Medical management of PDP attempts to decrease psychotic symptoms without impeding motor symptom control. The first step in treatment involves reducing the dose of antiparkinson drugs, starting with those with the least clinical effect on motor symptoms.5 Dose reductions of anticholinergic agents, amantadine, and monoamine oxidase type B inhibitors should be considered first, with changes in doses of the more effective catechol-O-methyltransferase inhibitors, dopamine agonists, and carbidopa-levodopa being reserved for the most recalcitrant cases.5,13

If adjusting antiparkinson drugs fails to improve psychotic symptoms, additional treatment with atypical antipsychotics is warranted (Table 3).13 Treatment must be individualized for each patient, considering adverse effect profiles, overall cost to the patient, and the ultimate effectiveness of each drug.

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Low doses of atypical antipsychotic agents have long been used off-label for PDP treatment because their typical antipsychotic counterparts were associated with significant risk for extrapyramidal side effects.5 The 2 most commonly used atypical antipsychotics are clozapine and quetiapine, both of which have been shown to improve psychosis with minimal disruption of motor symptom control.5,9 Clozapine is used less often due to increased risks for agranulocytosis, myocarditis, and fatal arrhythmias and the strict monitoring protocol that these risks necessitate.13,14 Although quetiapine and clozapine rarely cause extrapyramidal symptoms, studies have shown that these antipsychotics can block the therapeutic effects of antiparkinson drugs on motor symptoms.9 This effect is thought to be attributed to the affinity of these agents for dopaminergic D2 receptors.9,13,14

The newest treatment for PDP is pimavanserin, which was approved by the US Food and Drug Administration in 2016 and is the only drug specifically indicated for the treatment of hallucinations and delusions in PD.13 Pimavanserin is a selective serotonin 5-HT2A receptor inverse agonist that does not affect dopaminergic receptors and, thus, preserves motor function.9,14 Pimavanserin initially was promoted as a safer treatment option for PDP for this reason, but multiple adverse reactions to pimavanserin have since been documented, including prolongation of the QT interval, peripheral edema, somnolence, and confusion.14,15 Although pimavanserin also carries the atypical antipsychotic black box warning of increased mortality in elderly patients with dementia-related psychosis, it is not approved for treatment of psychosis unrelated to PD.15 Following up on multiple patient reports suggesting that pimavanserin may increase the risk for death, in 2018 the FDA reviewed postmarketing reports of patient mortality and found no new safety risks associated with pimavanserin use in patients with PDP.15


Psychosis is a frequent and challenging symptom of PD. Due to its tremendous effect on caregiver burden, psychosis surpasses motor dysfunction as the greatest risk factor for nursing home admission in patients with PD.8 The course of PDP is progressive, eventually advancing from hallucinations or delusions with insight to the more stereotypical and disabling psychosis without insight.5 These psychotic symptoms herald a decline in patient function — as these symptoms progress, rates of patient morbidity and mortality significantly increase.6,16,17

Increasing severity of psychosis and comorbidities such as dementia are risk factors for a poorer prognosis in patients with PDP.16,17 Even with appropriate recognition of symptoms and subsequent treatment, PDP poses a clinical challenge; no single agent has proven effective for all patients with PDP.9,16,17 Management of PDP requires meticulous clinical adjustments and interdisciplinary follow-up, regardless of the clinician’s treatment decision, because reducing the severity of psychotic symptoms can significantly improve quality of life for both patients and caregivers.

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S. Hayden Newman, MPAS, PA-C, is a physician assistant who graduated from the Physician Assistant Department of Augusta University in Augusta, Georgia. Lisa Daitch, MPAS, PA-C, is an associate professor in the Physician Assistant Department of Augusta University, in Augusta, Georgia.


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