New Drug Shows Promise in Treating Parkinson's Disease Psychosis

By Jaimie Lazare

Off-label drugs have been used to manage psychotic-related symptoms in Parkinson's disease patients, but they worsen motor symptoms by reducing dopamine levels. Nuplazid is the only FDA-approved drug that treats Parkinson's disease psychosis without impairing motor function.

Parkinson's disease (PD) is a progressive neurodegenerative condition marked by bradykinesia, rigidity, tremor, and postural instability. While therapeutic advances have been made to improve motor-related symptoms, many older adults affected by this disease also develop Parkinson's disease psychosis (PDP). Psychotic symptoms such as hallucinations and delusions develop in more than 50% of PD patients and can lead to severe impairments in cognitive, behavioral, and emotional function.1

PDP Drives Nursing Home Placement
According to the Parkinson's Disease Foundation, 1 million people have been diagnosed with PD in the United States, and between 7 million and 10 million people worldwide have the condition. Hallucinations and delusions drive the nursing home placement and hospitalization of patients diagnosed with PDP, says Jason Kellogg, MD, chief of staff at Newport Bay Hospital in Newport Beach, California.

Approximately 75% of PD patients develop psychosis-related symptoms such as hallucinations and delusions.2 "The tremor is disturbing to the patient, but it's usually something that can be managed at home. It's when these patients start having agitation, delusions, and hallucinations—[those symptoms] end up driving a higher level of care," Kellogg says.

He adds that the delusions and hallucinations observed in PDP tend to be more dramatic in nature. For instance, these patients are usually high-functioning, well-dressed men and women. But their hallucinations are quite striking because they have delusions of persecution and visual hallucinations.

He recalls a patient who insisted there were ants all over the walls, another who saw people holding rifles as they passed by his room, and a patient who was convinced that a small child was outside her nursing home window. What makes their psychosis striking is that these patients had had no hallucinations and delusions previously throughout their lives. It's a drastic change from their baseline compared with that of a schizophrenic patient who may have started having hallucinations at the age of 18 and goes on to develop poor grooming and hygiene and appears paranoid. In those patients, it's not surprising when they have delusions because they've experienced them their entire life, whereas PDP patients develop hallucinations and delusions that are sudden and distinctive, Kellogg explains.

PDP patients have insight, which is a short window of time in which they recognize what they are seeing doesn't make sense; however, this period of insight disappears, at which point he or she tries to convince everyone else that the hallucinations are real, Kellogg says.

Kellogg explains that most families make efforts to do all they can when the disease is purely medical, involving only tremors or slow movements. But when patients begin to display signs of delusions that lead to ideations of people conspiring against them or stealing their money, the caregiver burden becomes excessive. Consequently, families often begin with in-home help, but when that eventually fails, these patients often are admitted to long term care.

Nuplazid: Breakthrough Therapy for PDP
Nuplazid met the criteria for the FDA's Breakthrough Therapy and Priority Review designations because the drug has been shown to have preliminary clinical evidence of efficacy, and no other drug had been approved specifically to treat the hallucinations or delusions of PD, says Mitchell Mathis, MD, director of the division of psychiatry products in the FDA's Center for Drug Evaluation and Research.

PD patients are prescribed dopamine-enhancing drugs that treat their motor symptoms, but these drugs can cause or exacerbate hallucinations and delusions, which are the primary symptoms seen in PDP, Mathis says.

"While in the atypical antipsychotic class of drugs, the pharmacology of Nuplazid is different from other drugs because Nuplazid binds primarily to serotonin receptors with very little binding to dopamine receptors. The other drugs in the class bind to dopamine receptors as part of their primary mechanism of action," Mathis says. As a result, because dopamine must be replaced to treat PD, and that replacement can exacerbate hallucinations and delusions, Nuplazid could be considered to treat the psychiatric symptoms without interfering with the motor symptoms of PD, he says.

PD patients experience a dopamine deficiency. Every antipsychotic prior to Nuplazid lowers dopamine, which worsens a patient's motor symptoms. Even though the delusions may improve as the level of dopamine decreases, the fundamental symptoms of PD become worse, Kellogg says. Nuplazid treats psychosis-related symptoms in PD without producing any type of dopamine blockade. Because this medication has zero dopamine affinity, it's ideal for PD patients because they already have low levels of dopamine, he says.

In the clinical trial, the medication was effective at reducing delusions and hallucinations, and an open-label extension of the trial was also conducted, Kellogg says. "What we learned is that there was durability of effect, and it was appearing that over time the delusions were coming down, albeit at a slower rate, but they were still coming down. So we won't need a lot of add-on therapy with this particular medication."

According to Mathis, "Experience with other antipsychotic drugs in older people has indicated an increased risk of death. There was an increased number of deaths in patients taking Nuplazid compared with patients taking the placebo in the clinical trials, but the difference was small, and the risk was not related to any one organ system. There were three deaths on Nuplazid and one on placebo in the trial, but a lack of any unifying mechanism leaves us unable to draw any conclusion about causality." Because a similar pattern had been seen in other drugs in the antipsychotic class, those drugs along with Nuplazid have a boxed warning to alert clinicians and patients about the increased risk of death in elderly demented patients, he says. 

Considerations in the Cost of Treatment
Kellogg points out that it's important to keep the entire picture in mind. "The cost per pill on some of these breakthrough therapies can seem high when you look at them at first glance. But when you look at them at second glance, it's the Parkinson's disease psychosis that drives nursing home care and hospitalizations," he says.

"It's essential to look at the big picture. When you look at the data, these medications are actually preventing relapses and the push to put these patients in long term care facilities. It's the hospitalizations and the long term care that really cost society a lot of money," Kellogg says.

Most of the PDP patients already take antipsychotic medications, so it's necessary to factor in the cost of not only the hospitalizations and the long term care placement but also the fact that these patients already take medicine. Those other antipsychotics are expensive, Kellogg says. "When you look at the cost of Nuplazid, you can subtract out the cost of the other drug that you're replacing because these patients must be treated with medication for their psychosis. If not, they will end up in intensive care units or even worse, homeless," he says.

Kellogg recalls an untreated PDP patient whom he treated when the patient was brought to the hospital after being found wandering on a highway. "These patients end up having severely adverse outcomes such as intensive care unit placement, homelessness, and psychiatric hospitalizations if we do not treat them," he says.

"Other drugs in the atypical antipsychotic class are used off label to treat the hallucinations and delusions of Parkinson's disease," Mathis says. "But this has been done without the benefit of a drug development program to specifically demonstrate efficacy and to delineate the safety of the drugs in this population."

"PDP patients were treated off-label with nonapproved antipsychotics that were actually FDA-approved for schizophrenia," Kellogg says. "So we're using drugs like clozapine and quetiapine." These off-label medications could be toxic in this condition. Patients who had been treated with those medications can now be tapered off and be prescribed a much more appropriate drug, he says.

"We always talk about medications and surgeries and therapies, but we can't forget the fact that nonpharmacological methods may help and should be explored," Kellogg says. He notes that it's crucial that patients with PD maintain good sleep patterns. They also need to have consistency in the home environment; the love and support PD patients receive from their families are essential.

— Jaimie Lazare is a freelance writer based in Brooklyn, New York.

References
1. Hermanowicz N, Edwards K. Parkinson's disease psychosis: symptoms, management, and economic burden. Am J Managed Care. 2015;21(10 Suppl):s199-s206.

2. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540.