Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease, and the number of people with PD is expected to reach 9 million worldwide by 2030. So, what drugs should be chosen for the initial treatment of different PD patients? A recent review published in the BMJ reviewed the currently available drugs for initial therapy and some of the drugs that are still being investigated.
Pathophysiology and epidemiology
The prevalence of PD is approximately 0.3%, increasing to 1% in people over 60 years of age, and the incidence of PD is approximately 8-18 per 100,000 person-years. The disease usually develops after 50 years of age, with peak incidence after 60 years of age, and previous studies have shown a higher incidence in men than in women.
The pathogenesis of PD is mainly based on cell degeneration and dopaminergic defects. Many studies have been conducted to explore the mechanism of neuronal degeneration and death, with the aim of developing neuroprotective drugs to delay or stop the degeneration process. On the other hand, symptomatic treatment is currently focused on dopamine replacement therapy to improve motor symptoms. Regardless of which of these treatment strategies is applied, early treatment of PD patients must include patient education, support, medication guidance, and non-pharmacological interventions.
Neuroprotective drug therapy
Although studies related to drugs such as resagiline, pramipexole and ropinirole have not yet suggested a clear neuroprotective benefit, neuroprotective drug research continues and involves many different pathways, such as reducing oxidative stress, altering apoptotic pathways, inducing neurotrophic factor production, and modulating cell signaling.
1. Glutathione.
It has been shown that the increase of oxidative stress may lead to the death of dopaminergic neurons, so glutathione is used as an antioxidant in the study of PD. Oral glutathione does not cross the blood-brain barrier, and studies have been conducted to try to increase the effect of glutathione through other mechanisms. A phase I clinical study is evaluating the safety and tolerability of transnasally administered glutathione; another study is attempting to increase glutathione concentrations by way of dietary supplementation.
2. Nicotine.
Smokers have a lower incidence of PD, and studies have shown that nicotine may alter calcium-related signaling pathways as well as the immune response system, thereby reducing or preventing neuronal damage. An RCT study is evaluating the efficacy of a 52-week treatment with nicotine transdermal patches in PD patients, with the primary endpoint being the change in UPDRS (Parkinson’s Disease Rating Scale) scores before and after treatment.
3. Pioglitazone.
Studies have shown that pioglitazone reduces microglia activation as well as oxidative stress and restores mitochondrial function. Since pioglitazone inhibits MAO-B activity, it is unclear whether it has a true neuroprotective effect or simply reflects the effect of inhibiting MAO-B activity.
4. Granulocyte colony-stimulating factor.
Although granulocyte colony-stimulating factor is commonly used to treat leukopenia, a PD mouse study showed that it can exert long-term neuroprotective effects and improve motor function in animals. Possible mechanisms of action include anti-apoptosis, reduction of inflammatory response, and induction of neurogenesis.
5. GM608.
GM608 is an endogenous human neuromodulatory and signaling-related peptide that occurs at the cellular stage, and a phase II RCT study is currently evaluating the efficacy of intravenous GM608 as a neuroprotective agent for PD.
6. Physical exercise.
Animal models show that exercise induces brain-derived neurotrophic factor production, exerting a potential neuroprotective effect. Human studies on different types of exercise are underway, including moderate or vigorous intensity treadmill exercise, brisk walking or simulated cycling. A systematic review has shown that treadmill exercise can improve gait abnormalities in patients, however, the amount and duration of exercise is unclear.
7. Surgery.
Animal studies have shown improvement in dopaminergic neuron survival after pharmacological ablation or DBS.
Symptomatic treatment of Parkinson’s disease: non-motor symptoms
Non-motor symptoms can appear very early in PD and commonly include depression, fatigue, sleep and wakefulness disturbances; their impact on patients’ quality of life is more prominent than motor symptoms.
1. Depression.
The two drugs that have shown to be “effective” or “clinically useful” for the treatment of depressive symptoms are pramipexole and venlafaxine. Tricyclic antidepressants are considered “probably effective” or “probably clinically useful”. Other medications and TMS treatments are currently showing insufficient evidence. Interestingly, cognitive-behavioral therapy has been shown to be “possibly effective,” but further research is needed to confirm this.
2. Fatigue.
Drugs that may be considered for fatigue include methylphenidate and modafinil. Since the current study period has not yet exceeded 8 weeks, the current drug efficacy is limited to short-term treatment effectiveness. Based on this, both are currently considered “insufficient evidence” for the treatment of fatigue, and further studies are needed to confirm their efficacy.
3. Sleep disorders.
The drugs currently under investigation include pergolide, carbidopa-levodopa, eszopiclone, and melatonin. All drugs have shown “insufficient evidence” for their current efficacy. However, the exception is melatonin, which “may be useful” for PD patients with insomnia. There are no good quality RCTs on sudden sleep onset, but there are three RCTs evaluating wake-promoting medications, but the findings are inconsistent.
4. Other non-motor symptoms.
There are no high-quality RCT studies evaluating REM behavior disorders and anxiety therapy. The effects of therapeutic medications for other non-motor symptoms were not significant.
Outlook and conclusion
Parkinson’s disease is a complex disease with multiple treatment options, especially in the early stages of the disease. When patients are first diagnosed with PD, they need to be aware of two different treatment approaches – neuroprotective therapies and symptomatic treatments that target neurotransmitter function. In many cases, the treatment strategy requires consideration of when to start treatment and which symptoms need to be treated. This requires a discussion of the pros and cons of treatment based on the patient’s level of disability and treatment goals. As the patient’s disease progresses, treatment endpoints may change and other medications or complementary drug therapy may be required.
Gene and cellular therapies are invasive and are currently only being considered for patients with intermediate to advanced PD. In the future, once the safety, tolerability, and efficacy of potential therapies are clarified, clinicians will intervene early in the disease with both symptomatic and neuroprotective treatments.