Tera Raymond, PharmD; PGY-1 Pharmacy Resident: Kansas City VA Medical Center
Keith Anderson, PharmD, BCPP: Kansas City VA Medical Center
Rachel Walker, PharmD, BCPP: Kansas City VA Medical Center
Parkinson’s disease, a chronic and progressive neurologic disorder, afflicts nearly 10 million people worldwide.1 The characteristic motor symptoms of Parkinson’s disease, including bradykinesia, muscular rigidity, resting tremor, and postural instability, are thought to be caused by a loss of dopamine producing cells, along with decreased dopamine concentrations within the brain.2 Many of the common therapies available for Parkinson’s disease work to alleviate these motor symptoms through either dopamine agonism or blockade of dopamine metabolism in the brain. Despite medication strategies being available to manage bothersome motor symptoms, no therapies exist for the prevention or cure of Parkinson’s disease. While medication therapies are available for managing the burden that may arise with progressive motor symptoms, even fewer treatment options are available for non-motor symptoms, which are often reported by patients and caregivers as more troublesome and distressing.2
Non-motor symptoms, such as depression, dementia, and sleep disturbances are associated with a decreased quality of life and increased lifestyle strain to patients and their caregivers than the more well-known motor symptoms.3 Psychosis is the most frequently reported non-motor symptom, and is often the most debilitating, affecting more than 50% of patients with Parkinson’s disease.4,5 The clinical presentation may vary, but is generally characterized by features such as visual and presence hallucinations and less commonly delusions and illusions.6 Previously, there had been no standard diagnostic criteria for Parkinson’s disease psychosis. However, in 2007 a new set of criteria was proposed by the National Institutes of Neurological Disorders and Stroke-National Institute of Mental Health (NINDS-NIMH).7 This new criteria defines Parkinson’s disease psychosis as the presence of illusions, hallucinations, delusions, or a false sense of presence that is recurrent or continuous for one month after the onset of Parkinson’s disease, and cannot be attributed to another cause.7
The underlying pathophysiology of Parkinson’s disease psychosis is associated with three main neurotransmitter systems: dopaminergic, cholinergic, and serotonergic.3 The primary hypothesis for psychosis previously revolved around the overstimulation of dopamine receptors in the brain, and subsequently involved dose reduction of dopaminergic medications as initial therapy for psychosis.3 However, several observations have shown no difference in resolution of psychotic symptoms with dopaminergic medication adjustments.3 Additional neurotransmitter pathways have become entwined in the mechanism, specifically an imbalance of anticholinergic and dopaminergic systems in the striatum and a loss of serotonergic neurons and dysregulation in the brain.3 In addition, other factors of Parkinson’s disease outside of neurotransmitters may also play a part in the development of psychosis, including advanced Parkinson’s disease, patient age, and cognitive decline.3 Despite a proposed mechanism for the development of psychosis and the neurotransmitters thought to play a part in developing symptoms, the therapies available for treatment are sparse.
Historically, antipsychotic medications have been the primary treatment modality studied in regards to managing Parkinson’s disease psychosis. Prior to initiating or adjusting medication therapy for symptom management, any potential underlying causes for acute psychosis should be addressed, such as including acute infections or ingestion of stimulants.8 Medication adjustments and tailoring of therapies to remove any non-essential medications that may exacerbate or worsen psychosis symptoms, such as anticholinergic medications or benzodiazepines, is a key first step.9 This may also require a step-wise approach to remove dopaminergic medications, while still maintaining motor function.7 At this step in therapy, patients and caregivers may have to consider initiation of additional medications if psychosis symptoms are not effectively managed with adjustments of dopaminergic medications.7
Currently, the medications commonly utilized in Parkinson’s disease psychosis include quetiapine and clozapine. However, more recently, pimavanserin has been studied as a novel therapy for this unique niche of patients.3 While these antipsychotics are the mainstay of therapy, it is important to note that the second generation antipsychotics still carry a black box warning in patients with dementia in regards to concern for causing sudden death.9 First generation antipsychotics are often not utilized in this population due to lack of data supporting improvement of psychosis symptoms, and the tendency to cause worsening of motor symptoms.10 Second generation antipsychotics, including olanzapine, aripiprazole, and risperidone have also been studied. The data is limited supporting the use of these medications to improve psychosis symptoms and have not shown statistical significance for symptom relief but instead have shown a worsening of motor symptoms.3 In patients with both psychosis and dementia, cholinesterase inhibitors have also been studied. Although data from these trials show improvement in cognitive function, there was no significant changes in psychotic symptoms.3
Clozapine is the most heavily-studied therapy for Parkinson’s disease psychosis, with evidence to support its use in minimizing psychosis symptoms, including hallucinations, due to its unique mechanism of action involving all three neurotransmitters affected in psychosis.3,7 Although recommended in guidelines and showing promise in clinical trials, clozapine requires extensive monitoring and frequent laboratory draws due to the risk of agranulocytosis.3,11 At the lower doses utilized in Parkinson’s disease, clozapine has not been shown to cause long-term metabolic problems as seen with higher doses. However, other side effects, such as hypotension and sedation, are still commonly encountered.9 While effective for symptom control and with little to no worsening of motor symptoms, the intense monitoring makes it a less favorable choice for initial management.9 Despite the data that supports clozapine’s use in therapy, quetiapine is often utilized as first-line therapy. Quetiapine is similar to clozapine in structure and mechanism, but with less frequent required monitoring.9 Although quetiapine has been studied in the treatment of Parkinson’s disease psychosis, evidence is lacking regarding its efficacy in managing psychosis symptoms, specifically hallucinations.3 Regardless of the data, use of quetiapine is still recommended by the American Academy of Neurology guidelines and has not been shown to worsen motor symptoms.11
Pimavanserin, a novel therapy, has recently received FDA approval for hallucinations and delusions associated with Parkinson’s disease psychosis.12 Pimavanserin acts via a combination of selective serotonin antagonism and inverse agonism, and demonstrated beneficial results in clinical trials by reducing non-motor symptoms associated with psychosis, including minimization of hallucinations and delusions.12 When compared to placebo, pimavanserin did not show an effect on worsening motor function, and was the first medication to show a beneficial effect in reducing caregiver burden.12,4 The most common adverse reactions noted in clinical trials were nausea, constipation, peripheral edema, and confusion. Post-marketing monitoring has also noted adverse effects including somnolence, rash, and reactions similar to angioedema.12 Pimavanserin is classified as an atypical antipsychotic and still carries a warning for increased mortality in elderly patients with dementia and risk for increased QT prolongation, similar to warnings and precautions with other antipsychotics.12
Pimavanserin shows potential as a novel agent for management of non-motor symptoms associated with Parkinson’s disease psychosis. However, more data and clinical trials are needed comparing pimavanserin versus current treatments to determine its appropriate place in therapy. In addition, the guidelines for non-motor symptoms in Parkinson’s disease by the American Academy of Neurology have not been updated since 2006. Consequently, quetiapine and clozapine are still recommended as first-line agents.11 Despite the lack of support within guidelines at this time, pimavanserin shows promise for use in patients suffering from hallucinations and delusions caused from Parkinson’s disease. With less rigorous monitoring and clinical data supporting its effect on psychosis, pimavanserin may soon find a place in the guidelines as recommended therapy for Parkinson’s disease patients.
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11. Miyasaki JM, Shannon K, Voon V, et al. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006 Apr 11;66(7):996-1002.
12. Neuplazid [package insert]. San Diego, CA: ACADIA Pharmaceuticals Inc.; 2017.