Rotigotine in the treatment of nonmotor symptoms of Parkinson’s disease
At the 1st Quarterly Scientific Meeting 2022 of the Hong Kong Movement Disorder Society, Professor Ray Chaudhuri lectured on personalized medicine in Parkinson’s disease (PD), featuring a nonmotor perspective and delivering medicine based on PD subtypes. Of note, he highlighted the role of rotigotine in the treatment of nonmotor symptoms of PD.
PD is a syndrome rather than a single disease
PD is considered a syndrome rather than a single disease, in terms of the clinical, phenotypic and pathophysiological heterogeneity between patients.1,2 For instance, there are differences between genetic and epigenetic, alpha-synuclein abnormalities, amyloid and Tau deposition, as well as differences between mitochondrial dysfunction, neuroinflammation, altered gut microbiota, and neurotransmitter-linked abnormalities.1 It is, therefore, important for modern physicians to treat PD by considering the differences in the subgroups and subtypes.
Although the motor aspects of PD are well established, the spectrum of PD symptoms extends to nonmotor problems, including autonomic dysfunction, neuropsychiatric, cognitive, drug-induced, sensory disorders, urinary disorders, fatigue, sexual dysfunction, sleep disorders, and gastrointestinal disorders.3 All of these are likely to present through a patient’s PD journey and in the prodromal stage, which can help to predict the development of PD before the condition starts.4
The neuropathology of PD suggests that it is not just a brain disorder, but also a multi-organ disorder involving the central nervous system (CNS) and extra-CNS.1,5 PD is a multi-peptide dysfunction-related disorder rather than just a disorder of dopamine, which can include cholinergic, serotonergic and noradrenergic dysfunctions.1,6 Non-dopaminergic involvement may be greater than dopaminergic involvement. Therefore, physicians cannot treat all patients using the same principles.
The link between nonmotor subtypes of PD and personalized medicine
Previously, PD subtyping focused entirely on the motor symptoms. However, the modern concept is different, where PD can be classified by age (young vs. older onset), motor (tremor vs. akinesis dominant), nonmotor (cholinergic, noradrenergic, serotonergic, which are the three other emerging subtypes that require different patterns of treatment), and genetic subtypes (GBA-PD vs. LRRK2-PD).
PD is not a uniform or homogeneous condition.2 Though guidelines are important, clinical treatment should remain bespoke and personalized, particularly for the nonmotor aspects of PD. The concept of nonmotor subtypes is based on the biomarker-driven identification of phenotypes comprising cholinergic, noradrenergic, serotonergic, and mixed neurotransmitter dysfunction underpinned by dopamine deficiency (figure 1).6 The resulting clinical phenotypes are likely to have nonmotor symptoms ranging from cognitive to sleep dysfunction.
Personalized medicine for these subtypes involves the treatment of specific nonmotor symptoms and consideration of the nonmotor side effects of dopaminergic drugs.6 This can be achieved by a multi-modal approach which includes imaging, and the detection of genetics and pharmacogenetics, resulting in a subtype-specific treatment strategy.6
The future concepts for personalized medicine, like genetic analyses in patients, can be utilized to determine if a patient has a GBA mutation or LRRK2 mutation in the prodromal stage of PD to assist in tailoring treatment for the individual. During the clinical stage of PD, nonmotor treatments can be driven by the cholinergic (cognitive issues), serotonergic (fatigue issues), noradrenergic (dysautonomia issues), or mixed (sleeping issues) subtypes. Lastly, clinicians should consider personalized medicine through pharmacogenetics, specifically dopamine replacement therapy (DRT) and its related clinical responses and side effects. For example, there are mutations which can make a patient more susceptible to hallucinations, psychosis, sleep events, or impulse control disorders, which would all require different treatment approaches.
The use of rotigotine for treating nonmotor symptoms in PD patients
The efficacy, safety and tolerability of rotigotine for the treatment of motor symptoms of PD are well-established.7 Although it has been shown that rotigotine may improve nonmotor symptoms such as fatigue, depression, anhedonia and apathy in PD patients, further studies are required to confirm its effects in the nonmotor aspect.7,8
Patients grouped under the cholinergic subtype present with early cognitive decline, falls and apathy.6 Treatment considerations for the early use of cholinesterase inhibitors along with DRT are recommended, with the avoidance of anticholinergic drugs.9 There is also a need for early cognitive back-ups (cognitive training, brain/memory exercises), forward planning (due to early onset of dementia) and gait training.9 Constipation is a problem in this group of patients, and therefore, probiotics are important.9
Patients grouped under the serotonergic subtype present with somnolence, insomnia and fatigue. While depression and anxiety are common in PD, and are frequently comorbid, they also can occur separately. They also fit in the serotonergic subtype of PD, together with apathy (dopaminergic vs. non-dopaminergic). This group of patients also present with nonmotor fluctuations, including features like fatigue, depression, anxiety, inner restlessness, concentration, attention issues, and sweating. Treatment options can be dopamine agonists for apathy (i.e., rotigotine), while the avoidance of dopamine agonists with a D3 activity is also important (i.e., pramipexole and ropinirole).10
Patients grouped under the noradrenergic subtype present with dysautonomia. The recommended treatment would be non-oral dopaminergic therapies such as rotigotine.
Rotigotine is a significant dopamine agonist for the treatment of nonmotor symptoms and its benefits include improving sleep quality/insomnia, effective in reducing off time, restless legs, periodic leg movement, and nocturia because of the D1 activity.11 The rotigotine patch is particularly useful for the anxiety fluctuation phenotype. Under many circumstances, using longer-acting, continuous drug delivery for patients who have fluctuations to relieve their apathy is of utmost significance.11
PD is regarded as a multi-system and syndromic condition. Personalized medicine should be provided based on genetics, subtypes and pharmacogenetics. The emerging endophenotypes of PD, including not only motor, but also nonmotor subtypes (cholinergic, noradrenergic, serotonergic), require different and individualized treatment options. DRTs, like rotigotine, that target multiple receptors may be the optimal drugs for treatment because they target many different neurotransmitters, like dopamine, serotonin and norepinephrine compared with single receptor drugs.
TWHK-N-DA-PD-2200001 Approved on: 10/6/2022