Parkinson’s disease (PD) is a disorder of unknown cause affecting 1% of people over 60 years of age, making it the second most common neurodegenerative disorder after Alzheimer’s disease in this population. The motor symptoms associated with PD are thought to arise from dopamine deficiency, although the pathophysiology of various Parkinsonian symptoms is not yet fully understood. Many axial motor symptoms – e.g. gait problems, postural instability – and non-motor symptoms – e.g. dysarthria, dysphagia, pain, diplopia and urinary urgency – do not respond to dopamine replacement and are thought to be due to degeneration of non-dopaminergic neurons.

As a dopamine replacement therapy, levodopa has become and remains the standard of care for patients with PD. While levodopa clearly improves motor symptoms, allowing many patients to better perform daily activities and continue working, a major disadvantage of long-term standard levodopa therapy is the development of disabling motor complications characterised by ‘wearing off’, dyskinesias and ‘on–off’, which occur in up to 80% of patients and can be even more disabling than the disease itself. Levodopa was introduced in the therapy of PD in 1968 and other drugs were introduced later, but questions remain: when should dopaminergic treatment be started, how should levodopa be administered when first introduced and is there a way to minimise motor complications?

When to Start Treatment
There is no evidence indicating when dopaminergic treatment should be started in PD patients. However, until now the recommendation that drug treatment should be delayed until the symptoms of PD significantly limit the patient’s motor functions has become established teaching and is included in many guidelines. The rationale for this is to protect the patients from unnecessary side effects, particularly the motor complications associated with levodopa. Moreover, a view also developed that patients in whom the introduction of pharmacological treatment is delayed would respond for longer when the drugs were introduced. Despite the lack of evidence supporting this theory, it is followed by the majority of clinicians.

The clinical onset of PD is directly associated with a series of functional changes in basal ganglia circuits and their target projections. Bearing in mind that denervation in PD begins approximately six years before the appearance of symptoms, basal ganglia have a remarkable capacity to cope with progressively lower levels of dopamine-activating compensatory mechanisms. The appearance of symptoms indicates the point of failure to adequately deal with dopamine depletion.

Recently, Schapira and Obeso proposed that early restoration of basal ganglia physiology could support compensatory events and delay the irreversible modification of circuitry that characterises the clinical progression of PD. This idea makes sense and may explain the results of the elledopa study and the rasagiline delayed start trial. In fact, in the elledopa study the patients treated with placebo showed a significant difference in disease severity compared with the patients treated with levodopa, even after two weeks of therapy washout. It may be argued that two weeks is not long enough to rule out the long duration response of levodopa and that rasagiline may have a neuroprotective effect. However, the theory that there is a connection between the early compensatory effect of a symptomatic drug and better long-term symptom control is fascinating. Moreover, some deformity of the hands or spine may be avoided by early therapy.