Management of Psychosis in Parkinson's Disease: Clinical Tidbits

Parkinson's disease (PD) psychosis is a significant symptomology that occurs in nearly 40% of patients with Parkinson's.¹ It can be difficult for patients, caregivers, and treatment teams to manage. The visual hallucinations and delusions are associated with increased caregiver burden, increased mortality, and quicker time to nursing home placement. Here are some clinical tidbits to consider when faced with PD psychosis:

Management of Contributing Agents

• Benign PD psychosis can be succesfully managed with observation and nonpharmacologic intervention. Problematic PD psychosis could put the patient or caregiver at increased risk of harm or lowered quality of life and benefits from intervention. Acute psychosis should be evaluated for nonpharmacologic causes (ex. urinary tract infection, encephalopathy). If no acute process is identified, the provider should turn to the medication profile and identify any potentially contributing non-PD medications, such as sedatives or anxiolytics. These offending agents should be stopped or dose reduced prior to adjusting PD medications.
• PD medications that could contribute to the psychosis should be reduced or stopped based on the efficacy of the agent in treating the underlying PD.² It is important to note abruptly discontinuing many of the PD medications (excluding anticholinergics) can lead to withdrawal symptoms and in rare instances neuroleptic malignant syndrome. Interventions should be gradual to minimize the risk of these complications.
• Geriatric patients are more susceptible to anticholinergic activity and are at an increased risk of anticholinergic delirium. Anticholinergics such as trihexyphenidyl and benztropine are a common treatment for early stage PD and can be safely reduced or interrupted in psychosis as a first-line intervention.
• Amantadine has less robust efficacy data supporting its use in PD, and it's mechanism is not well understood but may be related to NMDA receptor antagonism. It is most commonly used in early-stage PD or younger PD patients. It is the next agent recommended to be reduced or stopped in episodes of PD psychosis. Avoid abrupt discontinuation or significant dose reductions to minimize the risk of withdrawal syndromes.
• Dopamine agonists are commonly implicated in PD psychosis but should be adjusted after the agents associated with less efficacy have been reviewed. Levodopa therapy is the mainstay of PD treatment and should be reduced only if all other attempts to address the PD have not resolved the underlying issue. Avoid abrupt discontinuation or significant dose reductions to minimize the risk of withdrawal syndromes.
• If no improvement is seen, MAO-B inhibitors (selegeline) and COMT inhibitors (tolcapone and entacopone) are the next agents to be interrupted or reduced. COMT inhibitors prolong the patient's exposure to levodopa, so abrupt withdrawal or discontinuation should be avoided to minimize acute worsening of PD dyskinesia symptoms.

Medications for Neuropsychiatric Symptoms

• Cholinesterase inhibitors such as rivastigmine and donepezil have shown a small reduction in hallucinations and neuropsychiatric symptoms. Initiating a cholinesterase inhibitor is unlikely to provide significant benefit in an acute episode, but it may be reasonably considered given it's effect on cognitive scoring.
• Antipsychotic management of Parkinson's Disease psychosis should be limited to clozapine, quetiapine, or pimavanserin. Low dose clozapine has the strongest evidence in PD psychosis, but it is not often used in the due to the REMS program requirements and concerns over agranulocytosis.⁴ Clozapine is also associated with more anticholinergic activity, which could precipitate delirium in the geriatric population. Quetiapine is structurally similar to clozapine and has been shown to have a similar loose affinity for D2 receptors. The data on quetiapine is conflicting,^5,6 but due to the safer side effect profile and similar pharmacokinetics to clozapine, should be the treatment of choice.
• Typical antipsychotics and atypical antipsychotics (excluding clozapine and quetiapine) are associated with reduced levodopa efficacy and an increased risk of involuntary movements. They should also be avoided in patients receiving dopamine agonists for their PD due to the opposing mechanisms of action.
• Pimavanserin is a novel atypical antipsychotic currently only FDA approved for PD psychosis. It has no affinity to dopamine receptors allowing for concomitant administration with levodopa and dopamine agonists. The trial data showed no motor symptom worsening over a 6-week period and an improvement in psychosis.⁷ It is a promising agent that could be considered instead of clozapine or quetiapine with adequate insurance coverage. Pimvanserin is also being studied in Alzheimer's disease psychosis and completed a phase 2 trial in December 2016.

The management of Parkinson's associated psychosis can be a complicated medication therapy management process. Succesful improvement of PD psychosis requires thoughtful evaluation of symptomology, goals of care, and the patient's underlying Parkinson's disease.

References

1. F

é

nelon G, Mahieux F, Huon R, et al. Hallucinations in Parkinson's Disease: prevalence, phenomenology, and risk factors. Brain, Volume 123. (Pt 4):733-745.

2. Zahodne L, Fernandez HH. Pathophysiology and treatment of psychosis in Parkinson's Disease: a review. Drugs Aging. 2008; 25(8):665-682.

3. Emre M, Aarsland D, Albanese A et al. Rivastigmine for dementia associated with Parkinson's DIsease. N Engl J Med. 2004; 351: 2509-2518.

4. T

he Parkinsons Study Group. Low-Dose Clozapine for the Treatment of Drug-Induced Psychosis in Parkinson’s Disease. N Engl J Med. 1999. 340:757-763.

5.Morgante L, Epifanio A, Spina A. et al. Quetiapine versus Clozapine: A preliminary report of comparative effects on dopaminergic psychosis in patients with Parkinson's DIsease. Neurol Sci. 2002; 23(2):S89.

6. Ondo W, Tinter R, Voung KD, et al. Double-blind, placebo-controlled, unforced titration parallel trial of qeutiapine for dopaminergic-induced hallucinations in Parkinson's DIsease. Mov Disord. 2005; 20(8):958-963.

7. Cummins J, Isaacson S, Mills R. et al.Pimavanserin for patients with Parkinson's Disease Psychosis: A randomised, placebo-controlled phase 3 trial. Lancet. 2013; 383(9916):533-540.