Parkinson’s the current treatment was mainly directed at

            Parkinson’s
disease (PD) is the progressive neurodegenerative disorder that was mainly
caused by the death of dopamine producing neuron in the specific area of the
brain called substantia niagra (SN). Reduction in the dopamine level at the
basal ganglia caused disruption in the nigrostriatal pathway leading to
impairment of the motor control by an individual. Four hallmarks of the
Parkinson’s disease include tremor at rest, rigidity, slowness of movement
(bradykinesia) and postural instability. The symptoms usually develop over
years and occur mostly in the older patients, however younger population may be
also affected (Beitz,
2014). In terms of geographical location, American people
were more prone to develop this disease with incidence rate of 1602/100000
compared to 646/100000 in Asian population. The risk also increased by gender
in which male have higher risk to contact this disease than female (Pringsheim, Jette, Frolkis, & Steeves, 2014). The exact cause of the disease remains
unknown; however due to the complexity of the disease, there is still no
effective cure for PD and the current treatment was mainly directed at
controlling the symptoms.

            In
general, patient diagnosed with PD not only have to deal with the motor
symptoms, but they also have to cope with the non-motor symptoms. The non-motor
symptoms represent the greatest challenges to the treatment since they did not
respond well to the dopamine therapy and often unrecognised and undertreated in
the clinical setting (Beitz,
2014; Bonnet, Jutras, Czernecki, Corvol, & Vidailhet,
2012; Gallagher & Schrag, 2012). Erro
et al. (2013) reported that the non-motor symptoms
were mainly dominated by the neuropsychiatric disorders such as anxiety (54.9%)
and depression (43.9%), followed by sleep disturbance (32.9%) and apathy
(27.5%). The patient may also develop visual and auditory hallucination,
delusion, dysautonomia, unexplained pain as well as cognitive impairment that
eventually will disrupt the quality of life (Ferrer et al., 2012). To make the matter worse, the current
therapy used in the management of the PD can exacerbate or sometime induce the
non-motor symptoms. Almost 40% of the patients with PD treated with
anti-Parkinsonism drugs develop psychosis and hallucination due to the side
effects of the drugs (Beitz,
2014). Therefore, it is very important to monitor the
non-motor symptoms and manage the condition.

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Approaches done for the treatment
of non-motor symptoms of Parkinson’s disease

i)                   
Depression

                To date, there is no specific treatment
for the depression in PD. In a study conducted by Barone
et al. (2010), the efficacy of the pramipexole in the
treatment of depression was evaluated among the PD patients. A mean daily dose
of 2.18mg pramipexole was administered to PD patients for a period of twelve
weeks. The effectiveness of the pramipexole was evaluated by using Beck
Depression Inventory (BDI). A significant decrease in the BDI score by 50% was
observed in the patients treated with pramipexole compared to the placebo
group. The path analysis revealed that 80% of the total treatment was
contributed by the direct effect of pramipexole on the depressive symptoms,
leaving the other 20% caused by its effect on the motor symptoms. Other popular
antidepressant agents such as SSRIs, are considered to be the most commonly
used drugs in treatment of depression in PD in North America, however, many of
the studies revealed inconclusive evidences about their efficacy for the
treatment (Seppi et al., 2011). Nevertheless, in terms of safety,
SSRIs was more favoured compared to tricyclic antidepressants (TCA) and
monoamine oxidase inhibitors (MAOI – B).

            The
newer antidepressant agents such as atomoxetine was also failed to exhibit any
conclusive evidence for the treatment of depression in PD. The Inventory of
Depressive symptoms score (IDS) between atomoxetine-treated group (80mg/day)
and placebo treated group portrayed no significant difference with 7.3% and
6.7% respectively (Weintraub et al., 2010). This findings concluded that
atomoxetine was not efficacious in the treatment of depressive symptoms in PD,
however, it was associated with the improvement of the cognitive impairment (p
= 0.003) and daytime sleepiness (p = 0.001) (Seppi et al., 2011). In Parkinson’s patient with moderate
to severe depression, electroconvulsive therapy (ECT) may be beneficial through
stimulation of dopamine, noradrenaline and serotonin pathway. However, it used
was often limited due to the adverse effect of memory impairment (Aarsland, Påhlhagen, Ballard, Ehrt, &
Svenningsson, 2012). Thus, it was only considered in
patients who did not respond to the pharmacological treatments.

Table
1 : Summary of the
agents used in the treatment of depression in PD patients adapted from Seppi
et al. (2011).

Agents

Efficacy

Safety

Practice implications

Dopamine agonists

Pramipexole

Efficacious

Acceptable
risk without specialized monitoring

Clinically
useful

Pergolide

Insufficient
evidence

Acceptable
risk with specialized monitoring

Not
useful

TCA

Nortriptyline

Likely
efficacious

Acceptable
risk without specialized monitoring

Possibly
useful

Desipramine

Likely
efficacious

Acceptable
risk without specialized monitoring

Possibly
useful

Amitriptyline

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

SSRIs

Citalopram

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

Setraline

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

Paroxetine

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

Fluoxetine

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

MAOI – inhibitors

Moclobemide

Insufficient
evidence

Insufficient
evidence

Investigational

Selegiline

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

Newer agents

Atomoxetine

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

Nefazodone

Insufficient
evidence

Unacceptable
risk

Not
useful

Alternative treatment

Omega -3 fatty acids

Insufficient
evidence

Acceptable
risk with specialized monitoring

Investigational

 

ii)                 
Psychosis

            Another
non-motor symptoms associated with the Parkinson’s disease was psychosis. The
most common features of psychosis in PD patients were hallucinations and
delusions, but not all the patients will develop psychosis. However, once
develop, the symptoms were persistent and stressful (Bountouni, Zis, Chaudhuri, & Schrag, 2015). The treatment for psychosis mainly employed
the antipsychotic agents with clozapine being the most favourable agent. Seppi
et al. (2011) revealed that out of 55 patients
involved in the randomized, double-blinded study of 12 weeks period, 25
patients completely recovered from the psychosis. However, 19 persons
experienced relapse within one month after clozapine withdrawal. Many studies
had reported the efficacy of clozapine in the treatment of psychosis, yet it
used was restricted due to leucopenia, agranulocytosis and myocarditis. Thus,
clozapine utilization must be accompanied by regular blood monitoring (Seppi et al., 2011). The other atypical agents such as quetiapine
and olanzapine displayed no significant difference with placebo and they usage
were unlikely efficacious in the treatment of psychosis in PD. In case of
risperidone, improvement in the psychosis was detected, however, it can induce
worsening of the motor function (Ferreira et al., 2013).

            A
newer agent, Pimavanserin, provide alternative platform for the treatment of
psychosis with minimal affect on the motor symptoms. This agent served as a
selective serotonin 5-HT2A inverse agonist with high binding affinity towards 5-HT2A
receptors compared to 5-HT2C receptors (Cummings et al., 2014). The inverse agonist characteristics of
pimavanserin allowed this agent to not only block the action of agonist but
also modified the intrinsic activity of the receptor. This will prevent the
binding of 5-HT2A receptor, thus reducing the hallucinations and delusions (Stahl, 2016). The older generation of antipsychosis
agents blocked both the 5-HT2A receptor as well as dopaminergic receptor, D2
leading to various side effects. In addition, stimulation of D2 receptors by
the dopamine may also contributed to the development of the pyschosis often
seen with the used of dopaminergic drugs (Fox,
2014). Therefore, pimavanserin showed superior function
in terms of clinical effectiveness and adverse effect for the treatment of
psychosis without worsening of the motor symptoms. A 37% improvement in
psychosis was seen in patients treated with pimavanserin compared with 14% in
placebo in 6 weeks randomised, placebo controlled trial (Cummings et al., 2014).

iii)               
Anxiety

The treatment for
anxiety was almost similar with the treatment of depression. SSRI was the most
prescribed drugs for the treatment of anxiety among the PD patients with or
without depression eventhough the clinical effectiveness was not well
documented. In a study conducted by Richard
et al. (2012), there was no significant distinction
between placebo treated group and paroxetine and venlafaxine treated group.
However, the data from the uncontrolled studies suggested that paroxetine 20mg
daily was able to reduce somatic anxiety symptoms, but since anxiety was the
secondary outcome after depression, the findings from the study was not really
reliable (Chen
& Marsh, 2014). Furthermore, benzodiazepines were also
employed for the treatment of anxiety in Parkinson’s disease. Chen
and Marsh (2014) reported that clonazepam can be used in
the patients with anxiety that were unresponsive to the treatment with
alprazolam and lorazepam. Nevertheless, their used was often limited by the
side effects such as drowsiness, confusion, increase risk of falls and
exacerbation of existing motor symptoms like tremors and impaired coordination.

Another agent of
interest was buspirone. Buspirone was the partial agonist for 5-HT1A receptors
that was responsible for firing inhibition of 5-HT neurons, thus reducing the
activation of 5-HT receptors associated with anxiety. Low dose of buspirone
portrayed anxiolytic effect as well as reduction in levodopa induces
dyskenesias, without causing sedation and motor dysfunction. The clinical
response with buspirone can be seen as early as two weeks of the treatment. Although
well tolerated compared to benzodiazepine, high dose of this agent can lead to
worsening of motor symptoms and insomnia (Prediger, Matheus, Schwarzbold, Lima, & Vital,
2012).

iv)               
Autonomic dysfunction

Autonomic dysfunction
in Parkinson’s disease composed of many disorders including erectile
dysfunction, orthostatic hypotension, gastrointestinal motility
(constipation,nausea and vomiting), urinary frequency, urgency and
incontinence.

 In the treatment of constipation caused by
reduction in colonic transit, both pharmacological and non pharmacological
approaches can be taken. In the non pharmacological approaches, the PD patients
should be advised to increase the intake of fluid and fibres. Furthermore, they
also need to improve physical activity such as performing exercise for 30
minutes, three times in a week (Ferreira et al., 2013). In some cases, administration of
pharmacological agents may be needed. According to Rossi,
Merello, and Perez-Lloret (2015), the agents of choice include
polyethylene glycol and lubiprotone. As an osmotic agent, polyethylene glycol
relieved constipation by retaining the water in the colon, thus producing a
soft and watery stool. The efficacy of polyethylene glycol was evaluated among
57 PD patients for 8 weeks period. The result revealed that 80% of the patients
shown improvement in the stool frequency, straining, and stool consistency.
Generally, polyethylene glycol was well tolerated, however, during the study,
almost 14% of the patients discontinued to the adverse effects such as nausea
and diarrhea.

In addition,
lubiprostone was also the agent of choice for the treatment of constipation
among PD patients. This agent enhance the fluid secretion into the intestinal
lumen by activating type 2 chloride channels located in the apical membrane of
the gastrointestinal epithelium. This will facilitates the passage of the stool
throughout the gut with minimal alteration in sodium and potassium
concentrations (Jun,
2013). The efficacy of lubiprotone was evaluated in the
PD patients for a period of 4 weeks. At a dose of 24mcg twice daily,
lubiprostone treated group portrayed significant improvement in the stool
frequency compared to the placebo group. However, long term efficacy of
lubiprostone was not well established, thus regular monitoring was warranted
for long term treatment (Rossi et al., 2015).

Table
2 : Summary of the
agents used in the management of non-motor symptoms of PD adapted from Seppi
et al. (2011).

Agents

Efficacy

Safety

Practise implication

Psychosis

Clozapine

Efficacious

Acceptable
risk with closed monitoring

Clinically
useful

Olanzapine

Unlikely
efficacious

Unacceptable
risk

Not
useful

Quetiapine

Insufficient
evidence

Acceptable
risk without specialized monitoring

Investigational

Sexual dysfunction

Sildenafil

Insufficient
evidence

Insufficient
evidence

Investigational

Constipation

Polyethylene
glycol

Efficacious

Acceptable
risk but not recommended for long term treatment

Clinically
useful

Lubiprostone

Efficacious

Acceptable
risk but not recommended for long term treatment

Clinically
useful

Conclusion

            Management
of the non motor symptoms of Parkinson’s disease was quite challenging since
the symptoms did not respond to the treatment with dopaminergic drugs. To make
the matter complicated, the non motor symptoms can be induced or exacerbated by
the treatment with dopaminergic drugs. Therefore, the management of non-motor
symptoms in PD patients was important since most of them contributed to the
quality of life.