REVIEW ARTICLE

Non-dopaminergic Treatments for Motor Control in Parkinson’sDisease

Susan H. Fox

Published online: 6 August 2013

� Springer International Publishing Switzerland 2013

Abstract The pathological processes underlying Parkin-

son’s disease (PD) involve more than dopamine cell loss

within the midbrain. These non-dopaminergic neurotrans-

mitters include noradrenergic, serotonergic, glutamatergic,

and cholinergic systems within cortical, brainstem and

basal ganglia regions. Several non-dopaminergic treat-

ments are now in clinical use to treat motor symptoms of

PD, or are being evaluated as potential therapies. Agents

for symptomatic monotherapy and as adjunct to dopami-

nergic therapies for motor symptoms include adenosine

A2A antagonists and the mixed monoamine-B inhibitor

(MAO-BI) and glutamate release agent safinamide. The

largest area of potential use for non-dopaminergic drugs is

as add-on therapy for motor fluctuations. Thus adenosine

A2A antagonists, safinamide, and the antiepileptic agent

zonisamide can extend the duration of action of levodopa.

To reduce levodopa-induced dyskinesia, drugs that target

overactive glutamatergic neurotransmission can be used,

and include the non-selective N-methyl D-aspartate antag-

onist amantadine. More recently, selective metabotropic

glutamate receptor (mGluR5) antagonists are being evalu-

ated in phase II randomized controlled trials. Serotonergic

agents acting as 5-HT2A/2C antagonists, such as the atypical

antipsychotic clozapine, may also reduce dyskinesia.

5-HT1A agonists theoretically can reduce dyskinesia, but in

practice, may also worsen PD motor symptoms, and so

clinical applicability has not yet been shown. Noradrener-

gic a2A antagonism using fipamezole can potentially

reduce dyskinesia. Several non-dopaminergic agents have

also been investigated to reduce non-levodopa-responsive

motor symptoms such as gait and tremor. Thus the cho-

linesterase inhibitor donepezil showed mild benefit in gait,

while the predominantly noradrenergic re-uptake inhibitor

methylphenidate had conflicting results in advanced PD

subjects. Tremor in PD may respond to muscarinic M4

cholinergic antagonists (anticholinergics), but tolerability

is often poor. Alternatives include b-adrenergic antagonists

such as propranolol. Other options include 5-HT2A antag-

onists, and drugs that have mixed binding properties

involving serotonin and acetylcholine, such as clozapine

and the antidepressant mirtazapine, can be effective in

reducing PD tremor. Many other non-dopaminergic agents

are in preclinical and phase I/II early stages of study, and

the reader is directed to recent reviews. While levodopa

remains the most effective agent to treat motor symptoms

in PD, the overall approach to using non-dopaminergic

drugs in PD is to reduce reliance on levodopa and to target

non-levodopa-responsive symptoms.

1 Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder

primarily of the nigrostriatal dopaminergic pathway. Loss

of dopamine leads to the classical symptoms of bradyki-

nesia, rigidity, and tremor, which are improved with

dopamine-replacement therapies such as dopamine ago-

nists and levodopa. Over time, this benefit may fluctuate

and patients start to notice loss of benefit with each dose of

levodopa, termed wearing-off, as well as involuntary

movements, levodopa-induced dyskinesia (LID). In addi-

tion, several parkinsonian symptoms such as gait and tre-

mor may become resistant to dopaminergic drugs. The

neurodegenerative processes underlying PD involves many

S. H. Fox (&)

Movement Disorders Clinic, Division of Neurology, University

of Toronto, Toronto Western Hospital, 399 Bathurst Street

MCL7-412, Toronto, ON M5T 2S8, Canada

e-mail: sfox@uhnresearch.ca

Drugs (2013) 73:1405–1415

DOI 10.1007/s40265-013-0105-4

non-dopaminergic neurotransmitters, including acetylcho-

line, noradrenaline, serotonin, and other neurotransmitter

systems [1–6]. In addition, glutamate, adenosine, and

serotonin and other neurotransmitters within the basal

ganglia are involved in control of motor symptoms and

mediate problems occurring after long-term levodopa

treatment, such as dyskinesia. Targeting non-dopaminergic

systems is thus an alternative approach to improve such

motor complications, improving efficacy and removing the

need for further increases in levodopa, which may thus

worsen motor fluctuations [7, 8].

The basal ganglia circuitry involves many non-dopami-

nergic neurotransmitters and neuromodulators that have been

implicated in the neural mechanisms underlying the motor

symptoms of PD as well as the development of motor fluc-

tuations and dyskinesia following long-term levodopa ther-

apy [9, 10]. There are many recent reviews on this topic [11,

12]. The potential advantages of such approaches are (a) use

of non-dopaminergic drugs as symptomatic monotherapy to

delay the need for levodopa or dopamine agonists; (b) use of

non-dopaminergic drugs as add-on therapy to levodopa or

dopamine agonists to keep doses of dopaminergic agents low

and thus reduce development of long-term levodopa-induced

motor fluctuations; (c) use of non-dopaminergic drugs to

treat motor fluctuations directly allows continued use of

optimal doses of levodopa, the most effective antiparkinso-

nian agent; and (d) use of non-dopaminergic drugs to target

levodopa-resistant motor symptoms, such as gait and balance

and some severe PD tremors. Here, clinically available

agents (Table 1) and those in phase IIb/phase III clinical

trials are reviewed (Table 2).

2 Search Strategy and Selection Criteria

References for this review were obtained from PubMed

searches of literature published between 1990 and April

2013, using the key words ‘Parkinson’s disease’ and

‘clinical trial’ and ‘serotonin,’ ‘5HT,’ ‘acetylcholine,’

noradrenaline,’ ‘adenosine,’ ‘glutamate,’ ‘dyskinesia,’ and

‘motor fluctuations,’ and websites for active clinical trials

(currently recruiting), including http://www.clinicaltrials.

gov/. Other sources included conference proceedings. Only

articles or abstracts in English were reviewed.

3 Non-Dopaminergic Symptomatic Monotherapy

in Early Parkinson’s Disease (PD)

Many non-dopaminergic agents have been evaluated pre-

clinically [11–14], but to date, very few have demonstrated

significant clinical benefit as monotherapy in PD patients.

Certainly, no non-dopaminergic drug has shown significant

benefit on the key parkinsonian symptoms of bradykinesia

and rigidity comparable with a dopaminergic drug (drugs

for PD tremor are discussed below).

3.1 Adenosine A2A Antagonists

One potential therapeutic target for monotherapy is the

adenosine A2A antagonist istradefylline, which may

improve motor symptoms without inducing dyskinesia.

Adenosine A2A receptors are selectively located on the

GABAergic cell bodies and terminals of the indirect stri-

atopallidal pathway. Adenosine, via the A2A receptor, is

functionally linked to the dopamine D2 receptor and

enhances GABA release in the external globus pallidus; a

mechanism that contributes to the overactivity of the

indirect pathway that is a key component of the neural

mechanism underlying PD [15]. In addition, overactive

corticostriatal glutamatergic activity via the N-methyl

D-aspartate (NMDA) receptor stimulation that occurs in PD

also leads to adenosine release and stimulation of A2A

receptors [16]. Preclinical studies have shown that adeno-

sine A2A antagonists can improve motor symptoms without

inducing dyskinesia [17] due to an action on the indirect

pathway while allowing dopaminergic action via the

dopamine D1-mediated direct pathway.

A randomized controlled trial (RCT) of istradefylline

(40 mg/day) was performed in 176 early untreated PD sub-

jects; after 12 weeks there was no significant improvement in

motor function, as assessed using the Unified Parkinson Dis-

ease Rating Scale part III (UPDRS-III) compared with pla-

cebo [18].

Another A2A antagonist that has been evaluated for

symptomatic treatment in early PD is preladenant. A phase

III trial assessing preladenant as monotherapy in early PD

has been completed and full results are pending; however,

preliminary company press release reports are that the

study is negative [19]. This trial also included a delayed-

start group to explore the potential neuroprotective prop-

erties of adenosine A2A receptor antagonists. Thus overall,

monotherapy with istradefylline and preladenant does not

appear to be an effective treatment option for PD. Further

adenosine A2A receptor antagonists are in much earlier

stages of evaluation, and it is thus unclear if lack of benefit

is a class effect or specific to these two agents.

4 Non-Dopaminergic Symptomatic Adjunct Therapy

4.1 Mixed Monoamine-B (MAO-B) Inhibitors

and Glutamate Release Inhibition

Safinamide is an agent that influences both dopaminergic and

non-dopaminergic systems with multiple mechanisms of

1406 S. H. Fox

action including MAO-B inhibition and inhibition of gluta-

mate release by blockade of voltage-gated sodium and cal-

cium channels. A phase III RCT investigating safinamide as

an add-on to dopamine agonist therapy in early PD reported a

significant improvement in motor symptoms as measured

using the UPDRS-III with safinamide 100 mg/day but not

with safinamide 200 mg/day [20]. The reason for a lack of a

response with the higher dose of safinamide is not known but

may be due to underpowering, due to a higher dropout rate in

the 200-mg group. A second phase III double-blind RCT

(MOTION) over 24 weeks also evaluated safinamide, 50 and

100 mg/day, as add-on to a dopamine agonist, in early PD

patients (n = 679) [21]. Preliminary results reported that sa-

finamide 100 mg/day significantly improved motor symp-

toms (UPDRS-III, P = 0.040) as well as quality of life (PD

questionnaire-39 [PDQ-39] and EuroQual 5D [EQ5D])

measures compared with placebo. Thus the dose of safinamide

appears to be important in efficacy in early PD, possibly

implicating variable mechanisms, i.e., MAO-B inhibition

versus glutamate release at differing doses. Tolerability of

safinamide was generally good.

The use of such an agent in the early stages of PD may be

useful to reduce the need to start levodopa, and thus delay the

development of motor complications. Long-term follow-up is

needed to determine whether early use of safinamide reduces

long-term motor complications when levodopa is added in. In

addition, many PD subjects do not tolerate dopamine agonists,

and doses need to be reduced; addition of another agent such

as safinamide would thus be clinically useful.

5 Non-Dopaminergic Therapies for Motor

Complications

The largest area of development in non-dopaminergic

therapies has been as treatments for levodopa-induced

Table 1 Non-dopaminergic drugs currently clinically available for use in Parkinson’s disease (PD) to treat motor symptoms

Drug Mechanism of action Clinical benefit References

Levodopa-induced dyskinesia

Amantadine Non-selective NMDA receptor

antagonist

Several RCTs reported significant benefit; recommended as clinically

useful. Improvement in peak-dose and diphasic dyskinesia in about

one-third of patients. Some loss of benefit over time. Side effects:

livedo reticularis, ankle edema, confusion, hallucinations, myoclonus

(check renal function)

[38]

Clozapine 5-HT2A/2C antagonists One RCT reported significant improvement in on time with dyskinesia

by av 1.7 h over placebo, using clozapine 25–50 mg/day, without

worsening motor scores. Side effects: mandatory blood monitoring

required for risk of agranulocytosis. Off label

[60]

Buspirone 5-HT1A agonist Improved dyskinesia without worsening PD in one small study (n = 10).

Off label

[54]

Levetiracetam Binds synaptic vesicle protein 2A;

reduces neurotransmitter release

Three RCTs; one showed significant improvement in on time with

dyskinesia by av 1.1 h for levetiracetam 500–1000 mg/day over

5 weeks (n = 38). Two studies’ results were not significant. Side

effects: dizziness, somnolence. Off label

[65–67]

Gait

Methylphenidate Enhances noradrenaline and

dopamine

Two trials. One trial: significant improvement in gait in stand-walk-sit

test by two steps over placebo, using methylphenidate 1 mg/kg/day

over 90 days (n = 69, advanced PD post-STN DBS). One trial: no

significant benefit of methylphenidate 80 mg/day (n = 23). Side

effects: increased heart rate, weight loss. Off label

[76, 77]

Donepezil Cholinesterase inhibitor Significant reduction in falls by 0.1/day over placebo, using donepezil

5 mg/day for 12 weeks (n = 23, including six post-STN DBS). Side

effects: nausea, insomnia, headache, abnormal sweating. Off label

[80]

Tremor

Anticholinergics

(various)

Muscarinic acetylcholine receptor

antagonists

Several RCTs report benefit on PD tremor. Side effects: dry mouth,

urinary retention, constipation, confusion and memory loss

[38]

Clozapine Mixed

5-HT2A/2C antagonists;

anticholinergic

RCT and retrospective reports show significant improved tremor, using

25–50 mg clozapine. Side effects: mandatory monitoring for risk of

agranulocytosis. Off label

[91–93]

Mirtazapine Single study reported benefit with 15–45 mg/day. Off label [94]

Propranolol b-blocker Few trials; clinically maybe useful for postural component of PD tremor [95]

Av average, NMDA N-methyl D-aspartate, RCT randomized controlled trial, STN-DBS subthalamic nucleus deep brain stimulation

Non-dopaminergic Treatments for Parkinson’s Disease 1407

motor complications including predictable wearing-off and

dyskinesia. These symptoms occur in more advanced dis-

ease following long-term levodopa use. Wearing-off is the

re-emergence of PD symptoms at the end of each dose

cycle, which initially occurs around 4 h but can become

shorter with ongoing disease progression. Involuntary

movements, dyskinesia, typically occur at the peak-dose

effect of levodopa and result in chorea and dystonia pre-

dominantly of the neck and limbs. The pathophysiology of

these motor complications involves many non-dopaminergic

neurotransmitter systems within the basal ganglia [9, 10].

5.1 Wearing-Off

Treatment strategies for reducing wearing-off include

inhibiting enzymes that metabolize levodopa, such as cat-

echol-O-methyltransferase (COMT) and MAO, and so

increase the half-life of levodopa. These drugs are not

reviewed as the main action is on dopamine. However,

there are two new agents, safinamide and zonisamide, that

work via MAO-B but with additional mechanisms includ-

ing glutamate, and these are discussed below. The alter-

native approach is improving PD motor symptoms directly

with a pharmacological target, which is the mechanism

behind adenosine A2A antagonists.

5.1.1 Mixed MAO-B Inhibitors and Glutamate Release

Inhibition

Safinamide is also being studied for motor complications in

advanced PD. A phase III double-blind RCT (SETTLE)

evaluated safinamide in 549 patients with motor fluctua-

tions over 24 weeks, and preliminary reports, in abstract,

showed significant benefit of safinamide 50–100 mg, with

a mean change from baseline in daily ‘on’ time over pla-

cebo of 0.96 h [(95 % CI 0.56–1.37) P \ 0.001]. There

was no increase in troublesome dyskinesia, and tolerability

was good [22].

Zonisamide has multiple mechanisms of action includ-

ing MAO-B inhibition and inhibition of glutamate release

by blockade of voltage-gated sodium channel. It is avail-

able in several countries for the treatment of epilepsy. A

phase III RCT in Japan reported a significant reduction in

‘off’ time from baseline [-1.1 h (50 mg) and -1.43 h

(100 mg)] versus placebo [23]; however, PD subjects were

on relatively low doses of levodopa. There was no increase

in dyskinesia. At this stage, no further studies are reported

as ongoing.

5.1.2 Adenosine A2A Antagonists

As reviewed above, adenosine A2A receptors may be

involved in the pathophysiology of PD motor symptoms

via an action that increases activity of the indirect striato-

pallidal pathway. The theoretical action is that A2A

antagonists may reduce PD symptoms via the indirect

pathway without worsening dyskinesia (via the direct

pathway). The agent furthest along the development path-

way is the A2A antagonist istradefylline. To date, there

have been seven RCTs [24–30], using a range of doses,

10–40 mg/day (Table 2). While there was a significant

effect of placebo on improving off time versus pre-treat-

ment that impacted on statistical outcomes of the istra-

defylline treatment arm (placebo effects are a common

issue in trials in PD), overall the improvement in off time

with istradefylline, above placebo, was approximately

1.0 h/day. Increased dyskinesia was reported, but this was

generally non-disabling, and tolerability overall was good.

Istradefylline is approved in Japan; however, istradefylline

did not receive US FDA approval for PD, and future

development plans are unclear.

Other adenosine A2A antagonists, in earlier stages of

assessment, are being evaluated as add-on therapy in PD

subjects with wearing-off. A phase II RCT evaluated

preladenant in 253 advanced PD subjects with wearing-off;

preladenant significantly reduced mean daily off time by

-1.0 h for preladenant 10 mg/day and -1.2 h for prelad-

enant 20 mg/day versus -0.5 h for placebo (P \ 0.05)

over 12 weeks. There was no significant increase in trou-

blesome dyskinesia [31]. Further studies are ongoing;

preliminary company press release reports, however, sug-

gest that the studies were negative [32]. Tozadenant was

evaluated in a phase II RCT in 420 PD subjects with motor

fluctuations over 12 weeks, and a preliminary abstract

publication reported an improved off time of 1.1 h versus

placebo at 240 and 360 mg/day; there was no significant

increase in on time with troublesome dyskinesia [33].

Overall, adenosine A2A antagonists appear to have a

benefit in reducing wearing-off comparable with currently

available add-on agents (MAO-B inhibitors and COMT

inhibitors) that enhance availability of levodopa. The

potential advantage of adenosine A2A antagonists is that

theoretically there should be less of a tendency to induce

dyskinesia, which is a common side effect of MAO-B

inhibitors and COMT inhibitors. To date, however, clinical

studies using the A2A antagonists have reported that dys-

kinesia does occur, although it is non-significant. In clinical

practice, one option is to reduce individual doses of levo-

dopa to reduce this side effect. To date, no RCTs have used

lower or subtherapeutic doses of levodopa in combination

with adenosine A2A antagonists to evaluate this potentially

better approach to using such drugs in clinical practice.

Safinamide also appears to be a potentially useful agent,

with perhaps the added benefit of an action on reducing

wearing-off without inducing dyskinesia. Tolerability of all

these new drugs also appears to be good.

1408 S. H. Fox

Table 2 Non-dopaminergic treatments in development for motor symptoms in Parkinson’s disease (PD)

Drug Mechanism of action Phase ofdevelopment

Outcome References

Symptomatic monotherapy

Istradefylline Adenosine A2A

antagonistIII Non-significant: 176 early PD subjects; 40 mg/day istradefylline

resulted in a non-significant change from baseline to end pointin UPDRS-III score above placebo

[18]

Preladenant III Preliminary results are negative [19]

Symptomatic adjunct therapy

Safinamide Glutamate releaseinhibition and MAO-B inhibition

III Significant improvement in UPDRS-III score by mean 3 pointsfor safinamide 100 mg above placebo as add-on to a singledopamine agonist (n = 948 combined, two studies) over24 weeks. No significant effects seen with 50 mg/day or200 mg/day. Side effects: nausea, headache, abdominal pain,blurred vision

[20, 21]

Motor fluctuations

Safinamide Glutamate releaseinhibition and MAO-B inhibition

III Significant improvement in levodopa-induced on time (withoutworsening troublesome dyskinesia) and reduced off time, usingsafinamide 50–100 mg/day, by av 1 h for both measures aboveplacebo (n = 549) over 24 weeks. Side effects: dyskinesia,fall, headache, nausea, and urinary tract infection

[22]

Zonisamide III Significant improvement in UPDRS-III motor scores by 2–3points with 25 and 50 mg/day zonisamide over placebo andsignificant improvement in off time by av 1–1.5 h overplacebo, with 50–100 mg/day zonisamide over 12 weeks(n = 347). Side effects: somnolence, reduced appetite, apathy

[23]

Istradefylline Adenosine A2A

antagonistII/III Variable outcomes; overall significant improvement in daily off

time of av 1 h above placebo for istradefylline over 12 weeks.Side effects: dyskinesia

[24–30]

Preladenant IIb Significant reduction in off time by 0.5–0.6 h/day over placebo,using preladenant (10–20 mg/day) over 12 weeks (n = 253).Side effects: worsening of PD, somnolence, dyskinesia,nausea, constipation, insomnia

[31]

Tozadenant II Significant improvement in off time of 1 h over placebo, usingtozadenant 240–360 mg/day) (n = 420). No significant effectat lower doses. Side effects: dyskinesia, nausea (full data notyet reported)

[33]

Levodopa-induced dyskinesia

ADS-5102(extended-releaseamantadine HCl)

Non-selective NMDAreceptor antagonist

II Ongoing [40]

Mavoglurant(AFQ056)

mGluR5 antagonist II (two trialscombined)[45]

Significant improvement in daily dyskinesia and objectivedyskinesia scores by av 3 points, using mavoglurant 300 mg/day, above placebo over 16 days (n = 59 total). Not significantat day 2. Side effects: dizziness

[45]

Dipraglurant(ADX48621)

II Significant improvement in objective dyskinesia (AIMS), usingdipraglurant 300 mg/day, at day 14 by 2.4 points aboveplacebo (n = 76). Not significant at day 28. Increased daily ontime without dyskinesia by 2.3 h at 28 days (full data not yetreported)

[46]

Fipamezole a2A/2C adrenoreceptorantagonist

II No significant improvement using total study population.Significant improvement in objective measure of dyskinesia by1.9 points over placebo with fipamezole 90 mg/day after28 days in country-specific subgroup (n = 115). Side effects:hypertension, nausea, vomiting, dysgeusia, facial flushing

[52]

Piclozotan IIa Significant increase in on time without dyskinesia by 22 % overplacebo using IV piclozotan over 2 days (n = 25). Sideeffects: nausea (full data not reported)

[57]

Treatment of non-levodopa-responsive symptoms: gait

Varenicline Nicotinic agonist II Ongoing [81]

AIMS abnormal involuntary movement scale, Av average, IV intravenous, MAO-B monoamine-B, mGluR metabotropic glutamate receptor,UPDRS Unified Parkinson Disease Rating Scale

Non-dopaminergic Treatments for Parkinson’s Disease 1409

5.2 Treatment of Levodopa-Induced Dyskinesia

The challenge of treating LID is to reduce symptoms

without impairing the motor benefit of levodopa. Thus

targeting non-dopaminergic pathways has been a major

area of research over the past 2 decades [8, 10, 12]. Several

targets have been indentified including glutamate, other

monoamines, serotonin and noradrenaline, opioids, hista-

mine, and peptides. The scope of this article is not to cover

all these targets, and readers are directed towards recent

reviews on new drugs and drugs in preclinical and early

stages of study [8, 10, 12, 34]. This section will focus on

clinically available drugs or agents in later stages of

development.

5.2.1 Glutamatergic Antagonists

A key abnormality underlying peak-dose dyskinesia is

abnormal enhancement of glutamatergic activity within

the striatum, involving ionotropic NMDA and 2-amino-3-

(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)

glutamate receptors and metabotropic glutamate receptors

(mGluRs) [35, 36]. This increased glutamatergic trans-

mission drives activity of the dopamine D1-mediated direct

striatopallidal pathway, with resultant inhibition of the

basal ganglia outputs and the generation of dyskinesia [10,

37]. The current recommended treatment for dyskinesia is

the non-selective NMDA receptor antagonist amantadine

(100–300 mg/day) [38]. A reduction in dyskinesia by about

one-third is seen in clinical practice. Tolerance can be an

issue, and side effects include hallucinations, leg edema,

and livedo reticularis. Long-term efficacy has been ques-

tioned as a waning benefit over time may occur. A study

following 332 PD subjects over 1 year, however, did not

show any significant loss of benefit [39]. An extended-

release version of amantadine (ADS-5102) is in develop-

ment [40]. The rationale is that higher daytime drug levels

and lower night time levels may avoid nocturnal side

effects of confusion and hallucinations.

Tolerability of glutamatergic drugs has been the main

stumbling block in the treatment of PD. Reduction in side

effects may be possible with more selective targeting of

glutamate receptor subtypes within affected basal ganglia

regions. Thus several subtype-selective NMDA and AMPA

receptor antagonists have been investigated in preclinical

and clinical studies, but with conflicting results and poor

clinical benefit [41–43]. The most recent glutamate target

to generate interest is the metabotropic subtype of gluta-

mate receptor (mGluR) that has been suggested as a better

option for PD because of a wider therapeutic index

(reviewed in [44]). There are several antagonists at the

mGluR5 subtype of mGluR that are being assessed in PD

(Table 2). These include mavoglurant (AFQ056) [45] and

dipraglurant (ADX48621) [46]. Both drugs have been

evaluated over short periods only (\1 month duration), and

show tolerability and some efficacy against dyskinesia.

Further studies are needed to fully evaluate the clinical

potential of this target in PD.

5.2.2 Adrenergic Receptor Antagonists

The pathology of PD also involves noradrenergic degen-

eration of the locus ceruleus [2, 47, 48]. However, the role

of noradrenergic neurotransmission in PD remains unclear.

Noradrenergic receptors are present within the striatum, but

their role in modulating basal ganglia function is not really

well defined. Possible suggestions include modulation of

GABA release and thus a contribution to the overactivity of

the direct striatopallidal pathway resulting in dyskinesia

[10]. Antagonists at a2A/2C receptors have thus been sug-

gested to reduce dyskinesia [49, 50]. There are no clinically

available a2A antagonists that have shown efficacy in

dyskinesia. One selective a2A/2C receptor antagonist, fipa-

mezole, has been assessed in PD subjects with dyskinesia

in a phase IIb multicenter RCT over 28 days [51]. Overall

benefit on an objective dyskinesia score (LIDS) was small,

and only significant compared with placebo in a subgroup

of patients from US centers [-1.9 ± 0.9 points (95 % CI

0.0–3.8), P = 0.047]. There was no significant change in

PD subjects recruited from India, possibly because of

heterogeneity in subjects in terms of body mass and levo-

dopa use. Tolerability was good, with no worsening of PD

motor scores. Mild elevation of blood pressure was noted

that may be beneficial to advanced PD subjects with

symptomatic postural hypotension. Further studies are

required over a longer period to determine clinical utility of

this agent.

5.2.3 Serotonergic Agents

5.2.3.1 5-HT1A Agonists Serotonergic neurotransmission

is involved in many aspects of basal ganglia function. In

general, 5-HT receptors modulate neurotransmitter release

within basal ganglia circuits, including 5-HT, dopamine,

GABA or glutamate, and thus can affect motor function.

The neurodegenerative processes in PD also affect the

serotonergic neurons within the raphe nucleus of the

brainstem, resulting in loss of 5-HT input to the striatum [1,

4, 6]. Loss of 5-HT is less than dopamine loss affecting the

nigrostriatal pathway, and as a consequence levodopa is

converted to dopamine in remaining serotonergic neurons.

Non-physiological release of dopamine by these seroto-

nergic neurons can thus cause abnormal dopamine receptor

1410 S. H. Fox

stimulation within the striatum and has been suggested as a

cause of dyskinesia [52]. Presynaptic 5-HT1A receptor

agonists can reduce dopamine release from these seroto-

nergic striatal terminals and thus potentially reduce dys-

kinesia [53]. Clinically available antidepressants that partly

act as 5-HT1A agonists have thus been assessed in PD

subjects, e.g., buspirone reduced dyskinesia without

worsening parkinsonian disability in a small study of ten

PD patients [54]. A selective 5-HT1A agonist, sarizotan,

was evaluated in phase III clinical studies but failed to

increase on time without dyskinesia compared with pla-

cebo; higher doses were associated with increased off times

[55, 56] possibly because of non-selectivity as a dopamine

D2 antagonist as well as an action to reduce dopamine

release. Other agents that have been assessed include

piclozotan, a highly selective 5-HT1A agonist [57]. Pre-

liminary data was presented as an abstract only; no further

studies appear to be ongoing. The partial dopamine D2/D3

agonist pardoprunox, which also has 5-HT1A agonist

properties, has been evaluated in PD, although effects on

dyskinesia remains unknown as yet [58]. While a promis-

ing target, clinical applicability of 5-HT1A agonists as

treatments for dyskinesia has not proven as successful as

hoped. Thus 5-HT1A agonists also reduce dopamine release

and can potentially worsen parkinsonism. Other possible

sites where 5-HT1A agonists may have an anti-dyskinetic

action include reducing overactive glutamate release by

acting on 5-HT1A receptors on presynaptic corticostriatal

glutamate terminals [8]. Selective anatomical targeting of

these 5-HT1A receptors, rather than 5-HT1A agonists on

nigrostriatal terminals, is thus an interesting potential

option for future development of 5-HT1A agonists as

treatments for dyskinesia.

5.2.3.2 5-HT2A/2C Antagonists The 5-HT2A/2C receptor

has been implicated in the pathophysiology of PD possibly

via an action in the output regions of the basal ganglia to

modulate GABA release, or via an action within the stri-

atum to modulate dopamine [8]. The ability of so-called

atypical antipsychotics to bind to dopamine D2 receptors to

reduce psychosis without inducing parkinsonism is thought

in part to be due to additional actions as 5-HT2A/2C receptor

antagonists [59]. An RCT using low doses of the atypical

antipsychotic clozapine (25–50 mg/day) significantly

reduced LID without worsening PD [60]. Thus clozapine is

recommended as ‘‘efficacious for the treatment of dyski-

nesia’’ according to evidence-based medicine reviews [38].

However, use of clozapine for dyskinesia is rare in prac-

tice, because of the mandatory blood monitoring needed to

prevent agranulocytosis. The other atypical antipsychotic,

quetiapine (25 mg/day), which also has 5-HT2A/2C antag-

onist properties, did not show significant benefit on

reducing dyskinesia [61].

5.2.4 Multiple Non-dopaminergic Transmitters?

The anticonvulsant levetiracetam has effects on multiple

neurotransmitter systems via a presynaptic action on the

synaptic vesicle protein 2A. Altered release of glutamate

and GABA potentially could reduce dyskinesia, although

the exact mechanism is unknown. Preclinical studies

reported levetiracetam significantly reduces LID [62, 63]

and may act synergistically with amantadine [64]. Three

RCTs investigating the anti-dyskinetic action of leveti-

racetam (500–1000 mg/day) in PD patients, off amanta-

dine, revealed conflicting results [65–67]. One study in 38

subjects over 5 weeks demonstrated a significant reduction

in on time with dyskinesia of 75 min (95 % CI 3.31–12.4,

P = 0.002), using patient-completed diaries, for leveti-

racetam 1 g/day. Common adverse events included dizzi-

ness and somnolence (but only one subject withdrew) [66].

Two other trials demonstrated no significant differences

versus placebo [65, 67]. Earlier non-RCT studies in PD

showed poor tolerability of levetiracetam [68, 69], in

contrast to an overall generally good tolerability in subjects

with epilepsy. Thus larger trials would be required to

establish efficacy and tolerability of levetiracetam for

dyskinesia in PD subjects.

6 Non-Levodopa-Responsive Motor Symptoms

6.1 Gait

Gait and balance are initially responsive to levodopa, but

with ongoing disease progression, these symptoms gener-

ally lose dopaminergic sensitivity. The Sydney Multicentre

Study that followed a cohort of PD patients for over 2

decades reported that 81 % of patients experienced falls

after 15 years and 23 % had sustained fractures [70]. These

non-dopa-responsive features were deemed more disabling

than the motor fluctuations, which were also extremely

common in this cohort.

6.1.1 Noradrenergic Mechanisms

Brain-stem regions, including the noradrenergic locus

coeruleus, have been implicated in gait and balance [71,

72]. L-Threo-3,4-dihydroxyphenylserine (L-DOPS), a pre-

cursor of noradrenaline, has been evaluated and used in

Japan for treating freezing of gait [73]; however, there has

not been widespread use of the drug. The mixed dopamine

and noradrenergic reuptake inhibitor methylphenidate has

been shown to modulate noradrenergic function in the

locus ceruleus [74, 75]. Two recent RCTs using methyl-

phenidate (1 mg/kg/day) in PD subjects with gait and

balance issues have shown variable results. One cross-over

Non-dopaminergic Treatments for Parkinson’s Disease 1411

RCT in 23 PD patients with moderate gait impairment

(mean disease duration 10.9 years) demonstrated no benefit

from methylphenidate after 12 weeks in the primary out-

comes (change in a gait composite score of stride length

and velocity) or secondary outcomes [76]. Another RCT, in

69 patients with advanced PD and post-bilateral subtha-

lamic nucleus deep brain stimulation (STN-DBS)

(5–6 years prior) with moderate-to-severe gait difficulty

and freezing despite optimized treatment, showed a small

but significant benefit in objective gait measures after

90 days. However, there was no difference in on-medica-

tion state; thus the clinical importance of this measurement

is unclear [77]. In both studies, methylphenidate was

associated with some elevated blood pressure, heart rate,

and weight loss but was well tolerated, and there were no

serious adverse events.

6.1.2 Cholinesterase Inhibitors

The role of cholinergic transmission within the mesence-

phalic locomotor region, which includes the pedunculo-

pontine nucleus, has also been implicated in gait and

balance in PD [78, 79]. Enhancing cholinergic function has

thus been suggested to improve gait and balance in PD

subjects. The cholinesterase inhibitor donepezil (5 mg/day)

was evaluated over 12 weeks in a small cross-over RCT in

23 advanced PD subjects (six had prior STN-DBS) with

more than two falls per week. There was a small but sig-

nificant reduction in falls as assessed using weekly home-

completed diaries [0.13 (±0.03)/day with donepezil vs.

0.25 (±0.08)/day with placebo (P \ 0.05)]. There was no

change in other PD motor scores [80]. Donepezil is cur-

rently used as a treatment for cognitive impairment in PD;

thus a potential additional benefit on gait may be useful in

advanced PD subjects. However, further studies in larger

numbers of patients are needed to fully evaluate benefit and

tolerability. Other cholinergic agents that are being evalu-

ated include varenicline, a partial a4b2 nicotinic cholin-

ergic agonist and full a7 agonist originally developed as an

aid for smoking cessation and has been shown in initial

studies to improve imbalance in patients with inherited

spinocerebellar ataxia. Ongoing studies are planned to

investigate PD subjects with gait and balance outcomes

[81].

6.2 Tremor

Rest tremor is a core feature of PD. In the early stages of

the disease, PD rest tremor may respond to dopaminergic

drugs, although often higher doses are required than for

other PD motor symptoms. Often, however, tremor is fre-

quently not as responsive to dopaminergic medication.

Indeed, there is evidence that dopamine deficiency per se is

not correlated with rest tremor. Thus dopamine lesions

induced in vivo in animal models such as with 1-methyl-4-

phenyl-1,2,3,6-tetrahydropyridine (MPTP) rarely produce a

rest tremor [82]. In patients with PD, neuroimaging studies

with positron emission tomography (PET) and single

photon emission computed tomography (SPECT) demon-

strate dopaminergic deficiency in early PD [83, 84] that

correlates with bradykinesia and rigidity; however, there is

poor correlation between rest tremor and dopaminergic

deficit [85, 86].

6.2.1 Anticholinergics

Cholinergic antagonists have been used in PD since the

pre-levodopa era and have some anti-PD benefits, partic-

ularly on rest tremor. The mechanism of action is not

entirely clear, but dopamine depletion leads to loss of

muscarinic M4 autoreceptors on aspiny cholinergic inter-

neurons within the ventral putamen, resulting in increased

acetylcholine release; an effect that correlates with tremor

in animal models [87].

Muscarinic M4 receptor antagonists, including benztro-

pine and trihexyphenidyl, may be useful in PD tremor.

Evidence-based medicine reviews have concluded that

anticholinergics for PD tremor are likely efficacious and

clinically useful [38]. However, clinical use is often limited

because of anticholinergic side effects of sedation, dry

mouth, and sphincter dysfunction and memory loss.

6.2.2 Serotonergic Antagonists

Serotonergic mechanisms have also been implicated in PD

tremors. Thus rest tremor correlated well with a decreased

binding capacity of the 5-HT1A receptor in the median

raphe nuclei, suggesting an involvement of the serotonergic

system [88]. However, a recent study reported loss of 5-HT

in the raphe nuclei, caudate, and putamen, using11C-DASB, as a marker of presynaptic serotonin trans-

porter binding that correlated with action and postural

tremor but not rest tremor or bradykinesia in PD patients

[89]. Thus, 5-HT dysfunction in the raphe nuclei appears

implicated in action-postural tremors, while rest tremor

may be mediated by other pathophysiological mechanisms.

In clinical practice, PD patients often have a mixture of

both, and it is usually the postural and re-emergent rest

tremors that are the most functionally disabling. 5-HT2

receptor antagonists have also been shown to reduce tremor

in rodent models of PD tremor [90].

The atypical antipsychotic clozapine has been shown to

be efficacious against PD tremor [91–93]. Low-dose clo-

zapine (25–50 mg) as used in these studies acts as a

5-HT1A agonist, 5-HT2A/2C antagonist and has anticholin-

ergic properties; thus there is likely a combination of

1412 S. H. Fox

mechanisms contributing to the anti-tremor effects of clo-

zapine. Clinical use of clozapine for PD tremor is rare in

practice apart from intractable cases, not suitable for DBS,

because of the need for mandatory blood monitoring. The

antidepressant mirtazapine (15–45 mg/day) is another

agent with multiple sites of action. Mirtazapine has anti-

cholinergic and anti-serotonergic properties that may help

reduce tremor, but this has not been demonstrated in a

randomized, placebo-controlled trial [94].

6.2.3 b-Adrenergic Antagonists

Another option for tremor in PD includes the use of the

b-adrenergic antagonist propranolol, particularly if there is

a postural component and when worsening with anxiety or

stress is a major complaint. Despite widespread clinical

use, there is a paucity of evidence for this approach [95].

Long-acting propranolol, up to 160 mg daily, is generally

well tolerated, but care should be taken in advanced PD

because of the risk of bradycardia and significant postural

drop in blood pressure.

Pharmacological treatments for poorly controlled PD

tremor are difficult, and generally, if suitable, such individ-

uals maybe more appropriately considered for DBS surgery.

7 Conclusions

Targeting non-dopaminergic neurotransmitter systems may

improve some symptoms in PD, including wearing-off,

dyskinesia, and non-levodopa-responsive symptoms such

as gait and tremor. Several non-dopaminergic drugs are in

current clinical use, mostly ‘off-label’ and as a result of

indication-switching from other conditions. In addition,

many novel agents are being evaluated in clinical trials and

have shown good promise at the pre-clinical stage.

Translating these positive benefits into the clinic requires

the appropriate evaluation tools as several agents have

previously failed to progress despite efficacy at the pre-

clinical level [34]. The multiple targets of pathology in PD

mean that ongoing research into therapies will need to

continue to target non-dopamine cells involved in this

multisystem disease process.

Acknowledgments No funding was provided for preparation of the

paper and there are relevant conflicts of interest.

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