long-term studies with selegiline, however, have shown increased rates of dyskinesias in those initiated on the drug [67]. Long-term data for rasagiline and the incidence of dyskinesias are not available [30]. The symptomatic benefits of an early initiation of pharmacotherapy, however, need to be weighed against the

adverse effects of anti-parkinsonian agents. While generally well-tolerated and safe, levodopa treatment is known to be associated with nausea, dizziness, insomnia, somnolence and headache [28, 40, 41]. Moreover, about 30–40 % of patients experience wearing-off 5 years after the onset of levodopa treatment [52, 68]. Most importantly, levodopa therapy has shown to be associated with involuntary movements in about 50 % of patients treated for 5 years [52, 69], which has prompted many physicians to delay levodopa treatment and to initiate treatment with other anti-parkinsonian agents. Patients with onset of PD younger than age 55 years and females have a significantly greater risk of dyskinesias. The longer duration of disease and the greater the levodopa dose (especially per kg) all enhance dyskinesia risk. These observations have recently been confirmed in analyses of the STRIDE-PD (Stalevo Reduction in Dyskinesia Evaluation in Parkinson’s Disease) study [70]. This randomised controlled study compared the initiation of levodopa with levodopa-carbidopaentacapone (LCE, StalevoÒ) to determine if there was a difference in the incidence of motor complications (fluctuations, dyskinesias) between the two groups. StalevoÒ use was associated with a greater rate of incidence of motor complications. The most important determining risk factors

648

for the development of dyskinesias were levodopa dose ([400 mg/day), age (younger [ older), weight, sex (women [ men) and higher UPDRS II scores [71]. This analysis has enabled a risk calculator model to be developed to estimate the chances of a patient developing dyskinesias within 3 years [72]. Although females have a greater risk for dyskinesias, in clinical practice they take less levodopa than males [73], although this may reflect their lower average weight and therefore a similar dose/kg as males. It is not known if duration of levodopa dose per se is a risk factor for motor complications, or merely a surrogate marker of disease progression and severity. The STRIDE-PD risk assessment cannot predict the severity of dyskinesias, although it is likely that within the 3-year time frame of the evaluation, they are more than likely to be non-troublesome. The issue of severity of dyskinesias and their division into troublesome and non-troublesome is a complex issue. Many patients much prefer to be on than off and will tolerate what to the physician appear to be very intrusive dyskinesias [74, 75]. On the other hand, the patient’s carer is often more disconcerted than the patient given the potential social impact of the involuntary movements. Patients remain responsive to levodopa in latestage disease even after the onset of complications, and oral therapy may be combined with parenteral forms of treatment or deep brain stimulation (DBS) to help reduce dyskinesias [76]. Adverse effects are also frequently seen during treatment with dopamine agonists, which can cause nausea, somnolence, dizziness and oedema as well as neuropsychiatric problems, such as hallucinations, anxiety and impulse control disorders [4, 41, 53], with possible ethnic influences on the latter [77]. Dopamine agonists are also associated with sedation [78] and, in the case of ergot dopamine agonists, cardiac value fibrosis [79], and potential interactions with co-morbidities need to be considered [80–82]. MAO-B inhibitors are generally well-tolerated, including in the elderly [83, 84], which may favour their use in early PD, particularly in those patients with mild symptoms [85]. However, there is the potential for MAO-B inhibitors to have drug interactions, limiting, for instance, the use of antidepressants (although this does not appear to be a limitation in practice other than with fluoxetine) and the induction of the serotonin syndrome [86]. In addition to the adverse effects of anti-parkinsonian agents, another concern about early initiation of pharmacotherapy may be the relatively transient nature of motor improvement in comparison to baseline. In the ELLDOPA (Earlier versus Later Levodopa Therapy in Parkinson Disease) trial, levodopa treatment with 150, 300 or 600 mg/day led to a significant improvement of the total UPDRS score in comparison with placebo and baseline in a dose-dependent manner [28]. However, the symptomatic

M. Lo¨hle et al.

improvement to baseline in patients treated with the lower levodopa doses of 150 and 300 mg/day was of limited duration in this study, since these patient groups were back to their baseline UPDRS scores after 24 and 40 weeks of treatment, respectively. As levodopa treatment in early PD patients in clinical practice is often initiated at lower doses in order to prevent known long-term consequences such as dyskinesia and motor fluctuations, one may argue that even initiation of treatment with the most effective anti-parkinsonian agent is only capable of reversing PD symptoms temporarily before the ongoing underlying disease process eventually leads again to a progression of motor symptoms. Taking into account the magnitude of initial symptomatic effects of monotherapy in early PD and an estimated average progression of treated PD motor symptoms of about 3 points on the UPDRS score part III [87], it can be estimated that the majority of patients will either need higher doses or supplementary treatment within the first 2 years of monotherapy. In summary, early initiation of pharmacotherapy with levodopa, dopamine agonists and MAO-B inhibitors can be expected to result in a significant and, in most circumstances, also clinically meaningful improvement of motor symptoms in PD patients. Although one may argue that effects of symptomatic treatment in early PD should be reserved for a stage of greater motor impairment and that the worsening of motor impairments could still be reversed by a later initiation of pharmacological treatment, it should also be noted that disability has been shown to deteriorate continuously with advancing stages [8], and once developed may not be entirely reversed by delayed symptomatic treatment. The PROUD study showed that simply delaying initiation of treatment by 6–9 months resulted in a significant decline in motor function and quality-of-life measures, although patients who were then given pramipexole caught up with the earlier starters at 15 months for all these parameters [32]. At a practical level, delaying the initiation of therapy may deprive the patient of an opportunity for improved symptom control and better quality of life during the early phase of the disease. Ease of use as well as tolerability is important to patients when first starting treatment. Once-daily preparations are available for the MAO-B inhibitors and dopamine agonists [48, 49, 51, 88–94]. Studies demonstrate that such oncedaily preparations are preferred by patients compared with the same drug delivered by multiple daily dosing, and can be switched easily and overnight without titration [92–95]. Recent studies have shown that DBS may provide substantial benefit to patients in terms of motor control and quality of life, and it has been proposed that this treatment may reasonably be offered earlier in the course of PD than currently [96]. The multicentre EARLYSTIM (Controlled Trial of Deep Brain Stimulation in Early Patients with

Early vs. Delayed Initiation of Pharmacotherapy in PD

Parkinson’s Disease) trial comparing early DBS given at a mean of 7.5 years after diagnosis with best medical therapy has recently been published [97]. Subthalamic nucleus (STN) DBS was performed in 120 PD patients and compared with 127 patients in the medical therapy group. Mean age was 52 years, levodopa therapy duration was 4.9 years, and fluctuations and/or dyskinesias had been present for 1.5 or 1.7 years, respectively. The primary endpoint was quality of life at 24 months as determined by the Parkinson’s Disease Questionnaire (PDQ), and showed an 8-point difference in favour of the STN group. PDQ-39 benefit in the STN group was evident at 5 months, with a 10-point improvement over medical therapy. There were additional benefits for the STN group in relation to motor function, ADL, and levodopa-related motor complications. Serious adverse events occurred in 54.8 % of the STN group (17.7 % device-related) and 44.1 % of the medical group. These data are very encouraging, although DBS is unlikely to be a treatment to be considered at initiation of therapy for PD.

3 Effects of Early and Delayed PD Treatment on Disease Progression In recent years, increasing evidence from clinical trials with levodopa [28], dopamine agonists [98, 99] and MAOB inhibitors [30, 100, 101] has suggested that pharmacological intervention in PD may have a disease-modifying effect. Supported by these studies, it has been proposed that early dopaminergic support may lead to a correction of basal ganglia abnormalities caused by dopaminergic cell loss and dopamine deficiency, support intrinsic physiological compensatory mechanisms and delay the irreversible modification of basal ganglia circuitry characterising the clinical progression of PD [8]. If this hypothesis is correct, treatment for PD should be initiated soon after diagnosis, when it is estimated about 50 % of the dopaminergic neurons in the substantia nigra are still intact [36]. In the following sections, we discuss the clinical evidence for potential disease-modifying effects of levodopa, dopamine agonists and MAO-B inhibitors, which are licensed and widely used for symptomatic treatment in early PD patients. 3.1 Levodopa Potential disease-modifying effects of levodopa were examined in the ELLDOPA trial, in which 361 patients with early PD were randomly assigned to treatment with placebo, 150 mg of levodopa daily, 300 mg of levodopa daily or 600 mg of levodopa daily for 40 weeks, followed by a washout period of 2 weeks [28] (Table 2). The

649

primary outcome measure was the change in the total UPDRS scores between baseline and 42 weeks. Additionally, 142 study individuals underwent single photon emission computerised tomography (SPECT) imaging with the iodine-123-labeled radiotracer 2-beta-carboxymethoxy-3beta-(4-iodophenyl)tropane (123I-b-CIT), which was used as a marker for the dopamine transporter on remaining intact dopaminergic neurons. Levodopa treatment led to a dose-dependent improvement in the total UPDRS scores in all three actively treated groups. Despite a sharp deterioration during the washout period, the total UPDRS scores of the three levodopa-treated groups were still significantly lower than those of placebo-treated patients. These data might suggest that levodopa has a symptomatic effort extending beyond the washout or that levodopa has a disease-modifying effect. The neuroimaging data in ELLDOPA revealed that the mean percentage decline in 123I-b-CIT uptake was significantly greater in levodopa- than in placebo-treated patients, which indicates that levodopa either accelerates the loss of nigrostriatal dopamine nerve terminals or modifies the dopamine turnover by its pharmacological effect [102, 103]. External validation of the ELLDOPA data by clinical trial simulation has suggested that although the washout period was not adequate to eliminate completely symptomatic benefits, levodopa treatment was still capable of slowing the progression of the disease [104]. Due to the uncertainties arising from the trial design and the discordance of the clinical results and the radiotracer imaging, the ELLDOPA trial was unable to define whether levodopa treatment has beneficial effects on disease progression. 3.2 Dopamine Agonists There are substantial laboratory data supporting a neuroprotective effect of dopamine agonists [105]. The diseasemodifying potential of dopamine agonists has been examined in two large trials, which both combined clinical measures and radionuclide imaging to determine whether the non-ergoline dopamine agonists pramipexole and ropinirole would be neuroprotective in comparison with levodopa treatment (Table 2). In the CALM-PD (Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications of Parkinson’s Disease) trial, 301 patients with early PD were randomly assigned to initial treatment with pramipexole or levodopa [40, 99]. A subgroup of 82 patients underwent 123I-b-CIT SPECT imaging at baseline as well as after 22, 34 and 46 months of treatment. The primary outcome of this study was the percentage change from baseline in striatal 123I-b-CIT uptake after 46 months. Similarly, the REAL-PET (ReQuip as Early Therapy versus L-dopa positron emission

M. Lo¨hle et al.

650 Table 2 Large clinical trials examining potential disease-modifying effects of licensed anti-parkinsonian agents Substance

Study

N

Treatment length

Outcome parameters

Outcome

Levodopa Levodopa

123

Inconclusive

18

F-DOPA uptake

Inconclusive

I-b-CIT uptake

Inconclusive

ELLDOPA [28]

361

40 months

Total UPDRS (substudy:

REAL-PET [98]

186

24 months

Putaminal

I-b-CIT uptake)

Dopamine agonists Ropinirole Pramipexole

123

CALM-PD [99]

301

46 months

Striatal

PROUD [31]

535

15 months

Total UPDRS (substudy: DatSCAN uptake)

Negative

MAO-B inhibitors Selegiline

DATATOP [110]

800

Variable

Time to supplementary levodopa treatment

Inconclusive

Rasagiline

TEMPO [101]

404

12 months

Total UPDRS

Positive

ADAGIO [30]

1,176

72 weeks

Total UPDRS

123

Inconclusive 18

18

I-b-CIT iodine-123-labeled radiotracer 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane, F-DOPA F-3,4-dihydroxyphenylalanine, MAO-B monoamine oxidase type B, N number of randomised study participants, UPDRS Unified Parkinson’s Disease Rating Scale

tomography) trial used 18F-3,4-dihydroxyphenylalanine (18F-DOPA) PET analysis to measure disease progression in 186 patients, who were randomised to ropinirole or levodopa treatment [98]. The primary outcome measure of the REAL-PET trial was the reduction in putaminal 18FDOPA uptake between baseline and 2 years of treatment. The CALM-PD and the REAL-PET trials showed a slower loss of the respective imaging ligand with pramipexole and ropinirole than with levodopa. Although these results would be in keeping with a neuroprotective property of dopamine agonists, both trials were limited by the absence of a placebo arm and the trial designs could not account for possible drug effects on radionuclide tracer handling [106]. More recently, the PROUD study used a delayed-start onset trial design to investigate the disease-modifying effects of pramipexole in early PD patients [31]. The PROUD study was based on experimental data demonstrating protective properties of pramipexole in a range of model systems including non-human primates [107–109]. In PROUD, 535 untreated PD patients were randomly assigned to be uptitrated to 1.5 mg/day of pramipexole or matching placebo and maintained on the study drug for 6–9 months. In the second phase of this trial, all patients were uptitrated to 1.5 mg/day of pramipexole and maintained on the dopamine agonist until the end of the trial at 15 months. The primary outcome of this trial was the change in the total UPDRS from baseline to 15 months. A substudy investigated the change in striatal dopamine transporter imaging using SPECT uptake from baseline to the end of the study. The PROUD study did not meet its primary endpoint in that patients initiated on pramipexole at the start of the study or at 6–9 months had no significant difference in UPDRS at 15 months. There was also no change in the transporter imaging by SPECT between groups at endpoint [32]. At the end of the placebo-controlled phase, pramipexole-treated patients showed significantly less motor impairment (-4.8 UPDRS units) and an

improved quality of life on the PDQ-39 than placebotreated individuals, confirming the symptomatic efficacy of pramipexole as monotherapy in early PD. Taken together, the CALM-PD, REAL-PET and PROUD studies have failed to provide conclusive evidence for a disease-modifying effect of dopamine agonists in early PD. 3.3 Monoamine Oxidase Type B (MAO-B) Inhibitors One of the earliest attempts to assess the neuroprotective effects of anti-parkinsonian agents was the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinson) trial, which investigated disease-modifying capabilities of the MAO-B inhibitor selegiline (deprenyl) in early PD [110] (Table 2). In this trial, 800 untreated PD patients were randomised into four treatment arms: (1) tocopherol placebo and selegiline placebo; (2) 2,000 IU/ day tocopherol and selegiline placebo; (3) tocopherol placebo and 10 mg/day selegiline; and (4) 2,000 IU/day tocopherol and 10 mg/day selegiline. The primary endpoint of the study was the time to the onset of disability necessitating levodopa treatment. After an interim analysis had already shown that selegiline treatment reduced the risk of reaching the endpoint by 57 % [110], subsequent follow-up revealed that selegiline-treated patients required levodopa 9 months later than individuals who were not randomised to selegiline treatment [26]. A second, independent randomisation of 368 DATATOP subjects who had required levodopa showed that patients treated with selegiline for up to 7 years experienced slower motor decline than individuals who were changed to placebo after about 5 years of selegiline treatment [100]. Although one may argue that these beneficial effects of selegiline may have been caused by symptomatic rather than neuroprotective properties, pharmacodynamic modelling of the DATATOP study has provided evidence for a slowing of disease progression with selegiline treatment [111]. Moreover, the DATATOP

Early vs. Delayed Initiation of Pharmacotherapy in PD

findings have been supported by similar observations in other clinical studies, which also suggested a diseasemodifying effect of selegiline treatment in early PD [61, 63, 112, 113]. More recently, two large clinical trials have used the delayed-start onset design in order to investigate the disease-modifying effects of rasagiline (N-Propargyl1[R] aminoindan or TVP-1012), a highly selective secondgeneration MAO-B inhibitor (Table 2). In the TEMPO (TVP-1012 in early monotherapy for PD outpatients) study, 404 patients with early PD were randomised to one of three treatment groups: (1) 1 mg/day rasagiline for 1 year; (2) 2 mg/day rasagiline for 1 year; or (3) placebo for 6 months followed by 2 mg/day rasagiline for 6 months [101]. The primary outcome measure was the change in total UPDRS score from baseline to 12 months. After 1 year, patients who were treated with 2 mg/day rasagiline from the beginning had a significantly smaller increase in the mean adjusted total UPDRS score than subjects in whom treatment with 2 mg/day of rasagiline was delayed for 6 months (-2.29 UPDRS units; P = 0.01). A similar trend was observed between the delayed treatment group and those receiving 1 mg/day of rasagiline from the beginning (-1.82 UPDRS units; P = 0.06). These findings were supported by results of an open-label extension in 306 participants of the TEMPO study, which revealed that early initiation of rasagiline provided long-term clinical benefit over 5 years, even in the face of treatment with other dopaminergic agents [114]. Although one needs to account for a potential differential dropout of placebo-treated patients [115, 116], the questionable clinical meaningfulness of the small differences and potential methodological shortcomings of the delayed-start onset trial design [117], the TEMPO trial has supported the view that earlier as opposed to later initiation of rasagiline had benefit over the duration of study. The ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) study investigated the diseasemodifying potential of rasagiline in 1,176 subjects with untreated PD [30]. Patients were randomised to rasagiline at a dose of either 1 or 2 mg/day for 72 weeks (the earlystart groups) or corresponding placebo for 36 weeks followed by rasagiline 1 or 2 mg/day for 36 weeks (the delayed-start groups). Three hierarchical endpoints had to be met by the early-start treatment group in order to declare positive results with either dose: superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36; superiority to delayed-start treatment in the change in the score between baseline and week 72; and non-inferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72. Early-start treatment with rasagiline 1 mg/day met all endpoints in the primary analysis, compatible with a disease-modifying effect of early

651

treatment with this dose in comparison to delayed treatment [30]. At the end of the study, patients treated with rasagiline 1 mg/day from the beginning had gained an advantage of -1.7 UPDRS units in comparison to those individuals in whom the same treatment was initiated with a delay of 9 months. However, the three predefined endpoints were not met with rasagiline at a daily dose of 2 mg, since the change in the UPDRS score between baseline and week 72 was not significantly different between the earlyand the delayed-start onset group for this dose [30]. The different outcome between the 1 and 2 mg doses makes interpretation of the results of the ADAGIO study difficult. In order to find out whether symptomatic effects of rasagiline 2 mg/day may have masked disease-modifying effects in patients with very mild disease, the ADAGIO investigators have performed a post hoc subgroup analysis comparing the treatment outcome in patients with a higher baseline UPDRS score ([25.5 units) with those patients with a lower UPDRS score. Indeed, this analysis revealed that the second endpoint was met in those subjects who were in the highest quartile of UPDRS scores at baseline, which supports the hypothesis of the ADAGIO investigators that any neuroprotective benefits of rasagiline 2 mg/ day were potentially masked by its symptomatic effects [30, 33]. Nonetheless, an application for a disease-modifying effect of rasagiline was rejected by the US Food and Drug Administration in 2011.

4 Effects of Early and Delayed PD Treatment on Quality of Life Aside from the effects of early or delayed treatment on parkinsonian symptoms and the course of the disease, it is crucial to define whether the timing of therapy also makes a difference for the quality of life of the patients. Given the importance of this question, it seems rather surprising that so few studies have aimed to compare the effect of treatment onset on the quality of life in early PD patients. A multicentre longitudinal observational study [118] investigated changes in the self-reported health status in 198 drug-naı¨ve PD patients over a mean period of 18 months using the PD-specific quality-of-life questionnaire PDQ-39 [118]. In this study, 61 and 32 % of patients were still untreated at follow-up after 9 and 18 months, respectively, whereas the remaining patients had been started on monotherapy with levodopa, dopamine agonists or other anti-parkinsonian agents. In patients who remained untreated, there was a progressive deterioration in the PDQ-39 scores at the first follow-up after 9 months with further worsening at the second follow-up after 18 months [118]. This deterioration was not only observed in the motor domains, but also affected non-motor domains of the

652

PDQ-39, such as cognition, bodily discomfort, emotional well-being and communication. In those patients in whom treatment was initiated between the first and the second follow-up consultation, the trend to deterioration in the PDQ-39 between baseline and the first follow-up could be arrested and partially improved following initiation of treatment. While age, Hoehn and Yahr score, co-morbidity and sociodemographic profile were similar between untreated and treated patients in this prospective study, the rate of depression was significantly higher in the treated group, which indicates that the decision to initiate treatment may not always purely be based on functional disability. Although this study may be criticised for incomplete follow-up, the lack of randomisation and the absence of UPDRS scoring as measure for motor impairment, it demonstrated in a natural setting that a delay in treatment of PD is associated with a clinically significant worsening in the quality of life in patients with early PD. Different results have been obtained in a smaller study that investigated the self-reported health status in a prospective cohort of 42 patients with incident PD by assessing the PDQ-39 over a period of 2 years [119]. After the baseline assessment, 26 patients started to take medication within the first year of the study, whereas the remaining 16 patients did not receive any anti-parkinsonian medication during the 2-year follow-up period. Patients who were provided with treatment, however, already had worse disease at baseline, as indicated by significantly higher UPDRS, Hoehn and Yahr and PDQ-39 scores. In this study, there was no significant difference in the change in the PDQ-39 summary index between drug-naı¨ve and treated patients, although untreated patients showed significantly greater worsening in the PDQ-39 domains stigma and ADL and, as expected, had to endure an objective deterioration in motor impairment on the UPDRS. The interpretation of the study results is limited by its small sample size and the higher baseline impairment in treated patients, which ultimately will lead to a bias in the comparison of both groups.

5 Economic Consequences of Early and Delayed Pharmacological Intervention in PD Due to the high prevalence of PD, the decreased ability of affected patients to work and the increased need for care and costly treatment, PD poses an enormous burden on healthcare systems, society, patients and their caregivers. The economic cost of PD escalates as the disease progresses and in the UK has been estimated to total between £449 million and £3.3 billion annually [120]. In a recent survey in six European countries, semi-annual costs per PD patient have been estimated to range from €2,620 to €9,820

M. Lo¨hle et al.

[121], and the mean annual costs in Germany have shown to total €20,095 per patient [2]. In times of growing economic pressure on healthcare systems worldwide, the decision to initiate anti-parkinsonian treatment in a patient will therefore increasingly also be dependent on cost effectiveness, since physicians need to justify their treatment plans to regulatory bodies and health insurance companies. The cost effectiveness of pharmacological interventions is nowadays commonly analysed by calculating the gain in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) per QALY. Recently, a prospective, population-based cohort study in 199 patients with newly diagnosed PD has shown that drug treatment is able to significantly increase health state values in early PD, but also revealed a high ICER of €45,259 per QALY [122]. Clarke et al. have estimated that immediate treatment of PD patients at diagnosis would lead to an additional cost of £3.2 million per year for the UK and have argued that there is no scientific evidence that this would be a cost-effective policy change [10]. However, the studies above and others [123] indicate that drug costs, especially early in the disease, are very small compared with the cost of care in late disease, and relieving disease burden in the patient and carer may more than compensate both in the short- and long-term for this cost. A Finnish questionnaire study in 937 working-aged PD patients found that only 16 % were still working and that PD patients had retired on average 6 years earlier than the age-matched general population [124]. Immediate or early treatment with anti-parkinsonian agents at the point of diagnosis could therefore still be cost effective if it were able to prevent or delay loss of productivity, hospitalisations or long-term care. Although there are no studies directly comparing the cost effectiveness of immediateand delayed-onset of pharmacotherapy in early PD, there are some indirect indications that early intervention with anti-parkinsonian agents may be helpful to reduce the indirect costs associated with PD. For example, an interim analysis of the DATATOP study, which has already been discussed above in detail, revealed that early treatment with 10 mg of selegiline significantly reduced the risk of having to give up full-time employment [110]. A delay of symptomatic treatment can conversely be expected to result in higher scores on the UPDRS, which have been identified as a cost-driving factor for total costs, direct costs and patient expenditure [2]. The potential cost-saving benefits of early initiation of anti-parkinsonian treatment, however, needs to be weighed against the costs of potential long-term complications of pharmacotherapy. For example, levodopa treatment in lateand young-onset PD patients is associated with a respective annual risk of 10 and 20 % for motor complications [125],

Early vs. Delayed Initiation of Pharmacotherapy in PD

which are associated with higher total costs [2]. To achieve a cost-effective treatment for PD patients in the long run, the initial selection of anti-parkinsonian agents is therefore of crucial importance and needs to be tailored to the individual characteristics of the patient, such as age, comorbidity, disease severity, employment status and quality of life [126, 127]. In younger and cognitively fit patients, MAO-B inhibitors and dopamine agonists should be considered in order to delay the onset of motor complications associated with the long-term use of levodopa. Conversely, levodopa may be the better choice for older patients, in whom the risk for motor complications is relatively lower and neuropsychiatric adverse effects of dopamine agonists or MAO-B inhibitors are more likely to occur [128]. Aside from an informed selection of initial pharmacotherapy, it is advisable to titrate anti-parkinsonian agents according to the actual clinical status of the individual patient in order to achieve an optimal cost–benefit relationship of the therapy and to reduce the incidence of adverse effects that are more likely to occur with high-dose treatments, such as excessive daytime sleepiness with dopamine agonists. Whenever possible, once-daily formulations should be preferred since they have been shown to be associated with a higher adherence to anti-parkinsonian therapy [44, 84, 88, 90, 129–131]. Although there is presently no direct proof that an onset of PD therapy at or soon after diagnosis is more cost effective than a delayed start of treatment, there is much indirect evidence that in the majority of patients this strategy is superior from an economic point of view, since it is more likely to maintain the patient’s socioeconomic status, prevent the loss of employment and independence and, hence, will potentially be able to save indirect costs, e.g. by delaying premature retirement. Conversely, a delayed onset of treatment may save the relatively modest direct costs of pharmacotherapy for 1 or at most 2 years, but at a cost of greater disability and hence a potential loss of employment in younger patients, which is unlikely to be reversed even if secondary improvement is achieved after the start of treatment. Moreover, careful titration of antiparkinsonian treatment may be more difficult once significant disability has already developed since physicians may feel driven to increase the medication dosages more rapidly in order to ensure a rapid improvement of motor dysfunction.

6 Conclusions Early initiation of pharmacotherapy in PD is able to ameliorate emerging motor symptoms of the disease, improves quality of life and may be cost effective by maintaining the productivity of affected patients. Several clinical studies

653

support the hypothesis that early pharmacological intervention with symptomatically active anti-parkinsonian agents may slow down the clinical progression of PD. Delayed initiation of PD treatment may spare patients the adverse effects of anti-parkinsonian medication in the beginning and may be helpful to reduce direct costs for health systems during the initial phase of PD, but may also be associated with a greater disability and a higher risk for productivity loss, and, hence, potentially be more costly to patients and society in the long-term. Of course, the introduction of therapy confirmed to slow the progression of PD will have the greatest economic as well as clinical benefit [132]. Eventually, the decision of when and how to initiate pharmacotherapy needs to be based on the individual characteristics of the patient and should be made after a detailed discussion about potential benefits and risks of the intended pharmacological intervention. It should not be forgotten that after the introduction of levodopa, studies in PD patients have been able to show clearly that early pharmacological intervention is capable of significantly reducing the mortality of PD [133, 134]. In our opinion, early initiation of pharmacotherapy at or soon after diagnosis should be advocated in order to allow PD patients to maintain their quality of life and secure their socioeconomic status as long as possible. Conflict of interest M. Lo¨hle has been funded by a research grant of the Center for Regenerative Therapies Dresden and received honoraria for presentations from Boehringer Ingelheim, GlaxoSmithKline and UCB Pharma. A.H.V. Schapira is an NIHR Senior Investigator. He has received honoraria for educational symposia and consultancy from Boehringer Ingelheim, Teva-Lundbeck, UCB, Merz, Merck and Orion-Novartis. H. Reichmann has acted on the Advisory Board and gave lectures and received research grants from Abbott, Bayer Healthcare, Boehringer Ingelheim, Brittania, Cephalon, Desitin, GSK, Lundbeck, Merck-Serono, Novartis, Orion, Pfizer, TEVA, UCB Pharma and Valeant. C.-J. Ramberg has no conflicts of interest to declare. No funding was provided to support the preparation of this manuscript.

References 1. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–6. 2. Winter Y, Balzer-Geldsetzer M, Spottke A, Reese JP, Baum E, Klotsche J, et al. Longitudinal study of the socioeconomic burden of Parkinson’s disease in Germany. Eur J Neurol. 2010;17(9):1156–63. 3. Muller T, Woitalla D. Quality of life, caregiver burden and insurance in patients with Parkinson’s disease in Germany. Eur J Neurol. 2010;17(11):1365–9. 4. Bauso DJ, Tartari JP, Stefani CV, Rojas JI, Giunta DH, Cristiano E. Incidence and prevalence of Parkinson’s disease in Buenos Aires City, Argentina. Eur J Neurol. 2012;19(8):1108–13.

654 5. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology. 2001;57(8):1497–9. 6. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol. 1993;50(2):140–8. 7. Berardelli A, Wenning GK, Antonini A, Berg D, Bloem BR, Bonifati V, et al. EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol. 2013;20(1):16–34. 8. Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol. 2006;59(3):559–62. 9. Aminoff MJ. Treatment should not be initiated too soon in Parkinson’s disease. Ann Neurol. 2006;59(3):562–4. 10. Clarke CE, Patel S, Ives N, Rick C, Wheatley K, Gray R. Should treatment for Parkinson’s disease start immediately on diagnosis or delayed until functional disability develops? Mov Disord. 2011;26(7):1187–93. 11. Ferreira JJ, Katzenschlager R, Bloem BR, Bonuccelli U, Burn D, Deuschl G, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson’s disease. Eur J Neurol. 2013;20(1):5–15. 12. Birkmayer W, Hornykiewicz O. The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia [in German]. Wien Klin Wochenschr. 1961;10(73):787–8. 13. Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5(3):235–45. 14. Becker C, Brobert GP, Johansson S, Jick SS, Meier CR. Risk of incident depression in patients with Parkinson disease in the UK. Eur J Neurol. 2011;18(3):448–53. 15. Barone P. Treatment of depressive symptoms in Parkinson’s disease. Eur J Neurol. 2011;18(Suppl 1):11–5. 16. Friedman JH. Is fatigue in early Parkinson’s disease a minor inconvenience or major distress? The answer is ‘Yes!’. Eur J Neurol. 2012;19(7):931–2. 17. Herlofson K, Ongre SO, Enger LK, Tysnes OB, Larsen JP. Fatigue in early Parkinson’s disease. Minor inconvenience or major distress? Eur J Neurol. 2012;19(7):963–8. 18. Stefansdottir S, Gjerstad MD, Tysnes OB, Larsen JP. Subjective sleep problems in patients with early Parkinson’s disease. Eur J Neurol. 2012;19(12):1575–81. 19. Ceravolo R, Frosini D, Poletti M, Kiferle L, Pagni C, Mazzucchi S, et al. Mild affective symptoms in de novo Parkinson’s disease patients: relationship with dopaminergic dysfunction. Eur J Neurol. 2013;20(3):480–5. 20. Lin CH, Wu RM, Chang HY, Chiang YT, Lin HH. Preceding pain symptoms and Parkinson’s disease: a nationwide population-based cohort study. Eur J Neurol. 2013;20(10):1398–404. 21. Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP. Progression of motor impairment and disability in Parkinson disease: a population-based study. Neurology. 2005;65(9):1436–41. 22. Schapira AH, Schrag A. Parkinson disease: Parkinson disease clinical subtypes and their implications. Nat Rev Neurol. 2011;7(5):247–8. 23. Hely MA, Morris JG, Reid WG, O’Sullivan DJ, Williamson PM, Broe GA, Adena MA. Age at onset: the major determinant of outcome in Parkinson’s disease. Acta Neurol Scand. 1995;92(6):455–63. 24. Louis ED, Tang MX, Cote L, Alfaro B, Mejia H, Marder K. Progression of parkinsonian signs in Parkinson disease. Arch Neurol. 1999;56(3):334–7. 25. van Rooden SM, Colas F, Martinez-Martin P, Visser M, Verbaan D, Marinus J, et al. Clinical subtypes of Parkinson’s disease. Mov Disord. 2011;26(1):51–8.

M. Lo¨hle et al. 26. The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1993;328(3):176–83. 27. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541–50. 28. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351(24):2498–508. 29. The Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol. 2002;59(12):1937–43. 30. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268–78. 31. Schapira AH, Albrecht S, Barone P, Comella CL, McDermott MP, Mizuno Y, et al. Rationale for delayed-start study of pramipexole in Parkinson’s disease: the PROUD study. Mov Disord. 2010;25(11):1627–32. 32. Schapira AH, McDermott MP, Barone P, Comella CL, Albrecht S, Hsu HH, et al. Pramipexole in patients with early Parkinson’s disease (PROUD): a randomised delayed-start trial. Lancet Neurol. 2013;12(8):747–55. 33. Rascol O, Fitzer-Attas CJ, Hauser R, Jankovic J, Lang A, Langston JW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011;10(5):415–23. 34. Schrag A, Dodel R, Spottke A, Bornschein B, Siebert U, Quinn NP. Rate of clinical progression in Parkinson’s disease. A prospective study. Mov Disord. 2007;22(7):938–45. 35. Hilker R, Schweitzer K, Coburger S, Ghaemi M, Weisenbach S, Jacobs AH, et al. Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity. Arch Neurol. 2005;62(3):378–82. 36. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain. 1991;114(Pt 5):2283–301. 37. Rossi C, Frosini D, Volterrani D, De FP, Unti E, Nicoletti V, et al. Differences in nigro-striatal impairment in clinical variants of early Parkinson’s disease: evidence from a FP-CIT SPECT study. Eur J Neurol. 2010;17(4):626–30. 38. Schrag A, Sampaio C, Counsell N, Poewe W. Minimal clinically important change on the unified Parkinson’s disease rating scale. Mov Disord. 2006;21(8):1200–7. 39. Fox SH, Katzenschlager R, Lim SY, Ravina B, Seppi K, Coelho M, et al. The movement disorder society evidence-based medicine review update: treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2011;26(Suppl 3):S2–41. 40. The Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA. 2000;284(15):1931–8. 41. Rascol O, Brooks DJ, Brunt ER, Korczyn AD, Poewe WH, Stocchi F. Ropinirole in the treatment of early Parkinson’s disease: a 6-month interim report of a 5-year levodopa-controlled study. 056 Study Group. Mov Disord. 1998;13(1):39–45. 42. Caslake R, Macleod A, Ives N, Stowe R, Counsell C. Monoamine oxidase B inhibitors versus other dopaminergic agents in early Parkinson’s disease. Cochrane Database Syst Rev. 2009;(4):CD006661. 43. Chaudhuri KR, Schapira AHV. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8:464–74.

Early vs. Delayed Initiation of Pharmacotherapy in PD 44. Chauchuri KR, Martinez-Martin P, Rolfe KA, Cooper J, Rockett CB, Giorgi L, Ondo WG. Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease. Eur J Neurol. 2012;19(1):105–13. 45. Miah IP, OldeDubbelink KT, Stoffers D, Deijen JB, Berendse HW. Early-stage cognitive impairment in Parkinson’s disease and the influence of dopamine replacement therapy. Eur J Neurol. 2012;19(3):510–6. 46. Singer C, Lamb J, Ellis A, Layton G. A comparison of sumanirole versus placebo or ropinirole for the treatment of patients with early Parkinson’s disease. Mov Disord. 2007;22(4):476–82. 47. Shannon KM, Bennett JP Jr, Friedman JH. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson’s disease. The Pramipexole Study Group. Neurology. 1997;49(3):724–8. 48. Poewe W, Rascol O, Barone P, Hauser RA, Mizuno Y, Haaksma M, et al. Extended-release pramipexole in early Parkinson disease: a 33-week randomized controlled trial. Neurology. 2011;77(8):759–66. 49. Giladi N, Boroojerdi B, Korczyn AD, Burn DJ, Clarke CE, Schapira AH. Rotigotine transdermal patch in early Parkinson’s disease: a randomized, double-blind, controlled study versus placebo and ropinirole. Mov Disord. 2007;22(16):2398–404. 50. Watts RL, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology. 2007;68(4):272–6. 51. Hauser RA, Schapira AH, Rascol O, Barone P, Mizuno Y, Salin L, et al. Randomized, double-blind, multicenter evaluation of pramipexole extended release once daily in early Parkinson’s disease. Mov Disord. 2010;25(15):2542–9. 52. Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(6):573–80. 53. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med. 2000;342(20):1484–91. 54. The Parkinson Study Group. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol. 2009;66(5):563–70. 55. Olanow W, Schapira AH, Rascol O. Continuous dopaminereceptor stimulation in early Parkinson’s disease. Trends Neurosci. 2000;23(10 Suppl):S117–26. 56. Schapira AH, Tan EK. Optimizing treatment for Parkinson’s disease. Eur J Neurol. 2012;19(12):1483–6. 57. Gershanik O, Jenner P. Moving from continuous dopaminergic stimulation to continuous drug delivery in the treatment of Parkinson’s disease. Eur J Neurol. 2012;19(12):1502–8. 58. Schapira AH, Agid Y, Barone P, Jenner P, Lemke MR, Poewe W, et al. Perspectives on recent advances in the understanding and treatment of Parkinson’s disease. Eur J Neurol. 2009;16(10):1090–9. 59. Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A, Lees AJ. Fourteen-year final report of the randomized PDRGUK trial comparing three initial treatments in PD. Neurology. 2008;71(7):474–80. 60. Hauser RA, Rascol O, Korczyn AD, Jon SA, Watts RL, Poewe W, et al. Ten-year follow-up of Parkinson’s disease patients randomized to initial therapy with ropinirole or levodopa. Mov Disord. 2007;22(16):2409–17. 61. Pa˚lhagen S, Heinonen EH, Hagglund J, Kaugesaar T, Kontants H, Maki-Ikola O, et al. Selegiline delays the onset of disability

655

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78. 79.

80.

in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology. 1998;51(2):520–5. Allain H, Pollak P, Neukirch HC. Symptomatic effect of selegiline in de novo Parkinsonian patients. The French Selegiline Multicenter Trial. Mov Disord. 1993;8(Suppl 1):S36–40. Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science. 1989;245(4917):519–22. Myllyla VV, Sotaniemi KA, Vuorinen JA, Heinonen EH. Selegiline as initial treatment in de novo parkinsonian patients. Neurology. 1992;42(2):339–43. Myllyla VV, Sotaniemi KA, Hakulinen P, Maki-Ikola O, Heinonen EH. Selegiline as the primary treatment of Parkinson’s disease—a long-term double-blind study. Acta Neurol Scand. 1997;95(4):211–8. Caraceni T, Musicco M. Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson’s disease. A randomized multicenter study. Parkinsonism Relat Disord. 2001;7(2):107–14. The Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa. Ann Neurol. 1996;39(1):29–36. Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study. Brain. 2000;123(Pt 11):2297–305. Poewe WH, Lees AJ, Stern GM. Low-dose L-dopa therapy in Parkinson’s disease: a 6-year follow-up study. Neurology. 1986;36(11):1528–30. Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol. 2010;68(1):18–27. Warren OC, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, et al. Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord. 2013;28:1064–71. Schapira AH, Poewe W, Kieburtz K, Rascol O, Stocchi F, Nissinen H, Leinonen M, Olanow CW. Development of a risk calculator based on the STRIDE-PD study for predicting dyskinesia in patients with Parkinson’s disease. Mov Disord. 2012;27(1):s138–S138 (meeting abstract 429). Nyholm D, Karlsson E, Lundberg M, Askmark H. Large differences in levodopa dose requirement in Parkinson’s disease: men use higher doses than women. Eur J Neurol. 2010;17(2):260–6. Van Gerpen JA, Kumar N, Bower JH, Weigand S, Ahlskog JE. Levodopa-associated dyskinesia risk among Parkinson disease patients in Olmsted County, Minnesota, 1976–1990. Arch Neurol. 2006;63(2):205–9. Marras C, Lang A, Krahn M, Tomlinson G, Naglie G. Quality of life in early Parkinson’s disease: impact of dyskinesias and motor fluctuations. Mov Disord. 2004;19(1):22–8. Elia AE, Dollenz C, Soliveri P, Albanese A. Motor features and response to oral levodopa in patients with Parkinson’s disease under continuous dopaminergic infusion or deep brain stimulation. Eur J Neurol. 2012;19(1):76–83. Chiang HL, Huang YS, Chen ST, Wu YR. Are there ethnic differences in impulsive/compulsive behaviors in Parkinson’s disease? Eur J Neurol. 2012;19(3):494–500. Olanow CW, Schapira AH, Roth T. Waking up to sleep episodes in Parkinson’s disease. Mov Disord. 2000;15(2):212–5. Bhattacharyya S, Schapira AH, Mikhailidis DP, Davar J. Druginduced fibrotic valvular heart disease. Lancet. 2009;374(9689):577–85. Haensch CA. Heart trouble comes early in Parkinson’s disease before blood pressure falls. Eur J Neurol. 2011;18(2):201–2.

M. Lo¨hle et al.

656 81. Chong RK, Morgan J, Mehta SH, Pawlikowska I, Hall P, Ellis AV, et al. Rapid assessment of postural instability in Parkinson’s disease (RAPID): a pilot study. Eur J Neurol. 2011;18(2):260–5. 82. Oka H, Toyoda C, Yogo M, Mochio S. Cardiovascular dysautonomia in de novo Parkinson’s disease without orthostatic hypotension. Eur J Neurol. 2011;18(2):286–92. 83. Ives NJ, Stowe RL, Marro J, Counsell C, Macleod A, Clarke CE, et al. Monoamine oxidase type B inhibitors in early Parkinson’s disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ. 2004;329(7466):593. 84. Tolosa E, Stern MB. Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson’s disease. Eur J Neurol. 2012;19(2):258–64. 85. Lohle M, Reichmann H. Controversies in neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson’s disease. BMC Neurol. 2011;11:112. 86. Schapira AHV. Rasagiline in neurodegeneration. Exp Neurol. 2008;212(2):255–7. 87. Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol. 2004;61(7):1044–53. 88. Schapira AH, Barone P, Hauser RA, Mizuno Y, Rascol O, Busse M, et al. Extended-release pramipexole in advanced Parkinson disease: a randomized controlled trial. Neurology. 2011;77(8):767–74. 89. Pahwa R, Stacy MA, Factor SA, Lyons KE, Stocchi F, Hersh BP, et al. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology. 2007;68(14):1108–15. 90. Stocchi F, Giorgi L, Hunter B, Schapira AH. PREPARED: comparison of prolonged and immediate release ropinirole in advanced Parkinson’s disease. Mov Disord. 2011;26(7):1259–65. 91. Poewe WH, Rascol O, Quinn N, Tolosa E, Oertel WH, Martignoni E, et al. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, doubledummy, randomised controlled trial. Lancet Neurol. 2007;6(6):513–20. 92. Rascol O, Barone P, Hauser RA, Mizuno Y, Poewe W, Schapira AH, et al. Efficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson’s disease. Mov Disord. 2010;25(14):2326–32. 93. Schapira AH, Barone P, Hauser RA, Mizuno Y, Rascol O, Busse M, et al. Success rate, efficacy, and safety/tolerability of overnight switching from immediate- to extended-release pramipexole in advanced Parkinson’s disease. Eur J Neurol. 2013;20(1):180–7. 94. Schapira AH, Barone P, Hauser RA, Mizuno Y, Rascol O, Busse M, et al. Patient-reported convenience of once-daily versus three-times-daily dosing during long-term studies of pramipexole in early and advanced Parkinson’s disease. Eur J Neurol. 2013;20(1):50–6. 95. Lim EC. Dosing issues in Parkinson’s disease—patient preferences and their influence on compliance. Eur J Neurol. 2013;20(1):1–2. 96. Desouza RM, Moro E, Lang AE, Schapira AH. Timing of deep brain stimulation in Parkinson disease: a need for reappraisal? Ann Neurol. 2013;73(5):565–75. 97. Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013;368(7):610–22. 98. Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, et al. Slower progression of Parkinson’s disease with

99.

100.

101.

102. 103.

104.

105. 106.

107.

108.

109.

110.

111.

112.

113.

114.

115. 116.

117.

118.

ropinirole versus levodopa: the REAL-PET study. Ann Neurol. 2003;54(1):93–101. The Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA. 2002;287(13):1653–61. Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, et al. Impact of sustained deprenyl (selegiline) in levodopatreated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol. 2002;51(5):604–12. The Parkinson Study Group. A controlled, randomized, delayedstart study of rasagiline in early Parkinson disease. Arch Neurol. 2004;61(4):561–6. Fahn S. Does levodopa slow or hasten the rate of progression of Parkinson’s disease? J Neurol. 2005;252 Suppl 4:IV37–42. Hauser RA, Zesiewicz TA. Clinical trials aimed at detecting neuroprotection in Parkinson’s disease. Neurology. 2006;66(10 Suppl 4):S58–68. Chan PL, Nutt JG, Holford NH. Levodopa slows progression of Parkinson’s disease: external validation by clinical trial simulation. Pharm Res. 2007;24(4):791–802. Schapira AH. Progress in neuroprotection in Parkinson’s disease. Eur J Neurol. 2008;15(Suppl 1):5–13. Olanow CW, Kieburtz K, Schapira AH. Why have we failed to achieve neuroprotection in Parkinson’s disease? Ann Neurol. 2008;64(Suppl 2):S101–10. Gu M, Iravani MM, Cooper JM, King D, Jenner P, Schapira AH. Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. J Neurochem. 2004;91(5):1075–81. Iravani MM, Sadeghian M, Leung CC, Tel BC, Rose S, Schapira AH, Jenner P. Continuous subcutaneous infusion of pramipexole protects against lipopolysaccharide-induced dopaminergic cell death without affecting the inflammatory response. Exp Neurol. 2008;212(2):522–31. Iravani MM, Haddon CO, Cooper JM, Jenner P, Schapira AH. Pramipexole protects against MPTP toxicity in non-human primates. J Neurochem. 2006;96(5):1315–21. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1989;321(20):1364–71. Holford NH, Chan PL, Nutt JG, Kieburtz K, Shoulson I. Disease progression and pharmacodynamics in Parkinson disease—evidence for functional protection with levodopa and other treatments. J Pharmacokinet Pharmacodyn. 2006;33(3):281–311. Larsen JP, Boas J, Erdal JE. Does selegiline modify the progression of early Parkinson’s disease? Results from a five-year study. The Norwegian-Danish Study Group. Eur J Neurol. 1999;6(5):539–47. Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, Hubble J, et al. The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol. 1995;38(5):771–7. Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson’s disease. Mov Disord. 2009;24(4):564–73. Biglan KM, Ravina B. Neuroprotection in Parkinson’s disease: an elusive goal. Semin Neurol. 2007;27(2):106–12. Siderowf A, Stern M. Clinical trials with rasagiline: evidence for short-term and long-term effects. Neurology. 2006;66(10 Suppl 4):S80–8. Clarke CE. Are delayed-start design trials to show neuroprotection in Parkinson’s disease fundamentally flawed? Mov Disord. 2008;23(6):784–9. Grosset D, Taurah L, Burn DJ, MacMahon D, Forbes A, Turner K, et al. A multicentre longitudinal observational study of

Early vs. Delayed Initiation of Pharmacotherapy in PD

119.

120. 121.

122.

123.

124. 125.

126. 127.

changes in self reported health status in people with Parkinson’s disease left untreated at diagnosis. J Neurol Neurosurg Psychiatry. 2007;78(5):465–9. Asimakopoulos P, Caslake R, Harris CE, Gordon JC, Taylor KS, Counsell C. Changes in quality of life in people with Parkinson’s disease left untreated at diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(6):716–8. Findley LJ. The economic impact of Parkinson’s disease. Parkinsonism Relat Disord. 2007;13(Suppl):S8–12. von Campenhausen S, Winter Y, Rodrigues e Silva A, Sampaio C, Ruzicka E, Barone P, et al. Costs of illness and care in Parkinson’s disease: an evaluation in six countries. Eur Neuropsychopharmacol. 2011;21(2):180–91. Vossius C, Nilsen OB, Larsen JP. Health state values during the first year of drug treatment in early-stage Parkinson’s disease: a prospective, population-based, cohort study. Drugs Aging. 2009;26(11):973–80. Zhao YJ, Tan LC, Li SC, Au WL, Seah SH, Lau PN, et al. Economic burden of Parkinson’s disease in Singapore. Eur J Neurol. 2011;18(3):519–26. Martikainen KK, Luukkaala TH, Marttila RJ. Parkinson’s disease and working capacity. Mov Disord. 2006;21(12):2187–91. Kostic VS, Marinkovic J, Svetel M, Stefanova E, Przedborski S. The effect of stage of Parkinson’s disease at the onset of levodopa therapy on development of motor complications. Eur J Neurol. 2002;9(1):9–14. Schapira AH. Treatment options in the modern management of Parkinson disease. Arch Neurol. 2007;64(8):1083–8. Schapira AH. The management of Parkinson’s disease—what is new? Eur J Neurol. 2011;18(Suppl 1):1–2.

657 128. Schapira AH, Olanow CW. Drug selection and timing of initiation of treatment in early Parkinson’s disease. Ann Neurol. 2008;64(Suppl 2):S47–55. 129. Rascol O. Drugs and drug delivery in PD: optimizing control of symptoms with pramipexole prolonged-release. Eur J Neurol. 2011;18(Suppl 1):3–10. 130. Grosset D, Antonini A, Canesi M, Pezzoli G, Lees A, Shaw K, et al. Adherence to antiparkinson medication in a multicenter European study. Mov Disord. 2009;24(6):826–32. 131. Valldeoriola F, Coronell C, Pont C, Buongiorno MT, Camara A, Gaig C, Compta Y. Socio-demographic and clinical factors influencing the adherence to treatment in Parkinson’s disease: the ADHESON study. Eur J Neurol. 2011;18(7):980–7. 132. Johnson SJ, Diener MD, Kaltenbroek A, Birnbaum HG, Siderowf AD. An economic model of Parkinson’s disease: implications for slowing progression in the United States. Mov Disord. 2013;28:319–26. 133. Scigliano G, Musicco M, Soliveri P, Piccolo I, Girotti F, Giovannini P, Caraceni T. Mortality associated with early and late levodopa therapy initiation in Parkinson’s disease. Neurology. 1990;40(2):265–9. 134. Diamond SG, Markham CH, Hoehn MM, McDowell FH, Muenter MD. Multi-center study of Parkinson mortality with early versus later dopa treatment. Ann Neurol. 1987;22(1):8–12. 135. Stocchi F, Hersh BP, Scott BL, Nausieda PA, Giorgi L. Ease-PD monotherapy study investigators. Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson’s disease: a randomized, double-blind, non-inferiority crossover study. Curr Med Res Opin. 2008;24(10):2883–95.