Treating Parkinson’s Psychosis Remains Challenging

“We have only one brain.”

This statement, offered by Kevin Black, M.D., a professor of psychiatry at Washington University in St. Louis, may seem obvious, but it also reflects the very real and very delicate game of tug-of-war facing the psychiatrists and neurologists who work with this most complex of organs.

Perhaps nowhere is this balance more prominent—and frustrating—than the psychosis that manifests in Parkinson’s disease (PD).

PD psychoses are common—around 30 percent of PD patients will develop them at some point—and serious, as psychosis is a strong risk factor for death in PD patients. It is also the single biggest reason people with PD end up in nursing homes.

Yet PD psychoses remain greatly underappreciated by the public. Black recalled talking to the husband of a PD patient who had been diagnosed with psychosis. “ ‘I knew my wife would have trouble walking,’ he told me, ‘but I didn’t know I was signing up for this.’ ”

The most common manifestations of psychosis in people with PD are hallucinations; conversations with dead relatives and watching imaginary parades are typical examples.

Rarer, but more troubling, neurologist Joseph Friedman, M.D., told Psychiatric News, are the delusions, which occur in 5 to 10 percent of PD patients. Friedman is chief of the Division of Movement Disorders in the Department of Neurology at the Alpert Medical School of Brown University.

“These delusions often revolve around family or paranoia over perceived spousal infidelity or the belief that their children are stealing from them,” he said. “This is problematic because it’s an embarrassing issue, so the patient won’t talk about it with his or her doctor, and it becomes difficult to identify.”

But while diagnosis can be tricky—psychoses frequently manifest later in the course of PD and are often accompanied by the onset of dementia—treatment is particularly difficult.

“Unlike mental problems like depression or anxiety that are an intrinsic part of a progressive, serious disease like Parkinson’s, psychoses only arise—except in very rare cases—because of dopamine therapy,” Friedman said.

Replacing dopamine—a critical neurotransmitter that controls diverse brain functions including motor movement and arousal—is standard for reducing PD symptoms, such as shaking and twitching. However, these drugs can alter the behavioral pathways also regulated by dopamine. Overactive dopamine activity is associated with schizophrenia, though the connection is not fully understood.

Efforts to treat psychosis in PD with antipsychotics such as those used for schizophrenia have proven mostly futile. Olanzapine generated excitement after it came out, but several trials testing it in PD patients had to be stopped early because of the potential risk of worsening PD symptoms. Quetiapine fared better in terms of adverse effects, but it has not been shown to be more effective than placebo in four clinical trials (still, quetiapine is the most prescribed antipsychotic for people with PD).

While Friedman noted the antipsychotic clozapine “works even better for PD psychoses than schizophrenia psychoses,” the drug carries big risks, including agranulocytosis, a sudden loss of white blood cells that can be fatal.

Patients on clozapine need to come in for weekly blood tests to make sure their counts are normal, explained Friedman, who was involved in the first clinical studies testing clozapine in PD patients in the United States. While a nuisance even for a relatively fit individual, it can be a real burden to an older person with severe movement problems. As such, clozapine is rarely given.

The search for new drugs is imperative, as the burden of PD psychoses will likely only increase as the overall U.S. population ages and those with PD live longer.

Hope may be on the horizon in the form of pimavanserin, a molecule that blocks the activity of the serotonin receptor but has no influence over the dopamine receptor.

This drug showed promise in preclinical studies, and in a recently completed phase 3 clinical trial of patients with PD psychosis, pimavanserin showed a significant reduction in psychosis severity compared with placebo while not worsening any motor symptoms. While patients in the pimavanserin group reported adverse side effects, the drug was well tolerated overall, and the results were enough for the Food and Drug Administration (FDA) to grant pimavanserin a Breakthrough Therapy designation, which will expedite the FDA’s development and review of the drug.

Until pimavanserin is ready for public use, there are treatment regimens that can be implemented to try to mitigate psychoses, such as using L-dopa instead of dopamine receptor agonists or reducing the use of other medications like cholinergic drugs (to treat dementia), if possible.

It is not an optimal solution, but Black noted that it is better now than 10 to 15 years ago: “Back then, when someone with Parkinson’s had a diagnosis of psychosis, it created a dilemma in which the person had to choose either not walking or living with hallucinations.” ■