Antipsychotics in Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative condition that affects approximately one in every 500 people in the UK. It is more prevalent in men than in women and it usually starts after the age of 50.

PD is caused by the loss of neurons in the substantia nigra in the brain, which is usually a slow process occurring over several years.

These nerve cells synthetise dopamine, a neurotransmitter involved in several body functions, including reward-motivated behaviours, endocrine control (especially inhibition of prolactin release by the pituitary) and movement. The nigro-striatal path controls our body motor system and that explains the main symptoms present in PD: tremor, bradykinesia, rigidity and postural instability. Along with these typical ‘parkinsonian’ symptoms, PD patients may experience the following at some stage of their illness: loss of sense of smell, depression, dementia, cognitive impairment, dizziness, fainting, erectile dysfunction, hyperhidrosis, dysphagia, drooling or insomnia. Moreover, psychotic symptoms, mainly hallucinations (visual) and delusions, are common in PD due to the nature of the condition. Sometimes, they may also manifest as a side effect of anti-parkinsonian medication such as levo-dopa, anticholinergics or dopamine agonists (ropinirole, pramipexole).

Clinicians often face a big dilemma if psychosis is present in PD, which is usually in the later stages of the illness associated with dementia. On one hand, reducing current antiparkinsonian drugs may have a negative impact on motor symptoms and most antipsychotics could aggravate movement disorders. On the other, untreated psychosis may affect the patient’s quality of life, their family members and carers. Looking at the evidence and currently available guidelines, there are a few points to consider when antipsychotic medication is deemed necessary in a patient with PD.

• Do not treat hallucinations and delusions in PD patients who tolerate them well and are not distressed by them.
• Before considering antipsychotic medication, other treatable causes of psychosis should be excluded, for example, UTI or pneumonia.
• It is generally accepted that a reduction of antiparkinsonian drugs may improve psychosis. This is often at the expense of mobility, so careful patient monitoring and small dose reductions are advised.
• Olanzapine is not helpful in improving psychosis in PD and worsens motor symptoms, therefore is not recommended.
• First-generation antipsychotics like haloperidol or chlorpromazine are best avoided in PD. They may worsen extra-pyramidal symptoms. The same goes for risperidone.
• Lower doses of antipsychotics are required in PD patients, who are usually very sensitive to medication.

In the UK, clozapine is the only licensed treatment for psychosis in Parkinson’s disease. The recommended therapeutic clozapine dose for this indication is around 50mg/day and a maximum dose of 100mg/day is specified in Clozaril® SPC. Clozapine may cause agranulocytosis and patients must undertake weekly blood tests during the first 18 weeks of treatment, every two weeks between weeks 18 and 52 and every four weeks thereafter. Clozapine is effective treating psychosis and also, in some cases, improves motor function.

The NICE guideline 71 ‘Parkinson’s disease in adults’ recommends low-dose quetiapine to treat psychosis in PD patients without cognitive impairment. Quetiapine has shown some effectivity reducing psychotic symptoms in PD but no benefit over clozapine. Despite the lack of clear evidence, quetiapine is widely used and normally well tolerated, with sedation and orthostatic hypotension as the two most common side effects.

A novel agent, pimavanserin, was approved in 2016 to treat hallucinations and delusions associated with PD in the United States. Pimavanserin does not affect the motor system or cause sedation, but may affect the QTc interval. Pimavanserin is yet to be licensed in the UK.

Rivastigmine, a cholinesterase inhibitor, is licensed to treat mild to moderately severe dementia in PD and it helps with behavioural and psychological symptoms.

In conclusion: clozapine is the only licensed antipsychotic in PD but it remains underutilised, due to concerns about adverse effects and the regular mandatory blood tests. Quetiapine is often clinicians’ first choice due to its safer side-effect profile although it is not licensed for this particular indication. Pimavanserin might soon be another effective treatment available but more research is needed to establish its current role in the UK and further benefit patients suffering from psychotic disturbances in PD.